Abstract 2539: Targeting therapy-resistant gastric and esophageal cancers with mTOR ATP site inhibitors

Abstract

Abstract Introduction: Despite a declining incidence, gastroesophagealcancer remains a leading cause of cancer death in the Western world. At time of diagnosis, most patients have advanced disease, for which treatment goals are palliative and options are limited. Available cytotoxic chemotherapy have not been successful in durable response or improving the survival… Developing rationale and novel therapy in gastroesophageal cancers is clearly an area of unmet need. Tumor recurrence is the persistence of a rare sub-population of cells with tumorigenic potential and stem cell markers that is intrinsically resistant to conventional therapy. Tumor-initiating or cancer stem cells have been described in many cancers, both hematologic and solid malignancies. Improving survival in patients with gastroesophageal cancer will require development of therapeutic agents targeting tumor initiating while, at the same time, sparing normal stem cells. Achieving this important goal will require increased knowledge of the signals required for maintenance and expansion of cancer vs. normal stem cells. Recent investigation by our group has demonstrated that ribosome biogenesis pathways have a major role to play in cancer and tumor initiation. mTOR plays a critical role in modulating the role of ribosomes in cancer, specifically its translational arm which can selectively regulate the translational complex in these cells and affecting their ability to proliferate, invade and metastasisze. Methods: Our goal is to study the role of mTOR pathway in treatment resistant gastric/GEJ cancer and target the same using ATP-site inhibitors of mTOR which target both the proliferation as well as the translational arm of mTOR. Results: Our results demonstrates that by targeting mTOR using ATP site inhibitors in therapy resistant gastric (KATOIII and NCI-N87) and esophageal cancer cell lines (KYSE30 and KYSE270) significantly (p<0.05) reduces proliferation. Combination of docetaxel and mTOR ATP site inhibitor led to dramatic reduction in proliferation in a dose dependent manner. Addition assays determined that reduced proliferation corresponds to an increase in apoptosis, which suggests that this cell killing may not cause major toxicity. We are currently examining the effects of these combinations in vivo. Conclusions: The combination of standard of care and mTOR ATP side inhibitor is potentially effective in reducing cell proliferation using apoptosis as the means of cell death. Our preliminary findings suggest that targeting the translational as well as the cell size arm of the mTOR signaling pathway may be a rationale and novel strategy to treat gastroesophageal cancer. Citation Format: Bhuvanesh Dave, Alexandria Phan. Targeting therapy-resistant gastric and esophageal cancers with mTOR ATP site inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2539. doi:10.1158/1538-7445.AM2015-2539