Disabled homolog 2-interacting protein (DAB2IP) is a novel tumor suppressor that belongs to the Ras-GTPase activating factor family, which negatively regulates Ras and multiple oncogenic signaling pathways. Loss of DAB2IP is often detected in prostate, renal and other cancers and is associated with aggressive disease and poor prognosis. DAB2IP loss is also associated with resistance to chemo-, radiation and other targeted therapies. Our retrospective investigation of high-risk prostate cancer patients concluded that a reduction of DAB2IP expression correlated with poor patient survival after radiation and androgen therapy. In addition, we recently reported that the loss of DAB2IP leads to a significant increase in chromosomal instability, which is a hallmark of cancer progression. DAB2IP physically interacts with critical mitotic regulators, such as Plk1 and Cdc20, and spatially locates at the kinetochores during mitosis. Loss of this protein functionally affects spindle assembly checkpoint (SAC) surveillance, resulting in increased aneuploidy. This increase in aneuploid cells associated with the loss of DAB2IP has been found not only in prostate cancer cells but also in normal prostate epithelial cells and in mouse embryo fibroblasts following DAB2IP knockdown, which suggests its genuine role in mitosis progression and maintaining chromosomal stability. A timely and robust SAC surveillance system is necessary to govern the precise and equal separation of sister chromatids during mitosis and to prevent premature mitotic exit. The long-term objective of this study is to use anti-mitotic strategies to significantly improve the overall survival and quality of life of patients with prostate cancer, especially those who are at higher risk of therapy failure due to the loss of DAB2IP. Our in vitro studies use wild type and various mutants of D2 expressed in prostate cancer and normal prostate epithelial cell lines to monitor SAC surveillance, kinetochore-microtubule stability, microtubule dynamics, and the interaction and activation of critical SAC regulators. Furthermore, we are testing several mitotic inhibitors in combination with chemo and radiation in animal models of DAB2IP-deficient prostate tumors.

My laboratory also develops physiologically relevant tumor models, which improve preclinical predictions and translational success. For the last several years, my laboratory has developed orthotopic tumor models of the lung and prostate that specifically mimic stereotactic radiation therapy in humans. We have now consistently grown solitary tumor nodules in an immune suppressed rat lung that can be targeted for radiotherapy. This particular lung tumor model is now widely used by multiple investigators at UTSW. In addition, we have developed an orthotopic locally advanced non-metastatic prostate tumor model. We are now working to develop both head and neck and pancreatic orthotopic tumor models for conventional and charged particle radiotherapy.