Targeting Early Drivers of Prostate Cancer Lineage Plasticity

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Lineage plasticity (LP)—most commonly exemplified by loss of androgen receptor (AR) signaling and switch from a luminal to an alternate differentiation program—is now recognized as a critical determinant of lethality. Most efforts in the field are focused on factors that promote terminal differentiation of specific LP subtypes such as neuroendocrine prostate cancer (NEPC). However, LP is a continuum, ranging from AR activity-low tumors with persistent AR expression but low AR signaling to those with alternate differentiation programs. Factors involved in the initiation and progression of LP have not been identified. The clarification of such factors is essential because there are no effective therapies for prostate tumors that have undergone LP. In this proposal we seek to target key factors involved in early LP events to prevent LP from occurring. Using an integrative genomic analysis of metastatic castration-resistant prostate cancer patient biopsies, we determined that key transcriptional regulators are upregulated early on in the LP continuum in AR activity- low tumors and that these factors progressively increase in terminally differentiated LP subtypes. Importantly, gain of function studies of these transcriptional regulators in AR-driven tumors and loss of function studies in tumors representing the continuum of LP demonstrate that these regulators block AR signaling and cooperate with other factors to promote specific alternate differentiation programs. Targeting these transcriptional regulators or their key epigenetic cofactors reduces survival of LP tumor cells in vitro and in vivo with good animal tolerability, strongly suggesting we have a promising approach to block LP. We hypothesize that key transcriptional regulators we have identified are early drivers of LP that control prostate cancer cell fate decisions by: 1) repressing AR signaling and luminal differentiation and 2) activating alternate differentiation programs in concert with key cofactors. Aim 1: Determine mechanisms by which key transcriptional regulators modulate differentiation state and cancer hallmarks. Completion of this aim will provide a detailed understanding of how key transcriptional regulators block epithelial differentiation and activate alternate differentiation programs so we can prevent this. Aim 2: Determine mechanisms by which key transcriptional regulators are upregulated in human tumors. Completion of this aim will determine how key transcriptional regulators are upregulated as tumors undergo LP and determine the association between upregulation of these regulators and patient outcomes. Aim 3: Target key transcriptional regulators in vivo and determine the effect on LP and other hallmarks. Completion of this aim will identify response biomarkers, measure safety, and provide the rationale to test the combination in future clinical trials focused on patients with tumors across the LP continuum. We expect the proposed studies will clarify the function of a network that is critical for prostate cancer lineage plasticity, so we may translate new strategies to block this network to the clinic in the near-term.