Abstract B48: Exploiting aberrant mTOR signaling in hematological malignancies to preferentially enlarge cells for physicochemical destruction

Abstract

Abstract The mammalian target of rapamycin (mTOR) pathway has received considerable attention as a potential target for cancer chemotherapy, as aberrant mTOR regulation has been found in a tremendous diversity of malignancies. Such targeted therapies are designed to inhibit mTOR, thereby decreasing oncogenic potential within the cell. However, overexpression of mTOR may also be exploited to further increase the size differential between malignant and normal cells, a hallmark that is the basis of physicochemical therapeutic approaches. Therefore, this study sought to compare the physiological responses of malignant and normal blood cells after exposure to rapamycin, a known inhibitor of mTOR. U937 human promyelocytic leukemia cells were compared with human hematopoietic stem cells (hHSCs) at varying rapamycin concentrations to assess which cell type was more sensitive to mTOR inhibition. Subsequent results indicated that while both cell lines exhibited a marked reduction in cell volume, only U937 cells were able to readily proliferate in the presence of rapamycin. These effects were readily observed in as little as 2nM rapamycin, demonstrating the profound affinity the inhibitor has for mTOR. Further, size reduction could be rescued in U937 cells using vincristine, creating a substantial size differential between malignant and normal blood cell populations. This ultimately suggests that mTOR can be exploited to preferentially enlarge malignant cells for physicochemical destruction, providing a novel therapeutic approach for leukemia and other hematological malignancies. Citation Format: Matthew Trendowski, Gabriela Krawiec, Thomas P. Fondy. Exploiting aberrant mTOR signaling in hematological malignancies to preferentially enlarge cells for physicochemical destruction. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B48.