Presentation Abstract

Abstract Number: 1868
Presentation Title: Response biomarkers to IGF1R and mTOR inhibitor combination therapy in ovarian carcinoma
Presentation Time: Monday, Apr 02, 2012, 8:00 AM -12:00 PM
Location: McCormick Place West (Hall F), Poster Section 32
Poster Section: 32
Poster Board Number: 4
Author Block: Brian B. Haines1, Michael J. Wick2, Kyriakos P. Papadopoulos2, Anthony W. Tolcher2, Jennifer G. Tammam1, Marya F. Chaney3, Michael Nebozhyn3, Theresa Zhang1, Scot W. Ebbinghaus3, Jonathan D. Cheng3, Leigh Zawel1, Sriram Sathyanarayanan1. 1Merck Research Laboratories, Boston, MA; 2South Texas Accelerated Research and Therapeutics, San Antonio, TX; 3Merck Research Laboratories, Upper Gwynedd, PA
Abstract Body: Ovarian cancer, the sixth most frequent cause of cancer death among women in the developed world, is a heterogeneous disease characterized by a diverse set of genetic alterations. These factors underscore the need for more effective treatment options accompanied by biomarker strategies to identify patients who will have a greater likelihood to respond to novel therapy. A combination strategy to target the PI3K pathway with the mTOR inhibitor ridaforolimus and anti-IGF1R antibody dalotuzumab is currently undergoing clinical development. Previous translational work has suggested that low RAS activity, as determined by a RAS gene expression signature score, and high levels of IGF1R pathway activation may enrich for response to this combination therapy. Ranking of tumors in the Moffitt tumor database with a low RAS and high IGF profile suggested that ER+ breast and ovarian cancers are enriched for these putative response biomarkers. Consistent with these observations, clinical responses were noted for several ER+ breast or ovarian cancer patients in a Phase I trial for ridaforolimus and dalotuzumab combination therapy. To provide further support for low RAS and high IGF as response biomarkers, the anti-tumor activity of ridaforolimus and dalotuzumab was assessed in 12 patient derived primary ovarian cancer xenograft models developed at START. These models have been extensively characterized by the South Texas Accelerated Research and Therapeutics (START) group for response to standard of care drugs, and the status of many commonly mutated genes in ovarian cancer. Molecular analyses of these tumors suggest that they represent a diverse cross section of ovarian cancer. Similarly, responses to ridaforolimus and dalotuzumab combination therapy ranged from minimal to significant regression. Importantly, the responsive tumor models were associated with a low RAS gene signature and a moderate to high IGF expression level. Tumors with KRAS mutations or a high RAS gene score were generally resistant to therapy. These results support the further development of low RAS and high IGF as enrichment biomarkers for ridaforolimus and dalotuzumab combination therapy in ovarian carcinoma.