Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-27
2001-09-18
Eyler, Yvonne (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C435S007230, C424S130100, C424S138100, C424S143100, C424S155100, C424S156100, C548S220000
Reexamination Certificate
active
06291496
ABSTRACT:
TECHNICAL FIELD
This invention is directed to treatment of class I family of receptor tyrosine kinases overexpressing cancers.
BACKGROUND OF THE INVENTION
The class I family of receptor tyrosine kinases is described in Reese, M. D., et al, Stem Cells, 15, pages 1-8 (1997), the whole of which is incorporated herein by reference. Members of this family include HER-2
eu, HER-3, HER-4 and epidermal growth factor receptor (EGFR) and are single-chain membrane spanning proteins which have significant homology to one another including about 80% amino acid identity in the tyrosine kinase domain.
HER-2
eu (erbB-2) gene product is a 185-kDA transmembrane receptor tyrosine kinase that is described in some detail in said Reese et al publication and overexpression thereof has been associated with tumor growth in several kinds of cancer.
Recently enormous attention has been given to the importance of HER-2
eu in breast cancer. HER-2
eu is overexpressed in 20-30% of breast cancers and the increased expression has been associated with poor patient prognosis. This discovery has led to the development of HERCEPTIN®, an antibody to HER-2
eu, which in tests has been found to lengthen remission time in metastatic breast cancer. HER-2
eu is a cell-surface receptor that transmits growth signals to the cell nucleus. HERCEPTIN® appears to block these signals thereby apparently inhibiting proliferation of cells mediated by HER-2
eu in HER-2
eu positive breast cancer.
Epidermal growth factor receptor (EGFR) is a 170 kDA glycoprotein. It is a prototypical transmembrane protein that consists of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain that possesses intrinsic tyrosine kinase activity. After ligand binding, EGFR undergoes dimerization which is essential for activation of its enzymatic kinase activity. EGFR is thus autophosphorylated and transphosphorylated on tyrosine residues, and the phosphorylated residues become the sites of association of effector proteins. Overexpressed EGFR is intimately involved in modulating the epidermal growth factor growth signal and is considered as likely to confer a growth advantage. This conclusion is supported by the observation that tumor growth in nude mice is inhibited by treatment with anti-EGFR antibodies and tumorigenicity in nude mice is inhibited through blockage of the tyrosine kinase activity of the receptor. EGFR has been found to be overexpressed in many malignancies. Anti-EGFR antibodies are being tested as therapy for malignancies overexpressing EGFR.
Peroxisome proliferator-activated receptor &ggr; (PPAR&ggr;) ligands are currently being used for treatment of type 2 diabetes. Moreover, MCF-7 and T47D human breast cancer cells have been found to contain a functional PPAR response; see Kilgour, M. W., et al, Mol. Cell Endocrinol, 129:2, 229-235 (May 5, 1997). Furthermore, a ligand for PPAR-&ggr; has been found to inhibit rat mammary carcinogenesis in NMU injected female Sprague Dawley rats; see Suh, N., et al, Cancer Research 59, 5671-5673 (Nov. 15, 1999). However, administration of PPAR&ggr; ligands has not heretofore been associated with decreasing levels of HER-2
eu or EGFR or of having therapeutic benefit based thereon in treating cancers associated with overexpression of these including the subset of breast cancer associated with overexpression of HER-2
eu.
SUMMARY OF THE INVENTION
It has been discovered that PPAR&ggr; ligands cause dose dependent decreases in levels of HER-2
eu and EGFR in cultured human mammary epithelial cells. This led to the conception that cancers associated with overexpression of one or more class I family of receptor tyrosine kinases would be effectively treated with such PPAR&ggr; ligands.
The broad invention herein is directed at a method for treating cancer associated with overexpression of at least one member of the class I family of receptor tyrosine kinases in a patient affected with this condition, comprising administering to said patient a therapeutically effective amount of a ligand of peroxisome proliferator-activated receptor gamma (PPAR&ggr;) which has a pK
i
of at least 4.0, preferably of at least 5.0, in a binding assay using the human PPAR&ggr; binding domain.
In the case where the member of the class I family of receptor tyrosine kinases is HER-2
eu, the PPAR&ggr; ligand can be administered as the only therapy or in a combination regimen with a therapeutically effective amount of HERCEPTIN®, a HER-2
eu antibody available from Genentech, and/or conventional therapy for the kind of cancer being treated.
In the case where the member of the class I family of receptor tyrosine kinases is EGFR, the PPAR&ggr; ligand can be administered as the only therapy or in a combination therapy with a therapeutically effective amount of anti-epidermal growth factor receptor antibody, e.g., Cetuximab®, a chimeric antibody to epidermal growth factor receptor, supplied by ImClone Systems Incorporated, and/or conventional therapy for the kind of cancer being treated.
In a narrower embodiment, the invention is directed at a method of treating breast cancer associated with overexpression of HER-2
eu and/or EGFR in a patient affected with this condition, comprising administering to said patient a therapeutically effective amount of a PPAR&ggr; ligand which has a pK
i
of at least 4.0, preferably of at least 5.0, in a binding assay using the human PPAR&ggr; binding domain. The PPAR&ggr; ligand can be administered for or as part of adjuvant therapy for HER-2
eu positive and or EGFR positive breast cancer or for treatment of or as part treatment of HER-2
eu positive and/or EGFR positive breast cancer that has metastasized. The PPAR&ggr; ligand is preferably administered in combination therapy with HERCEPTIN® for HER-2
eu positive breast cancer and with Cetuximab® for EGFR-positive breast cancer and preferably also is administered in combination regimen with standard chemotherapy and/or endocrine therapy and/or radiation treatment.
The terms “cancer associated with overexpression of at least one member of the class I family of receptor tyrosine kinases”/“cancer associated with overexpression of HER-2
eu”/ “cancer associated with overexpression of EGFR” are used to mean the cancerous tissue contains more of the member of the class I family of receptor tyrosine kinases than non-cancerous tissue from the same portion of the body.
The term “HER-2
eu positive breast cancer” is used to refer to cancer associated with overexpression of HER-2
eu.
The term “EGFR positive breast cancer” is used to refer to cancer associated with overexpression of EGFR.
The terms “peroxisome proliferator-activated receptor gamma ligand,” “ligand of peroxisome proliferator-activated receptor gamma,” and “PPAR&ggr; ligand” are used to mean agent that binds to the human PPAR&ggr; binding domain as determined in a scintillation proximity assay with K
i
being determined in said assay as described below. The human PPAR&ggr; gene structure has been found to include two isoforms of PPAR&ggr;, denoted PPAR&ggr;1 and PPAR&ggr;2, with a common ligand binding domain.
REFERENCES:
patent: 4980160 (1990-12-01), Goldberg et al.
patent: 5081105 (1992-01-01), Bistrian
patent: 5639738 (1997-06-01), Falk et al.
patent: 5766571 (1998-06-01), Ceriani et al.
patent: 5766920 (1998-06-01), Babbitt et al.
patent: 5776891 (1998-07-01), Coon et al.
patent: 5776913 (1998-07-01), Ogilvie et al.
patent: 5814647 (1998-09-01), Urban et al.
patent: 5861274 (1999-01-01), Evans et al.
patent: 5869524 (1999-02-01), Failli
patent: 5874235 (1999-02-01), Chan et al.
patent: 5902726 (1999-05-01), Kliewer et al.
patent: 5914322 (1999-06-01), Falk et al.
patent: 5925657 (1999-07-01), Seed et al.
patent: 5939442 (1999-08-01), Evans et al.
Physician's Desk Reference, 2001, Medical Economics Co., pp. 1055, 1056, 1062.*
Beers, M.H. et al., The Merck manual of diagnosis and therapy. 1999, 17th ed. Merck Research Laboratories, pp. 1980-1982.*
Gusterson, B.A. et al., J. Clinical Oncology, 1992, vol. 10, No. 7, pp. 1049-1056.*
Yu et al., BioEs
Dannenberg Andrew J.
Subbaramaiah Kotha
Andres J.
Eyler Yvonne
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