A group of researchers led by Andrew Armstrong, MD, MSc, professor of medicine and surgery at Duke Cancer Institute, has recently been awarded $2,500,000 from the National Institutes of Health (NIH) to investigate the connection between hormonal resistance in prostate cancer with metastasis and immune evasion.
Armstrong leads a team of basic science and clinical science investigators who have discovered key molecules that are activated in resistant prostate cancer cells which lead to aggressive behavior and spread into the bloodstream to distant sites, and which simultaneously may lead to escape from T cell recognition.
The goal of this laboratory and translational project is to test whether blocking this pathway, called the p38/MAP kinase pathway, with specific therapies with or without immune checkpoint inhibition, can be effective in restoring hormone sensitivity and reversing metastasis and immune escape. Armstrong’s team project, entitled “Targeting convergent oncogenic signaling during AR inhibition to overcome metastasis and immune evasion in prostate cancer,” is co-led with Jason Somarelli, PhD; Kathryn Ware, PhD; Brent Hanks, MD, PhD; Susan Halabi, PhD; David Hsu, MD, PhD and Yubin Kang, MD all at Duke University.
“Many men with metastatic prostate cancer today are treated with new hormonal therapies such as enzalutamide (Xtandi) or abiraterone (Zytiga) or other similar agents, and despite great success with these agents in improving survival, resistance commonly develops over time. The purpose of this grant is to determine how prostate cancer cells adapt and develop resistance to these hormone therapies and how we can overcome this resistance through a newly discovered pathway that is found to be activated across many prostate cancer models and metastatic patient samples,” described Armstrong. “Discoveries from this research should help identify new targets for therapies to overcome this resistance, including new immunotherapies with the goal of helping men with aggressive prostate cancer to prevent or treat metastatic disease and improve their survival.”
Prostate cancer in the United States is responsible for nearly 80 deaths per day. Current standard-of-care treatments for prostate cancer have significantly prolonged survival; however, acquired resistance to these drugs is inevitable.
To study immune evasion, Duke immunotherapy researchers lead by Kang and Hsu, created patient-derived xenograft (PDX) models that mirror human immune systems. Historically, cancer cells are grown in PDX models by removing their immune systems. However, Kang and Hsu collaborated with Dr. Armstrong to grow cancer cells taken directly from human patients in the PDX models while also incorporating the matched human immune systems into those same models. These unique models allow the investigators to test new immune therapies against prostate cancer with an intact and humanized immune system. The researchers will validate their findings in human circulating tumor cells from the Duke-led PROPHECY study and in tissue samples.
“Through this grant, we get to explore cancer cell mechanisms of resistance to current drug therapies,” said Kathryn Ware, PhD. “The current issue with therapy resistance is a lack of combination therapies, and ones that target multiple convergent pathways at once. As we continue to learn more about the mechanisms to drug resistance, inhibiting multiple convergent pathways simultaneously could be beneficial.”
Typically, when resources such as hormones or nutrients, become depleted, cancer cells: 1) Turn on pro-survival phenotypes (stress responses); 2) Escape predation (immune evasion); and 3) Disperse to a new location with more access to resources (migration/invasion).
“Together, these adaptations present a formidable clinical challenge. Our lab is interested in how all three of these key pathways can possibly be targeted to provide clinical benefit to patients," says Jason Somarelli, PhD. "Fortunately, our data provides strong evidence that these responses are controlled by converging pathways that can be targeted by two promising therapies to treat advanced prostate cancer.”
Brent Hanks, MD, PhD, manages a basic/translational research lab at Duke that focuses on understanding how cancers evade the immune system. “We are finding that many intrinsic mechanisms previously known to promote tumor survival and metastasis are also involved in cloaking the same tumors from the immune system. Understanding how these pathways are tied together via the p38/MAP kinase pathway may provide novel markers and immunotherapeutic strategies for managing hormone-resistant prostate cancer,” explains Hanks.
This NIH grant will provide the funding to determine if these new therapies can be used to kill therapy-resistant cancer and prevent the cancer cells from spreading. The lab’s work will uncover new ways to halt therapy resistance and the further spread of cancer cell spreading not only for prostate cancer, but for multiple other types of cancer.