AU2001284297A1 - Prognostic indicator - Google Patents
Prognostic indicatorInfo
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- AU2001284297A1 AU2001284297A1 AU2001284297A AU2001284297A AU2001284297A1 AU 2001284297 A1 AU2001284297 A1 AU 2001284297A1 AU 2001284297 A AU2001284297 A AU 2001284297A AU 2001284297 A AU2001284297 A AU 2001284297A AU 2001284297 A1 AU2001284297 A1 AU 2001284297A1
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Description
DESCRIPTION
PROGNOSTIC INDICATOR
The present invention relates to a prognostic indicator for metastasis, a
vaccine against metastatic cancer, a method for treating metastases and a kit for
diagnosing life threatening metastases.
Most cancers are thought to be due to alterations in specific genes caused
either by mutation making their gene-product in someway more effective or by over
expression of a normal gene giving an enhanced effect. These oncogenes have
largely been identified by introducing gene-length fragments of DNA from human
cancers into a mouse fibroblast cell line, in culture, and selecting those cell lines that
grow in an uncontrolled manner in liquid or semi-solid medium. The oncogenes
themselves have been isolated by cloning the human DNA fragments away from the
mouse DNA by standard recombinatorial techniques. Alternatively mutations can
arise in genes that suppress the activity of oncogenes such as, for example, P53 or
Rb, or which suppress the levels of their product such as, for example NM-23. These
are referred to as tumor suppressor genes. In the commonly occurring cancers it is
believed that between 5 and 7 such changes in oncogenes or tumor suppressor genes
are required to produce a full-blown cancer.
The major forms of cancer, including breast cancer, lung cancer and colonic
cancer, cannot be cured effectively because, although the current therapies may be
effective against the primary tumors, they are largely ineffective against the
disseminating or metastasizing cells, which ultimately kill the patient. Despite the
enormous effort in cancer research very little is known at the molecular level about
the most important like-threatening process, that of metastasis. Most of the
oncogenes and suppressor genes that have been discovered have been found from
their ability to promote uncontrolled growth of the mouse fibroblast cell line. The
major problem in this field is that determining cell growth does not a give a measure
of the process of metastasis. In fact, although uncontrolled growth is an important
aspect of the initial events in the development of a cancer, the rate of growth of
distant metastases can be remarkably slow. Hence the process of metastasis is largely
independent of processes involving cell growth, except in its final phases. Therefore,
it is unlikely that oncogenes and tumor suppressor genes will have much involvement
in the process of metastasis and be useful diagnostic or therapeutic targets for control
and elimination of metastatic disease.
A protein which has been implicated in the formation of metastasis in cancers
is osteopontin (Oates, A.J. et al 1997 Invasion and Metastasis 17, 1-15). Osteopontin
(OPN) is a secreted, integrin binding, calcium binding, negatively charged,
glycosylated phosphoprotein of approximately 44 to 60 KDa molecular mass that has
been implicated in both normal and pathological processes. OPN is found in all body
fluids and in the extra cellular matrix of mineralized tissues, and is one of the more
abundant members of the non-collagenous proteins in bone. Typically, it is found in
bone, kidney, blood vessels, the inner ear, epithelial cells of the gall bladder,
gastrointestinal tract, bronchi, mammary gland, urinary and reproductive tracts and
salivary and sweat ducts, tissues subject to continuous renewal in addition to
activated T lymphocytes. OPN has been shown to be expressed at high levels in
malignant cells and in the blood of patients with metastatic disease, and consequently
a role for OPN in malignancy has been postulated (Singer D.R. et al. Secreted
phosphoproteins associated with neoplastic transformation, Cancer Res 48: 5770 to
5774, 1988). There are also a number of studies to show that blood OPN levels in
breast cancer are markedly elevated by metastasis, with higher OPN levels
corresponding to decreased survival rate (Singhal, H Clinic Cancer Res 3: 605-611,
1997; Bellahcene, A and Castranovo V Am. J. Pathol 146:95-100, 1995).
The sequence of human OPN precursor has been elucidated, the translation
of which is as follows (SEQ ID No. 1):
MRIANI CFCLLGITCA IPNKQADSGS SEEKQLYΝKY PDANATWLΝP DPSQKQΝLLA PQΝANSSEET ΝDFKQETLPS KSΝESHDHMD DMDDEDDDDH NDSQDSIDSΝ DSDDNDDTDD SHQSDESHHS DESDELNTDF PTDLPATENF
TPNVPTNDTY DGRGDSNNYG LRSKSKKFRR PDIQYPDATD
EDITSHMESE ELΝGAYKAI PVAQDLΝAPSD WDSRGKDSYE
TSQLDDQSAE THSHKQSRLY KRKAΝDESΝE HSDNIDSQEL
SKNSREFHSH EFHSHEDMLN VDPKSKEEDK HLKFRISHEL DSASSENΝ
(Crosby, A.H. et al. Genomic organization of the human osteopontin gene; exclusion
of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta
type II. Genomics 27(1), 155-160, 1995).
Osteopontin has also been shown previously as a prognostic indicator both
for gastric (Ue, T et al Int J Cancer 79; 127-132, 1998) and breast cancer (Tuck, AB
et al Int J Cancer 79; 502-508, 1998) but the differences in prognosis were far from
absolute.
Despite such a large body of work relating to the presence of OPN in
cancerous cells, it has not been possible to elucidate a role for OPN in cancer
generally or metastasis in particular. It is an object of the invention to determine a
practical benefit for patients in connection with the known presence of OPN in
cancerous cells.
In accordance with the first aspect of the present invention there is provided
a prognostic indicator for metastases comprising an antibody directed against
osteopontin.
The applicant has found surprisingly that the spread of life-threatening
metastasis is absent in individuals with breast cancer in which osteopontin is not
expressed.
OPN expression may thus be causative in the process of metastasis. Thus, a
means for alleviating or curing life threatening cancer by preventing expression of
OPN may be possible by means of the invention.
The antibody useful in the present invention may be employed histologically
for in situ detection of osteopontin gene products or conserved variants or peptide
fragments thereof. In situ detection may be accomplished by removing a histological
specimen from a patient, then applying thereto an antibody of the present invention
directed against osteopontin which may subsequently be visualized using a second
labeled antibody. Through a use of such a procedure, it is possible to determine not
only the presence of the osteopontin gene product, or conserved variants or peptide
fragments, but also its distribution in the examined tissue. Using the present
invention, those of ordinary skill will readily perceive that any other wide variety of
histological methods, such as staining procedures, can be modified in order to
achieve such in situ detection. Preferably only epithelial cells of the carcinoma are
examined; staining due to macrophages, host stroma, etc. is ignored.
For example, antibodies, or fragments of antibodies, such as those
described hereabove may be used to detect the presence of osteopontin or conserved
variants or peptide fragments thereof or labelled cDNA antisense probes may be used
to detect the mRNA. This can be accomplished, for example, by immunofluorescent
techniques employing a fluorescently labeled antibody coupled with light
microscopic, flow cytometric, or fluorometric detection.
Assays for osteopontin gene products or conserved variants or peptide
fragments thereof will typically comprise incubating a sample, such as a tissue
extract, freshly harvested cells or ly sates of cells which have been incubated in cell
culture, in the presence of a detectably labeled antibody capable of identifying
osteopontin gene products or conserved variants or peptide fragments thereof, and
detecting the bound antibody by any of a number of techniques well known in the art.
The biological sample may be brought into contact with and immobilized
onto a solid support or carrier such as nitro cellulose, or other solid support which is
capable of immobilizing cells, cell particles or soluble protein. The support may
then be washed followed by treatment with detectably labeled osteopontin specific
antibody or fragments of antibodies. The solid support may then be washed with a
buffer a second time to remove unbound antibody. The amount of bound label on
solid support may then be detected by conventional means.
In accordance with a second aspect of the present invention there is provided
a vaccine comprising an antigenic peptide that will generate an antibody directed
against osteopontin.
The peptide may be derived from at least 10 consecutive amino acids of
osteopontin. Preferably the peptide is derived from 14 to 20 consecutive amino acids
of osteopontin. More preferably the peptide is derived from the amino acids from the
amino teπninus of osteopontin, since the amino terminus is extracellularly exposed.
More preferably still the peptide is derived from amino acids from the region 28 to
48 (SEQ ID No. 2) of the human OPN precursor sequence described hereinabove:
EEKQLYNKY PDAVATWLNP DP.
Even more preferably still, the peptide is derived from amino acids from the
region 32 to 45 (SEQ. ID No. 3) of the human OPN precursor sequence described
hereinabove: QLYNKYPDANATWL.
The peptide may comprise an amino acid sequence which is at least 70%
homologous to SEQ ID No. 2, preferably the peptide comprises at least 80%
homology with SEQ ID No. 2 and more preferably the peptide comprises at least
90% homology with SEQ ID No. 2. Still more preferably the peptide comprises at
least 70% sequence homology with SEQ ID No. 3, even more preferably still, the
peptide comprises at least 80% sequence at least homology with SEQ ID No. 3 and
most preferably the peptide comprises at least 90% sequency homology with SEQ
ID No. 3.
Preferably the vaccine further comprises adjuvant: presently, alum
(aluminium hydroxide and/or aluminium phosphate) is the only adjuvant approved
for general use in human vaccines. Other adjuvants, notably Freund's complete, have
been used in animals and are more effective, but toxic side effects have so far
precluded their use in humans. Aluminium salt adjuvants are typically used with
protein adjuvants in two manners, (a) as alum-precipitated vaccines and (b) as alum-
adsorbed vaccines (Harlow, E & D. Lane, 1988, Antibodies: A Laboratory Manual
Cold Spring Harbor Laboratory; Nicklas, W., 1992, Aluminium salts. Research in
Immunology 143:489-493. Alum is typically commercially available as Al (OH)3
(Al hydrogel-superfos of Denmark/ Accurate Chemical and Scientic Co, Westbury,
New York).
In one embodiment of the second aspect of the present invention the antigenic
peptide may be coupled to a carrier protein.
In accordance with a third aspect of the present invention there is provided
a method for treating metastases comprising administering a compound that
modulates the expression of osteopontin.
In one embodiment, the expression of osteopontin may be blocked.
The compound may be an antibody directed against osteopontin, it may
provide an antisense molecule that blocks translation of the osteopontin mRNAs or
it may provide a nucleic acid molecule that is complementary to the 5' region of the
osteopontin gene and blocks transcription.
The compound may also be any small molecule which modulates the
expression. The compound may block the induction of expression of osteopontin
either by blocking transcription or translation of osteopontin, or by preventing its
induction by interacting with T cell factor (TCF) 4 or the small molecule may interact
with a CAAAG sequence on DNA to prevent its sequestering of TCF4 and hence
prevent induction of osteopontin (El Tanani et al. Oncogene 20, 1793-97 (2001); El
Tanani et al. Cancer Research 61, 5619-5629 (2001)). The compound may also
prevent interaction of osteopantin with intergrin alpha nu beta 1, integrin alpha nu
beta 3, alpha nu beta 5 or alpha 4 beta 1 (Liaw L et al. J Clin Invest 95, 713-724
(1991); Miyaichi et al J. Biol Chem 266, 20369-20374 (1991); Bayless et al. J Cell
Science 111, 1165-1174 (1998)). Preferably, the small molecule has a molecular
weight less than 2kDa.
In accordance with the fourth aspect of the present invention there is provided
a kit for diagnosing metastasis comprising a prognostic indicator as described
hereinabove and one or more of a visual indicator.
In accordance with a fifth aspect of the present invention, there is provided
the use of a prognostic indicator as claimed in any one of claims 1 to 8 for
determining whether a subject is at risk of developing metastasis comprising
contacting a subject sample with the prognostic indicator and detecting the formation
of a complex between the prognostic indicator and subject sample.
In accordance with a further aspect of the present invention, there is provided
a method for determining whether a subject is at risk of developing metastasis
comprising contacting a subject sample with a prognostic indicator as claimed in any
one of claims 1 to 8 and detecting the formation of a complex between the prognostic
indicator and subject sample.
A method for detecting the presence of osteopontin will now be described, by
way of example only, with reference to the following examples and Figures:
Fig. 1 Kaplan Meier survival curve for breast cancer patients in which
primary tumor expressed different amounts of OPN, the positive staining groups are
amalgamated.
Fig.2 Kaplan Meier survival curve for breast cancer patients identified in
Fig.l where groups are shown separately indicating a dose-response effect of
expression of osteopontin.
Fig. 3 Western blot illustrating the detection of peptide by antiserum raised
against Cys + amino acids 32 - 45 of Rabbit osteopontin precursor SEQ ID No. 4
CQLYHKHPDALATWL
Fig. 1 and Fig 2 illustrate Kaplan Meier survival curves where breast cancer
tissues excised by surgery were collected from a group of 339 primary cancer
patients, presenting with operable stage I and stage II forms of the disease, from
within the Merseyside region, diagnosed between 1976 and 1982 at the Royal
University Hospital (Winstanley et al, 1991 Br J Cancer 63: 447-450; 1993 Br J
Cancer 67: 762-772). The age range was 29-92 (mean 57) at presentation. Specimen
tissues had been fixed routinely in neutral buffered formalin and preserved in paraffin
blocks. Follow-up information was obtained and up-dated for patient survival to 31
August 1995. The anti-osteopontin (alphaMBIII Bio (1) was from the Development
Studies Hybridoma Bank, University of Iowa and is a monoclonal mouse antibody
of IgGl isotype and was used at a dilution of 1/30 in PBS containing 0.05% BSA.
The second antibody was biotinylated sheep anti-mouse antibody (Amersham,
Bucks) used at a dilution of 1/200 in PBS containing 0.5% BSA. The antibody was
visualized using ABC complex (Dako, Bucks) and diaminobenzidine. Staining was
assessed by two independent observers, recording the percentage of carcinoma cells
with cytoplasmic staining for osteopontin from two sections of each specimen, 10
fields per section at 200x magnification. (Unstained cells were counterstained with
Mayer's Haemalum). Staining levels of in situ carcinomas were ignored, as were
staining of macrophages, lymphocyes, host stroma, spindle cells and blood vessels.
Groups were defined as having <1% cells stained =ve, <5% = +/-, 5-25% = +, 25-
50%=++, 50- 75% = +++, 75 - 100% = ++++. The groups contained 51 , 66, 60, 95
and 67 carcinomas, respectively. Referring to Figs. 1 and 2, differences between the
groups are significant at the 5% level for all groups except - vs +/ and +++ vs ++++.
The applicant has further shown that MCF-7 cells (a human breast metastatic
cell line) are recognised by the anti-osteopontin antibody described hereinabove
when the cells -ire alive in culture, a clear indication that in vivo, the vaccine will
work.
Fig. 3 illustrates a Western blot where Bovine osteopontin (3μg) was
electrophoresed in a 12% SDS gel and electroblotted onto a nitrocellulose membrane.
The membrane was cut into three sections and each incubated overnight at 4°C with
a 1:1000 dilution of antiserum in Tris-buffered saline pH 7 containing 0.05% (v/v)
TWEEN 20 (TBS-T). After washing in several changes of TBS-T, the membranes
were incubated for 2h at room temperature with a 1 : 1000 dilution of swine anti-rabbit
immunoglobulins conjugated to horseradish peroxidase (Dako). Bound antibodies
were visualized using an ECL luminescent substrate kit (BioRad) and photographic
film. By superimposing the developed film over the membrane, the positions of pre-
stained proteins of known molecular weight present on the membrane could be
indicated on the film. Anti-Peptide 1 antisera was raised against a 15 amino acid
peptide of the rabbit osteopontin sequence. GO61 and GO62 refer to antiserum from
two individual animals both inoculated with the peptide. LF123 was whole rabbit
serum raised against recombinant human osteopontin.
Peptide CQLYHKHPDALATWL (Cys + amino acids 32 - 45 of osteopontin
precursor) was synthesized commercially (Genosphere Biotechnologies, 2 Rue de
Gravillieres, 75003, Paris, France) and coupled via cysteine to Keyhole Limpet
Hemocyanin (KLH) (Lerner et al. 1981, PNAS 78,3404-3407). Two rabbits were
injected with the construct together with adjuvant (4 injections at 3 week intervals),
Freund's complete for first injection and Freund's incomplete for the others, and 2
weeks after the last injection were bled.
The antiserum, at 1 : 10,000 dilution with phosphate buffered saline containing
1% bovine serum albumin and 0.01% sodium azide, detected peptide in ELISA and
at 1:1,000 dilution detected bovine OPN by Western blot . One rabbit also
recognised a smaller polypeptide at ~ 35kDa on the Western blot.
This demonstrates (i) that the peptide is antigenic and (ii) does not cause harm
in the short term to the host.
Claims (1)
- 1. A prognostic indicator for metastases comprising an antibody directedagainst osteopontin.2. A prognostic indicator as claimed in claim 1 comprising an antibodydirected against an osteopontin gene product.3. A prognostic indicator as claimed in claim 2 wherein the antibody isdirected against a peptide derived from osteopontin.4. A prognostic indicator as claimed in claim 3 wherein the peptide is derivedfrom the amino acid terminus of osteopontin.5. A prognostic indicator as claimed in claim 3 wherein the peptidecomprises an amino acid sequence of at least 10 consecutive amino acids of SEQ IDNo. 1.6. A prognostic indicator as claimed in claim 5 wherein the peptidecomprises an amino acid sequence of 14 to 20 consecutive amino acids of SEQ IDNo. 1.7. A prognostic indicator as claimed in any one of claims 5 or 6 wherein thepeptide comprises an amino acid sequence which is at least 10% homologous to SEQID No. 2.8. A prognostic indicator as claimed in claim 7, wherein the peptidecomprises an amino acid sequence which is at least 90% homologous to SEQ ID No.2.9. A vaccine against metastatic cancer comprising an antigenic peptide derived from osteopontin.10. A vaccine as claimed in claim9, wherein the vaccine is against metastaticbreast cancer.11. A vaccine as claimed in any one of claims 9 or 10 wherein the antigenicpeptide is derived from the amino terminus of osteopontin.12. A vaccine as claimed in any one of claims 10 or 11 wherein the antigenicpeptide comprises an amino acid sequence of at least 10 consecutive amino acids ofSEQ ID No. 1.13. A vaccine as claimed in claim 12 wherein the antigenic peptide comprisesan amino acid sequence of 14 to 20 consecutive amino acids of SEQ ID No. 1.14. A vaccine as claimed in any one of claims 12 or 13 wherein the antigenicpeptide comprises an amino acid sequence which is at least 80% homologous to SEQID No. 2.15. A vaccine as claimed in claim 14 wherein the antigenic peptide comprisesan amino acid sequence which is at least 90% homologous to SEQ ID No. 2.16. A vaccine as claimed in any one of claims 9 to 15 wherein the antigenicpeptide is coupled to a carrier protein.17. A vaccine as claimed in any one of claims 9 to 16 comprising anadjuvant.18. A vaccine as claimed in claim 17 wherein the adjuvant is alum orFreund's Complete.19. A method for treating metastases comprising adn-unistering a compound that modulates the expression of osteopontin.20. A method as claimed in claim 19 wherein the expression of osteopontinis blocked.21. A method as claimed in claim 19 wherein the compound is an antibodydirected against osteopontin.22. A method as claimed in claim 19 wherein the compound provides anantisense molecule that blocks translation of the osteopontin mRNAs.23. A method as claimed in claim 19 wherein the compound provides anucleic acid molecule that is complementary to the 5' region of the osteopontin geneand blocks transcription.24. A method as claimed in claim 19 wherein the compound is a smallmolecule.25. A method as claimed in claim 24 wherein the compound has a molecularweight which is 2KDa or less.26. A kit for diagnosing metastases comprising a prognostic indicator asclaimed in any one of claims 1 to 8 and one or more of a visual indicator.27. The use of a prognostic indicator as claimed in any one of claims 1 to 8for determining whether a subject is at risk of developing metastasis comprisingcontacting a subject sample with the prognostic indicator and detecting the formationof a complex between the prognostic indicator and subject sample.28. A method for determining whether a subject is at risk of developingmetastasis comprising contacting a subject sample with a prognostic indicator as claimed in any one of claims 1 to 8 and detecting the formation of a complex betweenthe prognostic indicator and subject sample.SEQUENCE LISTING<110> University of Liverpool<120> Prognostic indicator<130> P403645Wθ/jdm/dgr<140> <141><150> 0023080.5 <151> 2000-09-20<160> 4<170> Patentln Ver. 2.1<210> 1 <211> 314 <212> PRT <213> human<400> 1 Met Arg lie Ala Val lie Cys Phe Cys Leu Leu Gly lie Thr Cys Ala1 5 10 15lie Pro Val Lys Gin Ala Asp Ser Gly Ser Ser Glu Glu Lys Gin Leu20 25 30Tyr Asn Lys Tyr Pro Asp Ala Val Ala Thr Trp Leu Asn Pro Asp Pro35 40 45Ser Gin Lys Gin Asn Leu Leu Ala Pro Gin Asn Ala Val Ser Ser Glu50 55 60Glu Thr Asn Asp Phe Lys Gin Glu Thr Leu Pro Ser Lys Ser Asn Glu65 70 7580 Ser His Asp His Met Asp Asp Met Asp Asp Glu Asp Asp Asp Asp His85 90 95Val Asp Ser Gin Asp Ser lie Asp Ser Asn Asp Ser Asp Asp Val Asp100 105 110Asp Thr Asp Asp Ser His Gin Ser Asp Glu Ser His His Ser Asp Glu115 120 125Ser Asp Glu Leu Val Thr Asp Phe Pro Thr Asp Leu Pro Ala Thr Glu130 135 140Val Phe Thr Pro Val Val Pro Thr Val Asp Thr Tyr Asp Gly ArgGly145 150 155160 Asp Ser Val Val Tyr Gly Leu Arg Ser Lys Ser Lys Lys Phe Arg Arg165 170 175Pro Asp lie Gin Tyr Pro Asp Ala Thr Asp Glu Asp lie Thr Ser His180 185 190Met Glu Ser Glu Glu Leu Asn Gly Ala Tyr Lys Ala lie Pro Val Ala195 200 205Gin Asp Leu Asn Ala Pro Ser Asp Trp Asp Ser Arg Gly Lys Asp Ser210 215 220Tyr Glu Thr Ser Gin Leu Asp Asp Gin Ser Ala Glu Thr His Ser His225 230 235240 Lys Gin Ser Arg Leu Tyr Lys Arg Lys Ala Asn Asp Glu Ser Asn Glu245 250 255His Ser Asp Val lie Asp Ser Gin Glu Leu Ser Lys Val Ser Arg Glu260 265 270Phe His Ser His Glu Phe His Ser His Glu Asp Met Leu Val Val Asp275 280 285Pro Lys Ser Lys Glu Glu Asp Lys His Leu Lys Phe Arg lie Ser His290 295 300Glu Leu Asp Ser Ala Ser Ser Glu Val Asn305 310 <210 > 2<211> 21 <212> PRT <213> Human<400> 2Glu Glu Lys Gin Leu Tyr Asn Lys Tyr Pro Asp Ala Val Ala ThrTrp1 5 10 15Leu Asn Pro Asp Pro20<210> 3 <211> 14 <212> PRT <213> Human<400> 3Gin Leu Tyr Asn Lys Tyr Pro Asp Ala Val Ala Thr Trp Leu10 <210> 4 <211> 15 <212> PRT <213> Rabbit<400> 4Cys Gin Leu Tyr His Lys His Pro Asp Ala Leu Ala Thr Trp Leu1 5 10 15
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0023080.5 | 2000-09-20 | ||
GBGB0023080.5A GB0023080D0 (en) | 2000-09-20 | 2000-09-20 | Prognostic indicator |
PCT/GB2001/004017 WO2002025285A1 (en) | 2000-09-20 | 2001-09-10 | Prognostic indicator |
Publications (2)
Publication Number | Publication Date |
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AU2001284297A1 true AU2001284297A1 (en) | 2002-06-20 |
AU2001284297B2 AU2001284297B2 (en) | 2006-12-21 |
Family
ID=9899821
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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AU8429701A Pending AU8429701A (en) | 2000-09-20 | 2001-09-10 | Prognostic indicator |
AU2001284297A Ceased AU2001284297B2 (en) | 2000-09-20 | 2001-09-10 | Prognostic indicator |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU8429701A Pending AU8429701A (en) | 2000-09-20 | 2001-09-10 | Prognostic indicator |
Country Status (8)
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US (4) | US20040072189A1 (en) |
EP (1) | EP1319186A1 (en) |
JP (1) | JP2004509357A (en) |
CN (1) | CN1275041C (en) |
AU (2) | AU8429701A (en) |
CA (1) | CA2422568A1 (en) |
GB (1) | GB0023080D0 (en) |
WO (1) | WO2002025285A1 (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004013311A2 (en) | 2002-08-06 | 2004-02-12 | Diadexus, Inc. | Compositions and methods relating to ovarian specific genes and proteins |
GB0222787D0 (en) * | 2002-10-02 | 2002-11-06 | Univ Liverpool | Metastasis inducing compounds |
EP1514929A1 (en) * | 2003-09-12 | 2005-03-16 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Antisense oligonucleotides for prevention of metastasis formation of cancer cells |
EP2336779B1 (en) | 2004-02-19 | 2013-07-31 | Yale University | Kit for the identification of ovarian cancer protein biomarkers using proteomic techniques |
EP1888631B1 (en) | 2005-05-31 | 2009-09-23 | Ralf Jochem | Therapeutic composition for use in the prevention and treatment of bone metastases |
WO2007110230A2 (en) * | 2006-03-27 | 2007-10-04 | Institut Pasteur | Secreted proteins as early markers and drug targets for autoimmunity, tumorigenesis and infections |
CN102016592A (en) * | 2008-04-29 | 2011-04-13 | 诺瓦提斯公司 | Methods of monitoring the modulation of the kinase activity of fibroblast growth factor receptor and uses of said methods |
EP2331711B1 (en) * | 2008-09-05 | 2017-02-22 | A & G Pharmaceutical, Inc. | Methods for diagnosing cancer and determining the overall survival and disease-free survival of cancer patients |
TW201623329A (en) * | 2014-06-30 | 2016-07-01 | 亞佛瑞司股份有限公司 | Vaccines and monoclonal antibodies targeting truncated variants of osteopontin and uses thereof |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5401638A (en) * | 1986-06-04 | 1995-03-28 | Oncogene Science, Inc. | Detection and quantification of neu related proteins in the biological fluids of humans |
US5229267A (en) * | 1991-08-26 | 1993-07-20 | Merck & Co., Inc. | Assay for evaluating inhibition of PMN elastase by N-substituted azetidinones |
CA2263942A1 (en) * | 1996-08-22 | 1998-02-26 | Children's Medical Center Corporation | Novel osteopontin derived chemotactic peptides and methods of use |
EP1064554A1 (en) * | 1998-03-27 | 2001-01-03 | Markus Seibel | Determination of the probability of bone metastases in patients with primary carcinomas |
US6517513B1 (en) * | 1999-01-21 | 2003-02-11 | Neomatrix, Llc | Intraductal breast fluid aspiration device |
MXPA01010403A (en) * | 1999-04-15 | 2004-09-10 | Childrens Medical Center | Osteopontin-derived chemotactic and inhibitory agents and uses therefor. |
US6743228B2 (en) * | 2001-09-12 | 2004-06-01 | Manoa Medical, Inc. | Devices and methods for tissue severing and removal |
-
2000
- 2000-09-20 GB GBGB0023080.5A patent/GB0023080D0/en not_active Ceased
-
2001
- 2001-09-10 JP JP2002528832A patent/JP2004509357A/en active Pending
- 2001-09-10 EP EP01963269A patent/EP1319186A1/en not_active Withdrawn
- 2001-09-10 WO PCT/GB2001/004017 patent/WO2002025285A1/en active Application Filing
- 2001-09-10 CA CA002422568A patent/CA2422568A1/en not_active Abandoned
- 2001-09-10 CN CNB01817048XA patent/CN1275041C/en not_active Expired - Fee Related
- 2001-09-10 AU AU8429701A patent/AU8429701A/en active Pending
- 2001-09-10 US US10/381,091 patent/US20040072189A1/en not_active Abandoned
- 2001-09-10 AU AU2001284297A patent/AU2001284297B2/en not_active Ceased
-
2006
- 2006-05-26 US US11/441,615 patent/US20060263371A1/en not_active Abandoned
- 2006-05-26 US US11/441,616 patent/US20060263383A1/en not_active Abandoned
- 2006-05-26 US US11/441,614 patent/US20060263370A1/en not_active Abandoned
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