Knight Cancer Pilot Project Awardee: Joshi Alumkal, M.D. and Laura Heiser, Ph.D.
Joshi Alumkal, M.D., Assistant Professor, Hematology & Medical Oncology and Laura Heiser, Ph.D., Research Assistant Professor, OCSSB
Knight Prostate Cancer Research & Treatment Fund Pilot Project
Title: "Identifying Acquired Tumor-Intrinsic MDV3100 Resistance Mechanisms in Castration-Resistant Prostate Cancer"
Abstract: Metastatic prostate cancer is the second-leading cause of cancer-related death in American men. The primary treatment for metastatic prostate cancer is lowering levels of androgens (male hormones). These male hormones act like fuel and activate the androgen receptor protein, the engine of prostate cancer cells. We now know that traditional male hormone lowering treatment (medical castration) does not lower levels of male hormones in prostate cancer cells to zero (that is, the fuel tank is not empty). Recently, more potent male hormone lowering drugs have been developed. MDV3100 is one example of this new type of drug, and MDV3100 treatment in a recent phase III clinical trial led to the largest increase in overall survival in the history of prostate cancer research. However, resistance, or eventual tumor growth, despite MDV3100 treatment is universal. Reasons that lead to MDV3100 resistance in tumors are unknown, and there are no effective treatments for men whose lethal tumors begin to grow despite MDV3100 treatment. The goal of this proposal is to understand why tumors grow despite MDV3100 treatment. Understanding these reasons is predicted to lead to new treatments that improve patient survival and decrease patient suffering.
We hypothesize that resistance to treatment with MDV3100 results from widespread changes in our DNA. DNA determines how cells function and grow. In normal cells, DNA is tightly regulated to ensure proper cell function. Cancer results from the accumulation of widespread changes in the sequence, structure, and expression of our DNA. Rather than being a collection of chaotic, unorganized changes, we believe that these changes in our DNA work in concert to sustain tumor cell survival. Moreover, we believe that these DNA changes can be organized into a few gene networks, or “electrical circuits,” that drive MDV3100-resistance in tumors. By identifying these gene networks, we can then identify new and effective treatments for patients with lethal, untreatable, MDV3100-resistant prostate cancer.
To clarify reasons that lethal prostate cancers grow despite MDV3100 treatment, we will utilize representative cell models of prostate cancer that were developed in mice treated with castration plus MDV3100 treatment akin to the way we treat human prostate cancer. First, we will measure the changes in cell appearance and behavior that distinguish an MDV3100-sensitive prostate cancer from an MDV3100-resistant prostate cancer. Second, we will identify the gene networks that are turned on in MDV3100-resistant cancers and that account for the changes in appearance and behavior of MDV3100-resistant cancers.