Crosstalk between Notch signaling and lineage-determining transcriptional factors drives neuroendocrine differentiation in advanced prostate cancer
Abstract
Scientific Objectives and Rationale: Prostate cancer is the most common non-skin cancer in men and a leading cause of mortality in the United States, with over 25,000 deaths each year from prostate cancer. Clinically localized prostate cancer is often cured by surgery or radiation. However, for men that relapse after local therapy or present with advanced disease, treatment with androgen deprivation therapy (ADT) is highly effective but not curative. Mechanisms of resistance to ADT most commonly are through reactivation of androgen receptor (AR) signaling, which has led to the development of highly potent AR-targeted drugs that are now used to treat patients in combination with ADT or at the time of castration resistance. While the AR is the main driver of most prostate cancers, increasingly a new form of resistant prostate cancer has emerged that is less dependent on AR signaling. Tumor biopsies in this setting may look less like a typical prostate cancer (adenocarcinoma) and more like small cell/neuroendocrine prostate cancer (NEPC). Recent work by our laboratory and others have pointed to a mechanism called lineage plasticity, whereby prostate cancer cells change their inherent features and develop an alternative neuroendocrine program as a means to bypass treatment. We have identified key pathways associated with lineage plasticity and NEPC, including loss of Notch signaling and overexpression of key transcription factor proteins called ASCL1 and INSM1. Through the use of patient relevant preclinical tools, we will deeply examine how this pathway contributes to treatment resistance in prostate cancer. We will dissect the process of lineage plasticity to understand how and why some patients develop this aggressive form of NEPC. This work will identify new strategies to treat or even prevent treatment resistance. Applicability of the Research: There are currently no effective therapies for patients with NEPC and prognosis remains poor. Knowledge regarding the underlying mechanisms that contribute to the development of NEPC are urgently needed. In this proposed work, we will address two FY19 PCRP Overarching Challenges: “Develop treatments that improve outcomes for men with lethal prostate cancer” and “Define the biology of lethal prostate cancer to reduce death.” By understanding what causes NEPC, we can learn how to prevent or treat it. In the near term, we will bridge the gap of knowledge of NEPC pathogenesis and test whether Notch signaling reactivation and inhibition of ASCL1 and INSM1 are able to stop NEPC development. A longer term goal of this work will be to develop new therapeutic approaches, potentially drugs that to modulate Notch signaling and/or block ASCL1 and INSM1 or other key components of this pathway. Career Goals in Prostate Cancer Research: My commitment to prostate cancer research began as a college student. At that time, I was studying the WNT/betacatenin signaling pathway in prostate cancer to understand how WNT signaling drives prostate tumorigenesis. Since then, I have continuously sought opportunities to build my experience in prostate cancer research by studying it from various directions. Over the years, I developed laboratory skills that have allowed me to interrogate how prostate cancer develops and understand what causes it to be so resistant or aggressive in certain genetic contexts. By genetically manipulating mice, I identified the combination of RB1 and TP53 loss as important drivers of NEPC. In my current laboratory, I strive to develop new ways to treat aggressive prostate cancer and to translate my work into the clinic. My mentor, Dr. Himisha Beltran, is a successful physician-scientist with tremendous experience and passion for studying prostate cancer and perceiving what is needed in the clinic. Under her mentorship, we always exchange a lot of thoughts from both basic and clinical perspectives to advance this field. I constantly learn from her and ret
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010033
Entities
People
- Sheng-yu Ku
Organizations
- Dana–Farber Cancer Institute
- United States Army