Aveo Pharmaceuticals, Inc.

Osi Pharmaceuticals, Inc.

Murray Robinson

Jie Lin

Bin Feng

Maria Isabel Chiu

Ronan O'Hagan

Yinghui Zhou

Joerg Heyer

Min Wu

Charlotte Kuperwasser

Steven C Clark

Tyler E Jacks

Lorena Lerner

Julie Kan

Stuart Thomson

Richard Nicoletti

Matthew O'Connor

William Rideout, Iii

Wenping Kathryn Sun

Karuppiah Kannan

Ti Cai

Ronald Depinho

Feng Jiang

Gretchen M Argast

Xiaojian Sun

The present invention provides diagnostic methods for assessing the EMT status of tumor cells, and for predicting the effectiveness of treatment of a cancer patient with an EGFR or IGF-1R kinase inhibitor, utilizing an EMT gene signature index score. The present invention further provides methods for treating patients with cancer that incorporate these methods.

Use of EMT gene signatures in cancer drug discovery, diagnostics, and treatment

A reconstituted human breast tumor model is disclosed. The model, which is incorporated into mice, provides actual tumors that arise spontaneously, thereby mimicking naturally occurring breast cancer. The tumors are genetically human, because they arise from human mammary tissues that develop from human mammary epithelial cells implanted into host mice. Prior to implantation, the mammary epithelial cells are genetically modified to contain a recombinant human oncogene and an SV40 early region.

Reconstituted human breast tumor model

Reconstituted human breast tumor models are disclosed. The models, which are incorporated into mice, provide actual tumors that arise spontaneously, thereby mimicking naturally occurring breast cancer. The tumors are genetically human, because they arise from human mammary tissues that develop from human mammary epithelial cells implanted into host mice. Prior to implantation, the mammary epithelial cells are genetically modified to contain either: (a) a recombinant human oncogene and an SV40er; or (b) a recombinant human oncogene, a transgene or shRNA that inhibits the p53 pathway, and a transgene or shRNA that inhibits the Rb pathway.

A diagnostic method for predicting whether a human tumor will be sensitive or resistant to treatment with tivozanib (AV-951) is disclosed. The method is based on measurement of macrophage content in a tissue sample from a tumor. Measurement of macrophage content can be based on analysis of macrophage marker gene expression, e.g., by RNA analysis or immunohistochemistry.

Tivozanib response prediction

Chimeric nonhuman mammals useful as inducible spontaneous cancer models are disclosed. The nonhuman mammals are obtained by introducing one or more genetically modified embryonic stem (ES) cells into an early stage embryo, and then implanting the manipulated embryo into a surrogate mother. The ES cells contain a recombinant oncogene, and also may contain a genetic mutation that deletes or inactivates a tumor suppressor gene. Models of different types of cancer are produced by introducing different combinations of genetic mutations into the ES cells that are introduced into the early stage embryo.

Chimeric cancer models

A diagnostic method for predicting quantitatively whether a human tumor will be responsive or resistant (non-responsive) to treatment with the VEGF inhibitor, tivozanib (AV-951), is disclosed. The test is based on application of an algorithm to measurements of expression levels of the genes in a predictive gene set.

A method of producing a tumorigenic mouse cell, the tumorigenicity of which depends on a recombinant gene of interest is disclosed. The method involves: (a) providing a conditionally tumorigenic mouse cell containing a recombinant oncogene operably linked to an inducible promoter, wherein (i) expression of the recombinant oncogene is necessary and sufficient for the tumorigenicity of the tumorigenic mouse cell, and (ii) the inducible promoter is in the uninduced state; and (b) introducing into the cell a recombinant gene of interest that functionally complements the oncogene, thereby restoring tumorigenicity without expression of the inducible recombinant oncogene. Also disclosed is a method of testing a compound for anti-tumor effects. The method includes producing tumorigenic mouse cells the tumorigenicity depends on expression of a recombinant gene of interest, implanting the cells in mice and obtaining tumors from the implanted cells, administering test compounds to the mice, and determining anti-tumor effects, if any, of the compounds.

Directed complementation

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Boston, MA, United States of America

Murray Robinson