Defining Therapeutic Approaches to Target AR Pathway-independent Prostate cancer (APIPC)

About Defining Therapeutic Approaches to Target AR Pathway-independent Prostate cancer (APIPC)

Androgens are male hormones such as testosterone. These hormones, and their receptor—the androgen receptor (AR)—are key drivers of prostate cancer (PCa) growth. Doctors have long used medical or surgical means to remove or block androgen sources in men with metastatic PCa. Such androgen deprivation therapy (ADT) is usually, highly effective initially at controlling these advanced cancers. ADT removes the androgens and suppresses signals from the AR to which tumor cells are “addicted.” However, in most cases, PCa treated with ADT eventually progress to ADT-resistant PCa, an aggressive and often lethal stage of PCa. Recently second-generation anti-androgens have come to market that extend survival times for men with ADT-resistant tumors, but ultimately most men develop resistance to these drugs as well—an almost uniformly fatal development.

In the majority of men with ADT-resistant prostate cancer, tumors remain dependent upon AR signaling. However, a subset of men with ADT-resistant PCa have tumors that can grow and thrive even when AR signaling is completely absent. When this occurs the PCa is unresponsive to therapies that target androgens and the AR. Currently there is no effective treatment for androgen pathway-independent PCa.

Dr. Nelson and his team will use this Challenge Award to discover new ways to treat androgen pathway-independent PCa. They hypothesize that in the future the use of multiple drugs—either those now on the market or yet to come—to completely extinguish androgens and AR signaling will cure some men with ADT-resistant PCa, but leave others with an evolved form of PCa that the team has dubbed Androgen Receptor Pathway Independent Prostate Cancer, or APIPC.

Drs. Nelson, Pienta, Antonarakis, Pritchard and Ittman will determine the molecular mechanisms that allow this evolution of cancer to occur and ways to prevent or delay the onset of APIPC. Preliminary work by this team strongly suggests that two protein groups, known as fibroblast growth factors (FGFs) and their receptors (FGFRs) are key drivers in the development of APIPC. In preclinical work they will validate the FGF/FGFR signaling pathway as an actionable driver of APIPC, and then design a clinical trial to test if inhibition of this pathway leads to improved outcomes for men suffering from advanced PCa. They will also develop novel PCa lab models that recapitulate the evolution of AR-dependent prostate cancers to APIPC to better understand this highly lethal subtype of disease and identify actionable drug targets to limit its development and progression.

What this means for patients: Dr. Nelson and his team will undertake extensive studies to determine how PCa that is dependent upon androgen signaling evolves to a state of AR-independence—the latter being extremely difficult to treat as currently no effective drug therapy exists. Based upon strong preliminary evidence by this research team that a group of proteins (FGFs and FGFRs) involved in embryonic development, wound healing and other critical cellular pathways likely serve as key drivers in the onset of androgen pathway-independent PCa, Nelson and colleagues will do the necessary preclinical work to bring FGF/FGFR inhibitors to clinical trials. They will also study human tissue samples derived from men who have expired from metastatic PCa to determine what other genes and proteins may be at play in the development of androgen pathway-independent PCa. This work will lead to novel drug targets against APIPC.

Principal Investigator:

Peter Nelson, MD (Fred Hutchinson Cancer Research Center)

Co-investigators:

Ken Pienta, MD (Johns Hopkins), Emmanuel Antonarakis, MD (Johns Hopkins), Michael Ittman, MD, PhD (Baylor College of Medicine), Colin Pritchard, MD, PhD (University of Washington).