Osi Pharmaceuticals, Inc.

Oncogene Science, Inc.

Other

Anaderm Research Corporation

Genentech, Inc.

John D Haley

J Gordon Foulkes

Kenneth K Iwata

Elizabeth Buck

Graeme Griffin

Peter Ten Dijke

David A Eberhard

Stuart Thomson

Lukas A Amler

Lee Daniel Arnold

Mark Joseph Mulvihill

Julie Kan

Salam A Shaaban

Qun-Sheng Ji

Stuart Thompson

Filippo Petti

Daniel Du

Peter T Dijke

The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an EGFR kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an EGFR kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by EGFR kinase inhibitors. Improved methods for treating cancer patients with EGFR kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to EGFR kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by EGFR kinase inhibitors are also provided.

Biological markers predictive of anti-cancer response to epidermal growth factor receptor kinase inhibitors

Methods and compositions for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially (a) a therapeutically effective amount of an anti-cancer agent and (b) an IGF1R inhibitor compound of Formula I, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy. Suitable IGF1R inhibitor may be represented by Formula I: wherein X, X, X, X, X, X, X, R, and Qare defined herein.

Combination cancer therapy

The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an IGF-1R kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an IGF-1R kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by IGF-1R kinase inhibitors. Improved methods for treating cancer patients with IGF-1R kinase inhibitors that incorporate the above methodology are also provided.

Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors

The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with inhibitors of EGFR kinase, PDGFR kinase, or FGFR kinase. Based on the surprising discovery that tumors cells after having undergone an EMT, while being mesenchymal-like, still express characteristics of both epithelial and mesenchymal cells, and that such cells have altered sensitivity to inhibition by receptor protein-tyrosine kinase inhibitors, in that they have become relatively insensitive to EGFR kinase inhibitors, but have frequently acquired sensitivity to inhibitors of other receptor protein-tyrosine kinases such as PDGFR or FGFR, methods have been devised for determining levels of specific epithelial and mesenchymal biomarkers that identify such 'hybrid' tumor cells (e.g. determination of co-expression of vimentin and epithelial keratins), and thus predict the tumor's likely sensitivity to inhibitors of EGFR kinase, PDGFR kinase, or FGFR kinase. Improved methods for treating cancer patients with EGFR, PDGFR or FGFR kinase inhibitors that incorporate such methodology are also provided.

Biological markers predictive of anti-cancer response to kinase inhibitors

The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an IGF-1R kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an IGF-1R kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by IGF-1R kinase inhibitors. Improved methods for treating cancer patients with IGF-1R kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to IGF-1R kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by IGF-1R kinase inhibitors are also provided.

The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an IGF-1R kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an IGF-1R kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by IGF-1R kinase inhibitors. Improved methods for treating cancer patients with IGF-1R kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to IGF-1R kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by IGF-1R kinase inhibitors are also provided. pErk, HER3 and pHER are also demonstrated to be effective biomarkers for predicting sensitivity of tumor cells to IGF-1R kinase inhibitors.

The present invention provides tumor cell preparations for use as models of the EMT process for use in the identification of anti-cancer agents, wherein said tumor cell preparations comprise cells of the epithelial tumor cell line H358, which are stimulated by receptor ligands to induce EMT, or which have been engineered to inducibly express a protein that stimulates EMT. The present invention also provides methods of identifying potential anti-cancer agents by using such tumor cell preparations to identify agents that inhibit EMT, stimulate MET, or inhibit the growth of mesenchymal-like cells. Such agents should be particularly useful when used in conjunction with other anti-cancer drugs such as EGFR and IGF-1R kinase inhibitors, which appear to be less effective at inhibiting tumor cells that have undergone an EMT.

Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation

The present invention relates to drug screening assays designed to identify non-immunosuppressive agents that modulate hair growth and the use of such agents for modulation of hair growth.

FKBP51/52 and CyP40-mediated mammalian hair growth

The present invention provides a method for inhibiting cytotoxic poisoning of normal cells in a subject which comprises administering to the subject an amount of a Transforming Growth Factor Beta effective to slow the growth of normal cells and thereby inhibit the cytotoxic poisoning of the normal cells in the subject. Typically, administration is topical and initiated prior to anti-neoplastic therapy such as radiation treatment or chemotherapy. The invention is particularly suited for pediatric patients.

Tissue-derived tumor growth inhibitors, methods of preparation and uses

The present invention provides methods of preventing oral mucositis in a subject susceptible to mucositis which comprises administering to the subject a prophylactically effective amount of Transforming Growth Factor Beta. Typically, administration is topical and initiated prior to anti-neoplastic therapy such as radiation treatment or chemotherapy. The invention is particularly suited for pediatric patients.

Methods of prevention of oral mucositis with transforming growth factor

The present invention provides methods of preventing oral mucositis in a subject susceptible to mucositis which comprises administering to the subject a prophylactically effective amount of TGF-.beta.3. Typically, administration is topical and initiated prior to anti-neoplastic therapy such as radiation treatment or chemotherapy. The invention is particularly suited for pediatric patients.

The present invention provides (1) an antibody which (a) specifically binds to human TGF-.beta.3 and (b) exhibits substantially no cross reactivity with TGF-.beta.1 or TGF-.beta.2 and (2) antibodies directed against the pro region of the TGF-.beta. precursor. Further, this invention provides a pharmaceutical composition comprising the pro region of the TGF-.beta. precursor. Also, this invention provides methods for diagnosing, detecting and treating subjects suffering from disorders associated with TGF-.beta.3.

Growing community of inventors

Great Neck, NY, United States of America

John D Haley