Targeting Adaptive Pathways in Abiraterone- and Enzalutamide-Refractory Intermediate Atypical Carcinoma
Abstract
Prostate cancer is the most commonly diagnosed cancer in American men. Once prostate cancer has spread to other sites in the body, it is termed "metastatic" disease. Metastatic prostate cancer is a lethal disease, and it is the second leading cause of cancer-related death among American men. Because prostate cancer grows under the influence of the male hormone testosterone, metastatic prostate cancer can be controlled for a period of time with hormonal therapy that reduces the level of testosterone. Ultimately, however, the cancer becomes resistant to hormonal therapy. One of the ways by which prostate cancer develops this resistance is by acquiring the capacity to survive and grow with only minute amounts of testosterone. A number of recent treatment breakthroughs in the field have resulted in prolonged survival for men with metastatic prostate cancer that is no longer responding to initial hormonal therapy. These advances include drugs such as Abiraterone Acetate (Zytiga®), and Enzalutamide (Xtandi®), which are capable of blocking the small amounts of residual testosterone that the cancer is able to use for growth. However, yet again, prostate cancers adapt to this therapy, and ultimately every prostate cancer patient who is treated with Zytiga and/or Xtandi becomes resistant to these new agents, sometimes over a period of only months, resulting in death, as well as significant pain and suffering. The mechanisms by which prostate cancers adapt to these new agents and develop resistance ("adaptive resistance") are not understood. Our project is focused on understanding the cause(s) of adaptive resistance in metastatic prostate cancer patients following hormonal therapy, with the goal of developing more effective treatment for these patients. By undertaking over 200 biopsies of metastases in treatment-resistant prostate cancer patients, we have observed that a highly aggressive variant called "small cell/neuroendocrine prostate cancer" (SCNC), which has been previously observed, but felt to be very rare, was found in a full 13% of patients with Zytiga or Xtandi-resistant disease. SCNC is generally believed to be minimally dependent on testosterone or affected by testosterone lowering agents like Zytiga or Xtandi. We also discovered a previously unidentified variant of prostate cancer in about one-quarter of the biopsies. We have shown this variant to be more aggressive. The biological characteristics of this type of tumor suggest that it is intermediate between being driven by testosterone and acquiring the characteristics of prostate cancers like SCNC. We have termed this variant "intermediate atypical carcinoma" or IAC. Together, IAC and SCNC, both highly aggressive cancers, account for nearly 40% of all Zytiga and Xtandi-resistant metastatic prostate cancer. Our hypothesis is that prostate cancer that is resistant to Zytiga or Xtandi evolves from a more testosterone-driven phase, through an intermediate phase, reflected by IAC, and on to the least testosterone-dependent phase, reflected by SCNC. Furthermore, we hypothesize that cancer cells use common cellular responses or pathways that can be identified in their genetic wiring to become resistant to therapy and that IAC will be characterized by a specific intermediate pattern of pathway activation. By identifying these pathways and subsequently identifying agents to inhibit these processes, we will be able to profoundly improve the care of men with this fatal disease and for whom no standard therapy exists. Furthermore, an understanding of the interplay of conserved testosterone-dependent pathways and activated adaptive resistance pathways in IAC allows the development of a therapeutic strategy in which testosterone-dependent pathways and adaptive pathways are treated simultaneously, termed "co-targeting." This approach has the potential to significantly improve patient outcomes. Perhaps more importantly, if IAC represents a transitional state be
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610495
Entities
People
- Eric J Small
Organizations
- United States Army
- University of California, San Francisco