Enhancing the Efficacy of Docetaxel in Prostate Cancer

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Project Summary Taxanes are the first and only line of chemotherapy shown to prolong survival in men with metastatic castration- resistant prostate cancer (mCRPC) who have progressed after androgen deprivation therapy (ADT). Taxanes have not only demonstrated clinical benefits in mCRPC, but also in men with castration-sensitive metastatic prostate cancer (mCSPC) who received docetaxel given at the time of standard ADT. Despite these clinical benefits of taxane treatment, not all men respond equally and resistance to therapy leads to significant morbidity and mortality. Currently, the molecular determinants of clinical response and resistance (intrinsic and acquired) to taxane chemotherapy remain poorly understood, and new taxane combinations could greatly help patients with metastatic prostate cancer. We have recently reported that one mechanism for taxane resistance in patients and mouse models is failure of the drug to stabilize microtubules. The subsequent loss of microtubule bundling can be quantitated as loss of drug target engagement (DTE), and may be a biomarker for resistance in patients. Using mouse models we find that increased expression of FOXJ1, a master transcription factor regulating microtubule-related proteins, as well as a downstream microtubule associated protein TPPP3, are associated with taxane resistance. Moreover, we find that FOXJ1 gene amplification is associated with taxane treatment in patients. Recently we have also shown that FOXJ1 overexpression leads to docetaxel resistance in vivo and that docetaxel treatment leads to an increase in FOXJ1 RNA and protein expression. Aim 1 will focus on increased FOXJ1 and TPPP3 as mechanisms of resistance, and identification of potential vulnerabilities in these tumors. In Aim 2 we will explore precision medicine approaches for taxane resistance by examining circulating tumor cells and plasma cell free DNA in prostate cancer patients being treated with docetaxel to identify mechanisms of intrinsic or acquired resistance. A goal would be to develop clinical trials of agents targeting specific resistance mechanisms in these patients. Identification of new mechanisms of resistance to docetaxel could imminently translate to development of therapeutic combinations to prevent or delay resistance. Our ultimate goal is to develop new combinations to increase response and survival of patients with metastatic CRPC.