Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-05-30
2003-10-21
Caputa, Anthony C. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007100, C435S007230, C436S501000
Reexamination Certificate
active
06635421
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides methods for the diagnosis and prognosis of cancer, particularly metastatic cancer.
BACKGROUND OF THE INVENTION
Cancer, its development and treatment is a major health concern. The standard treatments available are few and directed to specific types of cancer, and provide no absolute guarantee of success. Most treatments rely on an approach that involves killing off rapidly growing cells in the hope that rapidly growing cancerous cells will succumb, either to the treatment, or at least be sufficiently reduced in numbers to allow the body's system to eliminate the remainder. However most, of these treatments are non-specific to cancer cells and adversely effect non-malignant cells. Many cancers although having some phenotype relationship are quite diverse. Yet, what treatment works most effectively for one cancer may not be the best means for treating another cancer. Consequently, an appreciation of the severity of the condition must be made before beginning many therapies. In order to most effective, these treatments require not only an early detection of the malignancy, but an appreciation of the severity of the malignancy. Currently, it can be difficult to distinguish cells at a molecular level as it relates to effect on treatment. Thus, methods of being able to screen malignant cells and better understand their disease state are desirable.
While different forms of cancer have different properties, one factor which many cancers share is that they can metastasize. Until such time as metastasis occurs, a tumor, although it may be malignant, is confined to one area of the body. This may cause discomfort and/or pain, or even lead to more serious problems including death, but if it can be located, it may be surgically removed and, if done with adequate care, be treatable. However, once metastasis sets in, cancerous cells have invaded the body and while surgical resection may remove the parent tumor, this does not address other tumors. Only chemotherapy, or some particular form of targeting therapy, then stands any chance of success.
The process of tumor metastasis is a multistage event involving local invasion and destruction of intercellular matrix, intravasation into blood vessels, lymphatics or other channels of transport, survival in the circulation, extravasation out of the vessels in the secondary site and growth in the new location (Fidler, et al.,
Adv. Cancer Res.
28, 149-250 (1978), Liotta, et al.,
Cancer Treatment Res.
40, 223-238 (1988), Nicolson,
Biochim. Biophy. Acta
948, 175-224 (1988) and Zetter, V.
Eng. J. Med.
322, 605-612 (1990)). Success in establishing metastatic deposits requires tumor cells to be able to accomplish these steps sequentially. Common to many steps of the metastatic process is a requirement for motility. The enhanced movement of malignant tumor cells is a major contributor to the progression of the disease toward metastasis. Increased cell motility has been associated with enhanced metastatic potential in animal as well as human tumors (Hosaka, et al.,
Gann
69, 273-276 (1978) and Haemmerlin, et al.,
Int. J. Cancer
27, 603-610 (1981)).
Identifying factors that are associated with onset of tumor metastasis is extremely important. In addition, to using such factors for diagnosis and prognosis, those factors are an important site for identifying new compounds that can be used for treatment and as a target for treatment identifying new modes of treatment such as inhibition of metastasis is highly desirable.
Tumor angiogenesis is essential for both primary tumor expansion and metastatic tumor spread, and angiogenesis itself requires ECM degradation (Blood et al.,
Biochim. Biophys. Acta
1032:89-118 (1990)). Thus, malignancy is a systemic disease in which interactions between the neoplastic cells and their environment play a crucial role during evolution of the pathological process (Fidler, I.
J. Cancer Metastasis Rev.
5:29-49 (1986)).
There is mounting evidence that VEGF may be a major regulator of angiogenesis (reviewed in Ferrara, et al., Endocr. Rev., 13, 18-32 (1992); Klagsbrun, et al.,
Curr. Biol.,
3, 699-702 (1993); Ferrara, et al.,
Biochemi. Biophjs. Res. Commun.,
161, 851-858 (1989) ). VEGF was initially purified from the conditioned media of folliculostellate cells (Ferrara, et al.,
Biochem. Biophjs. Res. Common.,
161, 851-858 (1989)) and from a variety of tumor cell lines (Myoken, et al.,
Proc. Natl. Acad. Sci. USA,
88:5819-5823 (1991); Plouet. et al.,
EMBO. J.,
8:3801-3806 (1991)). VEGF was found to be identical to vascular permeability factor, a regulator of blood vessel permeability that was purified from the conditioned medium of U937 cells at the same time (Keck, et al.,
Science,
246:1309-1312 (1989)). VEGF is a specific mitogen for endothelial cells (EC) in vitro and a potent angiogenic factor in vivo. The expression of VEGF is up-regulated in tissue undergoing vascularization during embryogenesis and the female reproductive cycle (Brier, et al.,
Development,
114:521-532 (1992); Shweiki, et al.,
J. Clin. Invest.,
91:2235-2243 (1993)). High levels of VEGF are expressed in various types of tumors, but not in normal tissue, in response to tumor-induced hypoxia (Shweiki, et al.,
Nature
359:843-846 (1992); Dvorak et al.,
J. Exp. Med.,
174:1275-1278 (1991); Plate, et al.,
Cancer Res.,
53:5822-5827; Ikea, et al.,
J. Biol. Chem.,
270:19761-19766 (1986)). Treatment of tumors with monoclonal antibodies directed against VEGF resulted in a dramatic reduction in tumor mass due to the suppression of tumor angiogeneis (Kim, et al.,
Nature,
382:841-844 (1993)). VEGF appears to play a principle role in many pathological states and processes related to neovascularization. Regulation of VEGF expression in affected tissues could therefore be key in treatment or prevention of VEGF induced neovascularization/angiogenesis.
VEGF exists in a number of different isoforms that are produced by alternative splicing from a single gene containing eight exons (Ferrara, et al.,
Endocr. Rev.,
13:18-32 (1992); Tischer, et al.,
J. Biol. Chem.,
806:11947-11954 (1991); Ferrara, et al.,
Trends Cardio Med.,
3:244-250 (1993); Polterak, et al.,
J. Biol. Chem.,
272:7151-7158 (1997)). Human VEGF isoforms consists of monomers of 121, 145, 165, 189, and 206 amino acids, each capable of making an active homodimer (Polterak et al.,
J. Biol. Chem,
272:7151-7158 (1997); Houck, et al.,
Mol. Endocrinol.,
8:1806-1814 (1991)). The VEGF
121
and VEGF
165
isoforms are the most abundant. VEGF
121
is the only VEGF isoforms that does not bind to heparin and is totally secreted into the culture medium. VEGF
165
is functionally different than VEGF
121
in that it binds to heparin and cell surface heparin sulfate proteoglycans (HSPGs) and is only partially released into the culture medium (Houck. et al.,
J. Biol. Chem.,
247:28031-28037 (1992): Park, et al.,
Mol. Biol. Chem.,
4:1317-1326 (1993)). The remaining isoforms are entirely associated with cell surface and extracellular matrix HSPGs (Houck, et al.,
J. Biol. Chem.,
247:28031-28037 (1992); Park, et al.,
Mol. Biol. Chem.,
4:1317-1326 (1993)).
VEGF receptor tyrosine kinases, KDR/Flk-1 and/or Flt-1, are mostly expressed by EC (Terman, et al.,
Biochem. Biophys. Res. Commun.,
187:1579-1586 (1992); Shibuya, et al.,
Oncogene,
5:519-524 (1990); De Vries, et al.,
Science,
265:989-991 (1992); Gitay-Goran, et al.,
J. Biol. Chem.,
287:6003-6096 (1992); Jakeman, et al.,
J. Clin. Invest.,
89:244-253 (1992)). It appears that VEGF activities such as mitogenicity, chemotaxis, and induction of morphological changes are mediated by KDR/Flk-1 but not Flt-1, even though both receptors undergo phosphorylation upon binding of VEGF (Millauer, et al.,
Cell,
72:835-846 (1993); Waltenberger, et al.,
J. Biol. Chem.,
269:26988-26995 (1994); Seetharam, et al.,
Oncogene,
10:135-147 (1995); Yoshida, et al.,
Growth Factors,
7:131-138 (1996)). Recently, Soker et al., identified a new VEGF receptor which is expressed on EC and various tu
Klagsbrun Michael
Miao Hua-Quan
Soker Shay
Takashima Seiji
Caputa Anthony C.
Children's Medical Center Corporation
Nixon & Peabody LLP
Rawlings Stephen
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