WO2020097901A1 - Biomarqueurs pour la cancérothérapie - Google Patents

Biomarqueurs pour la cancérothérapie Download PDF

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WO2020097901A1
WO2020097901A1 PCT/CN2018/115826 CN2018115826W WO2020097901A1 WO 2020097901 A1 WO2020097901 A1 WO 2020097901A1 CN 2018115826 W CN2018115826 W CN 2018115826W WO 2020097901 A1 WO2020097901 A1 WO 2020097901A1
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cancer
myc gene
copy number
subject
tissue
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PCT/CN2018/115826
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English (en)
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Xiang Li
Yiyou Chen
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Beijing Percans Oncology Co. Ltd.
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Priority to PCT/CN2018/115826 priority Critical patent/WO2020097901A1/fr
Priority to MX2021001749A priority patent/MX2021001749A/es
Priority to PCT/US2019/046124 priority patent/WO2020036852A1/fr
Priority to BR112021002622-3A priority patent/BR112021002622A2/pt
Priority to KR1020217007013A priority patent/KR20210044251A/ko
Priority to AU2019321289A priority patent/AU2019321289A1/en
Priority to CN201980064957.3A priority patent/CN113226318A/zh
Priority to CA3109605A priority patent/CA3109605A1/fr
Priority to JP2021507694A priority patent/JP2021533774A/ja
Priority to US17/268,042 priority patent/US20210180141A1/en
Priority to SG11202101397TA priority patent/SG11202101397TA/en
Priority to EP19849633.3A priority patent/EP3836909A4/fr
Publication of WO2020097901A1 publication Critical patent/WO2020097901A1/fr
Priority to JP2023203145A priority patent/JP2024023480A/ja

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • Embodiments of the present disclosure relate to the use of a MYC gene as a biomarker for predicting therapeutic efficacy of survivin inhibitors such as YM155 monobromide in cancer therapy, and related kits, compositions, and methods for diagnosing and treating cancer in a subject in need thereof.
  • YM155 monobromide is a small-molecule survivin inhibitor that induces the down-regulation of survivin and exhibits potent antitumor activity (see, e.g., Minematsu et al., Drug Metabolism and Disposition, 37: 619-628, 2008) .
  • YM-155 exerts anti-tumor effects in various in vivo cancer models, including prostate, pancreatic, and lung cancer (see, e.g., Nakahara et al., Cancer Research 67: 8014-8021, 2007; and Na et al., PLoS One 7 (6) , 2012) .
  • Embodiments of the present disclosure include methods for treating cancer in a subject in need thereof, comprising:
  • Some embodiments include administering to the subject a chemotherapeutic agent excluding (or other than) YM155 monobromide if MYC gene copy number in the cancer tissue is not substantially increased relative to that of the MYC gene copy number reference, or if MYC gene chromosomal location site in the cancer tissue is not translocated relative to that of the MYC gene chromosomal location site reference.
  • Some embodiments include administering YM155 monobromide to the subject if the subject is characterized as responsive to YM155 monobromide therapy. Some embodiments include administering to the subject a chemotherapeutic agent excluding YM155 monobromide if the subject is characterized as non-responsive to YM155 monobromide therapy.
  • the MYC gene copy number in the cancer tissue is increased by about or at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold relative to that of the MYC gene copy number reference.
  • Some embodiments comprise determining MYC gene copy number in the cancer tissue by array comparative genome hybridization (aCGH) , single nucleotide polymorphism (SNP) array, copy number variation (CNV) sequencing, or multiplex ligation-dependent probe amplification (MLPA) .
  • Some embodiments comprise determining MYC gene chromosomal location site in the cancer tissue by in situ hybridization (ISH) , fluorescence in situ hybridization (FISH) , next generation sequencing (NGS) , or comparative genome hybridization (CGH) .
  • Some embodiments comprise obtaining the MYC gene copy number reference from a database, or determining the MYC gene copy number reference from a non-cancerous tissue from a control, optionally by aCGH, SNP array, CNV sequence, or MLPA. Some embodiments comprise obtaining the MYC gene chromosomal location site reference from a database, or determining the MYC gene chromosomal location site reference from a non-cancerous tissue from a control, optionally by ISH, FISH, NGS, or CGH.
  • Some embodiments comprise obtaining the sample of cancer tissue from the subject.
  • the sample of cancer tissue is a surgical sample, a biopsy sample, a pleural effusion sample, or an ascetic fluid sample obtained from the subject, optionally selected from one or more of lung, blood, breast, gastrointestinal (stomach, colon, rectal) , ovarian, pancreatic, liver, bladder, cervical, neuronal, uterine, salivary gland, kidney, prostate, thyroid, or muscle tissue.
  • the subject is a human subject.
  • the cancer is selected from one or more of carcinoma, sarcoma such as rhabdomyosarcoma, for example, alveolar rhabdomyosarcoma (including sarcoma originating in the bones, tendons, cartilage, muscle, fat, fibrous, blood vessels, adipose, and/or connective tissue) , neuroblastoma, medulloblastoma, astrocytoma, glioblastoma multiforme, retinoblastoma, myeloma, leukemia, lymphoma (including Hodgkin’s lymphoma and Non-Hodgkin’s lymphoma) , adenosquamous carcinoma, carcinosarcoma, mixed mesodermal tumor, teratocarcinoma, lung cancer (including non-small cell lung cancer, small cell lung cancer, adenocarcinoma, and squamous carcinoma of the lung) , breast cancer (including rhabdom
  • the MYC gene is selected from MYCC and MYCN.
  • the MYC gene is MYCC and the cancer is selected from lung cancers and blood cancers, optionally leukemias and lymphomas.
  • the MYC gene is MYCN and the cancer is selected from neuroblastoma, small cell lung cancer, prostate cancer, alveolar rhabdomyosarcoma, medulloblastoma, glioblastoma multiforme, retinoblastoma, and breast cancer.
  • a diagnostic kit for determining therapeutic response to YM155 monobromide [1- (2-Methoxyethyl) -2-methyl-4, 9-dioxo-3- (pyrazin-2-ylmethyl) -4, 9-dihydro-1H-naphtho [2, 3-d] imidazolium bromide] , or an analog or derivative thereof, therapy in a subject with cancer, comprising means for measuring MYC gene copy number, or MYC gene chromosomal location site, in a sample of tissue from the subject, including cancer tissue and non-cancerous tissue.
  • the means for measuring MYC gene copy number comprise reagents for performing a diagnostic assay selected from one or more of array comparative genome hybridization (aCGH) , single nucleotide polymorphism (SNP) array, copy number variation (CNV) sequencing, and multiplex ligation-dependent probe amplification (MLPA) on a human MYC gene.
  • aCGH array comparative genome hybridization
  • SNP single nucleotide polymorphism
  • CNV copy number variation
  • MLPA multiplex ligation-dependent probe amplification
  • the means for measuring MYC gene chromosomal location site comprise reagents for performing a diagnostic assay selected from one or more of in situ hybridization (ISH) , fluorescence in situ hybridization (FISH) , next generation sequencing (NGS) , and comparative genome hybridization (CGH) on a human MYC gene.
  • a diagnostic assay selected from one or more of in situ hybridization (ISH) , fluorescence in situ hybridization (FISH) , next generation sequencing (NGS) , and comparative genome hybridization (CGH) on a human MYC gene.
  • Some embodiments comprise a MYC gene copy number reference value obtained from a database, or determined from a non-cancerous tissue from a control.
  • Some embodiments comprise a MYC gene chromosomal location site reference obtained from a database, or determined from a non-cancerous tissue from a control.
  • patient care kits comprising:
  • the means for measuring MYC gene copy number comprise reagents for performing a diagnostic assay selected from one or more of array comparative genome hybridization (aCGH) , single nucleotide polymorphism (SNP) array, copy number variation (CNV) sequencing, and multiplex ligation-dependent probe amplification (MLPA) on a human MYC gene.
  • the means for measuring MYC gene chromosomal location site comprise reagents for performing a diagnostic assay selected from one or more of in situ hybridization (ISH) , fluorescence in situ hybridization (FISH) , next generation sequencing (NGS) , and comparative genome hybridization (CGH) on a human MYC gene.
  • ISH in situ hybridization
  • FISH fluorescence in situ hybridization
  • NGS next generation sequencing
  • CGH comparative genome hybridization
  • Some embodiments comprise a MYC gene copy number reference value obtained from a database, or determined from a non-cancerous tissue from a control. Some embodiments comprise a MYC gene chromosomal location site reference obtained from a database, or determined from a non-cancerous tissue from a control.
  • the cancer is selected from one or more of carcinoma, sarcoma such as rhabdomyosarcoma, for example, alveolar rhabdomyosarcoma, (including sarcoma originating in the bones, tendons, cartilage, muscle, fat, fibrous, blood vessels, adipose, and/or connective tissue) , neuroblastoma, medulloblastoma, astrocytoma, glioblastoma multiforme, retinoblastoma, myeloma, leukemia, lymphoma (including Hodgkin’s lymphoma and Non-Hodgkin’s lymphoma) , adenosquamous carcinoma, carcinosarcoma, mixed mesodermal tumor, teratocarcinoma) , lung cancer (including non-small cell lung cancer, small cell lung cancer, adenocarcinoma, and squamous carcinoma of the lung) ,
  • the MYC gene is selected from MYCC and MYCN.
  • the MYC gene is MYCC and the cancer is selected from lung cancers and blood cancers, optionally leukemias and lymphomas.
  • the MYC gene is MYCN and the cancer is selected from neuroblastoma, small cell lung cancer, prostate cancer, alveolar rhabdomyosarcoma, medulloblastoma, glioblastoma multiforme, retinoblastoma, and breast cancer.
  • Figure 1 shows the chemical structure of YM155 monobromide (CAS 781661-94-7) .
  • Figure 2 shows that YM155 inhibits cell proliferation of human lung cancer cell line.
  • NCI-H1975, HCC827, NCI-H226, and HCC4006 cells were cultured in 96-well plates and treated with YM155 at indicated dose (nM) .
  • Cell proliferation was detected by EdU proliferation assay. The data presented is mean ⁇ SEM.
  • FIG. 3 shows that YM155 inhibits cell proliferation of human acute myeloid leukemia (AML) cell line.
  • AML acute myeloid leukemia
  • FIG. 4 shows that YM155 inhibits cell proliferation of U937 and RAMOS cell line.
  • U937 and RAMOS cells were cultured in 96-well plates and treated with YM155 at indicated dose (nM) .
  • Cell proliferation was detected by XTT cell viability assay. The data presented is mean ⁇ SEM.
  • Figure 5 provides genomic information for the human MYC gene.
  • Figure 6 provides genomic information for the human MYC gene.
  • Figure 7 shows that YM155 inhibits cell proliferation of human neuroblastoma cell lines, especially cell lines characterized by increased copy number of N-MYC (see also Table E3) .
  • Cell proliferation was detected by EdU assay. The data presented is mean ⁇ SD.
  • Figure 8 provides genomic information for the human MYC gene.
  • Embodiments of the present disclosure relate to the surprising discovery that amplification and/or translocation of the MYC gene in human malignancies associate with increased anti-cancer efficacy of survivin inhibitors, such as YM155 monobromide, and can therefore be used as biomarker (s) to optimize cancer therapy by those agents and others.
  • survivin inhibitors such as YM155 monobromide
  • MYC oncogene expression in MYC-amplified or MYC-translocated cancer cells is otherwise pro-apoptotic, except that its pro-apoptotic signaling is negatively-regulated by survivin, a member of the inhibitor of apoptosis (IAP) protein family that inhibits caspases and blocks cell death.
  • IAP inhibitor of apoptosis
  • survivin inhibitors such as YM155 monobromide can be used to block the apoptosis-inhibiting activity of survivin in the context of MYC amplification and/or translocation, favor the pro-apoptotic signaling of MYC to increase cancer cell death, and thereby provide optimal therapeutic efficacy in this context.
  • an element means one element or more than one element.
  • an “antagonist” or “inhibitor” refers to biological structure or chemical agent that interferes with or otherwise reduces the physiological action of another molecule, such as a protein (e.g., survivin) .
  • the antagonist or inhibitor specifically binds to the other molecule and/or a functional ligand of the other molecule.
  • the antagonist or inhibitor down-regulates the expression of the other molecule (e.g., survivin) . Included are full and partial antagonists.
  • an “agonist” or “activator” refers to biological structure or chemical agent that increases or enhances the physiological action of another agent or molecule. In some instances, the agonist specifically binds to the other agent or molecule. Included are full and partial agonists.
  • the “half maximal inhibitory concentration” is a measure of the potency of an agent in inhibiting a specific biological or biochemical function. This quantitative measure indicates how much of a particular agent (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. The values are typically expressed as molar concentration. The concentration is commonly used as a measure of antagonist drug potency in pharmacological research. In some instances, IC 50 represents the concentration of an agent that is required for 50%inhibition in vitro. The IC 50 of an agent can be determined by constructing a dose-response curve and examining the effect of different concentrations of the agent on the desired activity, for example, inhibition of tumor cell proliferation, tumor-cell killing.
  • An “increased” or “enhanced” amount is typically a “statistically significant” amount, and may include an increase that is about or at least about 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or 1000 fold, or about or at least about 5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, relative to that of a reference or control (including all integers and ranges in between) .
  • a “decreased” or “reduced” amount is typically a “statistically significant” amount, and may include a decrease that is about or at least about 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 1000 fold, or about or at least about 5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, relative to that of a reference or control (including all integers and ranges in between) .
  • polynucleotide and “nucleic acid” includes mRNA, RNA, cRNA, cDNA, and DNA including genomic DNA.
  • the term typically refers to polymeric form of nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide.
  • the term includes single and double stranded forms of DNA.
  • a “gene” refers to a hereditary unit consisting of a sequence of DNA that occupies a specific location on a chromosome and codes for a functional molecule or protein.
  • the structure of a gene consists of many elements of which the actual protein coding sequence is often only a small part. These elements include DNA regions that are not transcribed as well as untranslated regions of the RNA. Additionally, genes can have expression-altering regulatory regions that lie many kilobases upstream or downstream of the coding sequence. The information in a gene can also be represented by (or found in) a sequence of RNA or encoded protein.
  • a “subject” or a “subject in need thereof” includes a mammalian subject such as a human subject.
  • Statistical significance it is meant that the result was unlikely to have occurred by chance.
  • Statistical significance can be determined by any method known in the art. Commonly used measures of significance include the p-value, which is the frequency or probability with which the observed event would occur, if the null hypothesis were true. If the obtained p-value is smaller than the significance level, then the null hypothesis is rejected. In simple cases, the significance level is defined at a p-value of 0.05 or less.
  • “Therapeutic response” refers to improvement of symptoms (whether or not sustained) based on the administration of the therapeutic response.
  • terapéuticaally effective amount is the amount of an agent needed to elicit the desired biological response following administration.
  • treatment of a subject (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the subject or cell.
  • Treatment includes, but is not limited to, administration of a pharmaceutical composition, and may be performed either prophylactically or subsequent to the initiation of a pathologic event or contact with an etiologic agent.
  • prophylactic treatments which can be directed to reducing the rate of progression of the disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset.
  • “Treatment” or “prophylaxis” does not necessarily indicate complete eradication, cure, or prevention of the disease or condition, or associated symptoms thereof.
  • wild-type refers to a gene or gene product (e.g., a polypeptide) that is most frequently observed in a population and is thus arbitrarily designed the “normal” or “wild-type” form of the gene.
  • the present disclosure relates, in part, to the surprising discovery that amplifications and/or translocations of the MYC gene in human malignancies associate with increased anti-cancer efficacy of the chemotherapeutic agent YM155 monobromide, and can thus be used as biomarkers to optimize cancer therapy by that agent and others.
  • Embodiments of the present disclosure therefore include methods for treating cancer in a subject in need thereof, comprising (a) determining MYC gene copy number, or MYC gene chromosomal location site, in a sample of cancer tissue from the subject; and (b) administering YM155 monobromide [1- (2-Methoxyethyl) -2-methyl-4, 9-dioxo-3- (pyrazin-2-ylmethyl) -4, 9-dihydro-1H-naphtho [2, 3-d] imidazolium bromide] to the subject if MYC gene copy number in the cancer tissue is increased relative to that of a MYC gene copy number reference, or if MYC gene chromosomal location site in the cancer tissue is translocated relative to that of a MYC gene chromosomal location site reference, thereby treating cancer in the subject in need thereof.
  • Certain embodiments include administering to the subject a chemotherapeutic agent excluding (or other than) YM155 monobromide if MYC gene copy number in the cancer tissue is not substantially increased (e.g., the same or less than about 1.1 fold increase) relative to that of the MYC gene copy number reference, or if MYC gene chromosomal location site in the cancer tissue is not translocated relative to that of the MYC gene chromosomal location site reference.
  • Also included are methods for predicting therapeutic response to YM155 monobromide [1- (2-Methoxyethyl) -2-methyl-4, 9-dioxo-3- (pyrazin-2-ylmethyl) -4, 9-dihydro-1H-naphtho [2, 3-d] imidazolium bromide] in a subject with cancer comprising (a) determining MYC gene copy number, or MYC gene chromosomal location site, in a sample of cancer tissue from the subject; and (b) (i) characterizing the subject as responsive to YM155 monobromide therapy if MYC gene copy number in the cancer tissue is increased relative to that of a MYC gene copy number reference, or if MYC gene chromosomal location site in the cancer tissue is translocated relative to that of a MYC gene chromosomal location site reference; or (ii) characterizing the subject as non-responsive to YM155 monobromide therapy if MYC gene copy
  • Certain embodiments include administering YM155 monobromide to the subject if the subject is characterized as responsive to YM155 monobromide therapy. Some embodiments include administering to the subject a chemotherapeutic agent excluding (or other than) YM155 monobromide if the subject is characterized as non-responsive to YM155 monobromide therapy.
  • MYC gene or “MYC oncogene” refers to a family of proto-oncogenes that encode transcription factors, examples of which include c-Myc (also MYCC) and N-myc (also MYCN) .
  • the MYCC gene encodes a nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis, and cellular transformation.
  • the encoded protein forms a heterodimer with the related transcription factor MAX.
  • This complex binds to the E box DNA consensus sequence and regulates the transcription of specific target genes.
  • the MYCC gene is located on chromosome 8: 127, 735, 434-127, 741, 434, forward strand (see, e.g., Figure 5 and Figure 6; and Gene: MYC ENSG00000136997) .
  • the MYCN gene encodes a protein with a basic helix-loop-helix (bHLH) domain. It is located in the cell nucleus and dimerizes with another bHLH protein to bind DNA. MYCN is over-expressed in a number of different types of cancer, including, for example, neuroblastoma, rhabdomyosarcoma, medulloblastoma, astrocytoma, glioblastoma, retinoblastoma, prostate cancer, breast cancer, Wilms’tumour, and small cell lung cancer (see, for example, Beltran, Mol Cancer Res. 12: 815-822, 2014) .
  • bHLH basic helix-loop-helix
  • MYCN amplification is an adverse prognostic factor in neuroblastoma.
  • the amplicon material co-amplified with MYCN
  • MYCN amplification correlates with a 1p36 deletion and a gain of chromosome 17q.
  • the MYCN gene is located on the which is the short (p) arm of chromosome 2 at position 24.3 (Cytogenetic Location at 2p24.3; Molecular Location at base pairs 15, 940, 438 to 15, 947, 007 on chromosome 2; see also Figure 8) .
  • the MYC gene is selected from MYCC and MYCN.
  • YM155 monobromide refers to the small molecule [1- (2-Methoxyethyl) -2-methyl-4, 9-dioxo-3- (pyrazin-2-ylmethyl) -4, 9-dihydro-1H-naphtho [2, 3-d] imidazolium bromide] , having the molecular formula C 20 H 19 N 4 O 3 ⁇ Br, and the CAS Number 781661-94-7, and includes pharmaceutically-acceptable salts and acids thereof. Also included are biologically-active or equivalent analogs and/or derivatives of YM155 monobromide.
  • the MYC gene copy number in the cancer tissue is increased relative to that of the MYC gene copy number reference.
  • the MYC gene copy number in the cancer tissue is increased by a statistically significant amount relative to that of the MYC gene copy number reference.
  • the MYC gene copy number in the cancer tissue is increased by about or at least about 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10-fold (or more) relative to that of the MYC gene copy number reference.
  • the MYC gene copy number in the cancer tissue can be determined by any variety of methods.
  • the MYC gene copy number is determined by array comparative genome hybridization (aCGH) , single nucleotide polymorphism (SNP) array, copy number variation (CNV) sequencing, or multiplex ligation-dependent probe amplification (MLPA) .
  • aCGH array comparative genome hybridization
  • SNP single nucleotide polymorphism
  • CNV copy number variation
  • MLPA multiplex ligation-dependent probe amplification
  • the MYC gene chromosomal location site in the cancer tissue can be determined by any variety of methods.
  • the MYC gene chromosomal location site in the cancer tissue is determined by in situ hybridization (ISH) , fluorescence in situ hybridization (FISH) , next generation sequencing (NGS) , or comparative genome hybridization (CGH) .
  • ISH in situ hybridization
  • FISH fluorescence in situ hybridization
  • NGS next generation sequencing
  • CGH comparative genome hybridization
  • Certain embodiments thus include the step of determining or detecting the MYC gene chromosomal location site in a sample of cancer tissue from a subject in need thereof. Also included is the step of comparing the MYC gene chromosomal location site in the cancer tissue relative to that of a MYC gene chromosomal site reference.
  • CGH refers to a molecular cytogenetic method for analyzing copy number variations (CNVs) relative to ploidy level in the DNA of a test sample compared to a reference sample, without the need for culturing cells.
  • This technique allows quick and efficient comparisons between two genomic DNA samples arising from two sources, which are most often closely related, because it is suspected that they contain differences in terms of either gains or losses of either whole chromosomes or subchromosomal regions (aportion of a whole chromosome) .
  • the technique was originally developed for the evaluation of the differences between the chromosomal complements of solid tumor and normal tissue (see, e.g., Kallioniemi et al., Science.
  • CGH array CGH
  • MLPA refers to a variation of the multiplex polymerase chain reaction that permits amplification of multiple targets with only a single primer pair (see, e.g., Schouten et al., Nucleic Acids Res. 30 (12) : e57, 2002) .
  • In situ hybridization (ISH) and fluorescent in situ hybridization (FISH) refer to a type of hybridization that uses a labeled complementary DNA, RNA or modified nucleic acids strand (i.e., probe) to localize a specific DNA or RNA sequence in a portion or section of tissue (in situ) (see, e.g., Parra & Windle, Nature Genetics.
  • the methods and kits described herein employ any one or more of the foregoing techniques and/or comprise reagents for performing the same.
  • Examples of a “reference” include a value or amount or location obtained from a database, for example, a value or amount of a “wild-type” MYC gene copy number or a “wild-type” MYC gene chromosomal location site (see, e.g., Figure 5 and Figure 6 for a human MYCC gene chromosomal site reference; and Figure 8 for a human MYCN gene chromosomal site reference) .
  • a “reference” also includes a value or amount or location obtained from a non-cancerous tissue from one or more controls, for example, one or more healthy or non-cancerous control subjects (e.g., a population of healthy or non-cancerous control subjects) , or one or more corresponding non-cancerous control tissues from the subject being tested.
  • a “corresponding” non-cancerous control tissue is obtained from the same type of tissue as the cancer tissue being tested.
  • the MYC gene copy number reference from a non-cancerous control can be determined by any variety of methods, including, for example, by aCGH, SNP array, CNV sequence, and/or MLPA (supra) .
  • the MYC gene chromosomal location site reference from a non-cancerous control can be determined by any variety of methods, including, for example, ISH, FISH, NGS, and/or CGH (supra) .
  • the sample of cancer tissue is a surgical sample, a biopsy sample, a pleural effusion sample, or an ascetic fluid sample from the subject.
  • samples of cancer tissues include lung, blood, breast, gastrointestinal (stomach, colon, rectal) , ovarian, pancreatic, liver, bladder, cervical, neuronal, uterine, salivary gland, kidney, prostate, thyroid, or muscle tissues.
  • Certain embodiments include the step of obtaining the sample of cancer tissue (or non-cancerous control tissue) from the subject, for example, prior to determining MYC gene copy levels or MYC gene chromosomal location site.
  • the subject is a human subject.
  • certain embodiments include administering to the subject an anti-cancer agent excluding (or other than) YM155 monobromide if the subject is characterized as non-responsive to YM155 monobromide therapy, for example, if the MYC gene copy number in the cancer tissue is not substantially increased relative to that of the MYC gene copy number reference, or if the MYC gene chromosomal location site in the cancer tissue is not translocated relative to that of the MYC gene chromosomal location site reference.
  • anti-cancer agents for administering to a subject characterized as non-responsive to YM155 monobromide therapy include small molecules such as cytotoxic, chemotherapeutic, and anti-angiogenic agents, for instance, those that have been considered useful in the treatment of various cancers.
  • General classes of anti-cancer agents include, without limitation, alkylating agents, anti-metabolites, anthracyclines, anti-tumor antibiotics, platinums, type I topoisomerase inhibitors, type II topoisomerase inhibitors, vinca alkaloids, and taxanes.
  • anti-cancer agents include imatinib, crizotinib, dasatinib, sorafenib, pazopanib, sunitinib, vatalanib, geftinib, erlotinib, AEE-788, dichoroacetate, tamoxifen, fasudil, SB-681323, and semaxanib (SU5416) (see Chico et al., Nat Rev Drug Discov. 8: 829-909, 2009) .
  • anti-cancer agents for administering to a subject characterized as non-responsive to YM155 monobromide therapy include alkylating agents such as thiotepa, cyclophosphamide (CYTOXAN TM ) ; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine
  • paclitaxel Bristol-Myers Squibb Oncology, Princeton, N.J.
  • docetaxel Rhne-Poulenc Rorer, Antony, France
  • platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16) ; ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO) ; retinoic acid derivatives such as Targretin TM (bexarotene) , Panretin TM (alitretinoin) ; ONTAK
  • anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4 (5) -imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,
  • the cancer is a primary cancer, i.e., a cancer growing at the anatomical site where tumor progression began and yielded a cancerous mass.
  • the cancer is a secondary or metastatic cancer, i.e., a cancer which has spread from the primary site or tissue of origin into one or more different sites or tissues.
  • the cancer is selected from one or more of carcinoma, sarcoma such as rhabdomyosarcoma, for example, alveolar rhabdomyosarcoma (including sarcoma originating in the bones, tendons, cartilage, muscle, fat, fibrous, blood vessels, adipose, and/or connective tissue ) , neuroblastoma, medulloblastoma, astrocytoma, glioblastoma multiforme, retinoblastoma, myeloma, leukemia, lymphoma (including Hodgkin’s lymphoma and Non-Hodgkin’s lymphoma) , adenosquamous carcinoma, carcinosarcoma, mixed mesodermal tumor, teratocarcinoma, lung cancer (including non-small cell lung cancer, small cell lung cancer, adenocarcinoma, and squamous carcinoma of the lung) , breast cancer (including rhab
  • the MYC gene is MYCC and the cancer is selected from lung cancers and blood cancers, optionally leukemias and lymphomas.
  • the MYC gene is MYCN and the cancer is selected from neuroblastoma, small cell lung cancer, prostate cancer, alveolar rhabdomyosarcoma, medulloblastoma, glioblastoma multiforme, retinoblastoma, and breast cancer.
  • the cancer or tumor is a metastatic cancer.
  • exemplary metastatic cancers include, without limitation, bladder cancers which have metastasized to the bone, liver, and/or lungs; breast cancers which have metastasized to the bone, brain, liver, and/or lungs; colorectal cancers which have metastasized to the liver, lungs, and/or peritoneum; kidney cancers which have metastasized to the adrenal glands, bone, brain, liver, and/or lungs; lung cancers which have metastasized to the adrenal glands, bone, brain, liver, and/or other lung sites; melanomas which have metastasized to the bone, brain, liver, lung, and/or skin/muscle; ovarian cancers which have metastasized to the liver, lung, and/or peritoneum; pancreatic cancers which have metastasized to the liver, lung, and/or peritoneum; prostate cancers which have metastasized to the adrenal glands, bone, liver, and/or peritoneum; prostate cancers which have metastasized
  • the methods described herein are sufficient to result in tumor regression, as indicated by a statistically significant decrease in the amount of viable tumor, for example, at least a 10%, 20%, 30%, 40%, 50%or greater decrease in tumor mass, or by altered (e.g., decreased with statistical significance) scan dimensions.
  • the methods described are sufficient to result in stable disease.
  • the methods described herein are sufficient to result in clinically relevant reduction in symptoms of a particular disease indication known to the skilled clinician.
  • a combination therapy described herein can be administered to a subject before, during, or after other therapeutic interventions, including symptomatic care, radiotherapy, surgery, transplantation, hormone therapy, photodynamic therapy, antibiotic therapy, or any combination thereof.
  • Symptomatic care includes administration of corticosteroids, to reduce cerebral edema, headaches, cognitive dysfunction, and emesis, and administration of anti-convulsants, to reduce seizures.
  • Radiotherapy includes whole-brain irradiation, fractionated radiotherapy, and radiosurgery, such as stereotactic radiosurgery, which can be further combined with traditional surgery.
  • the agents described herein are generally incorporated into one or more therapeutic or pharmaceutical compositions prior to administration.
  • an effective or desired amount of one or more agents is typically mixed with any pharmaceutical carrier (s) or excipient known to those skilled in the art to be suitable for the particular agent and/or mode of administration.
  • a pharmaceutical carrier may be liquid, semi-liquid or solid.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical application may include, for example, a sterile diluent (such as water) , saline solution (e.g., phosphate buffered saline; PBS) , fixed oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvent; antimicrobial agents (such as benzyl alcohol and methyl parabens) ; antioxidants (such as ascorbic acid and sodium bisulfite) and chelating agents (such as ethylenediaminetetraacetic acid (EDTA) ) ; buffers (such as acetates, citrates and phosphates) .
  • a sterile diluent such as water
  • saline solution e.g., phosphate buffered saline; PBS
  • PBS phosphate buffered saline
  • fixed oil polyethylene glycol, glycerin, propylene glyco
  • suitable carriers include physiological saline or phosphate buffered saline (PBS) , and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, polypropylene glycol and mixtures thereof.
  • PBS physiological saline or phosphate buffered saline
  • the therapeutic or pharmaceutical compositions can be prepared by combining an agent-containing composition with an appropriate physiologically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • an appropriate physiologically acceptable carrier such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • suitable excipients such as salts, buffers and stabilizers may, but need not, be present within the composition.
  • Administration may be achieved by a variety of different routes, including oral, parenteral, nasal, intravenous, intradermal, intramuscular, subcutaneous or topical. Preferred modes of administration depend upon the nature of the condition to be treated or prevented. Particular embodiments include administration by IV infusion.
  • Carriers can include, for example, pharmaceutically-or physiologically-acceptable carriers, excipients, or stabilizers that are non-toxic to the cell or mammal being exposed thereto at the dosages and concentrations employed.
  • physiologically-acceptable carrier is an aqueous pH buffered solution.
  • physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as polysorbate 20 (TWEEN TM ) polyethylene glycol (PEG) , and poloxamers (PLURONICS TM ) , and the like.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid
  • one or more agents can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively) , in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) , or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • the particle (s) or liposomes may further comprise other therapeutic or diagnostic agents.
  • the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by testing the compositions in model systems known in the art and extrapolating therefrom. Controlled clinical trials may also be performed. Dosages may also vary with the severity of the condition to be alleviated.
  • a pharmaceutical composition is generally formulated and administered to exert a therapeutically useful effect while minimizing undesirable side effects.
  • the composition may be administered one time, or may be divided into a number of smaller doses to be administered at intervals of time. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need.
  • Typical routes of administering these and related therapeutic or pharmaceutical compositions thus include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • Therapeutic or pharmaceutical compositions according to certain embodiments of the present disclosure are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a subject or patient.
  • compositions that will be administered to a subject or patient may take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a herein described agent in aerosol form may hold a plurality of dosage units.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000) .
  • the composition to be administered will typically contain a therapeutically effective amount of an agent described herein, for treatment of a disease or condition of interest.
  • a therapeutic or pharmaceutical composition may be in the form of a solid or liquid.
  • the carrier (s) are particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier (s) may be liquid, with the compositions being, for example, an oral oil, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.
  • the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid. Certain embodiments include sterile, injectable solutions.
  • the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like.
  • a solid composition will typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
  • a liquid carrier such as polyethylene glycol or oil.
  • the therapeutic or pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be for oral administration or for delivery by injection, as two examples.
  • preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
  • the liquid therapeutic or pharmaceutical compositions may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred adjuvant.
  • a liquid therapeutic or pharmaceutical composition intended for either parenteral or oral administration should contain an amount of an agent such that a suitable dosage will be obtained. Typically, this amount is at least 0.01%of the agent of interest in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70%of the weight of the composition. Certain oral therapeutic or pharmaceutical compositions contain between about 4%and about 75%of the agent of interest. In certain embodiments, therapeutic or pharmaceutical compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 10%by weight of the agent of interest prior to dilution.
  • the therapeutic or pharmaceutical composition may include various materials, which modify the physical form of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients may be encased in a gelatin capsule.
  • the therapeutic or pharmaceutical compositions in solid or liquid form may include a component that binds to agent and thereby assists in the delivery of the compound. Suitable components that may act in this capacity include monoclonal or polyclonal antibodies, one or more proteins or a liposome.
  • compositions described herein may be prepared with carriers that protect the agents against rapid elimination from the body, such as time release formulations or coatings.
  • carriers include controlled release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others known to those of ordinary skill in the art.
  • the therapeutic or pharmaceutical compositions may be prepared by methodology well known in the pharmaceutical art.
  • a therapeutic or pharmaceutical composition intended to be administered by injection may comprise one or more of salts, buffers and/or stabilizers, with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the agent so as to facilitate dissolution or homogeneous suspension of the agent in the aqueous delivery system.
  • Certain embodiments include the use of a diagnostic kit for determining or predicting a therapeutic response (or responsiveness) to YM155 monobromide [1- (2-Methoxyethyl) -2-methyl-4, 9-dioxo-3- (pyrazin-2-ylmethyl) -4, 9-dihydro-1H-naphtho [2, 3-d] imidazolium bromide] therapy in a subject with cancer, comprising means for measuring MYC gene copy number, or MYC gene chromosomal location site, in a sample of tissue from the subject, including cancer tissue and non-cancerous tissue.
  • patient care kits comprising: (a) means for measuring MYC gene copy number, or MYC gene chromosomal location site, in a sample of tissue from a subject, including cancer tissue and non-cancerous tissue; and (b) YM155 monobromide [1- (2-Methoxyethyl) -2-methyl-4, 9-dioxo-3- (pyrazin-2-ylmethyl) -4, 9-dihydro-1H-naphtho [2, 3-d] imidazolium bromide] .
  • the means for measuring MYC gene copy number comprise reagents for performing a diagnostic assay selected from one or more of array comparative genome hybridization (aCGH) , single nucleotide polymorphism (SNP) array, copy number variation (CNV) sequencing, and multiplex ligation-dependent probe amplification (MLPA) on a human MYC gene.
  • the means for measuring MYC gene chromosomal location site comprise reagents for performing a diagnostic assay selected from one or more of in situ hybridization (ISH) , fluorescence in situ hybridization (FISH) , next generation sequencing (NGS) , and comparative genome hybridization (CGH) on a human MYC gene.
  • ISH in situ hybridization
  • FISH fluorescence in situ hybridization
  • NGS next generation sequencing
  • CGH comparative genome hybridization
  • Certain diagnostic or patient care kits include a MYC gene copy number reference value obtained from a database, or determined from a non-cancerous tissue from a control.
  • Some diagnostic or patient care kits include a MYC gene chromosomal location site reference obtained from a database, or determined from a non-cancerous tissue from a control.
  • the kits can also include written instructions, for example, on how to determine MYC gene copy number and/or a MYC gene chromosomal location site in a sample of cancer tissue from a subject, and/or from a non-cancerous control.
  • a diagnostic or patient care kit contains separate containers, dividers, or compartments for the composition (s) and informational material (s) .
  • the composition (s) or reagents can be contained in a bottle, vial, or syringe, and the informational material (s) can be contained in association with the container.
  • the separate elements of the kit are contained within a single, undivided container.
  • the composition (s) or reagents are contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label.
  • the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more compositions, reagents, and/or unit dosage forms of YM155 monobromide.
  • the kit includes a plurality of syringes, ampules, foil packets, or blister packs, each containing a reagent or a single unit dose of YM155 monobromide.
  • the containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation) , and/or light-tight.
  • the patient care kit optionally includes a device suitable for administration of the agent (s) , e.g., a syringe, inhalant, dropper (e.g., eye dropper) , swab (e.g., a cotton swab or wooden swab) , or any such delivery device.
  • the device is an implantable device that dispenses metered doses of the agent (s) .
  • methods of providing a kit e.g., by combining the components described herein.
  • the diagnostic or therapeutic response tests or methods described herein are performed at a diagnostic laboratory, and the results are then provided to the subject, or to a physician or other healthcare provider that plays a role in the subject’s healthcare and cancer treatment.
  • Particular embodiments thus include methods for providing the results of the responsiveness test to the subject in need thereof, or to the physician or other healthcare provider.
  • results or data can be in the form of a hard-copy or paper-copy, or an electronic form, such as a computer-readable medium.
  • Human lung cancer cell line NCI-H1975, HCC827, NCI-H226 and HCC4006 cells were cultured in RPMI 1640 (Hyclone TM , SH30809.01B) supplemented with 10%fetal bovine serum (GEMINI, 900-108) . Cultures were incubated at 37°C in 5%CO 2 .
  • NCI-H1975, HCC827 and NCI-H226 were purchased from Cell Bank, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
  • HCC4006 was purchased from CoBioer Biosciences Corporation (Nanjing, China) .
  • NCI-H1975, HCC827, NCI-H226 and HCC4006 cell were seeded in 96-well plates (Corning-Costar, 3603) at 2000 cells/well in 200 ⁇ l culture medium for 24 hours, respectively. Then cells were treated with YM155 (50, 30, 20, 10, 2, 0.4, 0.08, 0.016 and 0.0032 nM; APExBIO, A4221) or DMSO (0.1%; Amresco, 67-68-5) . After 72 hour incubation, cells were labeled with 5-Ethynyl-2’-deoxyuridine (EdU, final concentration at 1uM; Sigma, 900584) for additional 4h under the same culture condition.
  • EdU 5-Ethynyl-2’-deoxyuridine
  • High content imaging analysis The treated cells were scanned for image acquisition with CellInsight TM CX5 High-Content Screening (HSC) Platform (Thermo Fisher) that was equipped with filters for Hoechst 33342 (Ex: 386nm) and EdU (Ex: 560nm) . The total cell count and EdU-positive cell count were analysis by measuring the signal intensity in the nuclear region.
  • HSC CellInsight TM CX5 High-Content Screening
  • EdU Ex: 560nm
  • YM155 inhibits cell proliferation of human lung cancer cell lines.
  • NCI-H1975, HCC827, NCI-H226, and HCC4006 were exposed to different concentrations of YM155 for 72 hours.
  • the proliferation inhibitory effects of YM155 were different in these cell lines, with the calculated IC 50 showed in Table E1 below.
  • NCI-H1975 and HCC827 with MYC gene amplification (increased MYC gene copy number relative to a reference) were significantly more sensitive to YM155 than NCI-H226 and HCC4006 without MYC gene amplification.
  • XTT labeling mixture 50 ⁇ l was added to each well, followed by incubation of the microplate for 4 hours in a humidified atmosphere.
  • the IC 50 was calculated by the value of OD 490- OD 650 .
  • YM155 inhibits cell proliferation of human acute myeloid leukemia cells and Human Burkitt’s lymphoma cells.
  • U937, HL-60, and Ramos were exposed to different concentrations of YM155 for 72 hours.
  • the proliferation inhibitory effects of YM155 were different in these cell lines, with the calculated IC 50 showed in Table E2 below 5.
  • HL-60 cells with MYC gene amplification (increased MYC gene copy number relative to a reference) and Ramos cells with MYC gene translocation were more sensitive to YM155 than U937 cells without MYC gene amplification or translocation.
  • Neuroblastoma Cell Culture Neuroblastoma cell lines IMR-32, NB-1, SK-N-SH and SH-SY5Y cells were cultured in 96-well plates and treated with YM155 at indicated doses (nM) , as described above. Cell proliferation was detected by EdU assay, as described above.
  • YM155 inhibits cell proliferation of neuroblastoma cell lines. It is especially effective at inhibiting cell proliferation of the IMR-32 and NB-1 neuroblastoma cell lines, which are characterized by increased copy number of NMYC.
  • MYC gene amplification i.e., increased MYC gene copy number relative to a reference
  • MYC gene translocation can be used to predict responsiveness to YM155 monobromide therapy in cancer, including lung cancers, blood cell cancers, neuroblastomas, and others.

Abstract

L'invention concerne des méthodes d'utilisation d'un gène MYC en tant que biomarqueur pour prédire l'efficacité thérapeutique d'inhibiteurs de la survivine tels que le monobromure de YM155 dans une cancérothérapie, et des kits, des compositions et des méthodes associés pour diagnostiquer et traiter le cancer chez un sujet qui en a besoin.
PCT/CN2018/115826 2018-08-13 2018-11-16 Biomarqueurs pour la cancérothérapie WO2020097901A1 (fr)

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PCT/CN2018/115826 WO2020097901A1 (fr) 2018-11-16 2018-11-16 Biomarqueurs pour la cancérothérapie
AU2019321289A AU2019321289A1 (en) 2018-08-13 2019-08-12 Biomarkers for cancer therapy
PCT/US2019/046124 WO2020036852A1 (fr) 2018-08-13 2019-08-12 Biomarqueurs pour la cancérothérapie
BR112021002622-3A BR112021002622A2 (pt) 2018-08-13 2019-08-12 biomarcadores para terapia de câncer
KR1020217007013A KR20210044251A (ko) 2018-08-13 2019-08-12 암 치료용 바이오마커
MX2021001749A MX2021001749A (es) 2018-08-13 2019-08-12 Biomarcadores para terapia contra el cancer.
CN201980064957.3A CN113226318A (zh) 2018-08-13 2019-08-12 用于癌症疗法的生物标记物
CA3109605A CA3109605A1 (fr) 2018-08-13 2019-08-12 Biomarqueurs pour la cancerotherapie
JP2021507694A JP2021533774A (ja) 2018-08-13 2019-08-12 癌治療のためのバイオマーカー
US17/268,042 US20210180141A1 (en) 2018-08-13 2019-08-12 Biomarkers for cancer therapy
SG11202101397TA SG11202101397TA (en) 2018-08-13 2019-08-12 Biomarkers for cancer therapy
EP19849633.3A EP3836909A4 (fr) 2018-08-13 2019-08-12 Biomarqueurs pour la cancérothérapie
JP2023203145A JP2024023480A (ja) 2018-08-13 2023-11-30 癌治療のためのバイオマーカー

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