Enhancing the Efficacy of Docetaxel in Prostate Cancer

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.

Grant Number: 5R01CA266704-04
NIH Institute/Center: NIH
Principal Investigator: Steven Balk