US20130089498A1 - Compositions and methods related to profiling a plurality of cells based on peptide binding - Google Patents

Compositions and methods related to profiling a plurality of cells based on peptide binding Download PDF

Info

Publication number
US20130089498A1
US20130089498A1 US13/629,067 US201213629067A US2013089498A1 US 20130089498 A1 US20130089498 A1 US 20130089498A1 US 201213629067 A US201213629067 A US 201213629067A US 2013089498 A1 US2013089498 A1 US 2013089498A1
Authority
US
United States
Prior art keywords
lung
leukemia
colon
cell
hop
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/629,067
Inventor
Renata Pasqualini
Wadih Arap
Mikhail Kolonin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Texas System
Original Assignee
University of Texas System
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Texas System filed Critical University of Texas System
Priority to US13/629,067 priority Critical patent/US20130089498A1/en
Publication of US20130089498A1 publication Critical patent/US20130089498A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1037—Screening libraries presented on the surface of microorganisms, e.g. phage display, E. coli display
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells

Definitions

  • the present invention is directed generally to method and compositions related to molecular biology, virology, and oncology. In certain aspects it is directed to compositions comprising and methods of profiling and/or classifying a plurality of cells or cell lines based on peptide binding characteristics.
  • An embodiment of the invention includes methods of profiling cell lines and/or identifying peptide sequences or structures that bind a target population or family of cells.
  • the methods include providing a plurality of cell lines; contacting each cell line with a library of phage displaying random heterologous peptides on their surface; obtaining phage that bind each of the cell lines; identifying peptides that bind each cell line; and classifying each cell line based on the identified peptides.
  • the method can further comprise classifying each identified peptide based on the cell lines that bind each identified peptide.
  • the cell lines include cancer cell lines.
  • Cancer cell lines may include, but are not limited to kidney, breast, colon, lung, prostate, brain, liver, pancreatic, uterine, neuronal, skin, head and neck, leukemic, lymphocytic, or ovarian cancer cell lines.
  • the panel is cancer cell lines.
  • the panel is a NCI 60 panel of cancer cell lines.
  • the methods further include identifying a peptide that binds to a majority of the cancer cell lines or cancer cells of common origin. Furthermore, methods can also include analyzing the identified peptides to identify similarities with known receptor ligands.
  • classifying the cell line is performed by clustering analysis.
  • Clustering analysis can be used to construct a clustered image map (CIM).
  • classifying the identified peptide is performed by clustering analysis.
  • Clustering analysis can be used to construct a clustered image map.
  • the methods may also include identifying receptors for at least one of the identified peptides comprising the steps of providing an identified peptide; labeling the identified peptide; contacting an appropriate cell line with the labeled peptide; isolating a receptor-peptide complex; and identifying the receptor bound to the labeled peptide.
  • a group of peptides comprising five or more peptides can be classified or identified as selectively bind to a sub-population of cell lines, wherein the peptides include, but are not limited to those listed in Table 3 and described herein.
  • a sub sequence of the peptide may be identified as conferring to the peptide a certain binding characteristic.
  • methods of the invention can be used to classify a cell or cell line.
  • Methods of classifying a cell line include, but are not limited to steps comprising: contacting a cell with a group of selected peptides or polypeptides that differentially bind cells of a known origin; detecting the peptides that bind the cell line; and assessing the classification of the cell line based on the peptide(s) that bind the cell line.
  • classifying a cell may comprise determining whether as cell expresses a certain receptor polypeptide, is susceptible to a particular therapy or determining the tissue of origin for the cell.
  • a group of selected peptide for use according to the invention are further defined as cyclic or partially peptides, such as peptides comprising a disulfide bond.
  • a group of selected peptides or polypeptides may comprise at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 or more distinct peptides or polypeptides.
  • a method for classifying a cell comprising obtaining or having a sample comprising a cell; contacting the cell with a group of peptides or polypeptides that differentially bind cells of a known origin or type; detecting the peptides that bind to the cell and classifying the cell based on the peptide binding.
  • a group of selected peptides or polypeptides comprise amino acid sequences selected from those provided in Table 3.
  • a group of selected peptides or polypeptides comprise 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 or more members that comprising an amino acid sequence according to Table 3.
  • selected peptide or polypeptides of the invention may in some aspects be labeled for example with an enzyme, a fluorophor or a radio isotope.
  • a selected peptide or polypeptide may be a cyclic or partially polypeptide such as a peptide or polypeptide comprising a disulfide bond.
  • the cyclic region of a peptide or polypeptide comprises 5, 6, 7, 8, 9, 10 or more amino acids.
  • a selected peptide or polypeptide comprises an amino acid sequence provided in Table 3 wherein the given amino acid sequence is comprised in the cyclic region of the polypeptide.
  • a selected peptide or polypeptide may comprise an amino acid sequence of Table 3 wherein the sequence is flanked by cysteine residues such that the cysteine residues may be linked by a disulfide bond.
  • a method for classifying a cell according to the invention may comprise comparing the binding profile of a group of selected peptides or polypeptides to a cell to a similar binding profile from a cell with a known classification. Such a comparison may be performed directly or may performed by consulting a chart or database of binding profiles.
  • a chart or database of binding profiles may comprise binding profiles from cells of 5, 10, 15, 20, 25 or more different classifications.
  • a chart or database of binding profiles may comprise clustering analysis of the binding of selected peptides or polypeptide to cells of different classification.
  • a chart or database of binding profiles may comprise a clustered image map (CIM).
  • CIM clustered image map
  • a method for treating a subject comprising obtaining or having a sample from the subject comprising a cell; classifying the cell (e.g., by the methods described supra); and treating the subject with a therapeutic based upon the classification of the cell.
  • a subject may be defined as a cancer patient.
  • a cancer cell from the subject may be classified.
  • Classification of the cell may for example comprising determining the tissue of origin, receptor status or susceptibility of the cell to particular anticancer therapy.
  • the subject may be treated with an appropriate anticancer therapy.
  • methods of the invention may be used to classify a cell as susceptible or resistant to radiation therapy, immunotherapy, surgical therapy or chemotherapy.
  • methods of the invention may be used to classify the cell as susceptible or resistant to a particular chemotherapeutic agent or class of chemotherapeutic agents.
  • methods of the invention may involve classifying a cancer cell from a subject as susceptible or resistant to an anticancer therapy and treating the subject with one or more anticancer therapies that the cell is susceptible to.
  • the invention concerns obtaining or having a sample such as a cell. It is contemplated that in cases where a sample is from a subject the sample may be directly obtained or may be obtained by a third party and subsequently subjected to methods described herein. Furthermore, in certain aspects it is contemplated that methods of the invention may be defined as a method for aiding in the therapy of a subject comprising classify a cell from the subject (e.g., as having certain protein receptor expression or being from a tissue of a particular origin) and providing the classification information to a third party such as a medical professional to aid in the therapy of the subject.
  • a third party such as a medical professional
  • Methods of peptide classification include, but are not limited to steps comprising: contacting a plurality of cell lines with a library of peptides that differentially bind the cells; detecting the peptides that bind the cell line; and classifying the peptides based on the cells that bind the peptide.
  • an EphA5 receptor can be targeted by using a composition comprising a peptide sequence of CSGIGSGGC (SEQ ID NO:2) or CRFESSGGC (SEQ ID NO:3).
  • a peptide targeting sequence of the invention is cyclic.
  • EphA5 receptor targeting composition comprising a cyclic polypeptide wherein the cyclic polypeptide comprises the amino acid sequence SGIGSGG (SEQ ID NO:4) or RFESSGG (SEQ ID NO:5).
  • an cyclic EphA5 targeting composition may comprise a peptide sequence according to SEQ ID NO:4 or SEQ ID NO:5 flanked by cysteine residues thereby forming a cyclic targeting agent via disulfide bonds between the cysteine residues.
  • flanked means that the indicated amino acid sequence are between two cysteine residues however it is contemplated that in some cases additional amino acids may also be comprised between the two cysteine residues.
  • a composition of the invention can be coupled (either non-covalently or covalently, or indirectly via an intermediate such as a liposome or directly) to a therapeutic or imaging agent.
  • the therapeutic can include, but is not limited to a small molecule, a drug, or a therapeutic peptide.
  • a therapeutic composition of the invention comprises a polypeptide.
  • the therapeutic Eph5A receptor targeting composition may comprise a fusion protein.
  • the therapeutic polypeptide may be a toxin or other cytotoxic molecule capable of inducing cell death in Eph5A receptor expressing cells.
  • Imaging agents for use in the invention include but are not limited to MRI contrast agents, radio isotopes, fluorophors and mass tags (e.g., for detection via mass spectrometry).
  • an EphA5 receptor agonist comprising the amino acid sequence SGIGSGG (SEQ ID NO:4) or RFESSGG (SEQ ID NO:5).
  • the EphA5 receptor agonist is a cyclic peptide or polypeptide wherein the cyclic region comprises the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5.
  • the agonist is a cyclic peptide or polypeptide comprising a disulfide bond such as a peptide or polypeptide wherein the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5 are flanked by cysteine residues (e.g., as in SEQ ID NO:2 or SEQ ID NO:3).
  • a method for treating an Eph5A receptor positive cell comprising administering to the cell an EphA5 receptor targeting therapeutic as described supra.
  • a method of the invention may be further defined as a methods for treating a subject comprising an EphA5 receptor positive cell by administering an effective amount of an EphA5 receptor targeting therapeutic.
  • a subject may be a cancer patient comprising an EphA5 receptor positive positive cancer such as a lung cancer or neuronal cancer.
  • a method for treating a subject with a an EphA5 receptor positive cancer by administering an EphA5 receptor targeting therapeutic wherein the therapeutic comprising a cytotoxic agent or an anticancer agent.
  • FIG. 1 Selectivity of broad-specificity tripeptides for clusters of NCI-60 cell lines. Two-dimensional hierarchical clustering was applied to the frequencies of 38 tripeptides (rows) encountered in CX 7 C peptides selected on NCI-60 cell lines (columns). Tripeptides selected on all but one cell line of common origin were clustered based on their correlations with cell lines; cell lines were clustered based on their correlations with the tripeptides. Tripeptide frequencies were mean subtracted and average linkage clustered with correlation metric. Amino acid color code: red, hydrophobic; green, neutral and polar; purple, basic. The color in each CIM segment ranges from blue (negative correlation) to red (positive correlation), as indicated by the scale bar.
  • Cell lines are color-coded based on previously defined histologic tumor origin (Monks et al., 1991, Weinstein et al., 1997. Bars underneath dendrogram, clusters of cells of similar tumor tissue origin (one exception allowed). Boxed, cluster of lung cancer-derived cell lines and associated/dissociated tripeptides.
  • FIGS. 2A-B Identification of peptides mimicking EGFR ligands.
  • FIG. 2A EGFR-binding peptide sequences isolated from the SKOV-3 selected phage pool were matched in each orientation to protein sequences of biological human EGFR ligands (leader peptide sequence underlined). Matches displayed are peptides with three or more amino acids being identical (red) and one or more being from the same class (green) as the correspondingly positioned protein amino acids. Tripeptides listed in Table 1 (yellow).
  • FIG. 2B isolation of peptides targeting EGFR. Binding of SKOV3-selected phage pool to immobilized EGFR compared with BSA in rounds 1 and 2 of biopanning of SKOV3-selected phage pool on immobilized human EGFR.
  • FIGS. 3A-3B Phage selection on immobilized EphA5 receptor.
  • FIG. 3A Ephrin-mimic phage displaying the enriched motif GGS were selected on EphA5-coated microtiter wells. Phage showing specific binding to EphA5 was analyzed for its distinctive binding to EphA5 compared to EphA4 receptor ( FIG. 3B ). BSA and fd-tet insertless phage were used as negative controls.
  • FIG. 5 EphA5 and EphA4 receptor expression by the lung cancer cell lines Hop92 and H460.
  • the OVCAR3 cell line was used as negative control. 10 ⁇ magnification.
  • FIG. 6 Specific binding of the CSGIGSGGC (SEQ ID NO:2) and CRFESSGGC (SEQ ID NO:3)-phage to lung cancer cells Hop92 and H460 but not to the ovarian cancer cell line OVCAR-3. Insertless phage (fd-tet) was used as negative control.
  • FIGS. 7A-B A. Clustered image map relating all isolated NCI-60-binding tripeptides to NCI-60 cell lines.
  • FIG. 7A Two-dimensional hierarchical clustering was applied to the frequencies of 3,280 unique tripeptides (rows) found in cell-binding CX7C peptides selected on the NCI-60 cells (columns). Tripeptides were clustered based on their correlations with cell lines; cell lines were clustered based on their correlations with tripeptides. Tripeptide frequencies were mean-subtracted and average-linkage clustered with correlation metric (the data were transformed to the mean of 0; variance of 1).
  • FIG. 7B A control two-dimensional hierarchical clustering applied under the Poisson assumption to 3,280 randomly simulated tripeptide frequencies (rows) showed no obvious pattern, thus indicating that clusters in A were not generated at random.
  • FIG. 8 Targeted peptides mediate ligand-receptor cell internalization.
  • CSGIGSGGC SEQ ID NO:2
  • CRFESSGGC SEQ ID NO:3
  • FIG. 9A-B Biological effects of the peptides CSGIGSGGC (SEQ ID NO:2) and CRFESSGGC (SEQ ID NO:3 on lung cancer cells. Promotion of cell survivial and proliferative response of starved lung cancer cells to the ephrin mimic peptides, control peptide and complete culture medium (A549 ( FIG. 9A ), H460 cells ( FIG. 9B )). Concentrations of peptide were optimized. Values in the Y-axis correspond to the number of viable cells under each experimental condition evaluated after a 72 h incubation period. Data bars represent the mean and corresponding standard error of the mean.
  • NCI-60 human tumors
  • the cell surface of the NCI-60 was profiled by high-throughput screening of a phage-displayed random peptide library and classified the cell lines according to the binding selectivity of 26,031 recovered tripeptide motifs.
  • the inventors By analyzing selected cell-homing peptide motifs and their NCI-60 recognition patterns, the inventors established that some of these motifs (a) are similar to domains of human proteins known as ligands for tumor cell receptors and (b) segregate among the NCI-60 in a pattern correlating with expression profiles of the corresponding receptors.
  • the inventors biochemically validated some of the motifs as mimic peptides of native ligands for the epidermal growth factor receptor.
  • the results indicate that ligand-directed profiling of tumor cell lines can select functional peptides from combinatorial libraries based on the expression of tumor cell surface molecules, which in turn could be exploited as “druggable” receptors in specific types of cancer (Kolonin et al., 2006).
  • NCI-60 National Cancer Institute panel of human cancer cell lines from different histologic origins and grades
  • the National Cancer Institute panel of human cancer cell lines from different histologic origins and grades has been extensively used to screen compounds for anticancer activity (Monks et al., 1991; Weinstein et al., 1997).
  • the NCI-60 includes carcinomas of several origins (kidney, breast, colon, lung, prostate, and ovarian), tumors of the central nervous system, malignant melanomas, leukemias, and lymphomas.
  • Peptide ligands selected from unbiased screens without any predetermined notions about the nature of the cellular receptor repertoire have been used for the subsequent identification of the corresponding target cell surface receptors (Giordano et al., 2001; Arap et al., 2002; Pasqualini et al., 2000; Kolonin et al., 2002; Kolonin et al., 2004; Pasqualini et al., 2001).
  • novel techniques such as the biopanning and rapid analysis of selective interactive ligands (BRASIL), have enabled high-throughput phage library screening on cells (Giordano et al., 2001).
  • the BRASIL method is used to systematically screen combinatorial libraries on tumor cells of the NCI-60 panel.
  • Modified cell targeting molecules of the present invention may be produced by chemical synthetic methods, by chemical linkage between the two moieties or in some cases by fusion of a second polypeptide coding sequence to the targeting moiety. It is contemplated that modified cell targeting molecules of the invention may be used as therapeutics and/or as imaging agents to target specific classes of cells.
  • a modified cell targeting moiety may comprise a second polypeptide wherein the two polypeptides together comprise a fusion protein.
  • the second polypeptide may be a therapeutic or cytotoxic (e.g., a toxin) polypeptide as exemplified below.
  • a fusion of two polypeptide coding sequences can be achieved by methods well known in the art of molecular biology. It is preferred that a fusion polynucleotide contain only the AUG translation initiation codon at the 5′ end of the first coding sequence without the initiation codon of the second coding sequence to avoid the production of two separate encoded products.
  • a leader sequence may be placed at the 5′ end of the polynucleotide in order to target the expressed product to a specific site or compartment within a host cell to facilitate secretion or subsequent purification after gene expression.
  • the two coding sequences can be fused directly without any linker or by using a flexible polylinker.
  • Cell targeting moities as provided here may, in some aspects, comprise peptides or polypeptides that exhibit binding to a specific class of cells.
  • the cell targeting moiety is selected from one of the polypeptide sequences provided in Table 3.
  • the skilled artisan will understand that such sequences may comprise additional amino acids or other covalent modifications.
  • a polypeptide sequence from Table 3 is provided a cyclic polypeptide.
  • an amino acid sequence from Table 3 is flanked by cysteine residues that may form a disulfide bond thereby providing a cyclic polypeptide.
  • the invention provides compositions and methods for targeting any of the classes of cells that bind to the peptides and polypeptides provided herein (e.g., as indicated in Table 3) such as leukemia cells, lung cancer cells, colon cancer cells, CNS cancer cells, melanoma cells, ovarian cancer cells, prostate cancer cells, renal cancer cells or breast cancer cells.
  • any of the classes of cells that bind to the peptides and polypeptides provided herein such as leukemia cells, lung cancer cells, colon cancer cells, CNS cancer cells, melanoma cells, ovarian cancer cells, prostate cancer cells, renal cancer cells or breast cancer cells.
  • a therapeutic moiety may be a toxin such as radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, cytotoxins (cytotoxic agents), or any molecules or enzymes not normally present in or on the surface of a cell that under defined conditions cause the cell's death.
  • a toxin such as radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, cytotoxins (cytotoxic agents), or any molecules or enzymes not normally present in or on the surface of a cell that under defined conditions cause the cell's death.
  • Toxins that may be used according to the methods of the invention include, but are not limited to, radioisotopes known in the art, compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin and cholera toxin.
  • radioisotopes known in the art
  • compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseu
  • Toxin also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213 Bi, or other radioisotopes such as, for example, 103 Pd, 133 Xe, 131 I, 68 Ge, 57 Co, 65 Zn, 85 Sr, 32 P, 35 S, 90 Y, 153 Sm, 153 Gd, 169 Yb, 51 Cr, 54 Mn, 75 Se, 113 Sn, 90 Yttrium, 117 Tin, 186 Rhenium, 166 Holmium, and 188 Rhenium; luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.
  • a therapeutic moiety may be a pro-apoptotic protein such as a BCL2 family member, a caspase or a granzyme.
  • a variety of conventional cancer therapies are currently used in the treatment of cancer.
  • methods for classifying cancer cells such as cells that are sensitive or resistant to an anticancer therapy.
  • Some examples of conventional cancer therapies discussed below. It is contemplated that methods according to the invention may be used to identify cells that are sensitive or resistant to any particular cancer treatment.
  • methods according to the invention concern compositions and methods for cell targeted anticancer therapy.
  • any anticancer method known to those in the art as exemplified below may be used in combination or conjunction with compositions and methods provided herein.
  • Cancer therapies also include a variety of combination therapies with both chemical and radiation based treatments.
  • Combination chemotherapies include, for example, cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol, gemcitabien, navelbine, farnesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil, vincristin, vinblastin and methotrexate, or any analog or derivative variant of the foregoing.
  • CDDP cisplatin
  • carboplatin carboplatin
  • Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 wk), to single doses of 2000 to 6000 roentgens.
  • Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.
  • contacted and “exposed,” when applied to a cell are used herein to describe the process by which a therapeutic construct and a chemotherapeutic or radiotherapeutic agent are delivered to a target cell or are placed in direct juxtaposition with the target cell.
  • both agents are delivered to a cell in a combined amount effective to kill the cell or prevent it from dividing.
  • Immunotherapeutics generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells.
  • the immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell.
  • the antibody alone may serve as an effector of therapy or it may recruit other cells to actually effect cell killing.
  • the antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve merely as a targeting agent.
  • the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target.
  • Various effector cells include cytotoxic T cells and NK cells.
  • Immunotherapy could be used as part of a combined therapy, in conjunction with gene therapy.
  • the general approach for combined therapy is discussed below.
  • the tumor cell must bear some marker that is amenable to targeting, i.e., is not present on the majority of other cells.
  • Common tumor markers include carcinoembryonic antigen, prostate specific antigen, urinary tumor associated antigen, fetal antigen, tyrosinase (p97), gp68, TAG-72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B and p155.
  • NCI-60 cell lines (1) except MDA-N (unavailable), were grown in RPMI 1640 supplemented with 5% fetal bovine serum (FBS) and 5 mmol/L L-glutamine.
  • FBS fetal bovine serum
  • a phage display random peptide library based on the vector fUSE5 displaying the insert CX 7 C (SEQ ID NO:1) was screened by using BRASIL as described (Giordano et al., 2001).
  • Exponentially growing cells were harvested with 0.5 mmol/L EDTA, 0.4 g/L KCl, 8 g/L NaCl, and 1 g/L dextrose, washed once with phosphate buffer saline (PBS), and resuspended in RPMI containing 1% bovine serum albumin (BSA) and 1 mmol/L HEPES.
  • PBS phosphate buffer saline
  • BSA bovine serum albumin
  • the inventors created an interactive sequence management database of all peptide sequences isolated in the screen. Calculation of tripeptide motif frequencies in CX 7 C peptides (in both directions) was done by using a character pattern recognition program based on SAS (version 8.1.2, SAS Institute, Cary, N.C.) and Perl (version 5.6.1) as described (Arap et al., 2002). To identify the most closely related tripeptides and cell lines, clustered image maps (CIM) were generated by using online software CIMminer available at discover.nci.nih.gov/tools.jsp. Data were centered (mean subtracted and divided by SD) on both cell lines and tripeptide motifs; correlation coefficient metric with average linkage algorithm was used as distance measurement.
  • CIM clustered image maps
  • the tripeptide motif frequencies across the NCI-60 cell lines formed a two-dimensional data matrix that was used to correlate motif enrichment with groups of cell lines.
  • CIMMiner algorithm is appropriate for clustering analysis of peptide frequency data.
  • the inventors simulated a random 3,280 ⁇ 59 data matrix of the dimension identical to that of tripeptide motif frequency data matrix (corresponding to the set of 3,280 tripeptides and 59 cell lines). These simulated data were centered the same way as the experimental data by transforming to mean of 0, variance of 1.
  • tripeptides selected on all but one cell line of common origin were used. Specificity of five tripeptides selectively overrepresented or underrepresented in lung tumor cell binding peptides for the 11 boxed cell lines (against the other 48 cell lines) was evaluated by using the R Package, version 2.0.0 (www.r-project.org) by performing two-sample t test (one tailed), as well as using Wilcoxon rank sum test (one tailed) and Fisher exact test (one tailed) as described (Arap et al., 2002).
  • the Molecular Target Database (found on the world wide web at dtp.nci.nih.gov) was screened to identify proteins, expression levels of which in individual cell lines of the NCI-60 correlated with frequencies of individual tripeptides from FIG. 1 in the corresponding cell lines.
  • the inventors used the COMPARE software (found on the world wide web at dtp.nci.nih.gov/docs/compare/compare.html) to calculate pairwise Pearson correlations between tripeptide frequencies in cell lines and the protein expression patterns in the database.
  • the inventors screened all 7-mer peptides selected in the screen by using online ClustalW software (www.ebi.ac.uk/clustalw/) to identify extended (four or longer amino acids) motifs shared between multiple peptides containing the broad-specificity tripeptides ( FIG. 1 ).
  • ClustalW software www.ebi.ac.uk/clustalw/
  • Nonredundant databases of human proteins were searched by the BLAST software (www.ncbi.nlm.nih.gov/BLAST/) for proteins containing the cell-targeting 4-mers under the condition that at least the tripeptide part of the motif is identical to the part of the BLAST match.
  • phage clones selected on SKOV3 in rounds 2 and 3 of the screening were individually amplified and pooled, and 10 9 transduction units of the mixed phage were incubated overnight at 4° C. with 10 ⁇ g of purified human EGFR (Sigma, St. Louis, Mo.), or BSA control immobilized on plastic. Unbound phages were extensively washed off with PBS, and then the bound phages were recovered by infecting host K91 Escherichia coli directly on the plate, and tetracycline-resistant clones were selected, quantified, and sequenced.
  • EGFR epidermal growth factor receptor
  • Preferential cell binding of specific cell-targeting peptides results in enrichment, defined by the increased recovery frequency of these peptide motifs in each subsequent round of the screen (Kolonin et al., 2001; Pasqualini et al., 2001).
  • the inventors set out to profile the expression of nonintegrin cell surface molecules among the cell lines of the NCI-60 according to the differential selection of motifs enriched in the screen.
  • a hierarchical clustering analysis of the 3,280 nonredundant tripeptides was done based on the frequency of association with the NCI-60 cell lines.
  • the inventors adapted a hierarchical clustering algorithm and a pseudo-color visualization matrix initially designed to address differential gene expression among the cells of the panel (Scherf et al., 2000; Zaharevitz et al., 2002; Blower et al., 2002; Rabow et al., 2002).
  • CIMMiner (Weinstein et al., 1997) was used for inference of the variation in peptide binding specificity across the cell lines by comparing relative frequencies of tripeptides found in 7-mer peptides binding to each cell. Clustering of peptide motifs with similar cell selectivity revealed that the peptide distribution of the combinatorial library within the NCI-60 set was nonrandom. Computer simulations of the permutated data set show that the observed pattern could not be generated by random chance, thus indicating that the discontinuous tripeptide frequency data is applicable for cluster analysis.
  • the selective spectra of peptide motifs interacting with the clustered cell lines suggest the existence of shared targeted surface receptor(s) expressed in these lines.
  • the inventors chose to focus on putative peptide-targeted receptors with broad cell line specificity, which would be more informative for an initial peptide binding/receptor expression correlation analysis. the inventors therefore excluded from the data set motifs selected only on a single or few cell lines. Instead, the inventors focused on 38 tripeptides that showed a semiubiquitous distribution among the NCI-60 lines ( FIG. 1 ).
  • a CIM constructed according to the isolation frequency of these broader-specificity tripeptides from each cell line revealed several apparent clusters of cell lines that displayed distinct profiles of association with certain classes of peptide motifs.
  • the inventors compared tripeptide frequencies for the 11 cell lines within this cluster with their frequencies for the rest of NCI-60 lines by using statistical tests (Fisher exact, Wilcoxon rank-sum, and t test). Consistently, the GGS motif was isolated for the clustered lines significantly (P ⁇ 0.05) more frequently than for the other NCI-60 cell lines.
  • FIG. 1 the distribution of cell lines in the dendrogram ( FIG. 1 ) was partially consistent with the reported association of cells derived from tumors with common tissue origin (Scherf et al., 2000; Nishizuka et al., 2003). This suggests that some of the receptors, such as the one presumably recognized by the lung tumor-specific tripeptide GGS ( FIG. 1 ), may be up-regulated only in certain cancer origins. However, the tumor cell phylogeny was recapitulated only to an extent; the majority of the observed clusters contained cell lines derived from unrelated tumor types ( FIG. 1 ).
  • the inventors proceeded to identify the targets for the 38 broad-specificity tripeptides, most of which presumably bind to receptors expressed by multiple NCI-60 cell lines.
  • the NCI Molecular Targets Database that contains detailed information on the expression and activity of 1,218 human proteins measured by nonarray methods was used (Holbeck, 2004).
  • the inventors correlated the selectivity profiles of the 38 tripeptide motifs with the expression profiles of the characterized molecular targets.
  • the peptide distribution-correlating tyrosine kinase receptors belonging to EGFR, FGFR, NGFR, and ephrin receptor families (Table 1), are often up-regulated in many types of cancer (Vogelstein and Kinzler, 2004).
  • the inventors employed the notion that receptor-binding peptide motifs often mimic natural ligands for these receptors (Giordano et al., 2001; Arap et al., 2002; Kolonin et al., 2002).
  • the selected motifs mimic ligands for the candidate tyrosine kinases were tested by determining whether tripeptides listed in Table 1 are embedded into longer peptides that may be responsible for cell surface binding.
  • the inventors analyzed the CX 7 C (SEQ ID NO:1) phage inserts containing the 38 tripeptides by using the ClustalW software and compiled extended motifs containing the tripeptides shared among multiple peptides selected during the screen (data not shown).
  • each of the ClustalW-extended motifs were screened against the nonredundant database of human proteins by using the BLAST software (National Center for Biotechnology Information).
  • the inventors chose to test if the EGFR is bound by any of the tripeptide motifs distributed in the panel in a profile correlating with EGFR expression. Consistently, 24 of 38 tripeptides surveyed displayed NCI-60 cell line association pattern consistent with that of EGFR expression (Table 1). Of these tripeptides, 22 were isolated in the screens on ovarian cancer cell lines SKOV3 and OVCAR4 (data not shown). Because EGFR is well known to be associated with ovarian cancer (Vogelstein and Kinzler, 2004), the inventors deemed these cell lines to be likely expressers of targetable EGFR, which would account for the selection of EGFR ligand-mimicking motifs.
  • the SKOV3-binding phage sublibrary (pooled clones recovered in rounds 2 and 3) were screened against immobilized human EGFR. After two rounds of selection, phage displaying the EGFR-binding peptides were analyzed: the majority were comprised by different 7-mer peptides ( FIG. 2A ) that contained 17 of 22 SKOV3-selected tripeptide motifs distributed in the panel in a profile correlating with EGFR expression (Table 1). Phage displaying these peptides had specific affinity to EGFR, as determined by subjecting the same sublibrary to immobilized BSA control binding ( FIG. 2B ). Remarkably, computer-assisted analysis of sequences ( FIG.
  • Expression profiles of the candidate receptor targets for peptides identified in the screen illustrate the concept that in cancer, at least some tumor-associated cell surface molecules seem up-regulated regardless of cancer tissue origin. As such, this is the case for the EGFR and other tyrosine kinases possibly targeted by peptide ligands selected on the NCI-60 cell panel. This may also be the case for many other receptors with a role in tumorigenesis, expression profiles of which may not correlate with the overall proteomic profile of the original tumor tissue. In fact, these observations may account for the relatively limited success in correlating drug toxicity profiles with the genomic and/or proteomic profiles of the NCI-60 panel (Walloyist et al., 2003). On the other hand, some of the receptors, such as EphA5 presumably targeted by GGS tripeptide and its derivatives predominantly selective for lung tumor-derived cell lines ( FIG. 1 ), seem to be at least partially specific for the progenitor cancer type.
  • the candidate ligand-receptor leads identified in this study can be characterized further for the development of targeted agents selective for tumors.
  • the peptides identified by the approach described here may map receptor interaction domains of biological (native) ligands. Similarity of peptides to the corresponding receptor-binding ligands has already been used for validation of the IL-11R ⁇ receptor as a target of an interleukin-11 mimic peptide homing to blood vessels in the prostate (Arap et al., 2002; Zurita et al., 2004).
  • the inventors and others have modeled the usage of peptides homing to receptors expressed by tumors (Pasqualini et al., 2000) or non-malignant tissues (Kolonin et al., 2002; Kolonin et al., 2004) for directing the delivery of cytotoxics, proapoptotic peptides, metalloprotease inhibitors, cytokines, fluorophores, and genes (Arap et al., 1998; Kolonin et al., 2001).
  • the approach provides a straightforward way to identify drug-accessible tumor cell surface receptors and to discover peptide ligands that can serve as mimetic prototype drugs.
  • this discovery platform directly addresses functional protein-protein interactions at the level of physical binding.
  • Ligand-directed screening of combinatorial libraries on tumor cell surfaces can lead to improved selection of functionally relevant peptides that can be developed for targeting “druggable” molecular targets.
  • Candidate peptide-mimicked receptor ligands are human proteins (identified by automated BLAST) that contained the corresponding tripeptides. Tripeptides in the column are ordered as in FIG. 1. Receptors of the same family and their corresponding candidate biological ligands identified based on tripeptide similarity are coded by the same color [EGFR, blue; FGFR, green; TRK receptor (NGFR), purple; ephrin receptor, red]. Tripeptides that both have a selectivity correlating with EGFR family receptor expression and are found within EGFR ligands (boldface). Tripeptides that were confirmed to reside within EGFR-binding SKOV3-slected peptides (FIG. 2; blue).
  • Proteomics can be defined as the systematic analysis of the proteins in biological samples that aims to document the overall distribution of proteins in tumor cells or tumor-associated cells, identify and characterize individual proteins of interest and to elucidate their relationships and functional roles.
  • proteome a protein-based fingerprint, for each tissue in humans and other species.
  • technologies related to proteomics advance, new approaches for systematic molecular analysis of cancer at the protein level are surfacing.
  • methods for systematic protein expression profiling may also easily overlook potential targets for intervention. These methods often do not take anatomical context into account.
  • Recognition of molecular diversity in human cancer is essential for the development of targeted therapies.
  • the methods developed have two main applications. First, they may identify ligands targeting human cancer. Second, the determination of molecular profiles of biomarkers in specific types of tumors may enable identification of differentially expressed cancer markers. Thus, the approach may lead to construction of a molecular profile of human tumors. Early identification of targets, optimized regimens tailored to molecular profile of individual cancer patients, combined with the identification of new vascular addresses may result in revisiting or salvaging of drug candidates that are ineffective or too toxic. Ultimately, it may be possible to guide imaging or therapeutic compounds to tumor targets in cancer patients.
  • the inventors By fingerprinting lung cancer cells the inventors have confirmed the expression of a previously characterized molecular target, EGFR, in multiple cancer origins, which demonstrates the power of the approach. Recently, the inventors used this approach to identify a new cancer origin-selective molecular target, Ephrin A5 receptor, which the inventors have preliminary validated in the context of human lung cancer cell lines and tissues.
  • EGF receptor EGF receptor
  • the inventors chose to test if the EGF receptor (EGFR) is bound by any of the tripeptide motifs distributed in the panel in a profile correlating with EGFR expression. Consistently, 24 out of 38 tripeptides surveyed displayed NCI-60 cell line association pattern consistent with that of EGFR expression (Kolonin et al., 2001). Of these, tripeptides, 22 were isolated in the screens on ovarian cancer cell lines SKOV3 and OVCAR4 (data not shown).
  • EGFR is well known to be associated with ovarian cancer (Vogelstein, 2004; Maihle and Lafky, 2002), the inventors deemed these cell lines to be likely expressers of targetable EGFR, which would account for the selection of EGFR ligand-mimicking motifs.
  • the SKOV3-binding phage sub-library (pooled clones recovered in rounds 2 and 3) were screened against immobilized human EGFR. After 2 rounds of selection, phage displaying the EGFR-binding peptides were analyzed: the majority were comprised by different seven-mer peptides ( FIG. 3A ) that contained 17 out of 22 SKOV3-selected tripeptide motifs distributed in the panel in a profile correlating with EGFR expression.
  • a phage-displayed combinatorial library was systematically screened for peptides capable of targeting the cell lines in the NCI-60 panel.
  • each NCI-60 cell line was assigned a unique set of peptide motifs that were isolated during the selection for cell surface binders. It was shown that tumor cells can be grouped by profiles of their phage display-derived peptide ligands directed to differentially expressed cell surface receptors.
  • Candidate targeted cell surface molecules were identified, which included a number of tyrosine kinase receptors.
  • EGFR a receptor known to be upregulated in various cancers
  • RVS tripeptides RVS, AGS, AGL, GVR, GGR, GGL, GSV, and GVS, which were The results described uncover a previously overlooked phenomenon.
  • the data support the notion that many tumor cell surface-exposed receptors are expressed irrespective of tumor origin, thus suggesting they could be explored as broad tumor targets.
  • Ephrin A5 Receptor as a Lung Cancer Cell Surface Marker
  • the peptide distribution-correlating tyrosine kinase receptors belonging to EGFR, FGFR, NGFR and Ephrin receptor families are often up-regulated in many types of cancer.
  • some of the receptors such as EphA5 presumably targeted by GGS tripeptide and its derivatives predominantly selective for lung tumor-derived cell lines appear to be at least partially specific for the progenitor cancer type. Since this approach clearly allowed identification of cell surface receptors ubiquitously upregulated in various cancers, the inventors took a step further to attempt identification of cancer type-specific receptors.
  • the inventors Having chosen lung cancer for the initial procedure establishment, the inventors identified a distinct cluster of five tripeptides associated with lung tumor-derived cell lines. The inventors compared tripeptide frequencies for the 11 cell lines within this cluster with their frequencies for the rest of NCI-60 lines by using statistical tests (Fisher exact, Wilcoxon rank-sum, and t-test). Consistently, the inventors observed that motif GGS was isolated for the clustered lines significantly (P ⁇ 0.05) more frequently than for the other NCI-60 cell lines (Table 2).
  • Ephrins (A and B) and their receptors (EphA and EphB) represent a large class of cell-cell communication molecules with well-defined developmental functions. Their role in healthy adult tissues and in human disease is still largely unknown, although diverse roles in carcinogenesis have been postulated and a number of Eph receptors have been found overexpressed by various cancers (Hafner et al., 2004).
  • EphA5 the receptor expressed in the corresponding pattern is EphA5.
  • the inventors tested phage binding to the EphA5 immobilized receptor.
  • the inventors started testing eight peptides (CAGLSGGTC (SEQ ID NO:2133), CSGIGSGGC (SEQ ID NO:2134), CSSGGVLGC (SEQ ID NO:2135), CSWGSGGSC (SEQ ID NO:2136), CTLVLGGSC (SEQ ID NO:2137), CRFESSGGC (SEQ ID NO:2138), CHVSGGSGC (SEQ ID NO:2139), CTGGSLGAC (SEQ ID NO:2140)) containing the enriched motif GGS, all of them displayed by phage clones obtained from the screening on different cell lines known to express the EphA5 receptor ( FIG.
  • the inventors used the BRASIL method (biopanning and rapid analysis of selective interactive ligands) to analyze binding of selected phage to lung cancer cells.
  • the inventors observed specific binding of phage displaying the sequences CSGIGSGGC and CRFESSGGC to Hop92 and H460, confirming the data obtained from the screening on the immobilized EphA5 receptor ( FIG. 6 ).
  • EphA5 protein is overexpressed by human lung adenocarcinoma epithelium.
  • Immunohistochemistry (polyclonal anti-prohibitin antibody) on formalin-fixed paraffin sections of human non-small cell lung cancer (NSLC) or normal prostate with EphA5 or EphA4-specific antibodies. Immunostaining demonstrates selective EphA5 upregulation of EphA5 protein expression in NSLC lung adenocarcinoma epithelium, but not stroma, as compared with the control prostate tissue.
  • EphA5 protein overexpression in lung cancer cells in light of candidate ephrin mimics (GGS peptides) targeting these cells provides an original evidence for EphA5 being a lung cancer marker and has potential functional implications.
  • cancer-associated motifs identified here can be used for the development of approaches for targeted imaging or therapy of breast tumors in patients.
  • Their receptors, including EGFR, EphA5, and other cell surface molecules, can be further explored for their oncogenic properties and the potential to serve as universal or origin/grade-selective targets of cancer.
  • the ability of ephrin-mimic peptides to mediate cell internaization was assessed.
  • the A549 cell line was used as a representative human lung cancer-derived cells expressing the EphA5 receptor on the cell surface. Each phage clone or control insertless phage was incubated with cells for 4 h at 37° C. Both CSGIGSGGC (SEQ ID NO:2) and CRFESSGGC (SEQ ID NO:3)-phage were internalized into A549 cells while only background fluorescence was obtained when nontargeted control phage was used (see FIG. 8 ).

Abstract

Methods and compositions are described for classifying cells and/or peptides that associate or bind with a particular characteristic pattern to a plurality of cells or cell lines. Aspects of the invention also include the use of peptide(s) having an appropriate binding characteristic to deliver a drug to a cell or cell population.

Description

  • The present application is a divisional of co-pending U.S. application Ser. No. 12/826,327, filed Jun. 29, 2010, which is a continuation of U.S. application Ser. No. 11/684,379, filed Mar. 9, 2007, which claims the benfit of U.S. Provisional Patent Application No. 60/780,893, filed Mar. 9, 2006, the entire contents of each of which are incorporated herein by reference in their entirety.
  • This invention was made with government support under grant number DAMD17-03-1-0638 awarded by the Department of Defense, and grant number CA103056 awarded by the National Institutes of Health. The government has certain rights in the invention.
    • TECHNICAL FIELD
  • The present invention is directed generally to method and compositions related to molecular biology, virology, and oncology. In certain aspects it is directed to compositions comprising and methods of profiling and/or classifying a plurality of cells or cell lines based on peptide binding characteristics.
    • BRIEF SUMMARY OF THE INVENTION
  • An embodiment of the invention includes methods of profiling cell lines and/or identifying peptide sequences or structures that bind a target population or family of cells. The methods include providing a plurality of cell lines; contacting each cell line with a library of phage displaying random heterologous peptides on their surface; obtaining phage that bind each of the cell lines; identifying peptides that bind each cell line; and classifying each cell line based on the identified peptides. The method can further comprise classifying each identified peptide based on the cell lines that bind each identified peptide. In one aspect, the cell lines include cancer cell lines. Cancer cell lines may include, but are not limited to kidney, breast, colon, lung, prostate, brain, liver, pancreatic, uterine, neuronal, skin, head and neck, leukemic, lymphocytic, or ovarian cancer cell lines. In another aspect, the panel is cancer cell lines. In a particular aspect, the panel is a NCI 60 panel of cancer cell lines. The methods further include identifying a peptide that binds to a majority of the cancer cell lines or cancer cells of common origin. Furthermore, methods can also include analyzing the identified peptides to identify similarities with known receptor ligands.
  • In certain aspects, classifying the cell line is performed by clustering analysis. Clustering analysis can be used to construct a clustered image map (CIM). In a particular aspect, classifying the identified peptide is performed by clustering analysis. Clustering analysis can be used to construct a clustered image map. In another aspect, the methods may also include identifying receptors for at least one of the identified peptides comprising the steps of providing an identified peptide; labeling the identified peptide; contacting an appropriate cell line with the labeled peptide; isolating a receptor-peptide complex; and identifying the receptor bound to the labeled peptide.
  • In another embodiment, a group of peptides comprising five or more peptides can be classified or identified as selectively bind to a sub-population of cell lines, wherein the peptides include, but are not limited to those listed in Table 3 and described herein. In certain aspects, a sub sequence of the peptide may be identified as conferring to the peptide a certain binding characteristic.
  • In still further embodiments, methods of the invention can be used to classify a cell or cell line. Methods of classifying a cell line include, but are not limited to steps comprising: contacting a cell with a group of selected peptides or polypeptides that differentially bind cells of a known origin; detecting the peptides that bind the cell line; and assessing the classification of the cell line based on the peptide(s) that bind the cell line. Thus, in certain aspects, classifying a cell may comprise determining whether as cell expresses a certain receptor polypeptide, is susceptible to a particular therapy or determining the tissue of origin for the cell. In certain aspects of the invention, a group of selected peptide for use according to the invention are further defined as cyclic or partially peptides, such as peptides comprising a disulfide bond. In certain cases, a group of selected peptides or polypeptides may comprise at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 or more distinct peptides or polypeptides.
  • Thus, in a further specific embodiment there is provided a method for classifying a cell comprising obtaining or having a sample comprising a cell; contacting the cell with a group of peptides or polypeptides that differentially bind cells of a known origin or type; detecting the peptides that bind to the cell and classifying the cell based on the peptide binding. As described supra, in certain aspects, a group of selected peptides or polypeptides comprise amino acid sequences selected from those provided in Table 3. Thus, in certain cases a group of selected peptides or polypeptides comprise 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 or more members that comprising an amino acid sequence according to Table 3. The skilled artisan will recognize that selected peptide or polypeptides of the invention may in some aspects be labeled for example with an enzyme, a fluorophor or a radio isotope.
  • In some aspects, a selected peptide or polypeptide may be a cyclic or partially polypeptide such as a peptide or polypeptide comprising a disulfide bond. In some preffered aspects, the cyclic region of a peptide or polypeptide comprises 5, 6, 7, 8, 9, 10 or more amino acids. For example, in certain aspects, a selected peptide or polypeptide comprises an amino acid sequence provided in Table 3 wherein the given amino acid sequence is comprised in the cyclic region of the polypeptide. Thus, it is contemplated that a selected peptide or polypeptide may comprise an amino acid sequence of Table 3 wherein the sequence is flanked by cysteine residues such that the cysteine residues may be linked by a disulfide bond.
  • In some aspects of the invention a method for classifying a cell according to the invention may comprise comparing the binding profile of a group of selected peptides or polypeptides to a cell to a similar binding profile from a cell with a known classification. Such a comparison may be performed directly or may performed by consulting a chart or database of binding profiles. For example, a chart or database of binding profiles may comprise binding profiles from cells of 5, 10, 15, 20, 25 or more different classifications. In certain aspects, a chart or database of binding profiles may comprise clustering analysis of the binding of selected peptides or polypeptide to cells of different classification. Thus, in some cases a chart or database of binding profiles may comprise a clustered image map (CIM). Thus, classifying a cell may be performed by for example clustering analysis.
  • In still further aspects of the invention there is provided a method for treating a subject comprising obtaining or having a sample from the subject comprising a cell; classifying the cell (e.g., by the methods described supra); and treating the subject with a therapeutic based upon the classification of the cell. For example, in some cases a subject may be defined as a cancer patient. In this case a cancer cell from the subject may be classified. Classification of the cell may for example comprising determining the tissue of origin, receptor status or susceptibility of the cell to particular anticancer therapy. Thus, based upon the classification of the cell the subject may be treated with an appropriate anticancer therapy. For example, methods of the invention may be used to classify a cell as susceptible or resistant to radiation therapy, immunotherapy, surgical therapy or chemotherapy. Furthermore, methods of the invention may be used to classify the cell as susceptible or resistant to a particular chemotherapeutic agent or class of chemotherapeutic agents. Thus, methods of the invention may involve classifying a cancer cell from a subject as susceptible or resistant to an anticancer therapy and treating the subject with one or more anticancer therapies that the cell is susceptible to.
  • In certain aspects the invention concerns obtaining or having a sample such as a cell. It is contemplated that in cases where a sample is from a subject the sample may be directly obtained or may be obtained by a third party and subsequently subjected to methods described herein. Furthermore, in certain aspects it is contemplated that methods of the invention may be defined as a method for aiding in the therapy of a subject comprising classify a cell from the subject (e.g., as having certain protein receptor expression or being from a tissue of a particular origin) and providing the classification information to a third party such as a medical professional to aid in the therapy of the subject.
  • In yet another embodiment of the invention includes a method of classifying a peptide(s). Methods of peptide classification include, but are not limited to steps comprising: contacting a plurality of cell lines with a library of peptides that differentially bind the cells; detecting the peptides that bind the cell line; and classifying the peptides based on the cells that bind the peptide.
  • In certain aspects an EphA5 receptor can be targeted by using a composition comprising a peptide sequence of CSGIGSGGC (SEQ ID NO:2) or CRFESSGGC (SEQ ID NO:3). The skilled artisan will further recognize that in certain aspects a peptide targeting sequence of the invention is cyclic. Thus, there is provided EphA5 receptor targeting composition comprising a cyclic polypeptide wherein the cyclic polypeptide comprises the amino acid sequence SGIGSGG (SEQ ID NO:4) or RFESSGG (SEQ ID NO:5). As exemplified herein in certain aspects an cyclic EphA5 targeting composition may comprise a peptide sequence according to SEQ ID NO:4 or SEQ ID NO:5 flanked by cysteine residues thereby forming a cyclic targeting agent via disulfide bonds between the cysteine residues. As used herein the termed flanked means that the indicated amino acid sequence are between two cysteine residues however it is contemplated that in some cases additional amino acids may also be comprised between the two cysteine residues.
  • A composition of the invention can be coupled (either non-covalently or covalently, or indirectly via an intermediate such as a liposome or directly) to a therapeutic or imaging agent. The therapeutic can include, but is not limited to a small molecule, a drug, or a therapeutic peptide. For example, in certain aspects, a therapeutic composition of the invention comprises a polypeptide. In these aspects the therapeutic Eph5A receptor targeting composition may comprise a fusion protein. Thus, in some very specific cases the therapeutic polypeptide may be a toxin or other cytotoxic molecule capable of inducing cell death in Eph5A receptor expressing cells. Imaging agents for use in the invention include but are not limited to MRI contrast agents, radio isotopes, fluorophors and mass tags (e.g., for detection via mass spectrometry).
  • In certain aspects there is provided an EphA5 receptor agonist comprising the amino acid sequence SGIGSGG (SEQ ID NO:4) or RFESSGG (SEQ ID NO:5). As described above in some cases the EphA5 receptor agonist is a cyclic peptide or polypeptide wherein the cyclic region comprises the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5. Thus, in some case the agonist is a cyclic peptide or polypeptide comprising a disulfide bond such as a peptide or polypeptide wherein the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:5 are flanked by cysteine residues (e.g., as in SEQ ID NO:2 or SEQ ID NO:3).
  • Thus, in still further aspects of the invention there is provided a method for treating an Eph5A receptor positive cell comprising administering to the cell an EphA5 receptor targeting therapeutic as described supra. Thus, in some aspects a method of the invention may be further defined as a methods for treating a subject comprising an EphA5 receptor positive cell by administering an effective amount of an EphA5 receptor targeting therapeutic. For example, in certain cases a subject may be a cancer patient comprising an EphA5 receptor positive positive cancer such as a lung cancer or neuronal cancer. In still further aspects there is provided a method for treating a subject with a an EphA5 receptor positive cancer by administering an EphA5 receptor targeting therapeutic wherein the therapeutic comprising a cytotoxic agent or an anticancer agent.
  • The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”
  • The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”
  • Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawing, in which:
  • FIG. 1: Selectivity of broad-specificity tripeptides for clusters of NCI-60 cell lines. Two-dimensional hierarchical clustering was applied to the frequencies of 38 tripeptides (rows) encountered in CX7C peptides selected on NCI-60 cell lines (columns). Tripeptides selected on all but one cell line of common origin were clustered based on their correlations with cell lines; cell lines were clustered based on their correlations with the tripeptides. Tripeptide frequencies were mean subtracted and average linkage clustered with correlation metric. Amino acid color code: red, hydrophobic; green, neutral and polar; purple, basic. The color in each CIM segment ranges from blue (negative correlation) to red (positive correlation), as indicated by the scale bar. Cell lines are color-coded based on previously defined histologic tumor origin (Monks et al., 1991, Weinstein et al., 1997. Bars underneath dendrogram, clusters of cells of similar tumor tissue origin (one exception allowed). Boxed, cluster of lung cancer-derived cell lines and associated/dissociated tripeptides.
  • FIGS. 2A-B: Identification of peptides mimicking EGFR ligands. FIG. 2A, EGFR-binding peptide sequences isolated from the SKOV-3 selected phage pool were matched in each orientation to protein sequences of biological human EGFR ligands (leader peptide sequence underlined). Matches displayed are peptides with three or more amino acids being identical (red) and one or more being from the same class (green) as the correspondingly positioned protein amino acids. Tripeptides listed in Table 1 (yellow). FIG. 2B, isolation of peptides targeting EGFR. Binding of SKOV3-selected phage pool to immobilized EGFR compared with BSA in rounds 1 and 2 of biopanning of SKOV3-selected phage pool on immobilized human EGFR.
  • FIGS. 3A-3B: Phage selection on immobilized EphA5 receptor. FIG. 3A, Ephrin-mimic phage displaying the enriched motif GGS were selected on EphA5-coated microtiter wells. Phage showing specific binding to EphA5 was analyzed for its distinctive binding to EphA5 compared to EphA4 receptor (FIG. 3B). BSA and fd-tet insertless phage were used as negative controls.
  • FIG. 4: EphA5 receptor expression in the NCI-60. From microarray analysis reported at dtp.nci.nih.gov/mtweb/servlet/moltidsearch?moltid=MT894.
  • FIG. 5: EphA5 and EphA4 receptor expression by the lung cancer cell lines Hop92 and H460. The OVCAR3 cell line was used as negative control. 10× magnification.
  • FIG. 6: Specific binding of the CSGIGSGGC (SEQ ID NO:2) and CRFESSGGC (SEQ ID NO:3)-phage to lung cancer cells Hop92 and H460 but not to the ovarian cancer cell line OVCAR-3. Insertless phage (fd-tet) was used as negative control.
  • FIGS. 7A-B: A. Clustered image map relating all isolated NCI-60-binding tripeptides to NCI-60 cell lines. FIG. 7A, Two-dimensional hierarchical clustering was applied to the frequencies of 3,280 unique tripeptides (rows) found in cell-binding CX7C peptides selected on the NCI-60 cells (columns). Tripeptides were clustered based on their correlations with cell lines; cell lines were clustered based on their correlations with tripeptides. Tripeptide frequencies were mean-subtracted and average-linkage clustered with correlation metric (the data were transformed to the mean of 0; variance of 1). The color in each CIM segment ranges from blue (high negative correlation) to red (high positive correlation), as indicated by the scale bar. Cell lines are color-coded based on previously defined histological tumor origin. FIG. 7B, A control two-dimensional hierarchical clustering applied under the Poisson assumption to 3,280 randomly simulated tripeptide frequencies (rows) showed no obvious pattern, thus indicating that clusters in A were not generated at random.
  • FIG. 8: Targeted peptides mediate ligand-receptor cell internalization. CSGIGSGGC (SEQ ID NO:2) and CRFESSGGC (SEQ ID NO:3)-phage were permeabilized into A549 cells. No internalization was observed when cells were incubated with insertless phage
  • FIG. 9A-B: Biological effects of the peptides CSGIGSGGC (SEQ ID NO:2) and CRFESSGGC (SEQ ID NO:3 on lung cancer cells. Promotion of cell survivial and proliferative response of starved lung cancer cells to the ephrin mimic peptides, control peptide and complete culture medium (A549 (FIG. 9A), H460 cells (FIG. 9B)). Concentrations of peptide were optimized. Values in the Y-axis correspond to the number of viable cells under each experimental condition evaluated after a 72 h incubation period. Data bars represent the mean and corresponding standard error of the mean.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • A collection of 60 cell lines derived from human tumors (NCI-60) has been widely explored as a tool for anticancer drug discovery. In one aspect of the invention, the cell surface of the NCI-60 was profiled by high-throughput screening of a phage-displayed random peptide library and classified the cell lines according to the binding selectivity of 26,031 recovered tripeptide motifs. By analyzing selected cell-homing peptide motifs and their NCI-60 recognition patterns, the inventors established that some of these motifs (a) are similar to domains of human proteins known as ligands for tumor cell receptors and (b) segregate among the NCI-60 in a pattern correlating with expression profiles of the corresponding receptors. The inventors biochemically validated some of the motifs as mimic peptides of native ligands for the epidermal growth factor receptor. The results indicate that ligand-directed profiling of tumor cell lines can select functional peptides from combinatorial libraries based on the expression of tumor cell surface molecules, which in turn could be exploited as “druggable” receptors in specific types of cancer (Kolonin et al., 2006).
  • The National Cancer Institute panel of human cancer cell lines from different histologic origins and grades (NCI-60) has been extensively used to screen compounds for anticancer activity (Monks et al., 1991; Weinstein et al., 1997). The NCI-60 includes carcinomas of several origins (kidney, breast, colon, lung, prostate, and ovarian), tumors of the central nervous system, malignant melanomas, leukemias, and lymphomas. Gene expression determined by high-throughput microarrays has been used to survey the variation in abundance of thousands of distinct transcripts in the NCI-60; such data provided functional insights about the corresponding gene products in tumor cell transformation (Weinstein et al., 1997; Scherf et al., 2000; Nishizuka et al., 2003). This information-intensive genomic approach has yielded candidate diagnostic tumor markers to be validated at the protein level in prospective studies (Nishizuka et al., 2003). Moreover, systematic proteomic studies based on two-dimensional PAGE (Myers et al., 1997) and protein microarrays (Nishizuka et al., 2003) have also been implemented. Finally, in parallel with the NCI-60 transcriptome and proteome initiatives, pharmacologic sensitivity of the cells to >105 different chemical compounds has been registered (Monks et al., 1991; Weinstein et al., 1997). Indeed, for some genes, correlation of expression data to drug sensitivity profiles has uncovered the mechanistic basis for the drug activity (Scherf et al., 2000; Zaharevitz et al., 2002; Blower et al., 2002; Rabow et al., 2002; Wallqvist et al., 2002; Szakacs et al., 2004). Thus, conventional genomic and proteomic approaches have identified several potential tumor markers and drug targets. However, despite such advances, correlation between drug activity and gene expression profiles has not as yet been established for most of the compounds tested (Wallqvist et al., 2002; Brown, 1997; Walloyist et al., 2003). This suggests the likely existence of unknown factors and the need to develop alternative methodology to discover “druggable” molecular targets.
  • Over the past few years, it has been proposed that (a) characterization of molecular diversity at the tumor cell surface level (represented primarily by membrane-associated proteins that are often modified by lipids and carbohydrates) is required for the development of ligand-directed anticancer therapies, and that (Zaharevitz et al., 2002) peptides binding to surface receptors preferentially expressed on tumor cells may be used to ligand-direct therapeutics to sites of disease with potential for increased therapeutic windows (Arap et al., 1998; Kolonin et al., 2001). It has become increasingly clear that selective cell surface features can be mapped by screening libraries of peptides (Kolonin et al., 2001; Pasqualini and Ruoslahti, 1996; Giordano et al., 2001; Arap et al., 2002). In fact, combinatorial peptide libraries displayed from pIII protein of an M13-derived phage have now been successfully screened on intact cells and in vivo (Arap et al., 1998; Kolonin et al., 2001; Pasqualini and Ruoslahti, 1996). Peptide ligands selected from unbiased screens without any predetermined notions about the nature of the cellular receptor repertoire have been used for the subsequent identification of the corresponding target cell surface receptors (Giordano et al., 2001; Arap et al., 2002; Pasqualini et al., 2000; Kolonin et al., 2002; Kolonin et al., 2004; Pasqualini et al., 2001). In addition, novel techniques, such as the biopanning and rapid analysis of selective interactive ligands (BRASIL), have enabled high-throughput phage library screening on cells (Giordano et al., 2001). Here, the BRASIL method is used to systematically screen combinatorial libraries on tumor cells of the NCI-60 panel. Results of this feasibility study suggest that tumor cells can be grouped by profiles of their peptide ligands directed to differentially expressed cell surface receptors. The data support the notion that many tumor cell surface-exposed receptors are expressed irrespective of tumor origin, thus suggesting they could be developed as broad tumor targets. Integration of ligand-directed surface profiling with other approaches related to the NCI-60 may uncover functional ligand-receptor pairs for the targeted drug delivery.
    • I. CELL TARGETING MOLECULES
  • Modified cell targeting molecules of the present invention may be produced by chemical synthetic methods, by chemical linkage between the two moieties or in some cases by fusion of a second polypeptide coding sequence to the targeting moiety. It is contemplated that modified cell targeting molecules of the invention may be used as therapeutics and/or as imaging agents to target specific classes of cells.
  • As mentioned above, in certain aspects of the invention, a modified cell targeting moiety may comprise a second polypeptide wherein the two polypeptides together comprise a fusion protein. For example, in certain aspects the second polypeptide may be a therapeutic or cytotoxic (e.g., a toxin) polypeptide as exemplified below. A fusion of two polypeptide coding sequences can be achieved by methods well known in the art of molecular biology. It is preferred that a fusion polynucleotide contain only the AUG translation initiation codon at the 5′ end of the first coding sequence without the initiation codon of the second coding sequence to avoid the production of two separate encoded products. In addition, a leader sequence may be placed at the 5′ end of the polynucleotide in order to target the expressed product to a specific site or compartment within a host cell to facilitate secretion or subsequent purification after gene expression. The two coding sequences can be fused directly without any linker or by using a flexible polylinker.
    • A. Cell Targeting Moieties
  • Cell targeting moities as provided here may, in some aspects, comprise peptides or polypeptides that exhibit binding to a specific class of cells. For example, in some cases the cell targeting moiety is selected from one of the polypeptide sequences provided in Table 3. The skilled artisan will understand that such sequences may comprise additional amino acids or other covalent modifications. For instance, in preferred embodiments a polypeptide sequence from Table 3 is provided a cyclic polypeptide. Thus, in some specific examples, an amino acid sequence from Table 3 is flanked by cysteine residues that may form a disulfide bond thereby providing a cyclic polypeptide. Thus, in some aspects the invention provides compositions and methods for targeting any of the classes of cells that bind to the peptides and polypeptides provided herein (e.g., as indicated in Table 3) such as leukemia cells, lung cancer cells, colon cancer cells, CNS cancer cells, melanoma cells, ovarian cancer cells, prostate cancer cells, renal cancer cells or breast cancer cells.
    • B. Therapeutic Moieties
  • As mentioned above in certain aspects, a therapeutic moiety may be a toxin such as radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, cytotoxins (cytotoxic agents), or any molecules or enzymes not normally present in or on the surface of a cell that under defined conditions cause the cell's death. Toxins that may be used according to the methods of the invention include, but are not limited to, radioisotopes known in the art, compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin and cholera toxin. “Toxin” also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213Bi, or other radioisotopes such as, for example, 103Pd, 133Xe, 131I, 68Ge, 57Co, 65Zn, 85Sr, 32P, 35S, 90Y, 153Sm, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn, 90Yttrium, 117Tin, 186Rhenium, 166Holmium, and 188Rhenium; luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin. Furthermore, a therapeutic moiety may be a pro-apoptotic protein such as a BCL2 family member, a caspase or a granzyme.
    • II. CANCER THERAPIES
  • A variety of conventional cancer therapies are currently used in the treatment of cancer. Thus, in some aspects of the invention there are provided methods for classifying cancer cells such as cells that are sensitive or resistant to an anticancer therapy. Some examples of conventional cancer therapies discussed below. It is contemplated that methods according to the invention may be used to identify cells that are sensitive or resistant to any particular cancer treatment. Furthermore, some aspects of the invention concern compositions and methods for cell targeted anticancer therapy. Thus, it is contemplated that any anticancer method known to those in the art (as exemplified below) may be used in combination or conjunction with compositions and methods provided herein.
    • A. Chemotherapy
  • Cancer therapies also include a variety of combination therapies with both chemical and radiation based treatments. Combination chemotherapies include, for example, cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol, gemcitabien, navelbine, farnesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil, vincristin, vinblastin and methotrexate, or any analog or derivative variant of the foregoing.
    • B. Radiotherapy
  • Other factors that cause DNA damage and have been used extensively include what are commonly known as γ-rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors are also contemplated such as microwaves and UV-irradiation. It is most likely that all of these factors effect a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes. Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 wk), to single doses of 2000 to 6000 roentgens. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.
  • The terms “contacted” and “exposed,” when applied to a cell, are used herein to describe the process by which a therapeutic construct and a chemotherapeutic or radiotherapeutic agent are delivered to a target cell or are placed in direct juxtaposition with the target cell. To achieve cell killing or stasis, both agents are delivered to a cell in a combined amount effective to kill the cell or prevent it from dividing.
    • C. Immunotherapy
  • Immunotherapeutics, generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells. The immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell. The antibody alone may serve as an effector of therapy or it may recruit other cells to actually effect cell killing. The antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve merely as a targeting agent. Alternatively, the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target. Various effector cells include cytotoxic T cells and NK cells.
  • Immunotherapy, thus, could be used as part of a combined therapy, in conjunction with gene therapy. The general approach for combined therapy is discussed below. Generally, the tumor cell must bear some marker that is amenable to targeting, i.e., is not present on the majority of other cells. Many tumor markers exist and any of these may be suitable for targeting in the context of the present invention. Common tumor markers include carcinoembryonic antigen, prostate specific antigen, urinary tumor associated antigen, fetal antigen, tyrosinase (p97), gp68, TAG-72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B and p155.
    • III. EXAMPLES Example 1 Combinatorial Library Screening on Cells
  • All the NCI-60 cell lines (1), except MDA-N (unavailable), were grown in RPMI 1640 supplemented with 5% fetal bovine serum (FBS) and 5 mmol/L L-glutamine. A phage display random peptide library based on the vector fUSE5 displaying the insert CX7C (SEQ ID NO:1) was screened by using BRASIL as described (Giordano et al., 2001). Exponentially growing cells were harvested with 0.5 mmol/L EDTA, 0.4 g/L KCl, 8 g/L NaCl, and 1 g/L dextrose, washed once with phosphate buffer saline (PBS), and resuspended in RPMI containing 1% bovine serum albumin (BSA) and 1 mmol/L HEPES. Cells (˜106) were incubated for 2 hours on ice with 109 transduction units (T.U.) of CX7C phage in 200-μL suspension, transferred to the top of a nonmiscible organic lower phase (dibutyl phtalate/cyclohexane, 9:1), and centrifuged at 10,000×g for 10 minutes. The phage-bound cell pellet was incubated with 200 μL of K91 bacterial culture, and the bound phages were amplified and used in the following round. To prevent preferential isolation of peptides containing the RGD motif, which is selected on tissue-cultured cells due to expression of cell adhesion molecules binding to vitronectin, library screening was done in the presence of 1 mg/mL of the synthetic peptide RGD-4C (AnaSpec, San Diego, Calif.) in each round. After three rounds of selection, phage peptide-encoding inserts were sequenced as described (Pasqualini and Ruoslahti, 1996; Arap et al., 2002; Pasqualini et al., 2001).
    • Example 2 Hierarchical Cluster Analysis of Peptide Motif/Cell Line Association
  • The inventors created an interactive sequence management database of all peptide sequences isolated in the screen. Calculation of tripeptide motif frequencies in CX7C peptides (in both directions) was done by using a character pattern recognition program based on SAS (version 8.1.2, SAS Institute, Cary, N.C.) and Perl (version 5.6.1) as described (Arap et al., 2002). To identify the most closely related tripeptides and cell lines, clustered image maps (CIM) were generated by using online software CIMminer available at discover.nci.nih.gov/tools.jsp. Data were centered (mean subtracted and divided by SD) on both cell lines and tripeptide motifs; correlation coefficient metric with average linkage algorithm was used as distance measurement. The tripeptide motif frequencies across the NCI-60 cell lines formed a two-dimensional data matrix that was used to correlate motif enrichment with groups of cell lines. To evaluate whether CIMMiner algorithm is appropriate for clustering analysis of peptide frequency data, a simulation test was devised assuming that the frequencies of tripeptide motifs in a given data set follow an independent Poisson distribution. The inventors simulated a random 3,280×59 data matrix of the dimension identical to that of tripeptide motif frequency data matrix (corresponding to the set of 3,280 tripeptides and 59 cell lines). These simulated data were centered the same way as the experimental data by transforming to mean of 0, variance of 1. For CIM in FIG. 1, tripeptides selected on all but one cell line of common origin (Arap et al., 2002) were used. Specificity of five tripeptides selectively overrepresented or underrepresented in lung tumor cell binding peptides for the 11 boxed cell lines (against the other 48 cell lines) was evaluated by using the R Package, version 2.0.0 (www.r-project.org) by performing two-sample t test (one tailed), as well as using Wilcoxon rank sum test (one tailed) and Fisher exact test (one tailed) as described (Arap et al., 2002).
    • Example 3 Identification of Candidate Targeted Receptors
  • To identify lead receptors targeted by tripeptide motifs, the Molecular Target Database (found on the world wide web at dtp.nci.nih.gov) was screened to identify proteins, expression levels of which in individual cell lines of the NCI-60 correlated with frequencies of individual tripeptides from FIG. 1 in the corresponding cell lines. The inventors used the COMPARE software (found on the world wide web at dtp.nci.nih.gov/docs/compare/compare.html) to calculate pairwise Pearson correlations between tripeptide frequencies in cell lines and the protein expression patterns in the database. Minimum Pearson correlation coefficient of 0.2 served as cutoff for the selection of lead receptors, as it provided a reasonable number of candidate molecular targets for which NCI-60 expression profiles and tripeptide frequency distribution profiles correlated. To initially restrict the candidate targets analyzed to broad-specificity receptors, only putative cell surface molecules (Table 1) were included, expression of which in the NCI-60 was found to correlate with the frequency profile of at least 25% of the tripeptides.
    • Example 4 Protein Database Screening for Peptide Motif Similarity
  • To identify natural prototype ligands of candidate receptors that are mimicked by selected peptides, the inventors screened all 7-mer peptides selected in the screen by using online ClustalW software (www.ebi.ac.uk/clustalw/) to identify extended (four or longer amino acids) motifs shared between multiple peptides containing the broad-specificity tripeptides (FIG. 1). Nonredundant databases of human proteins were searched by the BLAST software (www.ncbi.nlm.nih.gov/BLAST/) for proteins containing the cell-targeting 4-mers under the condition that at least the tripeptide part of the motif is identical to the part of the BLAST match.
    • Example 5 Validation of Epidermal Growth Factor Receptor as One of the Peptide Targets
  • To isolate peptides binding to epidermal growth factor receptor (EGFR), phage clones selected on SKOV3 in rounds 2 and 3 of the screening were individually amplified and pooled, and 109 transduction units of the mixed phage were incubated overnight at 4° C. with 10 μg of purified human EGFR (Sigma, St. Louis, Mo.), or BSA control immobilized on plastic. Unbound phages were extensively washed off with PBS, and then the bound phages were recovered by infecting host K91 Escherichia coli directly on the plate, and tetracycline-resistant clones were selected, quantified, and sequenced. To identify EGFR ligand-matching motifs among phage-displayed SKOV3-binding peptides, custom-designed Perl 5.8.1-based software was used to run peptide sequences against biological EGFR ligand sequences. Each 7-mer peptide sequence was aligned in each orientation against the EGFR ligand sequences from the NH2 to COOH terminus in one-amino-acid shifts. The peptide/protein similarity scores for each residue were calculated based on a BLOSUM62 matrix modified to identify peptide matches of at least three amino acids in any position being identical and one being similar to the corresponding amino acid positions in the EGFR ligands (FIG. 2A).
    • Example 6 Isolation of Peptides Binding to Surface of the NCI-60 Cancer Cells
  • As an initial attempt to profile cell surface of the tumor cell panel, a large (2×108 unique sequences) cyclic random peptide library was screened with the basic structure CX7C (C, cysteine; X any residue) on every cell line of the NCI-60. Phage selection was done in the excess of a competing Arg-Gly-Asp (RGD) synthetic integrin-binding peptide (Arap et al., 1009) to minimize the recovery of RGD-containing peptides. This strategy was designed to facilitate the recovery of ligands binding to nonintegrin families of cell surface receptors because RGD tends to become dominant in the screening due to the high levels of integrin expression in adherent cells (unpublished observation). Preferential cell binding of specific cell-targeting peptides results in enrichment, defined by the increased recovery frequency of these peptide motifs in each subsequent round of the screen (Kolonin et al., 2001; Pasqualini et al., 2001). Thus, the inventors set out to profile the expression of nonintegrin cell surface molecules among the cell lines of the NCI-60 according to the differential selection of motifs enriched in the screen.
    • Example 7 Hierarchical Cluster Analysis of Peptides Binding to the NCI-60 Cells
  • To analyze the spectrum of the peptides resulting from the screening and compare those among different cell lines of the panel, a combinatorial statistical approach was adopted based on the premise that three residue motifs (tripeptides) provide a sufficient structure for protein-peptide interactions in the context of phage display (Arap et al., 2002). For each NCI-60 cell line, CX7C peptide-encoding DNA inserts from 96 phage clones recovered after three rounds of selection were sequenced. A computer-assisted survey of all tripeptides within the library-derived sequences selected on each cell line by analyzing a database of 26,031 tripeptides contained within the 5,270 CX7C-encoded 7-mer peptides isolated (an average of eighty-nine 7-mer peptide sequences analyzed per each NCI-60 cell line) was performed. Thus, each cell line was assigned a unique set of tripeptides that was identified during the selection for cell surface binders, and the frequencies of each motif among all peptides for a given cell line were calculated.
  • To classify cell lines according to their association with particular motifs, which might provide inference on the targeted surface molecules, a hierarchical clustering analysis of the 3,280 nonredundant tripeptides was done based on the frequency of association with the NCI-60 cell lines. For the construction of a CIM, the inventors adapted a hierarchical clustering algorithm and a pseudo-color visualization matrix initially designed to address differential gene expression among the cells of the panel (Scherf et al., 2000; Zaharevitz et al., 2002; Blower et al., 2002; Rabow et al., 2002). CIMMiner (Weinstein et al., 1997) was used for inference of the variation in peptide binding specificity across the cell lines by comparing relative frequencies of tripeptides found in 7-mer peptides binding to each cell. Clustering of peptide motifs with similar cell selectivity revealed that the peptide distribution of the combinatorial library within the NCI-60 set was nonrandom. Computer simulations of the permutated data set show that the observed pattern could not be generated by random chance, thus indicating that the discontinuous tripeptide frequency data is applicable for cluster analysis.
  • The selective spectra of peptide motifs interacting with the clustered cell lines suggest the existence of shared targeted surface receptor(s) expressed in these lines. In this study, the inventors chose to focus on putative peptide-targeted receptors with broad cell line specificity, which would be more informative for an initial peptide binding/receptor expression correlation analysis. the inventors therefore excluded from the data set motifs selected only on a single or few cell lines. Instead, the inventors focused on 38 tripeptides that showed a semiubiquitous distribution among the NCI-60 lines (FIG. 1). A CIM constructed according to the isolation frequency of these broader-specificity tripeptides from each cell line revealed several apparent clusters of cell lines that displayed distinct profiles of association with certain classes of peptide motifs. For example, the majority of lung cancer-derived cell lines segregated as a separate group, suggesting that some of the receptors targeted may be conserved among cell lines derived from a common origin (FIG. 1). Thus, although the analysis was severely restricted by limiting it to semiubiquitous tripeptides, clustering of some of them (predominantly with cell lines derived from the same tumor type) is consistent with their relative tissue specificity. To evaluate individual motifs for selectivity, a distinct cluster of five tripeptides associated with lung tumor-derived cell lines (FIG. 1, boxed) were identified. The inventors compared tripeptide frequencies for the 11 cell lines within this cluster with their frequencies for the rest of NCI-60 lines by using statistical tests (Fisher exact, Wilcoxon rank-sum, and t test). Consistently, the GGS motif was isolated for the clustered lines significantly (P<0.05) more frequently than for the other NCI-60 cell lines.
  • Notably, the distribution of cell lines in the dendrogram (FIG. 1) was partially consistent with the reported association of cells derived from tumors with common tissue origin (Scherf et al., 2000; Nishizuka et al., 2003). This suggests that some of the receptors, such as the one presumably recognized by the lung tumor-specific tripeptide GGS (FIG. 1), may be up-regulated only in certain cancer origins. However, the tumor cell phylogeny was recapitulated only to an extent; the majority of the observed clusters contained cell lines derived from unrelated tumor types (FIG. 1). The limited grouping of lines derived from tumors of common origin is perhaps not surprising: the relationship between different cell lines in the study is based on peptide binding to putative cell surface molecules, many of which may be tumor induced rather than characteristic of the tissue of origin. If so, the analysis of broad-specificity motif distribution may be well suitable for identification of specific surface molecules that are generally up-regulated by tumors and thus may constitute broad drug targets against cancer.
    • Example 8 Identification of Candidate Receptor Targets for Peptide Motifs
  • The inventors proceeded to identify the targets for the 38 broad-specificity tripeptides, most of which presumably bind to receptors expressed by multiple NCI-60 cell lines. The NCI Molecular Targets Database that contains detailed information on the expression and activity of 1,218 human proteins measured by nonarray methods was used (Holbeck, 2004). By using the COMPARE algorithm (Zaharevitz et al., 2002), the inventors correlated the selectivity profiles of the 38 tripeptide motifs with the expression profiles of the characterized molecular targets. It was observed that several of the qualifying proteins, expression of which correlated with enrichment profiles of certain motifs, represented tyrosine kinase receptors, such as those for ligands belonging to families of EGFs, fibroblast growth factors (FGF), nerve growth factors (NGF), and ephrins (Table 1). When transferred to molecular target correlation data, the order of the 38-tripeptide motif set in the dendrogram (FIG. 1) revealed clusters of tripeptides for which cell line association profile correlated with expression profiles of EGF, FGF, NGF, or ephrin receptors (Table 1).
  • The peptide distribution-correlating tyrosine kinase receptors, belonging to EGFR, FGFR, NGFR, and ephrin receptor families (Table 1), are often up-regulated in many types of cancer (Vogelstein and Kinzler, 2004). To determine if the cell-binding peptides may target these tyrosine kinases, the inventors employed the notion that receptor-binding peptide motifs often mimic natural ligands for these receptors (Giordano et al., 2001; Arap et al., 2002; Kolonin et al., 2002). Thus, the selected motifs mimic ligands for the candidate tyrosine kinases were tested by determining whether tripeptides listed in Table 1 are embedded into longer peptides that may be responsible for cell surface binding. The inventors analyzed the CX7C (SEQ ID NO:1) phage inserts containing the 38 tripeptides by using the ClustalW software and compiled extended motifs containing the tripeptides shared among multiple peptides selected during the screen (data not shown). To identify candidate prototype human ligands, epitopes of which could be mimicked, each of the ClustalW-extended motifs were screened against the nonredundant database of human proteins by using the BLAST software (National Center for Biotechnology Information). As a result of this analysis, the inventors found the motifs containing 34 of 38 tripeptides (89%) to be identical or very similar to segments of proven or putative ligands for the tyrosine kinase receptors listed (Table 1).
    • Example 9 Validation of EGFR as a Targeted Receptor
  • To show that the approach taken can lead to actual targetable tumor cell surface proteins, the inventors chose to test if the EGFR is bound by any of the tripeptide motifs distributed in the panel in a profile correlating with EGFR expression. Consistently, 24 of 38 tripeptides surveyed displayed NCI-60 cell line association pattern consistent with that of EGFR expression (Table 1). Of these tripeptides, 22 were isolated in the screens on ovarian cancer cell lines SKOV3 and OVCAR4 (data not shown). Because EGFR is well known to be associated with ovarian cancer (Vogelstein and Kinzler, 2004), the inventors deemed these cell lines to be likely expressers of targetable EGFR, which would account for the selection of EGFR ligand-mimicking motifs. To validate EGFR binding by the selected motifs, the SKOV3-binding phage sublibrary (pooled clones recovered in rounds 2 and 3) were screened against immobilized human EGFR. After two rounds of selection, phage displaying the EGFR-binding peptides were analyzed: the majority were comprised by different 7-mer peptides (FIG. 2A) that contained 17 of 22 SKOV3-selected tripeptide motifs distributed in the panel in a profile correlating with EGFR expression (Table 1). Phage displaying these peptides had specific affinity to EGFR, as determined by subjecting the same sublibrary to immobilized BSA control binding (FIG. 2B). Remarkably, computer-assisted analysis of sequences (FIG. 2A) revealed that 12 of the 7-mer EGFR-binding peptides contained amino acid motifs similar to those present in some of the biological EGFR ligands (Vogelstein and Kinzler, 2004). These peptides, containing eight of the candidate tripeptides (RVS, AGS, AGL, GVR, GGR, GGL, GSV, and GVS), were found highly similar to fragments of EGF, amphiregulin, heparin-binding EGF-like growth factor, and epiregulin (FIG. 2A). Similarity search using the same algorithm on the same twelve 7-mers did not reveal any matches to two other EGFR ligands, transforming growth factor-α and β-cellulin, or randomly chosen control ligands of tyrosine kinase receptors from the three other candidate families listed in Table 1: ephrin A, NGF-β, and FGF6 (data not shown). Taken together, these data suggest that at least some of the peptides selected on the NCI-60 cells target EGFR, whereas others may bind to different tyrosine kinases, possibly including those from TRK, ephrin, or FGF receptor families.
  • Expression profiles of the candidate receptor targets for peptides identified in the screen illustrate the concept that in cancer, at least some tumor-associated cell surface molecules seem up-regulated regardless of cancer tissue origin. As such, this is the case for the EGFR and other tyrosine kinases possibly targeted by peptide ligands selected on the NCI-60 cell panel. This may also be the case for many other receptors with a role in tumorigenesis, expression profiles of which may not correlate with the overall proteomic profile of the original tumor tissue. In fact, these observations may account for the relatively limited success in correlating drug toxicity profiles with the genomic and/or proteomic profiles of the NCI-60 panel (Walloyist et al., 2003). On the other hand, some of the receptors, such as EphA5 presumably targeted by GGS tripeptide and its derivatives predominantly selective for lung tumor-derived cell lines (FIG. 1), seem to be at least partially specific for the progenitor cancer type.
  • The candidate ligand-receptor leads identified in this study can be characterized further for the development of targeted agents selective for tumors. Moreover, the peptides identified by the approach described here may map receptor interaction domains of biological (native) ligands. Similarity of peptides to the corresponding receptor-binding ligands has already been used for validation of the IL-11Rα receptor as a target of an interleukin-11 mimic peptide homing to blood vessels in the prostate (Arap et al., 2002; Zurita et al., 2004). The inventors and others have modeled the usage of peptides homing to receptors expressed by tumors (Pasqualini et al., 2000) or non-malignant tissues (Kolonin et al., 2002; Kolonin et al., 2004) for directing the delivery of cytotoxics, proapoptotic peptides, metalloprotease inhibitors, cytokines, fluorophores, and genes (Arap et al., 1998; Kolonin et al., 2001). Thus, the approach provides a straightforward way to identify drug-accessible tumor cell surface receptors and to discover peptide ligands that can serve as mimetic prototype drugs. Unlike genomic or proteomic-based approaches that rely on differential expression levels of transcripts or protein products, this discovery platform directly addresses functional protein-protein interactions at the level of physical binding. In contrast to protein array systems, it is possible to select binding peptides even if the ligand-receptor interaction is mediated by conformational (rather than linear) epitopes. Ligand-directed screening of combinatorial libraries on tumor cell surfaces can lead to improved selection of functionally relevant peptides that can be developed for targeting “druggable” molecular targets.
  • Figure US20130089498A1-20130411-C00001
  • TABLE 1
    Candidate ligand-receptor interactions mimicked*
    RLS ErbB2, ErbB4 FGF2, 4 EGF-TM7
    RGV
    RGS ErbB4 FGF2 EphA2, A3, A4, A8, B1 EGF-TM7, FGF-12b, FGF-5, NGF-beta
    RAV ErbB2 MEGF7, NGF-beta. NTF 6 alpha
    RAS TRKA FGF-20, NRG-3
    GAG EGFR FGF1, 2, 3 MEGF4, FGF6, NGF-beta
    AVS EGFR, ErbB2, FGF1 TRKB, C EphA2, A3, A4, A7, TRK1
    ErbB4 B1, B2, B3, B5
    LLS Amphlregulin
    LLR TRKA EphA4
    LRV EGFR, ErbB2, FGF3 TRKA, B, C EphA2, A3, A7 FGF-12b, Eph-B3
    ErbB4
    LRS ErbB3 MEGF4, MEGF5, MEGFS, NRG-3, NGF-beta
    RVS EGFR, ErbB2, FGF1, 2 TRKB EphA7 MEGF10, amphiregulin
    ErbB4
    RSS FGF3 TRKA EphAS EGF-TM7, FGF-S, NRG-3
    AGS EGFR TRKA MEGF6, brain NGF
    AGR MEGF2, MEGF4, FGF6, NTF-5, NTF-6
    AGL EGFR, ErbB2, FGF1, 3 EphAS, A6, A8 MEGF12
    ErbB3
    AGG EphA5 HB-EGF, Ephr-B3
    GVR EGFR, ErbB2, FGF1, 2 TRKB EphA7 MEGF4, MEGF6, MEGF8, FGF-5, bFGF,
    ErbB4 brain NGF
    GVL FGF1, 2 EphA2, A3, A5, A6, B3 NGF2, Ephrin-B3,
    GAV MEGFS, MEGF6, NGF-beta
    GLV ErbB4 FGF4 EphA5 ESF-TM7, betaceilulin, NTF 3, Eph-B3,
    GLR ErbB4 MEGF5, EGFL5, FGF-12b, FGF-16, NRG-3
    LVS FGF1, 4 EphA5, A6 EGFL5, FGF23, GDNF, Eph-B3
    ARG ErbB2 FGF2, 4 TRKA EphAI FGF-12b, FGF23, NGF-beta, GDNF, NTF 6
    ASL FGF1, 2 TRKC EGF-TM7, FGFR1
    AAV TRKB EphA2, A3, A4, A7, •
    B3, B5
    AAS FGF1, 2 TRKC •
    GGS EphA5 Eph-B3, Eph A4
    GGR EGFR · ErbB2 FGF2 EGF-TM7, HB-EGF, FGF23, Ephrin-B3
    GLG ErbB2, ErbB3 FGF2, 3, 4 EphA1, A6 heparin binding growth factor 8
    GGL ErbB2 HB-EGF, MEGF5, EGFL5, NRG-3
    GSS EGFR, ErbB2 FGF3 TRKA, C EphA5 MEGFS
    GSG EGFR EphA5
    GSV EGFR, ErbB2, FGF4 TRKB EphA7, B2 MEGF5, NRG-3, Ephrin-B3
    ErbB4
    GRV EGFR MEGFS, EGF-TM7, FGF23, NTF5
    GRL EGFR · ErbB2 EphAS, B1, B2, B4 betacellulin, EGFL5, NGF2, NTF5, EphB3,
    EphA4
    GPS EGFR, ErbB2, FGF3 TRKB EpnA2, A3, A4, A7, MEGFS, EGFL5, EGF-like EMR3, SPGF
    ERB4 B2, B5
    GVS EGFR FGF4 TRKA MEGF-1, MEGF5, NRG-3, NTF-6, NTF-5
    *NOTE:
    Candidate peptide motif receptors are the human cell surface proteins (identified by COMPARE) expressed in profiles correlating with the selectivity of the corresponding tripeptides. Candidate peptide-mimicked receptor ligands are human proteins (identified by automated BLAST) that contained the corresponding tripeptides. Tripeptides in the column are ordered as in FIG. 1. Receptors of the same family and their corresponding candidate biological ligands identified based on tripeptide similarity are coded by the same color [EGFR, blue; FGFR, green; TRK receptor (NGFR), purple; ephrin receptor, red]. Tripeptides that both have a selectivity correlating with EGFR family receptor expression and are found within EGFR ligands (boldface). Tripeptides that were confirmed to reside within EGFR-binding SKOV3-slected peptides (FIG. 2; blue).
    • Example 10 Molecular Fingerprinting of Cancer Cell Lines
  • Proteomics can be defined as the systematic analysis of the proteins in biological samples that aims to document the overall distribution of proteins in tumor cells or tumor-associated cells, identify and characterize individual proteins of interest and to elucidate their relationships and functional roles. Ultimately, high-throughput profiling of protein expression will lead to the “proteome”, a protein-based fingerprint, for each tissue in humans and other species. As technologies related to proteomics advance, new approaches for systematic molecular analysis of cancer at the protein level are surfacing. However, methods for systematic protein expression profiling may also easily overlook potential targets for intervention. These methods often do not take anatomical context into account. Therefore, for the generation of molecular map of accessible receptors that can be used for targeting therapeutics, information derived from conventional protein profiling approaches should be enhanced by integration with data from functional screenings ex vivo and in vivo. Studies by the inventors and others have advanced the concept of cancer proteomics: the molecular phenotyping of tumor cells and cells forming blood vessels at the protein-protein interaction level. Exploiting the molecular diversity of cell surface receptors expressed in cancer will eventually result in a ligand-receptor functional map for targeted delivery.
  • A major goal in drug development has long been to generate targeted therapies. This approach would improve drug therapeutic indexes by limiting the systemic exposure of other tissues to untoward or toxic effects. Thus, the promise for the identification of selectively expressed tumor-associated receptors and the ligands that home to these receptors is translation of this knowledge into the development of targeted therapeutics. Generally, coupling of homing peptides yields targeted compounds that are more effective and less toxic than the parental compound. So far, peptides selected by homing to tumor vasculature have been used as carriers to guide the delivery of cytotoxic drugs, pro-apoptotic peptides, metalloprotease inhibitors, cytokines, fluorofores, and genes in transgenic and xenograft mouse models of human disease.
  • Recognition of molecular diversity in human cancer is essential for the development of targeted therapies. The methods developed have two main applications. First, they may identify ligands targeting human cancer. Second, the determination of molecular profiles of biomarkers in specific types of tumors may enable identification of differentially expressed cancer markers. Thus, the approach may lead to construction of a molecular profile of human tumors. Early identification of targets, optimized regimens tailored to molecular profile of individual cancer patients, combined with the identification of new vascular addresses may result in revisiting or salvaging of drug candidates that are ineffective or too toxic. Ultimately, it may be possible to guide imaging or therapeutic compounds to tumor targets in cancer patients.
  • By fingerprinting lung cancer cells the inventors have confirmed the expression of a previously characterized molecular target, EGFR, in multiple cancer origins, which demonstrates the power of the approach. Recently, the inventors used this approach to identify a new cancer origin-selective molecular target, Ephrin A5 receptor, which the inventors have preliminary validated in the context of human lung cancer cell lines and tissues.
    • Example 11 Motifs Targeting NCI-60 Cells in Correlation with EGFR Expression Pattern are Found within Peptides Similar to Domains of Biological EGFR Ligands and Bind to EGFR
  • To show that the approach taken can lead to actual targetable tumor cell surface proteins, the inventors chose to test if the EGF receptor (EGFR) is bound by any of the tripeptide motifs distributed in the panel in a profile correlating with EGFR expression. Consistently, 24 out of 38 tripeptides surveyed displayed NCI-60 cell line association pattern consistent with that of EGFR expression (Kolonin et al., 2001). Of these, tripeptides, 22 were isolated in the screens on ovarian cancer cell lines SKOV3 and OVCAR4 (data not shown). Since EGFR is well known to be associated with ovarian cancer (Vogelstein, 2004; Maihle and Lafky, 2002), the inventors deemed these cell lines to be likely expressers of targetable EGFR, which would account for the selection of EGFR ligand-mimicking motifs. To validate EGFR binding by the selected motifs, the SKOV3-binding phage sub-library (pooled clones recovered in rounds 2 and 3) were screened against immobilized human EGFR. After 2 rounds of selection, phage displaying the EGFR-binding peptides were analyzed: the majority were comprised by different seven-mer peptides (FIG. 3A) that contained 17 out of 22 SKOV3-selected tripeptide motifs distributed in the panel in a profile correlating with EGFR expression.
  • Phage displaying these peptides had specific affinity to EGFR, as determined by subjecting the same sub-library to immobilized bovine serum albumin (BSA) control binding (FIG. 2B). Remarkably, computer-assisted analysis of sequences (FIG. 2A) revealed that 12 of the seven-mer EGFR-binding peptides contained amino acid motifs similar to those present in some of the biological EGFR ligands. These peptides, containing eight of the candidate tripeptides (RVS, AGS, AGL, GVR, GGR, GGL, GSV, and GVS) were found highly similar to fragments of EGF, Amphiregulin, heparin-binding EGF-like growth factor, and Epiregulin (FIG. 2A). Similarity search using the same algorithm on the same 12 seven-mers did not reveal any matches to two other EGFR ligands, TGF-α and betacellulin, or randomly chosen control ligands of tyrosine kinase receptors from the three other candidate families listed in Table 2 (Kolonin et al. 2001): Ephrin A, NGF-β, and FGF6. Taken together, these data suggest that at least some of the peptides selected on the NCI-60 cells target EGFR, while others may bind to different tyrosine kinases, possibly including those from TRK, Ephrin, or FGF receptor families.
  • A phage-displayed combinatorial library was systematically screened for peptides capable of targeting the cell lines in the NCI-60 panel. By statistical analysis of peptide motif sequences, each NCI-60 cell line was assigned a unique set of peptide motifs that were isolated during the selection for cell surface binders. It was shown that tumor cells can be grouped by profiles of their phage display-derived peptide ligands directed to differentially expressed cell surface receptors.
  • An approach for peptide-targeted receptor identification was designed. Profiles of peptide motif preference for specific lines of the NCI-60 were correlated with expression profiles of known breast cancer-related targets. Some of the peptide motifs were found within proteins known to bind the receptors that had NCI-60 expression profiles matching cell line recognition profiles of the peptides, and that are implicated in cancer.
  • Candidate targeted cell surface molecules were identified, which included a number of tyrosine kinase receptors. As a proof of principle, EGFR, a receptor known to be upregulated in various cancers, was validated as a target of tripeptides RVS, AGS, AGL, GVR, GGR, GGL, GSV, and GVS, which were The results described uncover a previously overlooked phenomenon. The data support the notion that many tumor cell surface-exposed receptors are expressed irrespective of tumor origin, thus suggesting they could be explored as broad tumor targets.
    • Example 12 Ephrin A5 Receptor as a Lung Cancer Cell Surface Marker
  • The peptide distribution-correlating tyrosine kinase receptors, belonging to EGFR, FGFR, NGFR and Ephrin receptor families are often up-regulated in many types of cancer. On the other hand, some of the receptors, such as EphA5 presumably targeted by GGS tripeptide and its derivatives predominantly selective for lung tumor-derived cell lines appear to be at least partially specific for the progenitor cancer type. Since this approach clearly allowed identification of cell surface receptors ubiquitously upregulated in various cancers, the inventors took a step further to attempt identification of cancer type-specific receptors.
  • Having chosen lung cancer for the initial procedure establishment, the inventors identified a distinct cluster of five tripeptides associated with lung tumor-derived cell lines. The inventors compared tripeptide frequencies for the 11 cell lines within this cluster with their frequencies for the rest of NCI-60 lines by using statistical tests (Fisher exact, Wilcoxon rank-sum, and t-test). Consistently, the inventors observed that motif GGS was isolated for the clustered lines significantly (P<0.05) more frequently than for the other NCI-60 cell lines (Table 2).
  • TABLE 2
    Association of specific tripeptides with lung cancer-derived cell lines:
    P value
    Mean motif count P value Wilcoxon P value
    (±SEM) inside vs. t-test, rank-sum Fisher exact
    Motif outside cluster 1-sided test, 1-sided test, 1-sided
    GGS 2.2 (±0.5) vs. 1.2 (±0.2) 0.0422 0.0407 0.0043
    GGR 1.3 (±0.3) vs. 1.5 (±0.2) 0.6991 0.6466 0.6739
    GLG 0.7 (±0.4) vs. 0.7 (±0.2) 0.5375 0.6888 0.5150
    GGL 1.2 (±0.2) vs. 1.3 (±0.2) 0.6457 0.4174 0.5485
    GSS 2.2 (±0.4) vs. 1.1 (±0.2) 0.0422 0.0026 0.0008
  • To determine statistical significance of association or dissociation between exemplary tripeptides and cell lines, normalized frequencies of five tripeptides predominantly associated (GGS, GGR, GLG, and GGL) or dissociated (GSS) with the cluster containing the majority of lung tumor-derived cell lines (FIG. 1, boxed) were compared for cell lines inside the cluster and outside the cluster. Selective association of tripeptide GGS with the clustered cell lines was found significant according to t-test, Fisher exact test and Wilcoxon rank-sum test (all tests one-tailed).
  • Based on the automated BLAST analysis (Table 2) the inventors identified proteins of the ephrin family candidate prototypes of the GGS-containing peptides: ephrins -B3 and A4 contain the GGS, consistent with a functional mimickry. Ephrins (A and B) and their receptors (EphA and EphB) represent a large class of cell-cell communication molecules with well-defined developmental functions. Their role in healthy adult tissues and in human disease is still largely unknown, although diverse roles in carcinogenesis have been postulated and a number of Eph receptors have been found overexpressed by various cancers (Hafner et al., 2004). Based on the COMPARE analysis of GGS distribution within NCI-60 (Kolonin et al., 2001, Table 2), the receptor expressed in the corresponding pattern is EphA5. The EphA5 expression (FIG. 4 has been explored using cDNA microarray analysis and is reported at the DTP server (dtp.nci.nih.gov/mtweb/servlet/moltidsearch?moltid=MT894), however, no studies of EphA5 function in cancer have been published. Intriguingly EphA5 is not expressed in normal lung and normally is only thought to have brain-specific functions.
    • Example 13 Validation of Ephrin-Mimic Peptides in Lung Cancer
  • To validate phage containing the motif GGS as a ligand of Eph receptors, the inventors tested phage binding to the EphA5 immobilized receptor. The inventors started testing eight peptides (CAGLSGGTC (SEQ ID NO:2133), CSGIGSGGC (SEQ ID NO:2134), CSSGGVLGC (SEQ ID NO:2135), CSWGSGGSC (SEQ ID NO:2136), CTLVLGGSC (SEQ ID NO:2137), CRFESSGGC (SEQ ID NO:2138), CHVSGGSGC (SEQ ID NO:2139), CTGGSLGAC (SEQ ID NO:2140)) containing the enriched motif GGS, all of them displayed by phage clones obtained from the screening on different cell lines known to express the EphA5 receptor (FIG. 3A). From this first round of selection, 5 clones (CAGLSGGTC (SEQ ID NO:2133), CSGIGSGGC (SEQ ID NO:2134), CSSGGVLGC (SEQ ID NO:2135), CRFESSGGC (SEQ ID NO:2138) and CSWGSGGSC (SEQ ID NO:2136) showed good binding to the receptor relative to the control (BSA) and were further analyzed by their ability to specifically bind to EphA5 but not to the control EphA4 receptor (FIG. 3B). Phage displaying the peptide sequences CSGIGSGGC (SEQ ID NO:2134) and CRFESSGGC (SEQ ID NO:2138) showed binding specificity and were chosen for characterization. The inventors investigated the binding of the selected phage to the lung cancer cells Hop92 and H460. These cells are known to express EphA5 receptor on its surface, as confirmed by immunofluorescence analysis (FIG. 5). The ovarian cancer cell line OVCAR-3, negative for EphA5 expression, was used as control.
  • Next, the inventors used the BRASIL method (biopanning and rapid analysis of selective interactive ligands) to analyze binding of selected phage to lung cancer cells. The inventors observed specific binding of phage displaying the sequences CSGIGSGGC and CRFESSGGC to Hop92 and H460, confirming the data obtained from the screening on the immobilized EphA5 receptor (FIG. 6).
  • Finally, by using banked sections or patient tissues from the MD Anderson Cancer Center, the inventors showed that EphA5 protein is overexpressed by human lung adenocarcinoma epithelium.
  • Immunohistochemistry (polyclonal anti-prohibitin antibody) on formalin-fixed paraffin sections of human non-small cell lung cancer (NSLC) or normal prostate with EphA5 or EphA4-specific antibodies. Immunostaining demonstrates selective EphA5 upregulation of EphA5 protein expression in NSLC lung adenocarcinoma epithelium, but not stroma, as compared with the control prostate tissue.
  • Taken together, these data suggest that the two selected phage displaying the motif GGS are ligands of EphA5 receptor. Upregulation of EphA5 in gliomas has been reported, without any functional connections, and, up to date, there has been no reports of investigation of this tyrosine kinase receptor in lung cancer. Therefore, EphA5 protein overexpression in lung cancer cells (FIG. 4) in light of candidate ephrin mimics (GGS peptides) targeting these cells provides an original evidence for EphA5 being a lung cancer marker and has potential functional implications.
  • It is contemplated by the inventors that the cancer-associated motifs identified here can be used for the development of approaches for targeted imaging or therapy of breast tumors in patients. Their receptors, including EGFR, EphA5, and other cell surface molecules, can be further explored for their oncogenic properties and the potential to serve as universal or origin/grade-selective targets of cancer.
    • Example 14 Cell Internalization of Ephrin-Mimic Peptides
  • The ability of ephrin-mimic peptides to mediate cell internaization was assessed. The A549 cell line was used as a representative human lung cancer-derived cells expressing the EphA5 receptor on the cell surface. Each phage clone or control insertless phage was incubated with cells for 4 h at 37° C. Both CSGIGSGGC (SEQ ID NO:2) and CRFESSGGC (SEQ ID NO:3)-phage were internalized into A549 cells while only background fluorescence was obtained when nontargeted control phage was used (see FIG. 8).
    • Example 15 Activation of Cells by Ephrin-Mimic Peptide
  • Activation of the EphA5 receptor by the peptides CSGIGSGGC (SEQ ID NO: 2) and CRFESSGGC (SEQ ID NO:3) lead to proliferation and/or survival of lung cancer cells. In the absence of sera, this peptides increased lung cancer cells proliferation by 4-fold (FIG. 9A-B). This effect was confirmed in two different human cell lines, which express the EphA5 receptor.
  • TABLE 3
    Peptides and Motifs Associated with
    NCI-60 cell lines.
    Peptide
    Motif w/Seq ID: No. Cell Line
    RLS LRLSSIP (6) CCRF-CEM Leukemia
    RGV ARGVLLM (7) CCRF-CEM Leukemia
    RGS RGSHLVP (8) CCRF-CEM Leukemia
    DVETRGS (9) CCRF-CEM Leukemia
    RAV SRAVIDM (10) CCRF-CEM Leukemia
    RAS CCRF-CEM Leukemia
    GAG CCRF-CEM Leukemia
    AVS CCRF-CEM Leukemia
    LLS GLLSLXL (11) CCRF-CEM Leukemia
    TSLLSFR (12) CCRF-CEM Leukemia
    LLR CCRF-CEM Leukemia
    LRV CCRF-CEM Leukemia
    LRS CCRF-CEM Leukemia
    RVS RRVSLVA (13) CCRF-CEM Leukemia
    SRFRVSI (14) CCRF-CEM Leukemia
    RSS CCRF-CEM Leukemia
    AGS AGSLSVF (15) CCRF-CEM Leukemia
    AGR AGRICEG (16) CCRF-CEM Leukemia
    QVAGRER (17) CCRF-CEM Leukemia
    VEYAAGR (18) CCRF-CEM Leukemia
    AGL YNRSAGL (19) CCRF-CEM Leukemia
    AGG AVLVAGG (20) CCRF-CEM Leukemia
    LAGGVPG (21) CCRF-CEM Leukemia
    GVR DWWAGVR (22) CCRF-CEM Leukemia
    EPDGVRS (23) CCRF-CEM Leukemia
    EQLSGVR (24) CCRF-CEM Leukemia
    GVL GVLARVT (25) CCRF-CEM Leukemia
    ARGVLLM (26) CCRF-CEM Leukemia
    GAV GGAVLVA (27) CCRF-CEM Leukemia
    RERGAVQ (28) CCRF-CEM Leukemia
    GLV RALGLVS (29) CCRF-CEM Leukemia
    GLR SLGLRNQ (30) CCRF-CEM Leukemia
    LVS RALGLVS (31) CCRF-CEM Leukemia
    GAYRLVS (32) CCRF-CEM Leukemia
    ARG FDARGGL (33) CCRF-CEM Leukemia
    MFARGWE (34) CCRF-CEM Leukemia
    ARGVLLM (35) CCRF-CEM Leukemia
    ASL CCRF-CEM Leukemia
    AAV CCRF-CEM Leukemia
    AAS CCRF-CEM Leukemia
    GGS GGGSDGV (36) CCRF-CEM Leukemia
    GGR LGGRADF (37) CCRF-CEM Leukemia
    CCRF-CEM Leukemia
    GLG CCRF-CEM Leukemia
    GGL EVGGGLT (38) CCRF-CEM Leukemia
    FDARGGL (39) CCRF-CEM Leukemia
    GSS CCRF-CEM Leukemia
    GSG CCRF-CEM Leukemia
    GSV CCRF-CEM Leukemia
    GRV TGRVVRR (40) CCRF-CEM Leukemia
    GRL CCRF-CEM Leukemia
    GPS MGMSGPS (41) CCRF-CEM Leukemia
    GVS CCRF-CEM Leukemia
    RLS HL-60-Leukemia
    RGV AVRGVAR (42) HL-60-Leukemia
    DRGVPGL (43) HL-60-Leukemia
    RGS LSFSRGS (44) HL-60-Leukemia
    RGSVRVL (45) HL-60-Leukemia
    PVRGSVD (46) HL-60-Leukemia
    QVMMRGS (47) HL-60-Leukemia
    NGRGSGW (48) HL-60-Leukemia
    RAV RAVGRVA (49) HL-60-Leukemia
    RAS RASCALT (50) HL-60-Leukemia
    GAG ADIGAGG (51) HL-60-Leukemia
    FMGAGFA (52) HL-60-Leukemia
    AVS AGVFAVS (53) HL-60-Leukemia
    LLS HL-60-Leukemia
    LLR VMLLRPE (54) HL-60-Leukemia
    LLRGLEL (55) HL-60-Leukemia
    LPLLRGI (56) HL-60-Leukemia
    LRV DPRGLRV (57) HL-60-Leukemia
    LRS HL-60-Leukemia
    RVS LVRVSGR (58) HL-60-Leukemia
    SGSRVSL (59) HL-60-Leukemia
    RSS HL-60-Leukemia
    AGS AGSIALR (60) HL-60-Leukemia
    AGR MLASAGR (61) HL-60-Leukemia
    AGL HL-60-Leukemia
    AGG ADIGAGG (62) HL-60-Leukemia
    FAGGSTD (63) HL-60-Leukemia
    GVR HL-60-Leukemia
    GVL HL-60-Leukemia
    GAV TGFGAVG (64) HL-60-Leukemia
    HL-60-Leukemia
    GLV HL-60-Leukemia
    GLR FGLRNSR (65) HL-60-Leukemia
    DPRGLRV (66) HL-60-Leukemia
    LVS LVSSGSK (67) HL-60-Leukemia
    LVSSSEP (68) HL-60-Leukemia
    ARG HL-60-Leukemia
    ASL HL-60-Leukemia
    AAV AAVWAAD (69) HL-60-Leukemia
    AAS HL-60-Leukemia
    GGS FAGGSTD (70) HL-60-Leukemia
    GGR HL-60-Leukemia
    GLG HL-60-Leukemia
    GGL TFGKGGL (71) HL-60-Leukemia
    GSS KSGSSVL (72) HL-60-Leukemia
    HL-60-Leukemia
    GSG WGSGRGN (73) HL-60-Leukemia
    GSV RGSVRVL (74) HL-60-Leukemia
    PVRGSVD (75) HL-60-Leukemia
    TEGSVTV (76) HL-60-Leukemia
    GRV RAVGRVA (77) HL-60-Leukemia
    DVSGRVP (78) HL-60-Leukemia
    LGQCGRV (79) HL-60-Leukemia
    GRL GRLRLTD (80) HL-60-Leukemia
    LELGRLL (81) HL-60-Leukemia
    IGRLLPL (82) HL-60-Leukemia
    SDENGRL (83) HL-60-Leukemia
    GPS HL-60-Leukemia
    GVS HL-60-Leukemia
    RLS K-562-Leukemia
    RGV ELHPRGV (84) K-562-Leukemia
    FDRGVEA (85) K-562-Leukemia
    RGS EAVSRGS (86) K-562-Leukemia
    WTKRGSV (87) K-562-Leukemia
    RAV K-562-Leukemia
    RAS ERASQTA (88) K-562-Leukemia
    GAG K-562-Leukemia
    AVS EAVSRGS (89) K-562-Leukemia
    LLS AATLLSF (90) K-562-Leukemia
    LLSASLV (91) K-562-Leukemia
    RRHGLLS (92) K-562-Leukemia
    LLR RYSTLLR (93) K-562-Leukemia
    LRV FTLRVDK (94) K-562-Leukemia
    LRS K-562-Leukemia
    RVS SHRVSDS (95) K-562-Leukemia
    K-562-Leukemia
    RSS NRSSAKF (96) K-562-Leukemia
    LRRSSFS (97) K-562-Leukemia
    AGS AIRAGSD (98) K-562-Leukemia
    VLFSAGS (99) K-562-Leukemia
    AGR K-562-Leukemia
    AGL K-562-Leukemia
    AGG K-562-Leukemia
    GVR K-562-Leukemia
    GVL GVLHSIA (100) K-562-Leukemia
    GAV RQTTGAV (101) K-562-Leukemia
    GLV CQGLVLQ (102) K-562-Leukemia
    GLR PPPWGLR (103) K-562-Leukemia
    LVS K-562-Leukemia
    ARG SNARGPR (104) K-562-Leukemia
    ASL LLSASLV (105) K-562-Leukemia
    AAV AAVFVRS (106) K-562-Leukemia
    AAS K-562-Leukemia
    GGS FFGGSRA (107) K-562-Leukemia
    GGSQCDT (108) K-562-Leukemia
    VWGVGGS (109) K-562-Leukemia
    GGR FAWGGRG (110) K-562-Leukemia
    GLG GLGIMGP (111) K-562-Leukemia
    GGL K-562-Leukemia
    GSS SSGSSNG (112) K-562-Leukemia
    GSG K-562-Leukemia
    GSV WTKRGSV (113) K-562-Leukemia
    GRV K-562-Leukemia
    GRL K-562-Leukemia
    GPS K-562-Leukemia
    GVS GVSTGFT (114) K-562-Leukemia
    RLS Molt-4-Leukemia
    RGV CHARGVT (115) Molt-4-Leukemia
    RGS WGRGSVA (116) Molt-4-Leukemia
    RAV Molt-4-Leukemia
    RAS Molt-4-Leukemia
    GAG LRSGAGS (117) Molt-4-Leukemia
    AVS RAAVSAI (118) Molt-4-Leukemia
    AVSGRGW (119) Molt-4-Leukemia
    LLS LLSFLGR (120) Molt-4-Leukemia
    LLR Molt-4-Leukemia
    LRV Molt-4-Leukemia
    LRS GFYWLRS (121) Molt-4-Leukemia
    RVS RGARVSA (122) Molt-4-Leukemia
    RSS GGRSSHP (123) Molt-4-Leukemia
    RSSIAPS (124) Molt-4-Leukemia
    AGS LAGSGSH (125) Molt-4-Leukemia
    LRSGAGS (126) Molt-4-Leukemia
    AGR ASVRAGR (127) Molt-4-Leukemia
    AGL Molt-4-Leukemia
    AGG Molt-4-Leukemia
    GVR IGVRGFF (128) Molt-4-Leukemia
    GVL ANGVLEL (129) Molt-4-Leukemia
    Molt-4-Leukemia
    GAV WFGAVGL (130) Molt-4-Leukemia
    GLV GLVRGTA (131) Molt-4-Leukemia
    GLVRGTA Molt-4-Leukemia
    EGLVSVV (132) Molt-4-Leukemia
    GLR DLGLRPV (133) Molt-4-Leukemia
    LVS ALVSRRG (134) Molt-4-Leukemia
    EVLVSGD (135) Molt-4-Leukemia
    EGLVSVV (136) Molt-4-Leukemia
    ARG CHARGVT (137) Molt-4-Leukemia
    ASL Molt-4-Leukemia
    AAV RAAVSAI (138) Molt-4-Leukemia
    AAS Molt-4-Leukemia
    GGS HRGGSQS (139) Molt-4-Leukemia
    GGR GGRSSHP (140) Molt-4-Leukemia
    SQSGGRH (141) Molt-4-Leukemia
    GLG ARAIGLG (142) Molt-4-Leukemia
    GGL STEGGGL (143) Molt-4-Leukemia
    GSS Molt-4-Leukemia
    GSG LAGSGSH (144) Molt-4-Leukemia
    GSV DGSVLVE (145) Molt-4-Leukemia
    WGRGSVA (146) Molt-4-Leukemia
    GRV ATGRVLG (147) Molt-4-Leukemia
    ATGRVLG (148) Molt-4-Leukemia
    FFGRVGI (149) Molt-4-Leukemia
    RIGRVWA (150) Molt-4-Leukemia
    GRL RGRLEVP (151) Molt-4-Leukemia
    GPS Molt-4-Leukemia
    GVS Molt-4-Leukemia
    RLS RRLSYRD (152) RPMI-8226-Leukemia
    SRLSYRG (153) RPMI-8226-Leukemia
    RGV FSSKRGV (154) RPMI-8226-Leukemia
    RGS RGSAQNF (155) RPMI-8226-Leukemia
    LRSGRGS (156) RPMI-8226-Leukemia
    LRSGRGS RPMI-8226-Leukemia
    LRSGRGS RPMI-8226-Leukemia
    YRGSSGK (157) RPMI-8226-Leukemia
    RAV RPMI-8226-Leukemia
    RAS FWISRAS (158) RPMI-8226-Leukemia
    GAG GAGSISD (159) RPMI-8226-Leukemia
    RAMGGAG (160) RPMI-8226-Leukemia
    AVS RPMI-8226-Leukemia
    LLS LLSTSIR (161) RPMI-8226-Leukemia
    LLR LLLRSGG (162) RPMI-8226-Leukemia
    LLRSAAP (163) RPMI-8226-Leukemia
    LRV RPMI-8226-Leukemia
    LRS LLLRSGG (164) RPMI-8226-Leukemia
    GRYSLRS (165) RPMI-8226-Leukemia
    LRSGRGS (166) RPMI-8226-Leukemia
    LRYDLRS (167) RPMI-8226-Leukemia
    LRYNLRS (168) RPMI-8226-Leukemia
    LLRSAAP (169) RPMI-8226-Leukemia
    SKYRLRS (170) RPMI-8226-Leukemia
    RVS VHRVSGG (171) RPMI-8226-Leukemia
    RSS RPMI-8226-Leukemia
    AGS GAGSISD (172) RPMI-8226-Leukemia
    AGR FAGRVPS (173) RPMI-8226-Leukemia
    AGL AGLSGSQ (174) RPMI-8226-Leukemia
    TDLAGLH (175) RPMI-8226-Leukemia
    AGG LAAGGEL (176) RPMI-8226-Leukemia
    GAGGMAR (177) RPMI-8226-Leukemia
    RAAGGSR (178) RPMI-8226-Leukemia
    GVR LYGVRYG (179) RPMI-8226-Leukemia
    PRYGVRA (180) RPMI-8226-Leukemia
    GVL RPMI-8226-Leukemia
    GAV GAVDGSR (181) RPMI-8226-Leukemia
    GLV ADFFGLV (182) RPMI-8226-Leukemia
    GLR KYYGLRR (183) RPMI-8226-Leukemia
    SRYGLRR (184) RPMI-8226-Leukemia
    LVS RPMI-8226-Leukemia
    ARG RPMI-8226-Leukemia
    ASL RPMI-8226-Leukemia
    AAV RPMI-8226-Leukemia
    AAS PAASRLL (185) RPMI-8226-Leukemia
    RLRAASY (186) RPMI-8226-Leukemia
    RPMI-8226-Leukemia
    GGS GGSRLLL (187) RPMI-8226-Leukemia
    RAAGGSR (188) RPMI-8226-Leukemia
    GGSVRHV (189) RPMI-8226-Leukemia
    GGR GGRSWVN (190) RPMI-8226-Leukemia
    GLG GLGNRPT (191) RPMI-8226-Leukemia
    HGLGSGT (192) RPMI-8226-Leukemia
    GGL RPMI-8226-Leukemia
    GSS GSSLHLL (193) RPMI-8226-Leukemia
    YRGSSGK (194) RPMI-8226-Leukemia
    GSG EGSGVDC (195) RPMI-8226-Leukemia
    HGLGSGT (196) RPMI-8226-Leukemia
    GSV SGSVNRG (197) RPMI-8226-Leukemia
    GGSVRHV (198) RPMI-8226-Leukemia
    GRV FAGRVPS (199) RPMI-8226-Leukemia
    GRL AMRPGRL (200) RPMI-8226-Leukemia
    GRLYYYR (201) RPMI-8226-Leukemia
    GPS PAFGPSR (202) RPMI-8226-Leukemia
    GVS HSGVSHG (203) RPMI-8226-Leukemia
    RLS VYYRLSA (204) SR Leukemia
    RGV SR Leukemia
    RGS GRGSFES (205) SR Leukemia
    RRGSSRN (206) SR Leukemia
    RAV HSRAVAP (207) SR Leukemia
    RAS RASFRAG (208) SR Leukemia
    LMGRASG (209) SR Leukemia
    WRASAFT (210) SR Leukemia
    GAG GAGRTVM (211) SR Leukemia
    AVS PLAVSMV (212) SR Leukemia
    LLS SR Leukemia
    LLR FLLRSSF (213) SR Leukemia
    WRLLRRQ (214) SR Leukemia
    LRS FLLRSSF (215) SR Leukemia
    LRSRLGF (216) SR Leukemia
    RVS GRRVSLV (217) SR Leukemia
    RSS FLLRSSF (218) SR Leukemia
    NRSSGRR (219) SR Leukemia
    VLGMRSS (220) SR Leukemia
    THRNRSS (221) SR Leukemia
    AGS LAGSTRR (222) SR Leukemia
    AGR AGRTGVG (223) SR Leukemia
    EFAVAGR (224) SR Leukemia
    GAGRTVM (225) SR Leukemia
    REEFAGR (226) SR Leukemia
    AGL SR Leukemia
    AGG AGGPTKY (227) SR Leukemia
    FHVAGGS (228) SR Leukemia
    WSAGGPH (229) SR Leukemia
    GVR SR Leukemia
    GVL SR Leukemia
    GAV RGAVAFE (230) SR Leukemia
    SGGAVHF (231) SR Leukemia
    GAVRARL (232) SR Leukemia
    GLV GLVRGFP (233) SR Leukemia
    GAHGLVR (234) SR Leukemia
    SSRMGLV (235) SR Leukemia
    YVGLVVS (236) SR Leukemia
    GLR GLRKAGF (237) SR Leukemia
    AVDGLRL (238) SR Leukemia
    FGLRSRL (239) SR Leukemia
    LVS SR Leukemia
    ARG SR Leukemia
    ERARGYP (240) SR Leukemia
    GSARGML (241) SR Leukemia
    ASL ASLRYYV (242) SR Leukemia
    NAASLPS (243) SR Leukemia
    WLDASLM (244) SR Leukemia
    AAV SR Leukemia
    AAS NAASLPS (245) SR Leukemia
    GGS FHVAGGS (246) SR Leukemia
    GEHLGGS (247) SR Leukemia
    GGR SR Leukemia
    GLG SR Leukemia
    GGL SGGLHEG (248) SR Leukemia
    LRV SR Leukemia
    RLS SRLSYRS (249) A549-Lung
    RGV GGLRGVR (250) A549-Lung
    VAWRGVS (251) A549-Lung
    SVEGRGV (252) A549-Lung
    RGS FWRGSVP (253) A549-Lung
    RAV A549-Lung
    RAS EFTRRAS (254) A549-Lung
    WGWRASS (255) A549-Lung
    GAG A549-Lung
    AVS A549-Lung
    LLS A549-Lung
    LLR A549-Lung
    LRV A549-Lung
    LRS RFYHLRS (256) A549-Lung
    SRYSLRS (257) A549-Lung
    RVS A549-Lung
    RSS RRSSKQA (258) A549-Lung
    DWGRSSF (259) A549-Lung
    RFTRSSG (260) A549-Lung
    VFQRSSG (261) A549-Lung
    AGS AGSQSWE (262) A549-Lung
    AGR A549-Lung
    AGL A549-Lung
    AGG EHPAGGM (263) A549-Lung
    GVR GVRTAGP (264) A549-Lung
    GGLRGVR (265) A549-Lung
    LYGGVRY (266) A549-Lung
    GVL PVGGVLL (267) A549-Lung
    GAV GAVVKPI (268) A549-Lung
    SVGAVGG (269) A549-Lung
    GLV GLVSVEA (270) A549-Lung
    GLR GGLRGVR (271) A549-Lung
    LVS DIALVSP (272) A549-Lung
    GLVSVEA (273) A549-Lung
    ARG A549-Lung
    ASL A549-Lung
    AAV A549-Lung
    AAS ARNAASP (274) A549-Lung
    GGS AEGGSGH (275) A549-Lung
    GGSFSGL (276) A549-Lung
    GGR VTGGRVD (277) A549-Lung
    GLG A549-Lung
    GGL GGLRGVR (278) A549-Lung
    A549-Lung
    GSS GSSWVVD (279) A549-Lung
    GSSRTFR (280) A549-Lung
    GSSRQFV (281) A549-Lung
    WVGSSKF (282) A549-Lung
    GSG AEGGSGH (283) A549-Lung
    EVIGSGI (284) A549-Lung
    GSV FWRGSVP (285) A549-Lung
    VGSVSVN (286) A549-Lung
    GRV VTGGRVD (287) A549-Lung
    GRVTVAV (288) A549-Lung
    GRL RVGRLGG (289) A549-Lung
    GPS NYMGPSA (290) A549-Lung
    GWHGPSH (291) A549-Lung
    GVS GGVSPVD (292) A549-Lung
    GVSKVRA (293) A549-Lung
    GGVAGVS (294) A549-Lung
    VAWRGVS (295) A549-Lung
    RLS VIGSRLS (296) EKVX-Lung
    RGV HLRGRGV (297) EKVX-Lung
    RGS EVRSRGS (298) EKVX-Lung
    RGSRLPA (299) EKVX-Lung
    RAV DVRAVSS (300) EKVX-Lung
    RAS EKVX-Lung
    GAG EKVX-Lung
    AVS DVRAVSS (301) EKVX-Lung
    LLS EKVX-Lung
    LLR EKVX-Lung
    LRV EKVX-Lung
    LRS APLRSGR (302) EKVX-Lung
    SLRSGIV (303) EKVX-Lung
    RVS EKVX-Lung
    RSS DGGRRSS (304) EKVX-Lung
    AGS QAGSFLR (305) EKVX-Lung
    DAGSDRR (306) EKVX-Lung
    AGR AGRRFGG (307) EKVX-Lung
    AGL AGLSGGT (308) EKVX-Lung
    AGG AGGGPPA (309) EKVX-Lung
    AGGGPPA (310) EKVX-Lung
    FFPAGGP (311) EKVX-Lung
    PRAGGRW (312) EKVX-Lung
    GVR DVPGVRF (313) EKVX-Lung
    GVL FGVLFRS (314) EKVX-Lung
    SRYGVLV (315) EKVX-Lung
    GAV EKVX-Lung
    GLV LRGGLVS (316) EKVX-Lung
    GLR KSGLRPA (317) EKVX-Lung
    LVS ALVSFSV (318) EKVX-Lung
    LRGGLVS (319) EKVX-Lung
    ARG HKLARGR (320) EKVX-Lung
    ASL ASLPPRA (321) EKVX-Lung
    AAV EKVX-Lung
    AAS EKVX-Lung
    GGS TGGSLGA (322) EKVX-Lung
    GGGSWLI (323) EKVX-Lung
    GGR DGGRRSS (324) EKVX-Lung
    SVLGGRL (325) EKVX-Lung
    PRAGGRW (326) EKVX-Lung
    GLG YWFIGLG (327) EKVX-Lung
    GGL GGLSVDL (328) EKVX-Lung
    LRGGLVS (329) EKVX-Lung
    GSS SGVGSSL (330) EKVX-Lung
    GSG GSGILDL (331) EKVX-Lung
    GSV SLGSVGS (332) EKVX-Lung
    GRV EKVX-Lung
    GRL VGRGRLH (333) EKVX-Lung
    SVLGGRL (334) EKVX-Lung
    MSAFGRL (335) EKVX-Lung
    GPS EKVX-Lung
    GVS SGVSGLS (336) EKVX-Lung
    RLS Hop-62-Lung
    RGV GDSRRGV (337) Hop-62-Lung
    GKALRGV (338) Hop-62-Lung
    RGS PKAGRGS (339) Hop-62-Lung
    RAV FDRAVAN (340) Hop-62-Lung
    LLRRAVF (341) Hop-62-Lung
    RAS FRASSEV (342) Hop-62-Lung
    PDRASDG (343) Hop-62-Lung
    FRASLQY (344) Hop-62-Lung
    GAG Hop-62-Lung
    AVS Hop-62-Lung
    LLS Hop-62-Lung
    LLR HVGLLRA (345) Hop-62-Lung
    QVLLRSF (346) Hop-62-Lung
    LLRRAVF (347) Hop-62-Lung
    LRV FLRVGEL (348) Hop-62-Lung
    LRS QVLLRSF (349) Hop-62-Lung
    RVS RRVSCDL (350) Hop-62-Lung
    RSS RSSGLGF (351) Hop-62-Lung
    SSGPRSS (352) Hop-62-Lung
    YSQRSSL (353) Hop-62-Lung
    Hop-62-Lung
    AGS Hop-62-Lung
    AGR DAGRTID (354) Hop-62-Lung
    AAGREFR (355) Hop-62-Lung
    PKAGRGS (356) Hop-62-Lung
    VRAAGRV (357) Hop-62-Lung
    Hop-62-Lung
    AGL Hop-62-Lung
    AGG HGYRAGG (358) Hop-62-Lung
    WGATAGG (359) Hop-62-Lung
    YYAGGLK (360) Hop-62-Lung
    GVR LEGVRLF (361) Hop-62-Lung
    GVRPFPR (362) Hop-62-Lung
    GVL GTFGVLG (363) Hop-62-Lung
    VWAGVLL (364) Hop-62-Lung
    GAV GAVLFRV (365) Hop-62-Lung
    GLV GLVGFTG (366) Hop-62-Lung
    GLVSAFY (367) Hop-62-Lung
    GLR ARAMGLR (368) Hop-62-Lung
    LVS GLVSAFY (369) Hop-62-Lung
    SWRPLVS (370) Hop-62-Lung
    ARG Hop-62-Lung
    ASL FRASLQY (371) Hop-62-Lung
    AAV HSESAAV (372) Hop-62-Lung
    LFAVAAV (373) Hop-62-Lung
    AAS VAASESH (374) Hop-62-Lung
    GGS Hop-62-Lung
    GGR HPSMGGR (375) Hop-62-Lung
    GLG GLGVSGV (376) Hop-62-Lung
    KRESGLG (377) Hop-62-Lung
    RSSGLGF (378) Hop-62-Lung
    VGLGHWP (379) Hop-62-Lung
    GGL YYAGGLK (380) Hop-62-Lung
    GSS NYGSSFH (381) Hop-62-Lung
    FGLGSSR (382) Hop-62-Lung
    SSRPGSS (383) Hop-62-Lung
    GSG Hop-62-Lung
    GSV VGSVGLG (384) Hop-62-Lung
    GRV VRAAGRV (385) Hop-62-Lung
    GRL HNGRLEV (386) Hop-62-Lung
    VGRLAKG (387) Hop-62-Lung
    GPS VMGGPSL (388) Hop-62-Lung
    GVS GLGVSGV (389) Hop-62-Lung
    SGVSVEG (390) Hop-62-Lung
    RLS GESGRLS (391) Hop-92-Lung
    RGV GSGRGVA (392) Hop-92-Lung
    RGVVSAK (393) Hop-92-Lung
    RGVVSGV (394) Hop-92-Lung
    RGS AVGRGSG (395) Hop-92-Lung
    SLRGSEG (396) Hop-92-Lung
    PATRGSV (397) Hop-92-Lung
    RAV SLTRAVR (398) Hop-92-Lung
    VARAVPC (399) Hop-92-Lung
    RAS EGARASD (400) Hop-92-Lung
    GAG Hop-92-Lung
    AVS MGSAVSL (401) Hop-92-Lung
    LLS Hop-92-Lung
    LLR GGALLRG (402) Hop-92-Lung
    LRV Hop-92-Lung
    LRS Hop-92-Lung
    RVS PNRRVSA (403) Hop-92-Lung
    QDRVSRS (404) Hop-92-Lung
    RSS SERSSLG (405) Hop-92-Lung
    LVRSSGL (406) Hop-92-Lung
    AGS Hop-92-Lung
    AGR Hop-92-Lung
    AGL INWAGLS (407) Hop-92-Lung
    WAGLSPS (408) Hop-92-Lung
    AGG GRLLAGG (409) Hop-92-Lung
    GVR Hop-92-Lung
    GVL Hop-92-Lung
    GAV Hop-92-Lung
    GLV SYGLVLP (410) Hop-92-Lung
    SGGLVLT (411) Hop-92-Lung
    HAAHGLV (412) Hop-92-Lung
    GLR GLRTRQV (413) Hop-92-Lung
    LVS LVSGYNG (414) Hop-92-Lung
    ARG AGIARGG (415) Hop-92-Lung
    ASL Hop-92-Lung
    AAV Hop-92-Lung
    AAS Hop-92-Lung
    GGS HVSGGSG (416) Hop-92-Lung
    GGSSEFR (417) Hop-92-Lung
    GGSGIGS (418) Hop-92-Lung
    SWGSGGS (419) Hop-92-Lung
    TLVLGGS (420) Hop-92-Lung
    GGR AVRGGRP (421) Hop-92-Lung
    GGRAIGA (422) Hop-92-Lung
    GLG Hop-92-Lung
    GGL SGGLVLT (423) Hop-92-Lung
    GSS RTGSSDL (424) Hop-92-Lung
    LGSSRVL (425) Hop-92-Lung
    GGSSEFR (426) Hop-92-Lung
    GSG AVGRGSG (427) Hop-92-Lung
    HVSGGSG (428) Hop-92-Lung
    SGIGSGG (429) Hop-92-Lung
    SWGSGGS (430) Hop-92-Lung
    WVGSGSP (431) Hop-92-Lung
    GSV GSGGSVH (432) Hop-92-Lung
    GNYGSVL (433) Hop-92-Lung
    VGSVVGR (434) Hop-92-Lung
    PATRGSV (435) Hop-92-Lung
    GRV PRGGRVA (436) Hop-92-Lung
    GRVHLMP (437) Hop-92-Lung
    GRL GESGRLS (438) Hop-92-Lung
    GRLLAGG (439) Hop-92-Lung
    GRLWWHT (440) Hop-92-Lung
    GRLWSRV (441) Hop-92-Lung
    GPS AGPSAWL (442) Hop-92-Lung
    GVS SGVSRGQ (443) Hop-92-Lung
    RLS H226-Lung
    RGV RGVSLKG (444) H226-Lung
    RGS H226-Lung
    RAV QMQGRAV (445) H226-Lung
    RAS H226-Lung
    GAG H226-Lung
    AVS H226-Lung
    LLS H226-Lung
    LLR H226-Lung
    LRV H226-Lung
    LRS RGLRSVN (446) H226-Lung
    RVS H226-Lung
    RSS RSSLGLP (447) H226-Lung
    AGS LEAGSQL (448) H226-Lung
    AGR H226-Lung
    AGL H226-Lung
    AGG AGGQSER (449) H226-Lung
    GVR H226-Lung
    GVL GGVLYLE (450) H226-Lung
    GAV H226-Lung
    GLV H226-Lung
    GLR RGLRSVN (451) H226-Lung
    LVS H226-Lung
    ARG VARGQMQ (452) H226-Lung
    ASL H226-Lung
    AAV H226-Lung
    AAS H226-Lung
    GGS GGSRNRW (453) H226-Lung
    GGR GGGRSGV (454) H226-Lung
    GLG GLGGWVA (455) H226-Lung
    GGL AVWGGLG (456) H226-Lung
    GGLSECV (457) H226-Lung
    GSS H226-Lung
    GSG H226-Lung
    GSV AKLGSVY (458) H226-Lung
    GRV QGRVNVK (459) H226-Lung
    GRL GRLWGFW (460) H226-Lung
    GPS H226-Lung
    GVS RGVSLKG (461) H226-Lung
    GSLGVSL (462) H226-Lung
    RLS LLRLSLA (463) H23-Lung
    RGV H23-Lung
    RGS RRGSGGL (464) H23-Lung
    VRGSVRA (465) H23-Lung
    RAV H23-Lung
    RAS H23-Lung
    GAG H23-Lung
    AVS H23-Lung
    LLS H23-Lung
    LLR LLRLSLA (466) H23-Lung
    LRV PLRVDNL (467) H23-Lung
    LRVGIGY (468) H23-Lung
    QGYALRV (469) H23-Lung
    LRS PLRSFDS (470) H23-Lung
    RVS ARVSGRV (471) H23-Lung
    RSS PFPARSS (472) H23-Lung
    AGS AGSPLAK (473) H23-Lung
    FVDIAGS (474) H23-Lung
    AGR SYFRAGR (475) H23-Lung
    AGL AGLGHEG (476) H23-Lung
    AGG AGGSLGS (477) H23-Lung
    GVR YGIGVRL (478) H23-Lung
    GVL RANGVLV (479) H23-Lung
    GAV H23-Lung
    GLV H23-Lung
    GLR H23-Lung
    LVS H23-Lung
    ARG H23-Lung
    ASL LASLGVG (480) H23-Lung
    AAV RAAVGAR (481) H23-Lung
    AAS H23-Lung
    GGS GCDGGSA (482) H23-Lung
    GGSGELG (483) H23-Lung
    LGGSGRR (484) H23-Lung
    AGGSLGS (485) H23-Lung
    GGR IGGREIT (486) H23-Lung
    GLG GEHGLGA (487) H23-Lung
    GGL RRGSGGL (488) H23-Lung
    GSS RSGSSVY (489) H23-Lung
    GSG GLEGSGG (490) H23-Lung
    LGGSGRR (491) H23-Lung
    GSV TTGSVIV (492) H23-Lung
    VRGSVRA (493) H23-Lung
    GRV HGRVHRL (494) H23-Lung
    ARVSGRV (495) H23-Lung
    GRL H23-Lung
    GPS H23-Lung
    GVS SGHGVSA (496) H23-Lung
    RLS AVWRLSH (497) H322-Lung
    RGV RGVFYGK (498) H322-Lung
    RGVGWAK (499) H322-Lung
    RGS SRGSTAG (500) H322-Lung
    RAV H322-Lung
    RAS H322-Lung
    GAG SEDEGAG (501) H322-Lung
    STSLGAG (502) H322-Lung
    AVS H322-Lung
    LLS H322-Lung
    LLR DLLRYLA (503) H322-Lung
    LRV LRVRYAV (504) H322-Lung
    LRS LRSSGAT (505) H322-Lung
    LSMLRSA (506) H322-Lung
    RVS REAERVS (507) H322-Lung
    RSS LRSSGAT (508) H322-Lung
    AGS TAGSSRL (509) H322-Lung
    AGR AAGRAGC (510) H322-Lung
    AGL GAGLSTS (511) H322-Lung
    AGG H322-Lung
    GVR PSVGVRA (512) H322-Lung
    GVL H322-Lung
    GAV VGAVYFL (513) H322-Lung
    GLV H322-Lung
    GLR LGLRAFV (514) H322-Lung
    LVS TELVSWS (515) H322-Lung
    ARG CGARGAA (516) H322-Lung
    ASL H322-Lung
    AAV H322-Lung
    AAS H322-Lung
    GGS GGSRAAE (517) H322-Lung
    VNLGGSW (518) H322-Lung
    GGR LIGPGGR (519) H322-Lung
    GLG H322-Lung
    GGL LGGLSPH (520) H322-Lung
    WSGGLNV (521) H322-Lung
    GSS TAGSSRL (522) H322-Lung
    SDVSGSS (523) H322-Lung
    WGSSTVR (524) H322-Lung
    GSG H322-Lung
    GSV NLADGSV (525) H322-Lung
    SSGSVDS (526) H322-Lung
    GRV GRVPGFE (527) H322-Lung
    GRVVGEA (528) H322-Lung
    GRL H322-Lung
    GPS SRFGPSV (529) H322-Lung
    GVS ARVGVSP (530) H322-Lung
    RLS H460-Lung
    RGV PGKRGVQ (531) H460-Lung
    RGVASRS (532) H460-Lung
    RGS ERGSPSR (533) H460-Lung
    RAV LIRAVSA (534) H460-Lung
    RAVEMGT (535) H460-Lung
    RAS H460-Lung
    GAG WGAGFWM (536) H460-Lung
    AVS LIRAVSA (537) H460-Lung
    LLS H460-Lung
    LLR H460-Lung
    LRV H460-Lung
    LRS DRYMLRS (538) H460-Lung
    RVS H460-Lung
    RSS PRSSYNE (539) H460-Lung
    PRSSLVV (540) H460-Lung
    AGS H460-Lung
    AGR H460-Lung
    AGL RRFWAGL (541) H460-Lung
    AGG PVHSAGG (542) H460-Lung
    GVR H460-Lung
    GVL FGGSGVL (543) H460-Lung
    SSGGVLG (544) H460-Lung
    GAV H460-Lung
    GLV GLVGGSS (545) H460-Lung
    LSSGLVS (546) H460-Lung
    GLR H460-Lung
    LVS LSSGLVS (547) H460-Lung
    WFSWLVS (548) H460-Lung
    ARG H460-Lung
    ASL GASLTGD (549) H460-Lung
    WSSTASL (550) H460-Lung
    AAV H460-Lung
    AAS H460-Lung
    GGS FGGSGVL (551) H460-Lung
    GLVGGSS (552) H460-Lung
    GGR H460-Lung
    GLG H460-Lung
    GGL GGLSPHR (553) H460-Lung
    GSS GLVGGSS (554) H460-Lung
    SVLGSSL (555) H460-Lung
    GSG FGGSGVL (556) H460-Lung
    GSV H460-Lung
    GRV DVRGRVW (557) H460-Lung
    AEPRGRV (558) H460-Lung
    GRL H460-Lung
    GPS SIGPSTN (559) H460-Lung
    GVS GVSIRQL (560) H460-Lung
    RLS H522-Lung
    RGV H522-Lung
    RGS H522-Lung
    RAV H522-Lung
    RAS H522-Lung
    GAG H522-Lung
    AVS AVSKRLP (561) H522-Lung
    RLAVSGY (562) H522-Lung
    H522-Lung
    LLS H522-Lung
    LLR H522-Lung
    LRV H522-Lung
    LRS RREGLRS (563) H522-Lung
    SRYWLRS (564) H522-Lung
    H522-Lung
    RVS H522-Lung
    RSS H522-Lung
    AGS H522-Lung
    AGR AVYRAGR (565) H522-Lung
    H522-Lung
    AGL H522-Lung
    AGG H522-Lung
    GVR H522-Lung
    GVL H522-Lung
    GAV H522-Lung
    GLV H522-Lung
    GLR RHFGLRE (566) H522-Lung
    RREGLRS (567) H522-Lung
    H522-Lung
    LVS H522-Lung
    ARG H522-Lung
    ASL GQGAASL (568) H522-Lung
    AAV H522-Lung
    AAS GQGAASL (569) H522-Lung
    H522-Lung
    GGS H522-Lung
    GGR H522-Lung
    GLG H522-Lung
    GGL H522-Lung
    GSS H522-Lung
    GSG H522-Lung
    GSV YGSVALR (570) H522-Lung
    H522-Lung
    GRV H522-Lung
    GRL H522-Lung
    GPS H522-Lung
    GVS H522-Lung
    RLS COLO-205-Colon
    RGV ARRGVLG (571) COLO-205-Colon
    LRIARGV (572) COLO-205-Colon
    RGS YRGSMVG (573) COLO-205-Colon
    GLRGSVW (574) COLO-205-Colon
    RAV GPFRAVP (575) COLO-205-Colon
    RAS COLO-205-Colon
    GAG COLO-205-Colon
    AVS COLO-205-Colon
    LLS COLO-205-Colon
    LLR COLO-205-Colon
    LRV COLO-205-Colon
    LRS AHYTLRS (576) COLO-205-Colon
    SELRSIR (577) COLO-205-Colon
    SVYALRS (578) COLO-205-Colon
    RVS COLO-205-Colon
    RSS COLO-205-Colon
    AGS COLO-205-Colon
    AGR COLO-205-Colon
    AGL COLO-205-Colon
    AGG COLO-205-Colon
    GVR COLO-205-Colon
    GVL ARRGVLG (579) COLO-205-Colon
    GAV PGAVLTV (580) COLO-205-Colon
    GLV GLVGRRA (581) COLO-205-Colon
    GLVRCVL (582) COLO-205-Colon
    YDGLVSG (583) COLO-205-Colon
    GLVTAPL (584) COLO-205-Colon
    RGLVRVV (585) COLO-205-Colon
    GLR GLRGSVW (586) COLO-205-Colon
    NSFGLRY (587) COLO-205-Colon
    LVS YDGLVSG (588) COLO-205-Colon
    ARG AARGLEA (589) COLO-205-Colon
    DNDGARG (590) COLO-205-Colon
    LRIARGV (591) COLO-205-Colon
    ASL COLO-205-Colon
    AAV MSNLAAV (592) COLO-205-Colon
    AAS COLO-205-Colon
    GGS COLO-205-Colon
    GGR COLO-205-Colon
    GLG COLO-205-Colon
    GGL COLO-205-Colon
    GSS YSGSSDF (593) COLO-205-Colon
    GSG COLO-205-Colon
    GSV GSVLGDY (594) COLO-205-Colon
    GLRGSVW (595) COLO-205-Colon
    GRV DLDGRVV (596) COLO-205-Colon
    GRL WVSGRLG (597) COLO-205-Colon
    GPS GPSSMTF (598) COLO-205-Colon
    GVS DGVSSDY (599) COLO-205-Colon
    FTSGVSW (600) COLO-205-Colon
    RLS HCC-2998-Colon
    RGV HCC-2998-Colon
    RGS HCC-2998-Colon
    RAV HCC-2998-Colon
    RAS VLTRAST (601) HCC-2998-Colon
    LRASLLW (602) HCC-2998-Colon
    GAG HCC-2998-Colon
    AVS HCC-2998-Colon
    LLS WLLSARL (603) HCC-2998-Colon
    LLR LLRPGTV (604) HCC-2998-Colon
    LRV HCC-2998-Colon
    LRS HCC-2998-Colon
    RVS HCC-2998-Colon
    RSS HCC-2998-Colon
    AGS HCC-2998-Colon
    AGR HCC-2998-Colon
    AGL HCC-2998-Colon
    AGG AAGGLLV (605) HCC-2998-Colon
    GVR HCC-2998-Colon
    GVL HCC-2998-Colon
    GAV HCC-2998-Colon
    GLV HCC-2998-Colon
    GLR HCC-2998-Colon
    LVS HCC-2998-Colon
    ARG HCC-2998-Colon
    ASL LRASLLW (606) HCC-2998-Colon
    AAV HCC-2998-Colon
    AAS HCC-2998-Colon
    GGS HCC-2998-Colon
    GGR HCC-2998-Colon
    GLG LWGLGWL (607) HCC-2998-Colon
    RRSGLGD (608) HCC-2998-Colon
    WWGLGWL (609) HCC-2998-Colon
    GGL AAGGLLV (610) HCC-2998-Colon
    GSS HCC-2998-Colon
    GSG HCC-2998-Colon
    GSV HCC-2998-Colon
    GRV HCC-2998-Colon
    GRL HCC-2998-Colon
    GPS HCC-2998-Colon
    GVS HCC-2998-Colon
    RLS HCT-116 Colon
    RGV GLRGVVK (611) HCT-116 Colon
    RGS AVEGRGS (612) HCT-116 Colon
    NAVRGSA (613) HCT-116 Colon
    RAV HCT-116 Colon
    RAS HCT-116 Colon
    GAG HCT-116 Colon
    AVS HCT-116 Colon
    LLS HCT-116 Colon
    LLR LLRSSLG (614) HCT-116 Colon
    MYLRLLR (615) HCT-116 Colon
    LRV HCT-116 Colon
    LRS LLRSSLG (616) HCT-116 Colon
    DEGLRSR (617) HCT-116 Colon
    RVS YWQHRVS (618) HCT-116 Colon
    RSS ARSSHRA (619) HCT-116 Colon
    LLRSSLG (620) HCT-116 Colon
    AGS HCT-116 Colon
    AGR AGRSCNL (621) HCT-116 Colon
    AGRPRAT (622) HCT-116 Colon
    AGL HCT-116 Colon
    AGG HCT-116 Colon
    GVR GGVRIAA (623) HCT-116 Colon
    GVRYLRT (624) HCT-116 Colon
    GVL HCT-116 Colon
    GAV HCT-116 Colon
    GLV PLAVGLV (625) HCT-116 Colon
    GLR GLRGVVK (626) HCT-ll6 Colon
    DEGLRSR (627) HCT-116 Colon
    LVS QLVSGSL (628) HCT-116 Colon
    ARG HCT-116 Colon
    ASL GWSASLG (629) HCT-116 Colon
    AAV IAAVWRS (630) HCT-116 Colon
    AAS HCT-116 Colon
    GGS GGSSLDA (631) HCT-116 Colon
    LGGSRDL (632) HCT-116 Colon
    GGR LIGGRNA (633) HCT-116 Colon
    GLG HCT-116 Colon
    GGL LDRSGGL (634) HCT-116 Colon
    GSS GGSSLDA (635) HCT-116 Colon
    GSSYSGP (636) HCT-116 Colon
    GSG TVGSGCL (637) HCT-116 Colon
    GSV LSGSVLQ (638) HCT-116 Colon
    GRV ASGRVAN (639) HCT-116 Colon
    GRL KVVGRLG (640) HCT-116 Colon
    GRLVWGL (641) HCT-116 Colon
    NEFLGRL (642) HCT-116 Colon
    GPS LCDAGPS (643) HCT-116 Colon
    GVS FRAGVSH (644) HCT-116 Colon
    RLS AGDSRLS (645) HCT-15 Colon
    RGV HCT-15 Colon
    RGS HCT-15 Colon
    RAV DWRRRAV (646) HCT-15 Colon
    RAS WTERASA (647) HCT-15 Colon
    GAG HCT-15 Colon
    AVS HCT-15 Colon
    LLS RLLSAFG (648) HCT-15 Colon
    LLR GFASLLR (649) HCT-15 Colon
    LRV GALRVPW (650) HCT-15 Colon
    GALRVPW HCT-15 Colon
    GALRVPW HCT-15 Colon
    LRS SLRSDGA (651) HCT-15 Colon
    DTLRSQW (652) HCT-15 Colon
    LRSVGSW (653) HCT-15 Colon
    RVS HCT-15 Colon
    RSS ISPRSSG (654) HCT-15 Colon
    WRVRSSG (655) HCT-15 Colon
    AGS HCT-15 Colon
    AGR AAGRIRP (656) HCT-15 Colon
    RAAGRVG (657) HCT-15 Colon
    AGL AGLQHAV (658) HCT-15 Colon
    AGG AGGWWVG (659) HCT-15 Colon
    GVR GVRGAAR (660) HCT-15 Colon
    GVL GVLPVVT (661) HCT-15 Colon
    GVLPVVT HCT-15 Colon
    GAV HCT-15 Colon
    GLV GLVSSLP (662) HCT-15 Colon
    SRHGLVR (663) HCT-15 Colon
    SDRGLVV (664) HCT-15 Colon
    SDRGLVV (665) HCT-15 Colon
    GLR HCT-15 Colon
    LVS GLVSSLP (666) HCT-15 Colon
    LVSVWSR (667) HCT-15 Colon
    ARG GSWARGY (668) HCT-15 Colon
    ASL GFASLLR (669) HCT-15 Colon
    AAV HAAVMSL (670) HCT-15 Colon
    AAS HCT-15 Colon
    GGS HCT-15 Colon
    GGR DGGRRTD (671) HCT-15 Colon
    GRPLGGR (672) HCT-15 Colon
    GRVTGGR (673) HCT-15 Colon
    GLG HCT-15 Colon
    GGL RGGLPRG (674) HCT-15 Colon
    YGQYGGL (675) HCT-15 Colon
    GSS GSSRPSI (676) HCT-15 Colon
    PGSSFVG (677) HCT-15 Colon
    GSSRVRW (678) HCT-15 Colon
    GSG HCT-15 Colon
    GSV HCT-15 Colon
    GRV RAAGRVG (679) HCT-15 Colon
    GRVTGGR (680) HCT-15 Colon
    YVRIGRV (681) HCT-15 Colon
    GRL MITRGRL (682) HCT-15 Colon
    GPS HCT-15 Colon
    GVS SVVGVST (683) HCT-15 Colon
    WSGVSRL (684) HCT-15 Colon
    RLS RRLSYFH (685) HT-29 Colon
    PRLSWVL (686) HT-29 Colon
    RLSALTD (687) HT-29 Colon
    RGV GRGVGTD (688) HT-29 Colon
    LKVRGVL (689) HT-29 Colon
    SSTRGVY (690) HT-29 Colon
    QVRRGVV (691) HT-29 Colon
    GRGVTIW (692) HT-29 Colon
    RGS RGSVASA (693) HT-29 Colon
    HFIRGSV (694) HT-29 Colon
    RGSWAGV (695) HT-29 Colon
    VRGSRWR (696) HT-29 Colon
    RAV LERAVRT (697) HT-29 Colon
    RAS GYSRASD (698) HT-29 Colon
    SRASGHG (699) HT-29 Colon
    GHYRASV (700) HT-29 Colon
    DWVCRAS (701) HT-29 Colon
    GAG GAGRGTP (702) HT-29 Colon
    LSLAGAG (703) HT-29 Colon
    AVS ASAVSGR (704) HT-29 Colon
    FSGDAVS (705) HT-29 Colon
    LLS LKLLSVP (706) HT-29 Colon
    LLR HT-29 Colon
    LRV GTLRVGS (707) HT-29 Colon
    LRS EHYRLRS (708) HT-29 Colon
    LRSWLLF (709) HT-29 Colon
    RRPGLRS (710) HT-29 Colon
    SKYNLRS (711) HT-29 Colon
    WQVALRS (712) HT-29 Colon
    LRSDPRS (713) HT-29 Colon
    VPLRSSA (714) HT-29 Colon
    RVS HT-29 Colon
    RSS GRSSGME (715) HT-29 Colon
    VPLRSSA (716) HT-29 Colon
    AGS AGSGFPF (717) HT-29 Colon
    AGR GAGRGTP (718) HT-29 Colon
    AGRIASK (719) HT-29 Colon
    AGL WGVAGLG (720) HT-29 Colon
    LAGLVSG (721) HT-29 Colon
    AGG DAGGMDL (722) HT-29 Colon
    AGGRWNL (723) HT-29 Colon
    GVR GCGGVRD (724) HT-29 Colon
    SGVRLTG (725) HT-29 Colon
    GVL LKVRGVL (726) HT-29 Colon
    GAV GLGAVGW (727) HT-29 Colon
    PGAVPGA (728) HT-29 Colon
    RIGAVWY (729) HT-29 Colon
    GLV FSGLVVA (730) HT-29 Colon
    PGGLVPG (731) HT-29 Colon
    LAGLVSG (732) HT-29 Colon
    LGLVSTT (733) HT-29 Colon
    GLR GLRLGVT (734) HT-29 Colon
    RRPGLRS (735) HT-29 Colon
    LVS LAGLVSG (736) HT-29 Colon
    LGLVSTT (737) HT-29 Colon
    RQLVSPA (738) HT-29 Colon
    ARG LRARGGH (739) HT-29 Colon
    ASL ELWASLG (740) HT-29 Colon
    DTLASLR (741) HT-29 Colon
    VVASLPH (742) HT-29 Colon
    AAV HT-29 Colon
    AAS VLRAASR (743) HT-29 Colon
    AASGSYY (744) HT-29 Colon
    GGS GGSALFG (745) HT-29 Colon
    GRGGSGY (746) HT-29 Colon
    GGR YGSGGRG (747) HT-29 Colon
    GTLGGRV (748) HT-29 Colon
    AGGRWNL (749) HT-29 Colon
    HGGRARL (750) HT-29 Colon
    RGGRSPS (751) HT-29 Colon
    RKPGGGR (752) HT-29 Colon
    EGGRTHW (753) HT-29 Colon
    GLG GEVGLGV (754) HT-29 Colon
    GLGAVGW (755) HT-29 Colon
    GGL PGGLVPG (756) HT-29 Colon
    VRGGLTG (757) HT-29 Colon
    RQKCGGL (758) HT-29 Colon
    RYGVGGL (759) HT-29 Colon
    GSS EMGSSRG (760) HT-29 Colon
    GSG AGSGFPF (761) HT-29 Colon
    GRGGSGY (762) HT-29 Colon
    GSV GSVSAGA (763) HT-29 Colon
    RGSVASA (764) HT-29 Colon
    DLGSVQH (765) HT-29 Colon
    HFIRGSV (766) HT-29 Colon
    GSVLGAL (767) HT-29 Colon
    GRV GTLGGRV (768) HT-29 Colon
    LGRVHVW (769) HT-29 Colon
    LVGRVKL (770) HT-29 Colon
    RWRSGRV (771) HT-29 Colon
    GRL RNPGRLA (772) HT-29 Colon
    PRGRLFD (773) HT-29 Colon
    GRLAVVA (774) HT-29 Colon
    LAQGRLA (775) HT-29 Colon
    GGMNGRL (776) HT-29 Colon
    GPS RSTLGPS (777) HT-29 Colon
    GVS GVSALSL (778) HT-29 Colon
    GGR KM-12C Colon
    RLS SRLSYYA (779) KM-12C Colon
    SRLSYYA KM-12C Colon
    RGV ARGVSAP (780) KM-12C Colon
    GRGVLAF (781) KM-12C Colon
    RGS MRGSGRN (782) KM-12C Colon
    RAV RDGRAVR (783) KM-12C Colon
    GRAVWMV (784) KM-12C Colon
    RAS KM-12C Colon
    GAG KM-12C Colon
    AVS KM-12C Colon
    LLS KM-12C Colon
    LLR KM-12C Colon
    LRV LRVPGGP (785) KM-12C Colon
    LRS AYYSLRS (786) KM-12C Colon
    AYYSLRS KM-12C Colon
    VLRSALQ (787) KM-12C Colon
    VYYALRS (788) KM-12C Colon
    VYYALRS KM-12C Colon
    VYYALRS KM-12C Colon
    VYYALRS KM-12C Colon
    VYYALRS KM-12C Colon
    VYYALRS KM-12C Colon
    VYYALRS KM-12C Colon
    RVS RYRVSVY (789) KM-12C Colon
    RSS KM-12C Colon
    AGS KM-12C Colon
    AGR KM-12C Colon
    AGL KM-12C Colon
    AGG AGGIWIR (790) KM-12C Colon
    GVR WQVSGVR (791) KM-12C Colon
    GVL GRGVLAF (792) KM-12C Colon
    GAV KM-12C Colon
    GLV KM-12C Colon
    GLR KM-12C Colon
    LVS HAELVSL (793) KM-12C Colon
    ARG ARGVSAP (794) KM-12C Colon
    RVARGDR (795) KM-12C Colon
    VMWVARG (796) KM-12C Colon
    ASL KM-12C Colon
    AAV AAVTVVR (797) KM-12C Colon
    AAS KM-12C Colon
    GGS KM-12C Colon
    GLG KM-12C Colon
    GGL TREGGLD (798) KM-12C Colon
    LGGGGLL (799) KM-12C Colon
    GSS KM-12C Colon
    GSG GSGHSFA (800) KM-12C Colon
    MRGSGRN (801) KM-12C Colon
    GSV RVGSVQW (802) KM-12C Colon
    EGTSGSV (803) KM-12C Colon
    GRV GRVPTVV (804) KM-12C Colon
    KM-12C Colon
    GRL ADGRLRY (805) KM-12C Colon
    GPS KM-12C Colon
    GVS ARGVSAP (806) KM-12C Colon
    RLS SW620-Colon
    RGV RGVKLGD (807) SW620-Colon
    RGS LRGSYVL (808) SW620-Colon
    RRGSLMF (809) SW620-Colon
    RGSVGPS (810) SW620-Colon
    RAV SW620-Colon
    RAS SRASDVT (811) SW620-Colon
    GAG SW620-Colon
    AVS SW620-Colon
    LLS AAKTLLS (812) SW620-Colon
    LLR SW620-Colon
    LRV SW620-Colon
    LRS RSYPLRS (813) SW620-Colon
    RVS YLGRRVS (814) SW620-Colon
    RSS RSSPVWT (815) SW620-Colon
    AGS DLRRAGS (816) SW620-Colon
    AGR SW620-Colon
    AGL GVAGLRW (817) SW620-Colon
    AGG RIDAGGG (818) SW620-Colon
    GVAGGAT (819) SW620-Colon
    GVR SW620-Colon
    GVL SW620-Colon
    GAV TAGGAVG (820) SW620-Colon
    WRLGAVG (821) SW620-Colon
    GLV SGLVAMV (822) SW620-Colon
    GLR VGLRDWG (823) SW620-Colon
    GVAGLRW (824) SW620-Colon
    LVS SW620-Colon
    ARG ARGIVRV (825) SW620-Colon
    ASL ASLHHRR (826) SW620-Colon
    AAV SW620-Colon
    AAS GAAASGY (827) SW620-Colon
    GGS SW620-Colon
    GGR SW620-Colon
    GLG LAIRGLG (828) SW620-Colon
    GGL GGLSNVV (829) SW620-Colon
    PPGGLKW (830) SW620-Colon
    GSS SW620-Colon
    GSG SW620-Colon
    GSV EGSVDAH (831) SW620-Colon
    RGSVGPS (832) SW620-Colon
    GRV SW620-Colon
    GRL LVYSGRL (833) SW620-Colon
    VEEGRLR (834) SW620-Colon
    GPS RGSVGPS (835) SW620-Colon
    GVS SPGVSGR (836) SW620-Colon
    RGV RVGRGVL (837) SF-268 CNS
    RGS SF-268 CNS
    RAV WIWRAVS (838) SF-268 CNS
    RAS SF-268 CNS
    GAG VTDGAGQ (839) SF-268 CNS
    AVS LGTAVSS (840) SF-268 CNS
    WIWRAVS (841) SF-268 CNS
    DTPSAVS (842) SF-268 CNS
    LLS GLLSAGI (843) SF-268 CNS
    LLR YLLRALG (844) SF-268 CNS
    LRV SF-268 CNS
    LRS LRSGSLG (845) SF-268 CNS
    PLRSVWS (846) SF-268 CNS
    RVS SF-268 CNS
    RSS ARSSIVR (847) SF-268 CNS
    AGS SF-268 CNS
    AGR SF-268 CNS
    AGL SF-268 CNS
    AGG AGGRLGL (848) SF-268 CNS
    AGGWRGR (849) SF-268 CNS
    GVR LVGRGVR (850) SF-268 CNS
    GVL DVVGVLK (851) SF-268 CNS
    RVGRGVL (852) SF-268 CNS
    GAV GAVTGYP (853) SF-268 CNS
    GLV WGLVRHA (854) SF-268 CNS
    GLR LGLRGGA (855) SF-268 CNS
    LVS SF-268 CNS
    ARG SF-268 CNS
    ASL IGASLLG (856) SF-268 CNS
    AAV AAVETGV (857) SF-268 CNS
    AAS SF-268 CNS
    GGS GLGGGGS (858) SF-268 CNS
    GGR EVLWGGR (859) SF-268 CNS
    AGGRLGL (860) SF-268 CNS
    GGRSKKV (861) SF-268 CNS
    GLG GLGGGGS (862) SF-268 CNS
    GGL SGGGGLG (863) SF-268 CNS
    GAYGGLL (864) SF-268 CNS
    GGLSRSN (865) SF-268 CNS
    GSS FGSSNRS (866) SF-268 CNS
    GSG SF-268 CNS
    GSV GSVSDRF (867) SF-268 CNS
    GRV SF-268 CNS
    GRL AGGRLGL (868) SF-268 CNS
    GPS WFKGPSV (869) SF-268 CNS
    GVS SF-268 CNS
    RLS SF-295 CNS
    RGV LSERRGV (870) SF-295 CNS
    ARGVAEY (871) SF-295 CNS
    SF-295 CNS
    RGS FDRGSLT (872) SF-295 CNS
    SF-295 CNS
    RAV SF-295 CNS
    RAS GRLRASL (873) SF-295 CNS
    SF-295 CNS
    GAG RDGRGAG (874) SF-295 CNS
    SF-295 CNS
    AVS GAVSVLA (875) SF-295 CNS
    TRGDAVS (876) SF-295 CNS
    SF-295 CNS
    LLS LLSPRGT (877) SF-295 CNS
    SF-295 CNS
    LLR LLRSHGV (878) SF-295 CNS
    SF-295 CNS
    LRV PLRVLKR (879) SF-295 CNS
    GRLRLRV (880) SF-295 CNS
    SF-295 CNS
    LRS LLRSHGV (881) SF-295 CNS
    VLRSGEL (882) SF-295 CNS
    VLRSIPS (883) SF-295 CNS
    VLRSIPS SF-295 CNS
    SF-295 CNS
    RVS GSMHRVS (884) SF-295 CNS
    YSIMRVS (885) SF-295 CNS
    SF-295 CNS
    RSS SF-295 CNS
    AGS RAGSRVQ (886) SF-295 CNS
    SF-295 CNS
    AGR RRDAGRM (887) SF-295 CNS
    GAGRGDR (888) SF-295 CNS
    SF-295 CNS
    AGL RWAGLVA (889) SF-295 CNS
    SF-295 CNS
    AGG QTLSAGG (890) SF-295 CNS
    LAGGWGS (891) SF-295 CNS
    SF-295 CNS
    GVR RHGVRSK (892) SF-295 CNS
    SF-295 CNS
    GVL SF-295 CNS
    GAV GAVSVLA (893) SF-295 CNS
    SF-295 CNS
    GLV RWAGLVA (894) SF-295 CNS
    SF-295 CNS
    GLR GRGLRTD (895) SF-295 CNS
    TLGGLRT (896) SF-295 CNS
    SF-295 CNS
    LVS ALVSVAG (897) SF-295 CNS
    SF-295 CNS
    ARG ARGVAEY (898) SF-295 CNS
    SF-295 CNS
    ASL GGASLTQ (899) SF-295 CNS
    GRLRASL (900) SF-295 CNS
    SNHTASL (901) SF-295 CNS
    SF-295 CNS
    AAV YADGAAV (902) SF-295 CNS
    SF-295 CNS
    AAS SF-295 CNS
    GGS SF-295 CNS
    GGR SF-295 CNS
    GLG LGGLGIH (903) SF-295 CNS
    SF-295 CNS
    GGL GGFTGGL (904) SF-295 CNS
    HIGLGGL (905) SF-295 CNS
    TRLGGLT (906) SF-295 CNS
    SF-295 CNS
    GSS SF-295 CNS
    GSG SF-295 CNS
    GSV VMPGSVV (907) SF-295 CNS
    SF-295 CNS
    GRV SF-295 CNS
    GRL GRLRASL (908) SF-295 CNS
    GRLYLGI (909) SF-295 CNS
    GRLRLRV (910) SF-295 CNS
    SF-295 CNS
    SF-295 CNS
    GPS SHCGPSN (911) SF-295 CNS
    SHCGPSN SF-295 CNS
    SF-295 CNS
    GVS SF-295 CNS
    RLS VRLSGRA (912) SNB-19 CNS
    RLSTFAG (913) SNB-19 CNS
    RGV SNB-19 CNS
    RGS ARGSLRV (914) SNB-19 CNS
    FSPRGSV (915) SNB-19 CNS
    RAV GGRLRAV (916) SNB-19 CNS
    RAS SNB-19 CNS
    GAG SNB-19 CNS
    AVS VLSAVSS (917) SNB-19 CNS
    LLS SNB-19 CNS
    LLR SNB-19 CNS
    LRV ARGSLRV (918) SNB-19 CNS
    LRS LRSYAWS (919) SNB-19 CNS
    RVS KGRVSAG (920) SNB-19 CNS
    RSS SNB-19 CNS
    AGS SNB-19 CNS
    AGR SNB-19 CNS
    AGL AGLTIGI (921) SNB-19 CNS
    AGG AWRHAGG (922) SNB-19 CNS
    WARAGGF (923) SNB-19 CNS
    GVR SNB-19 CNS
    GVL MGVLTAE (924) SNB-19 CNS
    FAGYGVL (925) SNB-19 CNS
    GAV RIFHGAV (926) SNB-19 CNS
    GLV EGLVVFE (927) SNB-19 CNS
    GLR REVPGLR (928) SNB-19 CNS
    LVS LVSVNGA (929) SNB-19 CNS
    HSLVSQP (930) SNB-19 CNS
    ARG ARGSLRV (931) SNB-19 CNS
    ASL SSVASLV (932) SNB-19 CNS
    AAV AAVWQMK (933) SNB-19 CNS
    QRAAVIV (934) SNB-19 CNS
    AAS SNB-19 CNS
    GGS PGGSDAA (935) SNB-19 CNS
    GGR GGRLRAV (936) SNB-19 CNS
    GLG SNB-19 CNS
    GGL LPCGGLA (937) SNB-19 CNS
    GSS GSSHDAL (938) SNB-19 CNS
    TQYYGSS (939) SNB-19 CNS
    GSG SNB-19 CNS
    GSV FSPRGSV (940) SNB-19 CNS
    GRV KGRVSAG (941) SNB-19 CNS
    QGRVNVK (942) SNB-19 CNS
    GRL GGRLRAV (943) SNB-19 CNS
    YDGRLAR (944) SNB-19 CNS
    GPS SNB-19 CNS
    GVS SNB-19 CNS
    RLS SNB-75 CNS
    RGV PQGRGVK (945) SNB-75 CNS
    RGS MVLRGSY (946) SNB-75 CNS
    RAV GGWARAV (947) SNB-75 CNS
    VRAVCLM (948) SNB-75 CNS
    RAS TRASRRG (949) SNB-75 CNS
    GAG LGAGEGD (950) SNB-75 CNS
    AVS IGAVSGW (951) SNB-75 CNS
    LLS LLSRRVG (952) SNB-75 CNS
    LELLSVV (953) SNB-75 CNS
    RLLSEGY (954) SNB-75 CNS
    LLR QLPGLLR (955) SNB-75 CNS
    YGESLLR (956) SNB-75 CNS
    LRV LRVYGEG (957) SNB-75 CNS
    LRS SNB-75 CNS
    RVS YRVSSGS (958) SNB-75 CNS
    RSS RSSSSTR (959) SNB-75 CNS
    AGS WAGSNYS (960) SNB-75 CNS
    AGR CAGRARR (961) SNB-75 CNS
    AGL IAGLAVV (962) SNB-75 CNS
    DGEGAGL (963) SNB-75 CNS
    AGG ALAGGGL (964) SNB-75 CNS
    GVR GVRRSLL (965) SNB-75 CNS
    GVL ADWGVLE (966) SNB-75 CNS
    GAV IGAVSGW (967) SNB-75 CNS
    GLV ASGLVVT (968) SNB-75 CNS
    GLR IGLRGEN (969) SNB-75 CNS
    LVS SNB-75 CNS
    ARG RRARGAC (970) SNB-75 CNS
    ASL YAASLMG (971) SNB-75 CNS
    AAV LTAAVMV (972) SNB-75 CNS
    AAS YAASLMG (973) SNB-75 CNS
    GGS RARTGGS (974) SNB-75 CNS
    VSGDGGS (975) SNB-75 CNS
    GGR FGGRSLS (976) SNB-75 CNS
    SLGGRTF (977) SNB-75 CNS
    GLG ARRGLGL (978) SNB-75 CNS
    GGL ALAGGGL (979) SNB-75 CNS
    FRALGGL (980) SNB-75 CNS
    FTRGGLS (981) SNB-75 CNS
    GSS SGSSVRY (982) SNB-75 CNS
    GSG SNB-75 CNS
    GSV WGSVAGI (983) SNB-75 CNS
    SGGDGSV (984) SNB-75 CNS
    GRV SNB-75 CNS
    GRL NEGRLGI (985) SNB-75 CNS
    YSGRLVM (986) SNB-75 CNS
    GPS DGPSGCS (987) SNB-75 CNS
    GVS SNB-75 CNS
    RLS U251 CNS
    RGV U251 CNS
    RGS RGSRTGP (988) U251 CNS
    RAV U251 CNS
    RAS U251 CNS
    GAG U251 CNS
    AVS U251 CNS
    LLS U251 CNS
    LLR U251 CNS
    LRV U251 CNS
    LRS U251 CNS
    RVS U251 CNS
    RSS U251 CNS
    AGS U251 CNS
    AGR U251 CNS
    AGL U251 CNS
    AGG U251 CNS
    GVR U251 CNS
    GVL U251 CNS
    GAV U251 CNS
    GLV U251 CNS
    GLR U251 CNS
    LVS U251 CNS
    ARG U251 CNS
    ASL U251 CNS
    AAV U251 CNS
    AAS U251 CNS
    GGS U251 CNS
    GGR U251 CNS
    GLG U251 CNS
    GGL U251 CNS
    GSS GSSACGA (989) U251 CNS
    GSG U251 CNS
    GSV U251 CNS
    GRV U251 CNS
    GRL U251 CNS
    GPS U251 CNS
    GVS U251 CNS
    RLS VRLSGRA (990) SF-539 CNS
    RLSTFAG (991) SF-539 CNS
    RGV SF-539 CNS
    RGS ARGSLRV (992) SF-539 CNS
    FSPRGSV (993) SF-539 CNS
    RAV GGRLRAV (994) SF-539 CNS
    RAS SF-539 CNS
    GAG SF-539 CNS
    AVS VLSAVSS (995) SF-539 CNS
    LLS SF-539 CNS
    LLR SF-539 CNS
    LRV ARGSLRV (996) SF-539 CNS
    LRS LRSYAWS (997) SF-539 CNS
    RVS KGRVSAG (998) SF-539 CNS
    RSS SF-539 CNS
    AGS SF-539 CNS
    AGR SF-539 CNS
    AGL AGLTIGI (999) SF-539 CNS
    AGG AWRHAGG (1000) SF-539 CNS
    WARAGGF (1001) SF-539 CNS
    GVR SF-539 CNS
    GVL MGVLTAE (1002) SF-539 CNS
    FAGYGVL (1003) SF-539 CNS
    GAV RIFHGAV (1004) SF-539 CNS
    GLV EGLVVFE (1005) SF-539 CNS
    GLR REVPGLR (1006) SF-539 CNS
    LVS LVSVNGA (1007) SF-539 CNS
    HSLVSQP (1008) SF-539 CNS
    ARG ARGSLRV (1009) SF-539 CNS
    ASL SSVASLV (1010) SF-539 CNS
    AAV AAVWQMK (1011) SF-539 CNS
    QRAAVIV (1012) SF-539 CNS
    AAS SF-539 CNS
    GGS SF-539 CNS
    GGR GGRLRAV (1013) SF-539 CNS
    GLG SF-539 CNS
    GGL LPCGGLA (1014) SF-539 CNS
    GSS GSSHDAL (1015) SF-539 CNS
    TQYYGSS (1016) SF-539 CNS
    GSG SF-539 CNS
    GSV FSPRGSV (1017) SF-539 CNS
    GRV KGRVSAG (1018) SF-539 CNS
    QGRVNVK (1019) SF-539 CNS
    GRL GGRLRAV (1020) SF-539 CNS
    YDGRLAR (1021) SF-539 CNS
    GPS SF-539 CNS
    GVS SF-539 CNS
    RLS SRLSYWQ (1022) LOX-IMVI Melanoma
    RGV FVGSRGV (1023) LOX-IMVI Melanoma
    SVDRGVI (1024) LOX-IMVI Melanoma
    RGS GRGSGGF (1025) LOX-IMVI Melanoma
    RAV LOX-IMVI Melanoma
    RAS LOX-IMVI Melanoma
    GAG IFGAGLR (1026) LOX-IMVI Melanoma
    AVS GWVAVSC (1027) LOX-IMVI Melanoma
    LLS LLSGVIL (1028) LOX-IMVI Melanoma
    GSTLLSR (1029) LOX-IMVI Melanoma
    LLR LOX-IMVI Melanoma
    LRV LOX-IMVI Melanoma
    LRS QWYSLRS (1030) LOX-IMVI Melanoma
    RVS TWIGRVS (1031) LOX-IMVI Melanoma
    RSS LOX-IMVI Melanoma
    AGS SVVLAGS (1032) LOX-IMVI Melanoma
    AGR LOX-IMVI Melanoma
    AGL IFGAGLR (1033) LOX-IMVI Melanoma
    AGG SAGGWCA (1034) LOX-IMVI Melanoma
    GVR RDGVRVG (1035) LOX-IMVI Melanoma
    VSRIGVR (1036) LOX-IMVI Melanoma
    GVRSMPV (1037) LOX-IMVI Melanoma
    GVL GGVLGSD (1038) LOX-IMVI Melanoma
    WGVLQLE (1039) LOX-IMVI Melanoma
    GAV HGGPGAV (1040) LOX-IMVI Melanoma
    GLV DSGLVGG (1041) LOX-IMVI Melanoma
    GLR IFGAGLR (1042) LOX-IMVI Melanoma
    RMGFGLR (1043) LOX-IMVI Melanoma
    LVS LOX-IMVI Melanoma
    ARG LOX-IMVI Melanoma
    ASL LOX-IMVI Melanoma
    AAV WLDAAVK (1044) LOX-IMVI Melanoma
    AAS IAASYRG (1045) LOX-IMVI Melanoma
    GGS ATIPGGS (1046) LOX-IMVI Melanoma
    DGGSLVV (1047) LOX-IMVI Melanoma
    FGGSGRG (1048) LOX-IMVI Melanoma
    GGR SPTGGRR (1049) LOX-IMVI Melanoma
    TWSTGGR (1050) LOX-IMVI Melanoma
    GLG LOX-IMVI Melanoma
    GGL SRSCGGL (1051) LOX-IMVI Melanoma
    GSS LOX-IMVI Melanoma
    GSG CPGSGII (1052) LOX-IMVI Melanoma
    FGGSGRG (1053) LOX-IMVI Melanoma
    GSV SGSVVQR (1054) LOX-IMVI Melanoma
    GRV TWIGRVS (1055) LOX-IMVI Melanoma
    GRL LOX-IMVI Melanoma
    GPS GPSWATV (1056) LOX-IMVI Melanoma
    GVS LOX-IMVI Melanoma
    RLS MALME-3M Melanoma
    RGV MALME-3M Melanoma
    RGS ARRGSGL (1057) MALME-3M Melanoma
    RAV RAVGYNA (1058) MALME-3M Melanoma
    LRAVEFL (1059) MALME-3M Melanoma
    RAS MALME-3M Melanoma
    GAG MALME-3M Melanoma
    AVS MALME-3M Melanoma
    LLS FEDLLSL (1060) MALME-3M Melanoma
    RWLSLLS (1061) MALME-3M Melanoma
    LLR MALME-3M Melanoma
    LRV HAPGLRV (1062) MALME-3M Melanoma
    LRS LRSSMML (1063) MALME-3M Melanoma
    RPKLRSV (1064) MALME-3M Melanoma
    RVS SRVSFHE (1065) MALME-3M Melanoma
    RSS LRSSMML (1066) MALME-3M Melanoma
    SSGGRSS (1067) MALME-3M Melanoma
    AGS MALME-3M Melanoma
    AGR VAGRVGI (1068) MALME-3M Melanoma
    AGL AGLALTV (1069) MALME-3M Melanoma
    AGG MALME-3M Melanoma
    GVR IGVRGAV (1070) MALME-3M Melanoma
    GVL LVRDGVL (1071) MALME-3M Melanoma
    GAV IGVRGAV (1072) MALME-3M Melanoma
    GLV HGLVTHN (1073) MALME-3M Melanoma
    GLR HAPGLRV (1074) MALME-3M Melanoma
    LVS MALME-3M Melanoma
    ARG VSSTARG (1075) MALME-3M Melanoma
    ASL MALME-3M Melanoma
    AAV RAAVIHT (1076) MALME-3M Melanoma
    AAS AASTRSL (1077) MALME-3M Melanoma
    GGS GWGGGSA (1078) MALME-3M Melanoma
    SSRGGSS (1079) MALME-3M Melanoma
    GGR SSGGRSS (1080) MALME-3M Melanoma
    GLG MALME-3M Melanoma
    GGL MALME-3M Melanoma
    GSS SSRGGSS (1081) MALME-3M Melanoma
    GSG ARRGSGL (1082) MALME-3M Melanoma
    GSV MALME-3M Melanoma
    GRV VAGRVGI (1083) MALME-3M Melanoma
    GRL EGRLMLA (1084) MALME-3M Melanoma
    GPS MALME-3M Melanoma
    GVS MALME-3M Melanoma
    RLS RLSSAPS (1085) M14 Melanoma
    RRLSYHS (1086) M14 Melanoma
    FLHMRLS (1087) M14 Melanoma
    RGV LARGVPP (1088) M14 Melanoma
    RGS LSRGSVA (1089) M14 Melanoma
    VWLRGST (1090) M14 Melanoma
    RAV M14 Melanoma
    RAS RGGQRAS (1091) M14 Melanoma
    GAG M14 Melanoma
    AVS AVSGRSL (1092) M14 Melanoma
    LLS GLLSSFS (1093) M14 Melanoma
    LLR RMGLLRQ (1094) M14 Melanoma
    LRV M14 Melanoma
    LRS RLHYLRS (1095) M14 Melanoma
    GGYWLRS (1096) M14 Melanoma
    RVS M14 Melanoma
    RSS NRSSHCG (1097) M14 Melanoma
    QRSSDLT (1098) M14 Melanoma
    AGS M14 Melanoma
    AGR AAGRSRI (1099) M14 Melanoma
    AGL M14 Melanoma
    AGG GRAGGNG (1100) M14 Melanoma
    GVR ANASGVR (1101) M14 Melanoma
    GVL WAHGVLS (1102) M14 Melanoma
    GAV M14 Melanoma
    GLV M14 Melanoma
    GLR SLYGLRW (1103) M14 Melanoma
    LVS M14 Melanoma
    ARG GNGGARG (1104) M14 Melanoma
    LARGVPP (1105) M14 Melanoma
    NWDARGR (1106) M14 Melanoma
    ASL ASLPVLD (1107) M14 Melanoma
    PPGASLY (1108) M14 Melanoma
    AAV AAVGGRV (1109) M14 Melanoma
    AAS AASSWAV (1110) M14 Melanoma
    GGS AFKTGGS (1111) M14 Melanoma
    GGR FEGGRSG (1112) M14 Melanoma
    RTWGGRM (1113) M14 Melanoma
    SARQGGR (lll4) M14 Melanoma
    AAVGGRV (1115) M14 Melanoma
    GLG M14 Melanoma
    GGL M14 Melanoma
    GSS ARHGSSV (1116) M14 Melanoma
    SNFYGSS (1117) M14 Melanoma
    GSG GSGQLIP (1118) M14 Melanoma
    GSV LSRGSVA (1119) M14 Melanoma
    GRV AEYGRVL (1120) M14 Melanoma
    RGRVLLP (1121) M14 Melanoma
    AAVGGRV (1122) M14 Melanoma
    GRL RGRLALL (1123) M14 Melanoma
    SGPGRLP (1124) M14 Melanoma
    TSGRLWV (1125) M14 Melanoma
    GPS M14 Melanoma
    GVS MVYSGVS (1126) M14 Melanoma
    RLS WRLSREG (1127) SK-MEL-2 Melanoma
    LLRRLSW (1128) SK-MEL-2 Melanoma
    RGV AARGVMV (1129) SK-MEL-2 Melanoma
    RGS ALARGSG (1130) SK-MEL-2 Melanoma
    NLRGSRS (1131) SK-MEL-2 Melanoma
    RAV RAVWRAS (1132) SK-MEL-2 Melanoma
    RAS RAVWRAS SK-MEL-2 Melanoma
    GAG GAGSFSS (1133) SK-MEL-2 Melanoma
    AVS SK-MEL-2 Melanoma
    LLS LLSSRRC (1134) SK-MEL-2 Melanoma
    LLSLDPG (1135) SK-MEL-2 Melanoma
    SSLLSSL (1136) SK-MEL-2 Melanoma
    LLR LLRPAHG (1137) SK-MEL-2 Melanoma
    LLRRLSW (1138) SK-MEL-2 Melanoma
    LRV SK-MEL-2 Melanoma
    LRS CMLRSAT (1139) SK-MEL-2 Melanoma
    SKAVLRS (1140) SK-MEL-2 Melanoma
    RVS SRVSNPS (1141) SK-MEL-2 Melanoma
    RSS CRRSSLL (1142) SK-MEL-2 Melanoma
    AGS GAGSFSS (1143) SK-MEL-2 Melanoma
    AGR SAAGRTF (1144) SK-MEL-2 Melanoma
    PAGRMLS (1145) SK-MEL-2 Melanoma
    AGL IAMAGLR (1146) SK-MEL-2 Melanoma
    AGG AGGFRFI (1147) SK-MEL-2 Melanoma
    GVR SGVRPVI (1148) SK-MEL-2 Melanoma
    GVL GVLSDRS (1149) SK-MEL-2 Melanoma
    GAV GAVTSAD (1150) SK-MEL-2 Melanoma
    GAVTSAD (1151) SK-MEL-2 Melanoma
    GAVNTPA (1152) SK-MEL-2 Melanoma
    GLV GGLVKRL (1153) SK-MEL-2 Melanoma
    EVASGLV (1154) SK-MEL-2 Melanoma
    GLR IAMAGLR (1155) SK-MEL-2 Melanoma
    GTHSGLR (1156) SK-MEL-2 Melanoma
    LVS LVSTSNR (1157) SK-MEL-2 Melanoma
    FSLVSFV (1158) SK-MEL-2 Melanoma
    ALVSSHV (1159) SK-MEL-2 Melanoma
    ARG AARGVMV (1160) SK-MEL-2 Melanoma
    ALARGSG (1161) SK-MEL-2 Melanoma
    ASL SK-MEL-2 Melanoma
    AAV LRYWAAV (1162) SK-MEL-2 Melanoma
    AAS FTRGAAS (1163) SK-MEL-2 Melanoma
    EWHAASG (1164) SK-MEL-2 Melanoma
    GGS FGGSMAP (1165) SK-MEL-2 Melanoma
    GGSLKWV (1166) SK-MEL-2 Melanoma
    GGR RGLQGGR (1167) SK-MEL-2 Melanoma
    TCGGRSY (1168) SK-MEL-2 Melanoma
    GLG GEALGLG (1169) SK-MEL-2 Melanoma
    PRGLGVG (1170) SK-MEL-2 Melanoma
    VGLGNSA (1171) SK-MEL-2 Melanoma
    GGL GGLVKRL (1172) SK-MEL-2 Melanoma
    GSS SK-MEL-2 Melanoma
    GSG GSGRALA (1173) SK-MEL-2 Melanoma
    GSV SK-MEL-2 Melanoma
    GRV SK-MEL-2 Melanoma
    GRL SRSGRLN (1174) SK-MEL-2 Melanoma
    GPS SK-MEL-2 Melanoma
    GVS SAGVSDS (1175) SK-MEL-2 Melanoma
    RLS PRLSDKS (1176) SK-MEL-28 Melanoma
    RGV GRGDRGV (1177) SK-MEL-28 Melanoma
    RGVSGRL (1178) SK-MEL-28 Melanoma
    RGS INRGSRE (1179) SK-MEL-28 Melanoma
    LRGSRQF (1180) SK-MEL-28 Melanoma
    LRGSVGR (1181) SK-MEL-28 Melanoma
    RAV GLWYRAV (1182) SK-MEL-28 Melanoma
    RVRAVLG (1183) SK-MEL-28 Melanoma
    RAVLELW (1184) SK-MEL-28 Melanoma
    RAS LVRASNG (1185) SK-MEL-28 Melanoma
    GAG SK-MEL-28 Melanoma
    AVS SK-MEL-28 Melanoma
    LLS SK-MEL-28 Melanoma
    LLR ASGTLLR (1186) SK-MEL-28 Melanoma
    LRV SK-MEL-28 Melanoma
    LRS SK-MEL-28 Melanoma
    RVS GSGVRVS (1187) SK-MEL-28 Melanoma
    RSS VGSTRSS (1188) SK-MEL-28 Melanoma
    AGS RAGSRYI (1189) SK-MEL-28 Melanoma
    AGR SK-MEL-28 Melanoma
    AGL SK-MEL-28 Melanoma
    AGG SK-MEL-28 Melanoma
    GVR VGVRFSR (1190) SK-MEL-28 Melanoma
    GSGVRVS (1191) SK-MEL-28 Melanoma
    GVL IGVLASA (1192) SK-MEL-28 Melanoma
    GAV SK-MEL-28 Melanoma
    GLV GLVARVR (1193) SK-MEL-28 Melanoma
    GLR SK-MEL-28 Melanoma
    LVS SK-MEL-28 Melanoma
    ARG SK-MEL-28 Melanoma
    ASL SK-MEL-28 Melanoma
    AAV SK-MEL-28 Melanoma
    AAS SK-MEL-28 Melanoma
    GGS LLGIGGS (1194) SK-MEL-28 Melanoma
    QLGGSFR (1195) SK-MEL-28 Melanoma
    GGR LFRWGGR (1196) SK-MEL-28 Melanoma
    GLG SK-MEL-28 Melanoma
    GGL RFSGGLQ (1197) SK-MEL-28 Melanoma
    GSS VGSSHGL (1198) SK-MEL-28 Melanoma
    GSG SVRVGSG (1199) SK-MEL-28 Melanoma
    GSV GVNGSVS (1200) SK-MEL-28 Melanoma
    LRGSVGR (1201) SK-MEL-28 Melanoma
    GRV HVKNGRV (1202) SK-MEL-28 Melanoma
    GRL FQRSGRL (1203) SK-MEL-28 Melanoma
    HGRLAFG (1204) SK-MEL-28 Melanoma
    RGVSGRL (1205) SK-MEL-28 Melanoma
    GPS SK-MEL-28 Melanoma
    GVS RGVSGRL (1206) SK-MEL-28 Melanoma
    RLS SK-MEL-5 Melanoma
    RGV FGIGRGV (1207) SK-MEL-5 Melanoma
    RGS SK-MEL-5 Melanoma
    RAV SK-MEL-5 Melanoma
    RAS SK-MEL-5 Melanoma
    GAG SK-MEL-5 Melanoma
    AVS GVVQAVS (1208) SK-MEL-5 Melanoma
    LSAVSVK (1209) SK-MEL-5 Melanoma
    LLS LYLLSSA (1210) SK-MEL-5 Melanoma
    LIGGLLS (1211) SK-MEL-5 Melanoma
    LLR LLRRGIG (1212) SK-MEL-5 Melanoma
    LRV SK-MEL-5 Melanoma
    LRS FLRSLSL (1213) SK-MEL-5 Melanoma
    RVS VRVSGLT (1214) SK-MEL-5 Melanoma
    RSS SK-MEL-5 Melanoma
    AGS AGSVDLV (1215) SK-MEL-5 Melanoma
    AGR GFVAGRT (1216) SK-MEL-5 Melanoma
    AGL SK-MEL-5 Melanoma
    AGG SK-MEL-5 Melanoma
    GVR SK-MEL-5 Melanoma
    GVL SK-MEL-5 Melanoma
    GAV TRGAVFG (1217) SK-MEL-5 Melanoma
    GLV IYGGLVI (1218) SK-MEL-5 Melanoma
    GLR PTGEGLR (1219) SK-MEL-5 Melanoma
    LVS SK-MEL-5 Melanoma
    ARG SK-MEL-5 Melanoma
    ASL KVSVASL (1220) SK-MEL-5 Melanoma
    RYSMASL (1221) SK-MEL-5 Melanoma
    AAV SK-MEL-5 Melanoma
    AAS ANAASSP (1222) SK-MEL-5 Melanoma
    GGS PGGSRHA (1223) SK-MEL-5 Melanoma
    GGSPGVW (1224) SK-MEL-5 Melanoma
    GGR SK-MEL-5 Melanoma
    GLG SK-MEL-5 Melanoma
    GGL IYGGLVI (1225) SK-MEL-5 Melanoma
    LIGGLLS (1226) SK-MEL-5 Melanoma
    GSS SK-MEL-5 Melanoma
    GSG ACGSGLD (1227) SK-MEL-5 Melanoma
    GSV AGSVDLV (1228) SK-MEL-5 Melanoma
    TLGSVRV (1229) SK-MEL-5 Melanoma
    GRV HVRGRVA (1230) SK-MEL-5 Melanoma
    IDLGRVN (1231) SK-MEL-5 Melanoma
    GRL GRLDAFG (1232) SK-MEL-5 Melanoma
    GPS WVGPSGG (1233) SK-MEL-5 Melanoma
    GVS SK-MEL-5 Melanoma
    GSS UACC 257 Melanoma
    RLS DLRLSFP (1234) UACC 257 Melanoma
    SARLSHV (1235) UACC 257 Melanoma
    RGV VMDRGVA (1236) UACC 257 Melanoma
    RGS RGSLLWA (1237) UACC 257 Melanoma
    RGSPLTK (1238) UACC 257 Melanoma
    RAV UACC 257 Melanoma
    RAS RASIGIE (1239) UACC 257 Melanoma
    VHSLRAS (1240) UACC 257 Melanoma
    GAG UACC 257 Melanoma
    AVS UACC 257 Melanoma
    LLS AWLLSGR (1241) UACC 257 Melanoma
    LLR UACC 257 Melanoma
    LRV UACC 257 Melanoma
    LRS LWLRSRE (1242) UACC 257 Melanoma
    RVS VTRIRVS (1243) UACC 257 Melanoma
    RSS NSQRSSV (1244) UACC 257 Melanoma
    AGS AATRAGS (1245) UACC 257 Melanoma
    AGR UACC 257 Melanoma
    AGL UACC 257 Melanoma
    AGG UACC 257 Melanoma
    GVR TDGVRAF (1246) UACC 257 Melanoma
    GVL FAASGVL (1247) UACC 257 Melanoma
    GVLEGRR (1248) UACC 257 Melanoma
    GAV EADPGAV (1249) UACC 257 Melanoma
    DGAVILH (1250) UACC 257 Melanoma
    RDGAVNL (1251) UACC 257 Melanoma
    GLV UACC 257 Melanoma
    GLR GLRPHGA (1252) UACC 257 Melanoma
    TSRGLRL (1253) UACC 257 Melanoma
    LVS RMLVSSF (1254) UACC 257 Melanoma
    ARG DVIARGW (1255) UACC 257 Melanoma
    UACC 257 Melanoma
    ASL UACC 257 Melanoma
    AAV TLTAAVF (1256) UACC 257 Melanoma
    GWLNAAV (1257) UACC 257 Melanoma
    AAS FAASGVL (1258) UACC 257 Melanoma
    GGS GGSKGSA (1259) UACC 257 Melanoma
    AVALGGS (1260) UACC 257 Melanoma
    GGR HGGRYRH (1261) UACC 257 Melanoma
    SGVGGRY (1262) UACC 257 Melanoma
    GLG UACC 257 Melanoma
    GGL SGGLAVA (1263) UACC 257 Melanoma
    GSG UACC 257 Melanoma
    GSV UACC 257 Melanoma
    GRV UACC 257 Melanoma
    GRL GRLAKSI (1264) UACC 257 Melanoma
    GPS AGPSRGP (1265) UACC 257 Melanoma
    UACC 257 Melanoma
    GVS UACC 257 Melanoma
    RLS GLMRLSH (1266) UACC62 Melanoma
    VRVGRLS (1267) UACC62 Melanoma
    TGRLSAA (1268) UACC62 Melanoma
    RGV SLRGVRV (1269) UACC62 Melanoma
    DNCERGV (1270) UACC62 Melanoma
    TTQLRGV (1271) UACC62 Melanoma
    RGS GVIGRGS (1272) UACC62 Melanoma
    LAGMRGS (1273) UACC62 Melanoma
    RAV VRPRAVL (1274) UACC62 Melanoma
    PPRAVTN (1275) UACC62 Melanoma
    RAS WRARASP (1276) UACC62 Melanoma
    GAG UACC62 Melanoma
    AVS UACC62 Melanoma
    LLS FGRLLSP (1277) UACC62 Melanoma
    LLR PSLLRGF (1278) UACC62 Melanoma
    LRV RDLRVHL (1279) UACC62 Melanoma
    LRVSNPR (1280) UACC62 Melanoma
    LRVDQLY (1281) UACC62 Melanoma
    LRS HRLRSMS (1282) UACC62 Melanoma
    RVS LRVSNPR (1283) UACC62 Melanoma
    RSS UACC62 Melanoma
    AGS PGFMAGS (1284) UACC62 Melanoma
    AGR AGRGISQ (1285) UACC62 Melanoma
    RAGRDAP (1286) UACC62 Melanoma
    RAGRGFE (1287) UACC62 Melanoma
    AGL UACC62 Melanoma
    AGG HQAGGVT (1288) UACC62 Melanoma
    GVR SLRGVRV (1289) UACC62 Melanoma
    GVL DWVGVLM (1290) UACC62 Melanoma
    GTLGVLS (1291) UACC62 Melanoma
    GVLLWRP (1292) UACC62 Melanoma
    GAV UACC62 Melanoma
    GLV UACC62 Melanoma
    GLR GLREAHV (1293) UACC62 Melanoma
    LVS UACC62 Melanoma
    ARG AARGELR (1294) UACC62 Melanoma
    ASL AASLRGT (1295) UACC62 Melanoma
    AAV PVGAAVA (1296) UACC62 Melanoma
    AAS AASLRGT (1297) UACC62 Melanoma
    GGS UACC62 Melanoma
    GGR UACC62 Melanoma
    GLG UACC62 Melanoma
    GGL UACC62 Melanoma
    GSS UACC62 Melanoma
    GSG SNPGSGS (1298) UACC62 Melanoma
    GSV UACC62 Melanoma
    GRV GRVRETP (1299) UACC62 Melanoma
    UACC62 Melanoma
    GRL FGRLLSP (1300) UACC62 Melanoma
    VRVGRLS (1301) UACC62 Melanoma
    TGRLSAA (1302) UACC62 Melanoma
    VGRLQTT (1303) UACC62 Melanoma
    GPS DGPSCVI (1304) UACC62 Melanoma
    UACC62 Melanoma
    GVS UACC62 Melanoma
    RLS IGROV1 Ovarian
    RGV IGROV1 Ovarian
    RGS IGROV1 Ovarian
    RAV RFSSRAV (1305) IGROV1 Ovarian
    RAS HAGSRAS (1306) IGROV1 Ovarian
    GAG GAGLGVS (1307) IGROV1 Ovarian
    LLGAGTP (1308) IGROV1 Ovarian
    AVS IGROV1 Ovarian
    LLS LLSILKA (1309) IGROV1 Ovarian
    GLLSGGT (1310) IGROV1 Ovarian
    LLR IGROV1 Ovarian
    LRV LSVLRVL (1311) IGROV1 Ovarian
    LRS SRYTLRS (1312) IGROV1 Ovarian
    RVS IGROV1 Ovarian
    RSS LFHTRSS (1313) IGROV1 Ovarian
    VARSSFR (1314) IGROV1 Ovarian
    AGS CTAGSVS (1315) IGROV1 Ovarian
    RAAGSAG (1316) IGROV1 Ovarian
    HAGSRAS (1317) IGROV1 Ovarian
    AGR IGROV1 Ovarian
    AGL GAGLGVS (1318) IGROV1 Ovarian
    PTGAGLL (1319) IGROV1 Ovarian
    ASYAGLV (2) IGROV1 Ovarian
    (1320)
    AGG AGGFGVL (1321) IGROV1 Ovarian
    NMAGGQE (1322) IGROV1 Ovarian
    LRAGGSY (1323) IGROV1 Ovarian
    YLAGGKA (1324) IGROV1 Ovarian
    GVR PYYNGVR (1325) IGROV1 Ovarian
    GVL AGGFGVL (1326) IGROV1 Ovarian
    LIGGVLH (1327) IGROV1 Ovarian
    GAV IGROV1 Ovarian
    GLV DGLVPVA (1328) IGROV1 Ovarian
    GLVASMP (1329) IGROV1 Ovarian
    ASYAGLV (2) IGROV1 Ovarian
    (1330)
    GLR IGROV1 Ovarian
    LVS LVRLVSL (1331) IGROV1 Ovarian
    ARG IGROV1 Ovarian
    ASL VLASLSG (1332) IGROV1 Ovarian
    AAV IGROV1 Ovarian
    AAS IGROV1 Ovarian
    GGS GSITGGS (1333) IGROV1 Ovarian
    LRAGGSY (1334) IGROV1 Ovarian
    TGGSLLG (1335) IGROV1 Ovarian
    DEGGSRW (1336) IGROV1 Ovarian
    GGR IGROV1 Ovarian
    GLG GAGLGVS (1337) IGROV1 Ovarian
    GGL IGROV1 Ovarian
    GSS WGSSAVK (1338) IGROV1 Ovarian
    QGSSNSV (1339) IGROV1 Ovarian
    GSG IGROV1 Ovarian
    GSV CTAGSVS (1340) IGROV1 Ovarian
    SVTGSVG (1341) IGROV1 Ovarian
    GRV SPGRVAD (1342) IGROV1 Ovarian
    GRL IGROV1 Ovarian
    GPS DAVRGPS (1343) IGROV1 Ovarian
    GVS GAGLGVS (1344) IGROV1 Ovarian
    GVSGTVS (1345) IGROV1 Ovarian
    SGVSISC (1346) IGROV1 Ovarian
    RLS RRLSYHS (65) OVCAR-3 Ovarian
    (1347)
    RGV OVCAR-3 Ovarian
    RGS OVCAR-3 Ovarian
    RAV OVCAR-3 Ovarian
    RAS OVCAR-3 Ovarian
    GAG OVCAR-3 Ovarian
    AVS OVCAR-3 Ovarian
    LLS OVCAR-3 Ovarian
    LLR OVCAR-3 Ovarian
    LRV OVCAR-3 Ovarian
    LRS RREGLRS (10) OVCAR-3 Ovarian
    (1348)
    RVS ERVSAAV (1349) OVCAR-3 Ovarian
    RSS OVCAR-3 Ovarian
    AGS AGSMMEF (1350) OVCAR-3 Ovarian
    AGR OVCAR-3 Ovarian
    AGL OVCAR-3 Ovarian
    AGG OVCAR-3 Ovarian
    GVR OVCAR-3 Ovarian
    GVL RHGPGVL (1351) OVCAR-3 Ovarian
    GAV OVCAR-3 Ovarian
    GLV OVCAR-3 Ovarian
    GLR GLRRDNG (1352) OVCAR-3 Ovarian
    RREGLRS (10) OVCAR-3 Ovarian
    (1353)
    LVS OVCAR-3 Ovarian
    ARG OVCAR-3 Ovarian
    ASL OVCAR-3 Ovarian
    AAV ERVSAAV (1354) OVCAR-3 Ovarian
    AAS VAASVRE (1355) OVCAR-3 Ovarian
    GGS OVCAR-3 Ovarian
    GGR OVCAR-3 Ovarian
    GLG OVCAR-3 Ovarian
    GGL OVCAR-3 Ovarian
    GSS OVCAR-3 Ovarian
    GSG OVCAR-3 Ovarian
    GSV PWYDGSV (1356) OVCAR-3 Ovarian
    GRV GRVTLES (1357) OVCAR-3 Ovarian
    GRL OVCAR-3 Ovarian
    GPS OVCAR-3 Ovarian
    GVS OVCAR-3 Ovarian
    RLS GRLSRAP (1358) OVCAR-4 Ovarian
    SRLSYCN (1359) OVCAR-4 Ovarian
    RGV OVCAR-4 Ovarian
    RGS QARGSWL (1360) OVCAR-4 Ovarian
    FVPRGSY (1361) OVCAR-4 Ovarian
    RAV AALLRAV (1362) OVCAR-4 Ovarian
    RAS LAGRASE (1363) OVCAR-4 Ovarian
    GAG AAGAGWR (1364) OVCAR-4 Ovarian
    ADLGAGW (1365) OVCAR-4 Ovarian
    ADLGAGW (1366) OVCAR-4 Ovarian
    GGAGRGA (1367) OVCAR-4 Ovarian
    AVS DVWVAVS (1368) OVCAR-4 Ovarian
    LLS OVCAR-4 Ovarian
    LLR AALLRAV (1369) OVCAR-4 Ovarian
    LRV NLRVGAE (1370) OVCAR-4 Ovarian
    LRS NCYSLRS (1371) OVCAR-4 Ovarian
    RVS LAGSRVS (1372) OVCAR-4 Ovarian
    RSS OVCAR-4 Ovarian
    AGS SGPAGSF (1373) OVCAR-4 Ovarian
    LAGSRVS (1374) OVCAR-4 Ovarian
    AGR GGAGRGA (1375) OVCAR-4 Ovarian
    LAGRASE (1376) OVCAR-4 Ovarian
    VAGRLQM (1377) OVCAR-4 Ovarian
    AGL WGAGLDA (1378) OVCAR-4 Ovarian
    WGAGLDA (1379) OVCAR-4 Ovarian
    AGG AGRGAGG (1380) OVCAR-4 Ovarian
    GVR EAGVRLN (1381) OVCAR-4 Ovarian
    GVL OVCAR-4 Ovarian
    GAV MQLRGAV (1382) OVCAR-4 Ovarian
    GLV GGPGLVM (1383) OVCAR-4 Ovarian
    QGLVRGG (1384) OVCAR-4 Ovarian
    GLR PGLRGPA (1385) OVCAR-4 Ovarian
    PGLRGPA (1386) OVCAR-4 Ovarian
    LVS GRMLVSG (1387) OVCAR-4 Ovarian
    ARG ESARGAL (1388) OVCAR-4 Ovarian
    QARGSWL (1389) OVCAR-4 Ovarian
    ASL OVCAR-4 Ovarian
    AAV OVCAR-4 Ovarian
    AAS OVCAR-4 Ovarian
    GGS GGGSGGG (1390) OVCAR-4 Ovarian
    NNVGGSS (1391) OVCAR-4 Ovarian
    GGR GGRVLGQ (1392) OVCAR-4 Ovarian
    GGRVRGG (1393) OVCAR-4 Ovarian
    GGRVRGG (1394) OVCAR-4 Ovarian
    WYGGRGN (1395) OVCAR-4 Ovarian
    GLG CVGLGCH (1396) OVCAR-4 Ovarian
    GGL OVCAR-4 Ovarian
    GSS NNVGGSS (1397) OVCAR-4 Ovarian
    GSG FMTYGSG (1398) OVCAR-4 Ovarian
    GGGSGGG (1399) OVCAR-4 Ovarian
    WDQGSGY (1400) OVCAR-4 Ovarian
    GSV GSVLMRG (1401) OVCAR-4 Ovarian
    GRV GGRVLGQ (1402) OVCAR-4 Ovarian
    GGRVRGG (1403) OVCAR-4 Ovarian
    GGRVRGG (1404) OVCAR-4 Ovarian
    YMYHGRV (1405) OVCAR-4 Ovarian
    GRL GRLSRAP (1406) OVCAR-4 Ovarian
    VAGRLQM (1407) OVCAR-4 Ovarian
    APGRLGP (1408) OVCAR-4 Ovarian
    APGRLGP (1409) OVCAR-4 Ovarian
    GPS RDLAGPS (1410) OVCAR-4 Ovarian
    GVS OVCAR-4 Ovarian
    RLS RLSGAGD (1411) OVCAR-5 Ovarian
    RGV LQRGVAR (1412) OVCAR-5 Ovarian
    RGS OVCAR-5 Ovarian
    RAV RAVGRQL (1413) OVCAR-5 Ovarian
    SRAVIRL (1414) OVCAR-5 Ovarian
    RAS VRASSKR (1415) OVCAR-5 Ovarian
    GAG DGAGSLR (1416) OVCAR-5 Ovarian
    SVSGAGS (1417) OVCAR-5 Ovarian
    AVS OVCAR-5 Ovarian
    LLS TTLLSRQ (1418) OVCAR-5 Ovarian
    VAELLSM (1419) OVCAR-5 Ovarian
    LLR OVCAR-5 Ovarian
    LRV LPGRLRV (1420) OVCAR-5 Ovarian
    LRS LKAGLRS (1421) OVCAR-5 Ovarian
    RVS HRVSESV (1422) OVCAR-5 Ovarian
    RSS YYGERSS (1423) OVCAR-5 Ovarian
    AGS DGAGSLR (1424) OVCAR-5 Ovarian
    SVSGAGS (1425) OVCAR-5 Ovarian
    AGSVYSV (1426) OVCAR-5 Ovarian
    AGR OVCAR-5 Ovarian
    AGL SAGLLPS (1427) OVCAR-5 Ovarian
    LKAGLRS (1428) OVCAR-5 Ovarian
    AGG RRAGGSV (1429) OVCAR-5 Ovarian
    GVR SWAGVRF (1430) OVCAR-5 Ovarian
    GVL OVCAR-5 Ovarian
    GAV IYPGAVL (1431) OVCAR-5 Ovarian
    GLV OVCAR-5 Ovarian
    GLR LKAGLRS (1432) OVCAR-5 Ovarian
    LVS SLVSPRT (1433) OVCAR-5 Ovarian
    ARG OVCAR-5 Ovarian
    ASL OVCAR-5 Ovarian
    AAV HAAVEPS (1434) OVCAR-5 Ovarian
    TAAAVLL (1435) OVCAR-5 Ovarian
    AAS OVCAR-5 Ovarian
    GGS FHFGGSG (1436) OVCAR-5 Ovarian
    GEGGSGG (1437) OVCAR-5 Ovarian
    RRAGGSV (1438) OVCAR-5 Ovarian
    GGR ALPGGGR (1439) OVCAR-5 Ovarian
    YVGGRLR (1440) OVCAR-5 Ovarian
    GLG GKGMGLG (1441) OVCAR-5 Ovarian
    SLGLGGL (1442) OVCAR-5 Ovarian
    GGL DGGLNDC (1443) OVCAR-5 Ovarian
    LGGLGLS (1444) OVCAR-5 Ovarian
    GSS OVCAR-5 Ovarian
    GSG FHFGGSG (1445) OVCAR-5 Ovarian
    GEGGSGG (1446) OVCAR-5 Ovarian
    GSV RRAGGSV (1447) OVCAR-5 Ovarian
    SGAGSVS (1448) OVCAR-5 Ovarian
    AGSVYSV (1449) OVCAR-5 Ovarian
    GRV GRVTWRS (1450) OVCAR-5 Ovarian
    GRL LPGRLRV (1451) OVCAR-5 Ovarian
    YVGGRLR (1452) OVCAR-5 Ovarian
    GPS GPSSAVE (1453) OVCAR-5 Ovarian
    GVS OVCAR-5 Ovarian
    RLS RRLSYRE (28) OVCAR-8 Ovarian
    (1454)
    RGV OVCAR-8 Ovarian
    RGS OVCAR-8 Ovarian
    RAV HTRAVSE (1455) OVCAR-8 Ovarian
    NVSRAVG (1456) OVCAR-8 Ovarian
    RAS PRHRASQ (1457) OVCAR-8 Ovarian
    GAG LGAGMIA (1458) OVCAR-8 Ovarian
    AVS AVSLVVL (1459) OVCAR-8 Ovarian
    HTRAVSE (1460) OVCAR-8 Ovarian
    LLS OVCAR-8 Ovarian
    LLR OVCAR-8 Ovarian
    LRV ELGLRVP (1461) OVCAR-8 Ovarian
    LRS OVCAR-8 Ovarian
    RVS OVCAR-8 Ovarian
    RSS GRSSVSD (1462) OVCAR-8 Ovarian
    AGS YAGSGQL (2) OVCAR-8 Ovarian
    (1463)
    AGR AGRFGAR (1464) OVCAR-8 Ovarian
    AGL AIMGAGL (1465) OVCAR-8 Ovarian
    AGG OVCAR-8 Ovarian
    GVR THVGGVR (1466) OVCAR-8 Ovarian
    GVL GVLTRGN (1467) OVCAR-8 Ovarian
    GAV OVCAR-8 Ovarian
    GLV OVCAR-8 Ovarian
    GLR ELGLRVP (1468) OVCAR-8 Ovarian
    GLGLRLG (1469) OVCAR-8 Ovarian
    LVS IDLVSPG (1470) OVCAR-8 Ovarian
    ARG OVCAR-8 Ovarian
    ASL OVCAR-8 Ovarian
    AAV OVCAR-8 Ovarian
    AAS OVCAR-8 Ovarian
    GGS GGSTVPQ (1471) OVCAR-8 Ovarian
    GGR OVCAR-8 Ovarian
    GLG GLGLRLG (1472) OVCAR-8 Ovarian
    GGL TATGGLL (1473) OVCAR-8 Ovarian
    GSS GSNGSSH (3) OVCAR-8 Ovarian
    (1474)
    GSG LQGSGAY (2) OVCAR-8 Ovarian
    (1475)
    LQHLGSG (1476) OVCAR-8 Ovarian
    GSV OVCAR-8 Ovarian
    GRV OVCAR-8 Ovarian
    GRL OVCAR-8 Ovarian
    GPS GPSVLDI (1477) OVCAR-8 Ovarian
    GVS GATGVSS (1478) OVCAR-8 Ovarian
    RLS TRLSFRH (1479) SK-OV-3-3 Ovarian
    RGV FLRGVEL (1480) SK-OV-3-3 Ovarian
    RGS NSVRGSR (1481) SK-OV-3-3 Ovarian
    RAV NRAVLSA (1482) SK-OV-3-3 Ovarian
    RAS LIGRASM (1483) SK-OV-3-3 Ovarian
    GAG RVGAGAF (1484) SK-OV-3-3 Ovarian
    AVS WISAVSK (1485) SK-OV-3-3 Ovarian
    SAVSESP (1486) SK-OV-3-3 Ovarian
    LLS SK-OV-3-3 Ovarian
    LLR SK-OV-3-3 Ovarian
    LRV RVGTLRV(4) SK-OV-3-3 Ovarian
    (1487)
    LRS SK-OV-3-3 Ovarian
    RVS RVSGDGK (1488) SK-OV-3-3 Ovarian
    RSGRVSN (1489) SK-OV-3-3 Ovarian
    RVSNEAL (1490) SK-OV-3-3 Ovarian
    RVSSDPI (1491) SK-OV-3-3 Ovarian
    RSS VRSSGVL (1492) SK-OV-3-3 Ovarian
    AGS SGWFAGS (1493) SK-OV-3-3 Ovarian
    AGR SK-OV-3-3 Ovarian
    AGL AGLGLLD (1494) SK-OV-3-3 Ovarian
    SAAGLAR (1495) SK-OV-3-3 Ovarian
    AGG SK-OV-3-3 Ovarian
    GVR FAGAGVR (1496) SK-OV-3-3 Ovarian
    VRLTGVR (4) SK-OV-3-3 Ovarian
    (1497)
    GVL VRSSGVL (1498) SK-OV-3-3 Ovarian
    GAV RPWGAVA (1499) SK-OV-3-3 Ovarian
    GLV PVSDGLV (1500) SK-OV-3-3 Ovarian
    GLR NKGGLRQ (1501) SK-OV-3-3 Ovarian
    LVS GGFLLVS (1502) SK-OV-3-3 Ovarian
    LVPLVSG (1503) SK-OV-3-3 Ovarian
    ARG ARGGESA (1504) SK-OV-3-3 Ovarian
    MSARGIL (1505) SK-OV-3-3 Ovarian
    ASL ASLVARN (1506) SK-OV-3-3 Ovarian
    AAV RVEAAVP (1507) SK-OV-3-3 Ovarian
    AAS RALGAAS (1508) SK-OV-3-3 Ovarian
    GGS SK-OV-3-3 Ovarian
    GGR ASEGGRA (1509) SK-OV-3-3 Ovarian
    IGGRWVV (1510) SK-OV-3-3 Ovarian
    GLG AGLGLLD (1511) SK-OV-3-3 Ovarian
    GGL LGGLSER (1512) SK-OV-3-3 Ovarian
    NKGGLRQ (1513) SK-OV-3-3 Ovarian
    GSS LVGSSRV (1514) SK-OV-3-3 Ovarian
    YTGSSPS (1515) SK-OV-3-3 Ovarian
    GSG SK-OV-3-3 Ovarian
    GSV GSVLPVL (1516) SK-OV-3-3 Ovarian
    KGDGSVR (1517) SK-OV-3-3 Ovarian
    GSVSHRR (1518) SK-OV-3-3 Ovarian
    RLWGSVV (1519) SK-OV-3-3 Ovarian
    GRV MQGRVIV (1520) SK-OV-3-3 Ovarian
    RSGRVSN (1521) SK-OV-3-3 Ovarian
    GRL LEVGRLF (1522) SK-OV-3-3 Ovarian
    GPS SQFGPSF (3) SK-OV-3-3 Ovarian
    (1523)
    GVS ATLDGVS (1524) SK-OV-3-3 Ovarian
    RLS RLSWTVL (1525) PC3 Prostate
    RGV LRFRRGV (1526) PC3 Prostate
    RGS ARGRGSQ (1527) PC3 Prostate
    VLRGSTP (1528) PC3 Prostate
    RAV PC3 Prostate
    RAS ARLRASR (1529) PC3 Prostate
    GAG RIGAGHR (1530) PC3 Prostate
    AVS PC3 Prostate
    LLS WLLSSEI (1531) PC3 Prostate
    LLR PC3 Prostate
    LRV GGLRVGG (1532) PC3 Prostate
    GLRVYEP (1533) PC3 Prostate
    LRS YLRSAGM (1534) PC3 Prostate
    RVS RVSRAGG (1535) PC3 Prostate
    RSS PC3 Prostate
    AGS PC3 Prostate
    AGR AGRPGGY (1536) PC3 Prostate
    AGL YGALAGL (1537) PC3 Prostate
    AGG RVSRAGG (1538) PC3 Prostate
    SHTAGGG (1539) PC3 Prostate
    AGGVRDL (1540) PC3 Prostate
    RPAGGRT (1541) PC3 Prostate
    GVR GGVRLGG (1542) PC3 Prostate
    AGGVRDL (1543) PC3 Prostate
    GVL GVLGCDG (1544) PC3 Prostate
    GAV CGAVAEW (1545) PC3 Prostate
    GLV GDCGLVG (1546) PC3 Prostate
    GLR GGLRVGG (1547) PC3 Prostate
    GLRVYEP (1548) PC3 Prostate
    LVS PC3 Prostate
    ARG ARGRGSQ (1549) PC3 Prostate
    ASL PC3 Prostate
    AAV PC3 Prostate
    AAS PC3 Prostate
    GGS PC3 Prostate
    GGR GGRELKA (1550) PC3 Prostate
    GGGRRAL (1551) PC3 Prostate
    RPAGGRT (1552) PC3 Prostate
    GLG PC3 Prostate
    GGL GGLKVWR (1553) PC3 Prostate
    GGLRVGG (1554) PC3 Prostate
    GGLPVQM (1555) PC3 Prostate
    RQDGGLY (1556) PC3 Prostate
    GSS YATLGSS (1557) PC3 Prostate
    GSG SGSGCVF (1558) PC3 Prostate
    VSGSGTA (1559) PC3 Prostate
    GSV VGSVKAS (1560) PC3 Prostate
    ATGSGSV (1561) PC3 Prostate
    GRV PC3 Prostate
    GRL PTSGRLV (1562) PC3 Prostate
    GPS LACRGPS (1563) PC3 Prostate
    RGPSQVL (1564) PC3 Prostate
    GVS PC3 Prostate
    RLS TLGRLSS (1565) DU-145 Prostate
    RGV AGDRGVA (1566) DU-145 Prostate
    RGS DU-145 Prostate
    RAV LPRRAVF (1567) DU-145 Prostate
    RAS RASCVWR (6) DU-145 Prostate
    (1568)
    FSKMRAS (1569) DU-145 Prostate
    GAG DYVGAGT (1570) DU-145 Prostate
    AVS DU-145 Prostate
    LLS DU-145 Prostate
    LLR ARLLRGG (1571) DU-145 Prostate
    LLRSVGY (1572) DU-145 Prostate
    LRV DU-145 Prostate
    LRS HLRSGFS (1573) DU-145 Prostate
    LLRSVGY (1574) DU-145 Prostate
    RVS DU-145 Prostate
    RSS DU-145 Prostate
    AGS DU-145 Prostate
    AGR AGRPDGV (1575) DU-145 Prostate
    AGL DENRAGL (1576) DU-145 Prostate
    AGG AWAGGDM (1577) DU-145 Prostate
    LNAGGSG (1578) DU-145 Prostate
    GVR DU-145 Prostate
    GVL DU-145 Prostate
    GAV NMGAVGS (1579) DU-145 Prostate
    PIGAVMN (1580) DU-145 Prostate
    GLV LTGGLVF (1581) DU-145 Prostate
    CGEGLVV (1582) DU-145 Prostate
    GLR SDLGLRR (1583) DU-145 Prostate
    LVS HADVLVS (1584) DU-145 Prostate
    ARG FSNARGY (1585) DU-145 Prostate
    ASL DU-145 Prostate
    AAV AAVWWAA (1586) DU-145 Prostate
    AAS DU-145 Prostate
    GGS LNAGGSG (1587) DU-145 Prostate
    GGSAWWG (1588) DU-145 Prostate
    VYGWGGS (1589) DU-145 Prostate
    GGR GGRLLRA (1590) DU-145 Prostate
    LGGRTIS (1591) DU-145 Prostate
    GLG YLGLGGL (1592) DU-145 Prostate
    GGL SITRGGL (1593) DU-145 Prostate
    LTGGLVF (1594) DU-145 Prostate
    LGGLGLY (1595) DU-145 Prostate
    GSS GSSELSR (1596) DU-145 Prostate
    GSG GSGGANL (1597) DU-145 Prostate
    VDGSGDD (1598) DU-145 Prostate
    GSV RSLGSVG (1599) DU-145 Prostate
    GRV GRVKPGA (1600) DU-145 Prostate
    GRL GGRLLRA (1601) DU-145 Prostate
    GRLWYVA (1602) DU-145 Prostate
    TLGRLSS (1603) DU-145 Prostate
    GPS DU-145 Prostate
    GVS GVSGLSR (1604) DU-145 Prostate
    YGVSRLL (1605) DU-145 Prostate
    RLS SRLSYRA (1606) 786-0 Renal
    RGV IHRGVWG (1607) 786-0 Renal
    RGS YFRARGS (1608) 786-0 Renal
    RAV 786-0 Renal
    RAS 786-0 Renal
    GAG GAGRFPH (1609) 786-0 Renal
    SGAGAAF (1610) 786-0 Renal
    VDVGGAG (1611) 786-0 Renal
    AVS ASAGAVS (1612) 786-0 Renal
    LLS 786-0 Renal
    LLR 786-0 Renal
    LRV 786-0 Renal
    LRS ARYSLRS (1613) 786-0 Renal
    RLRSYVA (1614) 786-0 Renal
    SRKGLRS (1615) 786-0 Renal
    RVS SVTGRVS (1616) 786-0 Renal
    RSS 786-0 Renal
    AGS AGSAFWA (1617) 786-0 Renal
    DQQEAGS (1618) 786-0 Renal
    FAAGAGS (1619) 786-0 Renal
    AGR GAGRFPH (1620) 786-0 Renal
    AGL 786-0 Renal
    AGG GAGGVDV (1621) 786-0 Renal
    GVR 786-0 Renal
    GVL 786-0 Renal
    GAV ASAGAVS (1622) 786-0 Renal
    GLV RRDGLVE (1623) 786-0 Renal
    GLR SRKGLRS (1624) 786-0 Renal
    LVS GDATLVS (1625) 786-0 Renal
    GDATLVS (1626) 786-0 Renal
    ARG YFRARGS (1627) 786-0 Renal
    ASL 786-0 Renal
    AAV 786-0 Renal
    AAS 786-0 Renal
    GGS 786-0 Renal
    GGR 786-0 Renal
    GLG DRGLGMS (1628) 786-0 Renal
    GGL 786-0 Renal
    GSS 786-0 Renal
    GSG GSGYFIT (1629) 786-0 Renal
    GSV 786-0 Renal
    GRV SVTGRVS (1630) 786-0 Renal
    GRL 786-0 Renal
    GPS VGPSVHL (1631) 786-0 Renal
    GVS 786-0 Renal
    RLS A498 Renal
    RGV EGVRGVF (1632) A498 Renal
    GDRGVRG (1633) A498 Renal
    MRGVARK (1634) A498 Renal
    RGS A498 Renal
    RAV KRAVGRM (1635) A498 Renal
    RAS DRASSWA (1636) A498 Renal
    GAG LQGAGIH (1637) A498 Renal
    AVS A498 Renal
    LLS A498 Renal
    LLR WLLRGFG (1638) A498 Renal
    LRV A498 Renal
    LRS ASPPLRS (1639) A498 Renal
    RVS RVSSETF (1640) A498 Renal
    RSS A498 Renal
    AGS ARAGSTF (1641) A498 Renal
    AGR TFAGRSL (1642) A498 Renal
    AGL A498 Renal
    AGG YAAGGST (1643) A498 Renal
    GVR EGVRGVF (1644) A498 Renal
    GDRGVRG (1645) A498 Renal
    GVL PGVLREP (1646) A498 Renal
    GAV A498 Renal
    GLV A498 Renal
    GLR GLRDGVE (1647) A498 Renal
    LVS A498 Renal
    ARG FPARGED (1648) A498 Renal
    ASL MLGSASL (1649) A498 Renal
    AAV A498 Renal
    AAS A498 Renal
    GGS HGGSNDR (1650) A498 Renal
    YAAGGST (1651) A498 Renal
    GGR QGGRSGV (1652) A498 Renal
    WTVGGRV (1653) A498 Renal
    GLG A498 Renal
    GGL A498 Renal
    GSS VKGSSMR (1654) A498 Renal
    GSG A498 Renal
    GSV A498 Renal
    GRV FVGRVGE (1655) A498 Renal
    GRVGRDG (1656) A498 Renal
    SVSRGRV (1657) A498 Renal
    WTVGGRV (1658) A498 Renal
    GRL GFGRLLW (1659) A498 Renal
    GPS AAYWGPS (1660) A498 Renal
    GVS MDGVSTE (1661) A498 Renal
    VYWWGVS (1662) A498 Renal
    RLS RLSMASR (1663) ACHN Renal
    GRLSFGV (1664) ACHN Renal
    RGV GLSRGVL (1665) ACHN Renal
    RGS LRGSHVA (1666) ACHN Renal
    NMGRGSL (1667) ACHN Renal
    SVVRRGS (1668) ACHN Renal
    RAV ACHN Renal
    RAS ACHN Renal
    GAG VMGAGVQ (1669) ACHN Renal
    AVS ACHN Renal
    LLS ACHN Renal
    LLR PLLRQQL (1670) ACHN Renal
    LRV SNGLRVV (1671) ACHN Renal
    LRS LRSMAVM (1672) ACHN Renal
    VDLRSAF (1673) ACHN Renal
    RVS FRVSLGY (1674) ACHN Renal
    RSS RSSYAPP (1675) ACHN Renal
    AGS FPGSAGS (1676) ACHN Renal
    AGR FAGRAPR (1677) ACHN Renal
    AGL ACHN Renal
    AGG FIAGGVG (1678) ACHN Renal
    LIHAGGQ (1679) ACHN Renal
    RAGGGAP (1680) ACHN Renal
    TWHAGGI (1681) ACHN Renal
    GVR GVRSITL (1682) ACHN Renal
    GVL GLSRGVL (1683) ACHN Renal
    GAV RVVGAVL (1684) ACHN Renal
    GLV ACHN Renal
    GLR FGLRMSN (1685) ACHN Renal
    LGLRGWT (1686) ACHN Renal
    AFFMGLR (1687) ACHN Renal
    SNGLRVV (1688) ACHN Renal
    LVS ACHN Renal
    ARG ARGTMTG (1689) ACHN Renal
    RPARGAF (1690) ACHN Renal
    ASL ASLPMLH (1691) ACHN Renal
    AAV ACHN Renal
    AAS ACHN Renal
    GGS GGSVEGQ (1692) ACHN Renal
    GGR LGGRQES (1693) ACHN Renal
    NGGRVLS (1694) ACHN Renal
    GLG ACHN Renal
    GGL PIGGLFG (1695) ACHN Renal
    AECCGGL (1696) ACHN Renal
    SEQRGGL (1697) ACHN Renal
    GSS DRFGSSA (1698) ACHN Renal
    GSG GHGSGSR (1699) ACHN Renal
    GSV GGSVEGQ (1700) ACHN Renal
    GSVVSSW (1701) ACHN Renal
    GRV NGGRVLS (1702) ACHN Renal
    GRL GRLMPGG (1703) ACHN Renal
    TWGRLGL (1704) ACHN Renal
    AVHSGRL (1705) ACHN Renal
    GRLSFGV (1706) ACHN Renal
    GPS PQGPSSV (1707) ACHN Renal
    GVS ACHN Renal
    RLS AGWRLSQ (1708) CAIK-1 Renal
    RGV CAIK-1 Renal
    RGS RVDRGSL (1709) CAIK-1 Renal
    RAV RAVCEWD (1710) CAIK-1 Renal
    RAVERVA (1711) CAIK-1 Renal
    RAS AVFRASR (1712) CAIK-1 Renal
    GAG GAGSSVW (1713) CAIK-1 Renal
    GAGSSVW (1714) CAIK-1 Renal
    AVS CAIK-1 Renal
    LLS CAIK-1 Renal
    LLR WLLRSWS (1715) CAIK-1 Renal
    LRV RKEALRV (1716) CAIK-1 Renal
    RLRVSVR (1717) CAIK-1 Renal
    LRS LRPGLRS (1718) CAIK-1 Renal
    QRYHLRS (13) CAIK-1 Renal
    (1719)
    WLLRSWS (1720) CAIK-1 Renal
    RVS GRERVSH (2) CAIK-1 Renal
    (1721)
    RVSVRLR (1722) CAIK-1 Renal
    RSS CAIK-1 Renal
    AGS GAGSSVW (1723) CAIK-1 Renal
    GAGSSVW (1724) CAIK-1 Renal
    AGR CAIK-1 Renal
    AGL AGLWPWN (1725) CAIK-1 Renal
    AGG CAIK-1 Renal
    GVR GVRGGGD (1726) CAIK-1 Renal
    GVL CAIK-1 Renal
    GAV CAIK-1 Renal
    GLV GLVRRVV (1727) CAIK-1 Renal
    GLR LRPGLRS (1728) CAIK-1 Renal
    LVS CAIK-1 Renal
    ARG CAIK-1 Renal
    ASL CAIK-1 Renal
    AAV CAIK-1 Renal
    AAS WAHAASY (1729) CAIK-1 Renal
    GGS CAIK-1 Renal
    GGR DGGGRVG (1730) CAIK-1 Renal
    VGVMGGR (1731) CAIK-1 Renal
    VYGGRSE (1732) CAIK-1 Renal
    GLG TICLGLG (1733) CAIK-1 Renal
    GGL CAIK-1 Renal
    GSS GAGSSVW (1734) CAIK-1 Renal
    GAGSSVW (1735) CAIK-1 Renal
    GSG CAIK-1 Renal
    GSV DHVSGSV (1736) CAIK-1 Renal
    GRV DGGGRVG (1737) CAIK-1 Renal
    GRL GEGRLCG (1738) CAIK-1 Renal
    GVAIGRL (1739) CAIK-1 Renal
    GPS CAIK-1 Renal
    GVS FGVSQVH (1740) CAIK-1 Renal
    GGVSRMR (1741) CAIK-1 Renal
    GGL RXF393 Renal
    RLS GRIRLSF (1742) RXF393 Renal
    RGV RGVNYRS (1743) RXF393 Renal
    TEGTRGV (1744) RXF393 Renal
    RGS GYARGSG (1745) RXF393 Renal
    GVWLRGS (1746) RXF393 Renal
    RAV AARAVWG (1747) RXF393 Renal
    RAS RASYYGV (1748) RXF393 Renal
    GAG GAGVEYF (1749) RXF393 Renal
    AVS RXF393 Renal
    LLS LLLLSGS (1750) RXF393 Renal
    VLLSAGL (1751) RXF393 Renal
    LLR TGLLRLY (1752) RXF393 Renal
    LRV RXF393 Renal
    LRS LRSSLVS (1753) RXF393 Renal
    RVS RXF393 Renal
    RSS LRSSLVS (1754) RXF393 Renal
    PRSSGPM (1755) RXF393 Renal
    AGS RXF393 Renal
    AGR TAGRLEV (1756) RXF393 Renal
    AGL AGLEDLG (1757) RXF393 Renal
    MPAGLGV (1758) RXF393 Renal
    VLLSAGL (1759) RXF393 Renal
    AGG RXF393 Renal
    GVR GVRWNWS (1760) RXF393 Renal
    TRDGVRW (1761) RXF393 Renal
    GVL RXF393 Renal
    GAV RXF393 Renal
    GLV RAHGLVC (1762) RXF393 Renal
    GLR LGSSGLR (1763) RXF393 Renal
    LVS LLVSLSS (1764) RXF393 Renal
    LRSSLVS (1765) RXF393 Renal
    LVSTRWA (1766) RXF393 Renal
    LVSYSAV (1767) RXF393 Renal
    ARG GYARGSG (1768) RXF393 Renal
    ASL LGASLLV (1769) RXF393 Renal
    AAV GTGAAVF (1770) RXF393 Renal
    AAVGTAL (1771) RXF393 Renal
    AAS VSAASSV (1772) RXF393 Renal
    GGS RGGSPPV (1773) RXF393 Renal
    GGR VPPSGGR (1774) RXF393 Renal
    GLG GLGSCAP (1775) RXF393 Renal
    MPAGLGV (1776) RXF393 Renal
    GSS MPGSSRP (1777) RXF393 Renal
    GSSLSRP (1778) RXF393 Renal
    RLGSSGL (1779) RXF393 Renal
    GSG GYARGSG (1780) RXF393 Renal
    GSV RXF393 Renal
    GRV RXF393 Renal
    GRL SGRLWVG (1781) RXF393 Renal
    TAGRLEV (1782) RXF393 Renal
    GPS GPSFDAK (1783) RXF393 Renal
    GVS ACTGVSR (1784) RXF393 Renal
    RLS SN12C Renal
    RGV LGMGRGV (1785) SN12C Renal
    RGS MLGRGSV (1786) SN12C Renal
    RAV SN12C Renal
    RAS PRASSTG (1787) SN12C Renal
    RASCFWD (1788) SN12C Renal
    RASCFWD (1789) SN12C Renal
    GAG SN12C Renal
    AVS SN12C Renal
    LLS FLLLSHR (1790) SN12C Renal
    LLSVTSX (1791) SN12C Renal
    LLR PLLREVG (1792) SN12C Renal
    LRV LRVGHAG (1793) SN12C Renal
    NELRVCR (1794) SN12C Renal
    LRS MRYELRS (1795) SN12C Renal
    RVS RVSVWWA (1796) SN12C Renal
    FAQRRVS (1797) SN12C Renal
    RSS SHHRSSI (1798) SN12C Renal
    AGS CMAGSQD (1799) SN12C Renal
    RYGTAGS (1800) SN12C Renal
    SAGSHPA (1801) SN12C Renal
    PNSAGSV (1802) SN12C Renal
    AGR KMRIAGR (1803) SN12C Renal
    MERVAGR (1804) SN12C Renal
    AGL WAGLSRP (1805) SN12C Renal
    AGG SN12C Renal
    GVR GAHGVRL (1806) SN12C Renal
    RVPTGVR (1807) SN12C Renal
    GVL SN12C Renal
    GAV RGAVREM (1808) SN12C Renal
    GLV SN12C Renal
    GLR FDPGGLR (1809) SN12C Renal
    LVS ILSDLVS (1810) SN12C Renal
    ARG LLNPARG (1811) SN12C Renal
    ASL SN12C Renal
    AAV WWAAVPG (1812) SN12C Renal
    AAS KAASTED (1813) SN12C Renal
    SYMGAAS (1814) SN12C Renal
    GGS GGSIDCC (1815) SN12C Renal
    GPGGSKR (1816) SN12C Renal
    AFGGGSM (1817) SN12C Renal
    GGR PEGGRRP (1818) SN12C Renal
    GLG SN12C Renal
    GGL GGLEQDG (1819) SN12C Renal
    FDPGGLR (1820) SN12C Renal
    GSS LFGSSVS (1821) SN12C Renal
    WDGSSVS (1822) SN12C Renal
    GSG SN12C Renal
    GSV PNSAGSV (1823) SN12C Renal
    MLGRGSV (1824) SN12C Renal
    GRV SN12C Renal
    GRL TRRGRLD (1825) SN12C Renal
    GPS SN12C Renal
    GVS GVSISDG (1826) SN12C Renal
    GVSIYDL (1827) SN12C Renal
    RLS ARLSLEL (1828) TK-10 Renal
    RLRLSSW (1829) TK-10 Renal
    RRLSSIA (1830) TK-10 Renal
    SRLSYRT (1831) TK-10 Renal
    RGV TK-10 Renal
    RGS ARGSWRE (1832) TK-10 Renal
    RAV VRLRAVF (1833) TK-10 Renal
    RAS RASRIGL (1834) TK-10 Renal
    GAG GAGTSEG (1835) TK-10 Renal
    AVS TK-10 Renal
    LLS LLSTVWV (1836) TK-10 Renal
    ELRRLLS (1837) TK-10 Renal
    LLR LLRGLRP (1838) TK-10 Renal
    SLLRRLE (1839) TK-10 Renal
    LRV LRVSRGL (1840) TK-10 Renal
    TLGLRVP (1841) TK-10 Renal
    FVARLRV (1842) TK-10 Renal
    LRS GVYWLRS (1843) TK-10 Renal
    SFWWLRS (1844) TK-10 Renal
    TRYSLRS (1845) TK-10 Renal
    RVS LRVSRGL (1846) TK-10 Renal
    RSS RSSSGSG (1847) TK-10 Renal
    TRSSLTH (1848) TK-10 Renal
    TGRSSFW (1849) TK-10 Renal
    AGS TK-10 Renal
    AGR NAGRGAS (1850) TK-10 Renal
    AGL HAGLLVV (1851) TK-10 Renal
    AGG TK-10 Renal
    GVR HTYGVRF (1852) TK-10 Renal
    GVL TK-10 Renal
    GAV GAVRSVM (1853) TK-10 Renal
    VLVEGAV (1854) TK-10 Renal
    GLV TK-10 Renal
    GLR LLRGLRP (1855) TK-10 Renal
    TLGLRVP (1856) TK-10 Renal
    LVS TK-10 Renal
    ARG ARGSWRE (1857) TK-10 Renal
    ASL TK-10 Renal
    AAV GLWAAVL (1858) TK-10 Renal
    AAS GWTMAAS (1859) TK-10 Renal
    GGS LYMGGSH (1860) TK-10 Renal
    GGR GVGGRQS (1861) TK-10 Renal
    GLG RRGLGDA (1862) TK-10 Renal
    GGL TGGLHWY (1863) TK-10 Renal
    GSS GSGSSSR (1864) TK-10 Renal
    GSSTLQW (1865) TK-10 Renal
    GSG RSSSGSG (1866) TK-10 Renal
    GSV DELGSVQ (1867) TK-10 Renal
    GRV TK-10 Renal
    GRL GRLRPFS (1868) TK-10 Renal
    PRLGRLL (1869) TK-10 Renal
    GPS TK-10 Renal
    GVS VGVSQEW (1870) TK-10 Renal
    DGVSPLW (1871) TK-10 Renal
    RLS UO31 Renal
    RGV UO31 Renal
    RGS PRGSLFA (1872) UO31 Renal
    VIVRGSL (1873) UO31 Renal
    RAV GDRAVGL (1874) UO31 Renal
    VHKRAVL (1875) UO31 Renal
    RAS UO31 Renal
    GAG GGAGSRR (1876) UO31 Renal
    AVS UO31 Renal
    LLS RLETLLS (1877) UO31 Renal
    LLR LLRAGVR (1878) UO31 Renal
    LRV PAILRVR (1879) UO31 Renal
    GDLRVSV (1880) UO31 Renal
    LRS UO31 Renal
    RVS GDLRVSV (1881) UO31 Renal
    RSS UO31 Renal
    AGS GGAGSRR (1882) UO31 Renal
    AGSVTEQ (1883) UO31 Renal
    SSSLAGS (1884) UO31 Renal
    AGR RSWNAGR (1885) UO31 Renal
    AGL AGLPHRF (1886) UO31 Renal
    RNSRAGL (1887) UO31 Renal
    AGG RRSGAGG (1888) UO31 Renal
    AGGPSSY (1889) UO31 Renal
    GVR TGVRNSP (1890) UO31 Renal
    LLRAGVR (1891) UO31 Renal
    GVL UO31 Renal
    GAV UO31 Renal
    GLV UO31 Renal
    GLR UO31 Renal
    LVS ALVSTIL (1892) UO31 Renal
    ARG ARGRDEG (1893) UO31 Renal
    ASL ASLSVVI (1894) UO31 Renal
    AAV UO31 Renal
    AAS UO31 Renal
    GGS GGSRGYR (1895) UO31 Renal
    YWGGSVP (1896) UO31 Renal
    GGR GGRPVER (1897) UO31 Renal
    GGRSQEG (1898) UO31 Renal
    PGGGRGR (1899) UO31 Renal
    GLG UO31 Renal
    GGL UO31 Renal
    GSS FSLGSSP (1900) UO31 Renal
    GSG UO31 Renal
    GSV GSVFGTP (1901) UO31 Renal
    AGSVTEQ (1902) UO31 Renal
    YWGGSVP (1903) UO31 Renal
    GRV LSGRVIV (1904) UO31 Renal
    LSTPGRV (1905) UO31 Renal
    GRL UO31 Renal
    GPS AGGPSSY (1906) UO31 Renal
    UO31 Renal
    GVS UO31 Renal
    RLS MCF-7 Breast
    RGV MCF-7 Breast
    RGS RVMRGSL (1907) MCF-7 Breast
    RAV MCF-7 Breast
    RAS RASCVWA (1908) MCF-7 Breast
    GAG MCF-7 Breast
    AVS MCF-7 Breast
    LLS QLLSQVY (1909) MCF-7 Breast
    LLR MCF-7 Breast
    LRV MCF-7 Breast
    LRS ERYYLRS (1910) MCF-7 Breast
    GLVKLRS (1911) MCF-7 Breast
    RVS MCF-7 Breast
    RSS MCF-7 Breast
    AGS GRLAAGS (1912) MCF-7 Breast
    AGR MCF-7 Breast
    AGL MCF-7 Breast
    AGG MCF-7 Breast
    GVR MCF-7 Breast
    GVL MCF-7 Breast
    GAV MCF-7 Breast
    GLV GLVKLRS (1913) MCF-7 Breast
    GLR MCF-7 Breast
    LVS LWFELVS (1914) MCF-7 Breast
    ARG MCF-7 Breast
    ASL MCF-7 Breast
    AAV MCF-7 Breast
    AAS IGAASWF (1915) MCF-7 Breast
    GGS MCF-7 Breast
    GGR GGRRGTS (1916) MCF-7 Breast
    RDLGGRW (1917) MCF-7 Breast
    GLG MCF-7 Breast
    GGL WRGGLDR (1918) MCF-7 Breast
    GSS GRWTGSS (1919) MCF-7 Breast
    SYWVGSS (1920) MCF-7 Breast
    GSG MCF-7 Breast
    GSV MCF-7 Breast
    GRV MCF-7 Breast
    GRL GRLAAGS (1921) MCF-7 Breast
    GPS MCF-7 Breast
    GVS AKAGVSR (1922) MCF-7 Breast
    RLS LRLSGHD (1923) NCI/ADR-RES Breast
    RGV RGVGAKA (1924) NCI/ADR-RES Breast
    LRGVYVA (1925) NCI/ADR-RES Breast
    RGS NCI/ADR-RES Breast
    RAV NCI/ADR-RES Breast
    RAS NCI/ADR-RES Breast
    GAG NCI/ADR-RES Breast
    AVS GTPAVSY (1926) NCI/ADR-RES Breast
    LLS FLLSRSA (1927) NCI/ADR-RES Breast
    AGLLSDV (1928) NCI/ADR-RES Breast
    LLR NCI/ADR-RES Breast
    LRV LRVGXPG (1929) NCI/ADR-RES Breast
    LRS NCI/ADR-RES Breast
    RVS RVSGSPV (1930) NCI/ADR-RES Breast
    RSS RSSIDVG (1931) NCI/ADR-RES Breast
    AGS NCI/ADR-RES Breast
    AGR AGRRLRD (1932) NCI/ADR-RES Breast
    AGL WRLAGLG (1933) NCI/ADR-RES Breast
    PTVSAGL (1934) NCI/ADR-RES Breast
    AGLLSDV (1935) NCI/ADR-RES Breast
    AGG NCI/ADR-RES Breast
    GVR NCI/ADR-RES Breast
    GVL TLGVLVT (1936) NCI/ADR-RES Breast
    GAV NCI/ADR-RES Breast
    GLV NCI/ADR-RES Breast
    GLR NCI/ADR-RES Breast
    LVS GDRRLVS (1937) NCI/ADR-RES Breast
    LMLVSGK (1938) NCI/ADR-RES Breast
    ARG DVHARGD (1939) NCI/ADR-RES Breast
    ASL NCI/ADR-RES Breast
    AAV NCI/ADR-RES Breast
    AAS NCI/ADR-RES Breast
    GGS REGGSDT (1940) NCI/ADR-RES Breast
    GGR GGRRVVV (1941) NCI/ADR-RES Breast
    NVGGGRF (1942) NCI/ADR-RES Breast
    GLG GLGALRW (1943) NCI/ADR-RES Breast
    LGLSGLG (1944) NCI/ADR-RES Breast
    RGLGRPV (1945) NCI/ADR-RES Breast
    GGL NCI/ADR-RES Breast
    GSS GSSGLLA (1946) NCI/ADR-RES Breast
    LGSSSHI (1947) NCI/ADR-RES Breast
    GSG IGSGVGV (1948) NCI/ADR-RES Breast
    GSV KGSVLML (1949) NCI/ADR-RES Breast
    VPSGSVR (1950) NCI/ADR-RES Breast
    GRV NCI/ADR-RES Breast
    GRL GYLGRLP (1951) NCI/ADR-RES Breast
    AVYVGRL (1952) NCI/ADR-RES Breast
    GPS NCI/ADR-RES Breast
    GVS NCI/ADR-RES Breast
    RLS LGGRLSL (1953) MDA-MB-231 Breast
    RGV RGVGKTK (1954) MDA-MB-231 Breast
    LGGARGV (1955) MDA-MB-231 Breast
    HAWDRGV (1956) MDA-MB-231 Breast
    DWGSRGV (1957) MDA-MB-231 Breast
    RGS PYRRGSC (1958) MDA-MB-231 Breast
    ALNRGSR (3) MDA-MB-231 Breast
    (1959)
    RAV MDA-MB-231 Breast
    RAS MDA-MB-231 Breast
    GAG TFRGAGV (1960) MDA-MB-231 Breast
    AVS MDA-MB-231 Breast
    LLS LLSAARF (1961) MDA-MB-231 Breast
    LLR MDA-MB-231 Breast
    LRV MDA-MB-231 Breast
    LRS MRPGLRS (1962) MDA-MB-231 Breast
    RVS PRVSALV (1963) MDA-MB-231 Breast
    VRVSLNS (1964) MDA-MB-231 Breast
    RSS GRSSAGP (1965) MDA-MB-231 Breast
    AGS LHAGSSV (1966) MDA-MB-231 Breast
    VVMIAGS (1967) MDA-MB-231 Breast
    AGR DTPAGRL (1968) MDA-MB-231 Breast
    VGAGRFT (1969) MDA-MB-231 Breast
    AGL MDA-MB-231 Breast
    AGG AGGTDRT (1970) MDA-MB-231 Breast
    FISAGGW (1971) MDA-MB-231 Breast
    TIPAGGG (1972) MDA-MB-231 Breast
    VGRAGGL (1973) MDA-MB-231 Breast
    GVR MDA-MB-231 Breast
    GVL MDA-MB-231 Breast
    GAV MDA-MB-231 Breast
    GLV NPGLVWN (1974) MDA-MB-231 Breast
    LGLVHWV (1975) MDA-MB-231 Breast
    GLR MRPGLRS (1976) MDA-MB-231 Breast
    LVS MDA-MB-231 Breast
    ARG ARGNVRF (1977) MDA-MB-231 Breast
    LGGARGV (1978) MDA-MB-231 Breast
    ASL FRAASLL (1979) MDA-MB-231 Breast
    AAV MDA-MB-231 Breast
    AAS AASVGVA (1980) MDA-MB-231 Breast
    FRAASLL (1981) MDA-MB-231 Breast
    GGS PVFRGGS (1982) MDA-MB-231 Breast
    SGGSVGF (1983) MDA-MB-231 Breast
    VRANGGS (1984) MDA-MB-231 Breast
    GGR FHIWGGR (1985) MDA-MB-231 Breast
    LGGRLSL (1986) MDA-MB-231 Breast
    SGGRFVP (1987) MDA-MB-231 Breast
    GLG MDA-MB-231 Breast
    GGL GGGLPVD (1988) MDA-MB-231 Breast
    LSLRGGL (1989) MDA-MB-231 Breast
    VGRAGGL (1990) MDA-MB-231 Breast
    GSS ANGSSKK (1991) MDA-MB-231 Breast
    DFTLGSS (1992) MDA-MB-231 Breast
    LHAGSSV (1993) MDA-MB-231 Breast
    GSG MDA-MB-231 Breast
    GSV NSGSVVS (1994) MDA-MB-231 Breast
    SGGSVGF (1995) MDA-MB-231 Breast
    WSISGSV (1996) MDA-MB-231 Breast
    GRV MDA-MB-231 Breast
    GRL DTPAGRL (1997) MDA-MB-231 Breast
    LGGRLSL (1998) MDA-MB-231 Breast
    GPS MDA-MB-231 Breast
    GVS AVGVSAA (1999) MDA-MB-231 Breast
    SGVSNPG (2000) MDA-MB-231 Breast
    FGVSGGS (2001) MDA-MB-231 Breast
    ESATGVS (2002) MDA-MB-231 Breast
    AAIVGVS (2003) MDA-MB-231 Breast
    RLS MDA-MB-435-Breast
    RGV MDA-MB-435-Breast
    RGS LRSGRGS (2004) MDA-MB-435-Breast
    LRSGRGS (2005) MDA-MB-435-Breast
    RGRGSTL (2006) MDA-MB-435-Breast
    RGSPAAA (2007) MDA-MB-435-Breast
    SRGSYGS (2008) MDA-MB-435-Breast
    MDA-MB-435-Breast
    RAV MDA-MB-435-Breast
    RAS MDA-MB-435-Breast
    GAG GVGGGAG (2009) MDA-MB-435-Breast
    MDA-MB-435-Breast
    AVS MDA-MB-435-Breast
    LLS MDA-MB-435-Breast
    LLR MDA-MB-435-Breast
    LRV MDA-MB-435-Breast
    LRS LRSGRGS (49) MDA-MB-435-Breast
    (2010)
    RVS MDA-MB-435-Breast
    RSS MDA-MB-435-Breast
    AGS MDA-MB-435-Breast
    AGR MDA-MB-435-Breast
    AGL MDA-MB-435-Breast
    AGG AGGGGYH (2011) MDA-MB-435-Breast
    GAGGGVG (2012) MDA-MB-435-Breast
    YRALAGG (2) MDA-MB-435-Breast
    (2013)
    MDA-MB-435-Breast
    GVR MDA-MB-435-Breast
    GVL MDA-MB-435-Breast
    GAV MDA-MB-435-Breast
    GLV MDA-MB-435-Breast
    GLR MDA-MB-435-Breast
    LVS MDA-MB-435-Breast
    ARG MDA-MB-435-Breast
    ASL LYVDASL (2014) MDA-MB-435-Breast
    AAV MDA-MB-435-Breast
    AAS MDA-MB-435-Breast
    GGS MDA-MB-435-Breast
    GGR MDA-MB-435-Breast
    GLG MDA-MB-435-Breast
    GGL MDA-MB-435-Breast
    GSS MDA-MB-435-Breast
    GSG GEGSGSA (2015) MDA-MB-435-Breast
    GSV MDA-MB-435-Breast
    GRV MDA-MB-435-Breast
    GRL MDA-MB-435-Breast
    GPS MDA-MB-435-Breast
    GVS MDA-MB-435-Breast
    RLS BT-549 Breast
    RGV RVRGVLD (2016) BT-549 Breast
    SMRGVLS (2017) BT-549 Breast
    EAGPRGV (2018) BT-549 Breast
    RGS CRGSIGA (2019) BT-549 Breast
    PLQRGSG (2020) BT-549 Breast
    RGSRWSS (2021) BT-549 Breast
    RGSYVER (2022) BT-549 Breast
    RAV TYCDRAV (2023) BT-549 Breast
    RAS LGVRASP (2024) BT-549 Breast
    WRASPGM (2025) BT-549 Breast
    PRASDIL (2026) BT-549 Breast
    GAG RVGAGWP (2027) BT-549 Breast
    AVS BT-549 Breast
    LLS LLSRAQA (2028) BT-549 Breast
    LLR BT-549 Breast
    LRV SALRVGL (2029) BT-549 Breast
    VGLRVRF (2030) BT-549 Breast
    LRS YGLRSLV (2031) BT-549 Breast
    RVS TRVSGSG (2032) BT-549 Breast
    RSS VRRSSKF (2033) BT-549 Breast
    AGS BT-549 Breast
    AGR BT-549 Breast
    AGL TFAGLAQ (2034) BT-549 Breast
    AGG BT-549 Breast
    GVR LGVRASP (2035) BT-549 Breast
    LGVRLAS (2036) BT-549 Breast
    PWGAGVR (2037) BT-549 Breast
    GVL GVLTIGA (2038) BT-549 Breast
    RVRGVLD (2039) BT-549 Breast
    IGWGVLG (2040) BT-549 Breast
    SMRGVLS (2041) BT-549 Breast
    GAV GAVLTSC (2042) BT-549 Breast
    GLV GLVSTLI (2043) BT-549 Breast
    GLVGWGI (2044) BT-549 Breast
    GLR VGLRCSV (2045) BT-549 Breast
    VGLRVRF (2046) BT-549 Breast
    YGLRSLV (2047) BT-549 Breast
    LVS GLVSTLI (2048) BT-549 Breast
    ARG PRGMARG (2049) BT-549 Breast
    ASL BT-549 Breast
    AAV BT-549 Breast
    AAS BT-549 Breast
    GGS RGGSDEA (2050) BT-549 Breast
    GGR AEDSGGR (2051) BT-549 Breast
    GGRCGAE (2052) BT-549 Breast
    GLG BT-549 Breast
    GGL GGLMPRY (2053) BT-549 Breast
    GSS GSSVSLG (2054) BT-549 Breast
    GSG GSGRQLP (2055) BT-549 Breast
    RKGSGTA (2056) BT-549 Breast
    TRVSGSG (2057) BT-549 Breast
    GSV GSGSVRT (2058) BT-549 Breast
    GRV DDGRVHR (2059) BT-549 Breast
    DLVGRVR (2060) BT-549 Breast
    GRL WGRLEST (2061) BT-549 Breast
    GPS MGPSARW (2062) BT-549 Breast
    GVS ISGVSDD (2063) BT-549 Breast
    RLS GHSERLS (2064) T-47D Breast
    RGV ERGVFVY (2065) T-47D Breast
    TRGVIGG (2066) T-47D Breast
    RGS RGSFGLG (2067) T-47D Breast
    RAV PFHRRAV (2068) T-47D Breast
    RAS T-47D Breast
    GAG VGIGAGG (2) T-47D Breast
    (2069)
    AVS AVSLAWQ (2070) T-47D Breast
    FPAVSTE (2071) T-47D Breast
    LLS T-47D Breast
    LLR T-47D Breast
    LRV T-47D Breast
    LRS SGARLRS (2072) T-47D Breast
    RVS T-47D Breast
    RSS SHRSSTG (2073) T-47D Breast
    AGS SRLRAGS (2074) T-47D Breast
    AGR SFAGRIL (2075) T-47D Breast
    AGL T-47D Breast
    AGG RVAAGGL (2076) T-47D Breast
    VGIGAGG (2077) T-47D Breast
    VGIGAGG (2078) T-47D Breast
    GVR T-47D Breast
    GVL T-47D Breast
    GAV QKPGAVG (2079) T-47D Breast
    LGYYGAV (2080) T-47D Breast
    GLV LPLGLVS (2081) T-47D Breast
    LGLVFTR (2082) T-47D Breast
    GLR T-47D Breast
    LVS LPLGLVS (2083) T-47D Breast
    NSKPLVS (2084) T-47D Breast
    ARG TNRFARG (2085) T-47D Breast
    ASL LASLARP (2086) T-47D Breast
    AAV LGGAAVR (2087) T-47D Breast
    AAS AASPHPG (2088) T-47D Breast
    GGS LSKGGSE (2089) T-47D Breast
    GGR T-47D Breast
    GLG GLGRSVN (2090) T-47D Breast
    PGLGYAL (2091) T-47D Breast
    RGSFGLG (2092) T-47D Breast
    GGL GRDWGGL (2093) T-47D Breast
    RVAAGGL (2094) T-47D Breast
    GSS TVGSSLG (2095) T-47D Breast
    GSG T-47D Breast
    GSV T-47D Breast
    GRV GRVDPVD (2096) T-47D Breast
    GRL SLYRGRL (2097) T-47D Breast
    GPS T-47D Breast
    GVS VALGVSS (2098) T-47D Breast
    RLS VSVTRLS (2099) HS 578 T Breast
    RGV HS  578 T Breast
    RGS AGATRGS (2100) HS 578 T Breast
    RRGSVAE (2101) HS 578 T Breast
    FRFVRGS (2102) HS 578 T Breast
    TRGSGAG (2103) HS 578 T Breast
    RAV GARAVAP (2104) HS 578 T Breast
    RAS HS 578 T Breast
    GAG TRGSGAG (2105) HS 578 T Breast
    AVS EAVSGRR (2106) HS 578 T Breast
    LLS HS 578 T Breast
    LLR HS 578 T Breast
    LRV HS 578 T Breast
    LRS HS 578 T Breast
    RVS PVRRVSS (2107) HS 578 T Breast
    IRVSAVV (2108) HS 578 T Breast
    RSS HVRSSYA (2109) HS 578 T Breast
    RVRSSLA (2110) HS 578 T Breast
    AGS TAAGSSF (2111) HS 578 T Breast
    GAGSGRT (2112) HS 578 T Breast
    PAVAGST (2113) HS 578 T Breast
    AGR AGRHLDA (2114) HS 578 T Breast
    DRQLAGR (2115) HS 578 T Breast
    AGL HS 578 T Breast
    AGG HS 578 T Breast
    GVR LGVREVG (2116) HS 578 T Breast
    VAVGVRS (2117) HS 578 T Breast
    GVL SFGVLSG (2118) HS 578 T Breast
    GAV TSGAVAP (2119) HS 578 T Breast
    GLV HS 578 T Breast
    GLR GLREVQD (2120) HS 578 T Breast
    LVS SLVSERA (2121) HS 578 T Breast
    SVHLVSG (2122) HS 578 T Breast
    ARG TQVEARG (2123) HS 578 T Breast
    ASL HS 578 T Breast
    AAV HS 578 T Breast
    AAS HS 578 T Breast
    GGS HS 578 T Breast
    GGR GGRPTVT (2124) HS 578 T Breast
    VVGGRRT (2125) HS 578 T Breast
    GLG HS 578 T Breast
    GGL GVGGLSS (2126) HS 578 T Breast
    GSS TAAGSSF (2127) HS 578 T Breast
    GSG TRGSGAG (2128) HS 578 T Breast
    GSV RRGSVAE (2129) HS 578 T Breast
    GSVLHVS (2130) HS 578 T Breast
    GRV SGRVFRF (2131) HS 578 T Breast
    GRL HS 578 T Breast
    GPS HS
     578 T Breast
    GVS WSATGVS (2132) HS 578 T Breast
    • REFERENCES
  • The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.
    • Arap et al., Nature Med. 8, 121-127, 2002.
    • Arap et al., Science, 279:377-80, 1998.
    • Blower et al., Pharmacogenomics J., 2:259-271, 2002.
    • Brown, Oncol. Res., 1997; 9:213-5, 1997.
    • Giordano et al., Nat. Med., 7:1249-1253, 2001.
    • Hafner et al., Clin. Chem., 50:490-499, 2004.
    • Holbeck, Eur. J. Cancer, 40:785-793, 2004.
    • Kolonin et al., Cancer Res., 66(1):1-7, 2006.
    • Kolonin et al., Curr. Opin. Chem. Biol., 5:308-13, 2001.
    • Kolonin et al., Nat. Med., 6:625-632, 2004.
    • Kolonin et al., Proc. Natl. Acad. Sci. USA, 99:13055-13060, 2002.
    • Maihle and Lafky, Trends Cell Biol., 12:160-161, 2002.
    • Monks et al., J. Natl. Cancer Inst., 1991; 83:757-66, 1991.
    • Myers et al., Electrophoresis, 18:647-653, 1997.
    • Nishizuka et al., Proc. Natl. Acad. Sci. USA, 100:14229-14234, 2003.
    • Pasqualini and Ruoslahti, Nature, 380:364-366, 1996.
    • Pasqualini et al., Cancer Res., 60:722-727, 2000.
    • Pasqualini et al., In: Phage Display, A Laboratory Manual, Barbas et al. (Eds.), NY, Cold Spring Harbor Laboratory Press, 22:1-24, 2001.
    • Rabow et al., J. Med. Chem., 45:818-40, 2002.
    • Scherf et al., Nat. Genet., 24:236-244, 2000.
    • Szakacs et al., Cancer Cell, 6:129-37, 2004.
    • Vogelstein and Kinzler, Nat. Med., 10:789-799, 2004.
    • Walloyist et al., Bioinformatics, 19:2212-24, 2003.
    • Wallqvist et al., Mol. Cancer Ther., 1:311-20, 2002.
    • Weinstein et al., Science, 275:343-349, 1997.
    • Zaharevitz et al., J. Mol. Graph. Model, 30:297-303, 2002.
    • Zurita et al., Cancer Res., 2004:64:435-9, 2004.

Claims (29)

1.-31. (canceled)
32. A method of targeting a therapeutic agent or an imaging agent to an EphA5 receptor positive cancer cell in a subject, the method comprising administering to the subject a pharmaceutical composition comprising:
a) the EphA5 cell targeting moiety; and
b) the therapeutic agent or the imaging agent.
33. The method of claim 32, wherein an EphA5 receptor is on a surface of the cancer cell.
34. The method of claim 32, wherein the subject is a human.
35. The method of claim 32, wherein the EphA5 cell targeting moiety comprises a peptide.
36. The method of claim 35, wherein the peptide is covalently modified.
37. The method of claim 35, wherein the peptide is cyclic.
38. The method of claim 32, wherein the EphA5 cell targeting moiety comprises an antibody.
39. The method of claim 38, wherein the antibody is specific for EphA5 receptor only when upregulated on a surface of the cancer cell.
40. The method of claim 32, wherein the therapeutic agent or the imaging agent comprises a radioisotope.
41. The method of claim 40,wherein the radioisotope is 213Bi, 103Pd, 133Xe, 131I, 68Ge, 57Co, 65Zn, 85Sr, 32P, 35S, 90Y, 153Sm, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn, 117Sn, 186Re, 166Ho or 188Re.
42. The method of claim 32, wherein the therapeutic agent is a polypeptide capable of inducing cell death in the cell.
43. The method of claim 32, wherein the therapeutic agent is an immunotherapeutic agent.
44. The method of claim 32, Wherein the therapeutic agent is a chemotherapeutic agent.
45. The method of claim 32, wherein the EphA5 cell targeting moiety is directly coupled to the therapeutic agent or the imaging agent.
46. A method of treating an EphA5 receptor positive cancer cell in a subject, the method comprising administering a pharmaceutical composition comprising:
a) an EphA5 cell targeting moiety; and
b) a therapeutic agent or an imaging agent,
to the subject.
47. The method of claim 46, wherein an EphA5 receptor is on a surface of the cancer cell.
48. The method of claim 46, wherein the subject is a human.
49. The method of claim 46, wherein the EphA5 cell targeting moiety comprises a peptide.
50. The method of claim 49, wherein the peptide is covalently modified.
51. The method of claim 50, wherein the peptide is cyclic.
52. The method of claim 46, wherein the EphA5 cell targeting moiety comprises an antibody.
53. The method of claim 52, wherein the antibody is specific for an EphA5 receptor only when upregulated on a surface of the cancer cell.
54. The method of claim 46, wherein the therapeutic agent or imaging agent comprises a radioisotope.
55. The method of claim 54,wherein the radioisotope is 213Bi, 103Pd, 133Xe, 131I, 68Ge, 57Co, 65Zn, 85Sr, 32P, 35S, 90Y, 153Sm, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn, 117Sn, 186Re, 166Ho or 188Re.
56. The method of claim 46, wherein the therapeutic agent is a polypeptide capable of inducing cell death in the cell.
57. The method of claim 46, wherein the therapeutic agent is an immunotherapeutic agent.
58. The method of claim 46, wherein the therapeutic agent is a chemotherapeutic agent.
59. The method of claim 46, wherein the EphA5 cell targeting moiety is directly coupled to the therapeutic agent or the imaging agent.
US13/629,067 2006-03-09 2012-09-27 Compositions and methods related to profiling a plurality of cells based on peptide binding Abandoned US20130089498A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/629,067 US20130089498A1 (en) 2006-03-09 2012-09-27 Compositions and methods related to profiling a plurality of cells based on peptide binding

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US78089306P 2006-03-09 2006-03-09
US11/684,379 US7781565B2 (en) 2006-03-09 2007-03-09 Compositions and methods related to profiling a plurality of cells based on peptide binding
US12/826,327 US20100298233A1 (en) 2006-03-09 2010-06-29 Compositions and methods related to profiling a plurality of cells based on peptide binding
US13/629,067 US20130089498A1 (en) 2006-03-09 2012-09-27 Compositions and methods related to profiling a plurality of cells based on peptide binding

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US12/826,327 Division US20100298233A1 (en) 2006-03-09 2010-06-29 Compositions and methods related to profiling a plurality of cells based on peptide binding

Publications (1)

Publication Number Publication Date
US20130089498A1 true US20130089498A1 (en) 2013-04-11

Family

ID=38475889

Family Applications (3)

Application Number Title Priority Date Filing Date
US11/684,379 Expired - Fee Related US7781565B2 (en) 2006-03-09 2007-03-09 Compositions and methods related to profiling a plurality of cells based on peptide binding
US12/826,327 Abandoned US20100298233A1 (en) 2006-03-09 2010-06-29 Compositions and methods related to profiling a plurality of cells based on peptide binding
US13/629,067 Abandoned US20130089498A1 (en) 2006-03-09 2012-09-27 Compositions and methods related to profiling a plurality of cells based on peptide binding

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US11/684,379 Expired - Fee Related US7781565B2 (en) 2006-03-09 2007-03-09 Compositions and methods related to profiling a plurality of cells based on peptide binding
US12/826,327 Abandoned US20100298233A1 (en) 2006-03-09 2010-06-29 Compositions and methods related to profiling a plurality of cells based on peptide binding

Country Status (6)

Country Link
US (3) US7781565B2 (en)
EP (2) EP2338898A1 (en)
JP (1) JP5167155B2 (en)
AU (1) AU2007222991A1 (en)
CA (1) CA2645277A1 (en)
WO (1) WO2007104062A2 (en)

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9575070B2 (en) * 2001-12-04 2017-02-21 Wayne State University Neoepitope detection of disease using protein arrays
US8168181B2 (en) 2006-02-13 2012-05-01 Alethia Biotherapeutics, Inc. Methods of impairing osteoclast differentiation using antibodies that bind siglec-15
US7989160B2 (en) 2006-02-13 2011-08-02 Alethia Biotherapeutics Inc. Polynucleotides and polypeptide sequences involved in the process of bone remodeling
CA2655933C (en) 2006-06-23 2014-09-09 Alethia Biotherapeutics Inc. Polynucleotides and polypeptide sequences involved in cancer
ITTO20060852A1 (en) * 2006-11-30 2008-06-01 Univ Degli Studi Torino METASTASE-SPECIFIC PEPTIDES AND THEIR DIAGNOSTIC AND THERAPEUTIC APPLICATIONS
US8722851B2 (en) 2007-11-02 2014-05-13 Pain Therapeutics, Inc. Analgesia with minimal tolerance and dependence by a mu opioid receptor agonist that also binds filamin A
JP2009126811A (en) * 2007-11-22 2009-06-11 Kyoto Univ Synthetic peptide and its use
CN102245773B (en) 2008-11-03 2014-08-27 阿莱斯亚生物疗法股份有限公司 Antibodies that specifically block the biological activity of a tumor antigen
GB0823366D0 (en) * 2008-12-22 2009-01-28 Uni I Oslo Synthesis
FR2961814B1 (en) * 2010-06-29 2014-09-26 Isp Investments Inc NOVEL SIRTUIN 6 ACTIVATOR PEPTIDES AND COSMETIC OR PHARMACEUTICAL COMPOSITION COMPRISING SAME.
US20120055055A1 (en) 2010-09-02 2012-03-08 Illumin8 Outdoor Media, LLC Systems and Method for Outdoor Media Signage
EP2444101A1 (en) * 2010-10-21 2012-04-25 Universitätsklinikum Freiburg Selective targeting of the CD40L/Mac-1 interaction by small peptide inhibitors and its use for the treatment of inflammation and atherogenesis
EP2648748A1 (en) 2010-12-08 2013-10-16 Stem Centrx, Inc. Novel modulators and methods of use
RS59080B1 (en) 2011-03-31 2019-09-30 Adc Therapeutics Sa Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
WO2012170975A1 (en) * 2011-06-10 2012-12-13 The United States Of America As Representrd By The Secretary Of The Navy Nano-encapsulated therapeutics for controlled treatment of infection and other diseases
WO2013009690A2 (en) 2011-07-09 2013-01-17 The Regents Of The University Of California Leukemia stem cell targeting ligands and methods of use
US20140377288A1 (en) * 2011-09-16 2014-12-25 The Board Of Regents Of The University Of Texas System Compositions and methods related to dna damage repair
US20170174753A1 (en) 2012-01-09 2017-06-22 Alethia Biotherapeutics Inc. Method for treating breast cancer
WO2013156493A1 (en) * 2012-04-16 2013-10-24 Lipotec S.A. Compounds for the treatment and/or care of the skin and/or mucous membranes and their use in cosmetic or pharmaceutical compositions
CN103387603B (en) * 2012-05-08 2015-07-15 复旦大学 Polypeptide related to RTN4B, and preparation and application thereof
CA2928851A1 (en) 2012-07-19 2014-01-23 Alethia Biotherapeutics Inc. Anti-siglec-15 antibodies
EP4029937A1 (en) 2012-10-04 2022-07-20 Research Development Foundation Serine protease molecules and therapies
US9267114B2 (en) 2012-11-07 2016-02-23 Southern Research Institute Flavivirus envelope protein mutations affecting virion disassembly
JP6474404B2 (en) 2013-08-14 2019-02-27 ウィリアム マーシュ ライス ユニバーシティＷｉｌｌｉａｍ Ｍａｒｓｈ Ｒｉｃｅ Ｕｎｉｖｅｒｓｉｔｙ Unsialamycin derivatives, synthetic methods and their use as antitumor agents
KR20160072268A (en) 2013-11-04 2016-06-22 화이자 인코포레이티드 Anti-efna4 antibody-drug conjugates
CN103804470B (en) * 2014-01-22 2016-08-17 深圳市奥尼克斯基因技术有限公司 The acquisition of the novel polypeptide TMVP1 of a kind of selectively targeted lymphangiogenesis and application
AU2016298210B2 (en) 2015-07-28 2021-12-09 Board Of Regents, The University Of Texas System Implant compositions for the unidirectional delivery of therapeutic compounds to the brain
JP6839447B2 (en) * 2015-10-01 2021-03-10 国立大学法人 新潟大学 Peptides with accumulation specific to biliary tract cancer and their use
US11193117B2 (en) 2016-02-16 2021-12-07 Research Development Foundation Cell-targeted cytotoxic constructs
WO2018102762A1 (en) 2016-12-02 2018-06-07 Avelas Biosciences, Inc. Nerve labeling compositions and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005117999A2 (en) * 2004-06-02 2005-12-15 Sidney Kimmel Cancer Center Imaging and therapeutic agents targeting proteins expressed on endothelial cell surface

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6372473B1 (en) * 1997-05-28 2002-04-16 Human Genome Sciences, Inc. Tissue plasminogen activator-like protease
US6974667B2 (en) 2000-06-14 2005-12-13 Gene Logic, Inc. Gene expression profiles in liver cancer
CA2421195A1 (en) * 2000-09-08 2002-03-14 Board Of Regents, The University Of Texas System Compositions and methods for targeting peptides in humans in vivo
AU2002234799A1 (en) 2000-12-08 2002-06-18 Ipsogen Gene expression profiling of primary breast carcinomas using arrays of candidate genes
US20040048243A1 (en) 2001-09-07 2004-03-11 Wadih Arap Methods and compositions for in vitro targeting
PL375041A1 (en) * 2002-04-05 2005-11-14 Amgen Inc. Human anti-opgl neutralizing antibodies as selective opgl pathway inhibitors
EP1369482A1 (en) 2002-06-07 2003-12-10 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Target genes for the diagnosis and treatment of cancer
AU2005206536B2 (en) * 2004-01-16 2010-09-02 Regeneron Pharmaceuticals, Inc. Fusion polypeptides capable of activating receptors
WO2006010070A2 (en) * 2004-07-10 2006-01-26 Board Of Regents, The University Of Texas System Compositions and methods related to peptides that selectively bind leukemia cells
AU2005277567A1 (en) * 2004-08-16 2006-03-02 Medimmune, Llc Integrin antagonists with enhanced antibody dependent cell-mediated cytotoxicity activity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005117999A2 (en) * 2004-06-02 2005-12-15 Sidney Kimmel Cancer Center Imaging and therapeutic agents targeting proteins expressed on endothelial cell surface

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Foster et al (Thromb Res, 1993, 72(3): Abstract) *
Horswill et al (Cell Cycle, 2005, 4(4): 552-555) *

Also Published As

Publication number Publication date
AU2007222991A8 (en) 2011-03-10
WO2007104062A3 (en) 2008-11-27
WO2007104062A8 (en) 2008-10-09
WO2007104062A2 (en) 2007-09-13
EP2002036A4 (en) 2010-01-27
US20100298233A1 (en) 2010-11-25
US20070248952A1 (en) 2007-10-25
EP2338898A1 (en) 2011-06-29
CA2645277A1 (en) 2007-09-13
AU2007222991A2 (en) 2009-03-12
JP2009529333A (en) 2009-08-20
US7781565B2 (en) 2010-08-24
EP2002036A2 (en) 2008-12-17
JP5167155B2 (en) 2013-03-21
AU2007222991A1 (en) 2007-09-13

Similar Documents

Publication Publication Date Title
US7781565B2 (en) Compositions and methods related to profiling a plurality of cells based on peptide binding
Kolonin et al. Ligand-directed surface profiling of human cancer cells with combinatorial peptide libraries
US11754559B2 (en) Methods of assaying proteins
US8163567B2 (en) Methods and compositions comprising capture agents
Shukla et al. Phage display selection for cell-specific ligands: development of a screening procedure suitable for small tumor specimens
Bacon et al. Isolation of chemically cyclized peptide binders using yeast surface display
Kodadek Synthetic receptors with antibody-like binding affinities
Oyama et al. Isolation of multiple cell-binding ligands from different phage displayed-peptide libraries
Helmer et al. Peptides and peptide analogs to inhibit protein-protein interactions
AU2012311542A1 (en) Screening methods and uses thereof
Zhang et al. Screening and selection of peptides specific for esophageal cancer cells from a phage display peptide library
Doran et al. A liquid array platform for the multiplexed analysis of synthetic molecule–protein interactions
US20240018216A1 (en) Methods and composition involving thermophilic fibronectin type iii (fn3) monobodies
KR20090021751A (en) Peptide aptamers against tenascin c
Wang et al. Distinguishing of tumor cell-targeting peptide ligands through a color-encoding microarray
Bakhshinejad et al. Identification of a novel tumor-binding peptide for lung Cancer through in-vitro panning
Staquicini et al. Combinatorial vascular targeting in translational medicine
Avital-Shmilovici et al. Mega-High-Throughput Screening Platform for the Discovery of Biologically Relevant Sequence-Defined Non-Natural Polymers
Ballard et al. Quantitative PCR-based approach for rapid phage display analysis: a foundation for high throughput vascular proteomic profiling
Hung et al. Phage Display for Imaging Agent Development
Bi et al. Detection of breast cancer-related antigens through cDNA phage-displayed protein microarray
Ben Abid et al. New Phage Display-Isolated Heptapeptide Recognizing the Regulatory Carboxy-Terminal Domain of Human Tumour Protein p53
Dane Isolation of specific tumor targeting peptides from fluorescent bacterial display libraries
Lahdenranta et al. The Use of Proteomics to Map Phenotypic Heterogeneity of the Endothelium

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION