Researchers uncover way to harness the power of immunotherapy for advanced prostate cancer

A protein called PIKfyve impacts multiple processes involved in metabolism and cell death; blocking it is key to making immunotherapy work in prostate cancer.

11:00 AM

Author | Nicole Fawcett

doctor and researchers in lab coat and white coat in lab looking at syringe injection
The authors discovered ESK981 directly targets PIKfyve, which affects processes involved in metabolism and cell death. Credit: Leisa Thompson

It's a scientific riddle tangled up in a complex web. How do you turn an immune cold cancer into one that responds to immunotherapy?

Researchers led by the University of Michigan Rogel Cancer Center started with a simple thread: an inhibitor that showed promise against metastatic castration-resistant prostate cancer cells. This is the most challenging type of prostate cancer – advanced disease that has become resistant to hormone-based treatment.

MORE FROM THE LAB: Subscribe to our weekly newsletter

From there, they continued to untangle the web to discover multiple levels of cellular processes that were preventing the immune system from mounting a response. Break past them with this inhibitor and suddenly what's considered an immune cold tumor turns red hot.

"Immunotherapy has dramatically improved outcomes for some types of cancer. But prostate cancers are typically immune cold, which means these patients have benefited little from immunotherapies. Finding a way to rev up the immune response would create tremendous opportunity to improve patient outcomes," said Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine. Chinnaiyan is senior author of the paper published in Nature Cancer.

Researchers started by screening a library of 167 inhibitors against prostate cancer cells. They found one, ESK981, had the most impact.

ESK981 is a class of drugs called multi-tyrosine kinase inhibitors, which are designed to hit multiple targets. This means it functions like a combination therapy, able to block cancer on more than one front. It was originally developed to check blood vessel growth and has already been tested in phase 1 clinical trials, which found it to be safe and well-tolerated.

In cell lines and mice with metastatic castration-resistant prostate cancer, researchers found ESK981 inhibited tumor growth.

SEE ALSO: New Connections Reveal How Cancer Evades the Immune System

"The response was intriguing, but we wanted to understand the mechanism at play with ESK981 in prostate cancer cells," Chinnaiyan said.

They discovered several cellular processes were occurring. First was the role of a type of cell death called autophagy. The authors surprisingly found that ESK981 was a potent inhibitor of autophagy in tumor cells. This caused the cancer cells to produce a protein called CXCL10, which led to recruitment of immune T cells to the tumor.

But there was one more layer to go. Ultimately, they traced it back to PIKfyve, a type of protein called a lipid kinase. The authors discovered that ESK981 directly targets PIKfyve, affecting these multiple processes involved in metabolism and cell death.

The researchers confirmed this by knocking down PIKfyve in cell lines and mice. They saw the same processes occur: tumors stopped growing, autophagy was controlled and more T cells were recruited to the tumor. When they added an immune checkpoint inhibitor to the PIKfyve knockdown, the impact was even greater, significantly reducing tumors.

"Overcoming resistance to immunotherapy is an urgent need in prostate cancer. PIKfyve is a promising target, especially combined with an immune checkpoint inhibitor. This combination has potential to extend the benefit of immunotherapy to patients whose tumors have previously not responded," Chinnaiyan said.

Based on these findings, researchers have begun phase 2 clinical trials using ESK981 alone or in combination with the immunotherapy nivolumab for metastatic castration-resistant prostate cancer.

Like Podcasts? Add the Michigan Medicine News Break on iTunes, Google Podcasts or anywhere you listen to podcasts.

Additional authors include Yuanyuan Qiao, Jae Eun Choi, Jean C. Tien, Stephanie A. Simko, Thekkelnaycke Rajendiran, Josh N. Vo, Andrew D. Delekta, Lisha Wang, Lanbo Xiao, Nathan B. Hodge, Parth Desai, Sergio Mendoza, Kristin Juckette, Alice Xu, Tanu Soni, Fengyun Su, Rui Wang, Xuhong Cao, Jiali Yu, Ilona Kryczek, Xiao-Ming Wang, Xiaoju Wang, Javed Siddiqui, Zhen Wang, Amelie Bernard, Ester Fernandez-Salas, Nora M. Navone, Stephanie J. Ellison, Ke Ding, Eeva-Liisa Eskelinen, Elisabeth I. Heath, Daniel J. Klionsky, Weiping Zou

Funding for this work comes from the Prostate Cancer Foundation Challenge Award, National Cancer Institute Prostate SPORE Grant P50CA186786, Department of Defense grant PC130151P1, National Institutes of Health grant GM131919. In addition, individual researchers are supported by NCI grant R35CA231996, Howard Hughes Medical Institute, A. Alfred Taubman Institute, American Cancer Society, PCF Young Investigator Awards, DoD Postdoctoral Award W81XWH-16-1-0195, and the Academy of Finland.

Disclosure: The University of Michigan has filed a disclosure on the findings based on this study. Chinnaiyan and Qiao are named as co-inventors. Esanik Therapeutics Inc. licensed ESK981 from Teva Pharmaceuticals. Chinnaiyan is a co-founder and serves on the scientific advisory board of Esanik Therapeutics Inc. Esanik Therapeutics or Teva Pharmaceuticals were not involved in the design or approval of this study, nor was this study funded by them.

Paper cited: "Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer," Nature Cancer. DOI: 10.1038/s43018-021-00237-1


More Articles About: Lab Report Cancer Research Basic Science and Laboratory Research Prostate Cancer Cancer: Help, Diagnosis & Treatment
Health Lab word mark overlaying blue cells
Health Lab

Explore a variety of healthcare news & stories by visiting the Health Lab home page for more articles.

Media Contact Public Relations

Department of Communication at Michigan Medicine

[email protected]

734-764-2220

Stay Informed

Want top health & research news weekly? Sign up for Health Lab’s newsletters today!

Subscribe
Featured News & Stories Graphic showing pills, a heart and brain with data on aspirin use
Health Lab
Aspirin can prevent a second heart attack or stroke, but many don’t use it
Washington University School of Medicine and Michigan Medicine researchers found that fewer than half of people who have experienced a heart attack or stroke use aspirin to prevent a second one.
Jianping Fu, Ph.D., Professor of Mechanical Engineering at the University of Michigan and the corresponding author of the paper being published at Nature discusses his team’s work in their lab with Jeyoon Bok, Ph.D. candidate at the Department of Mechanical Engineering.
Health Lab
Human stem cells coaxed to mimic the very early central nervous system
The first organized stem cell culture model that resembles all three sections of the embryonic brain and spinal cord could shed light on developmental brain diseases
Health care provider with stethoscope holds patient's hand
Health Lab
Combatting prostate cancer stigma
Prostate cancer is highly treatable and over 98% of men survive 10 years if the cancer is diagnosed and treated early.
Illustration of a microscope
Health Lab
Hippo signaling pathway gives new insight into systemic sclerosis
Study focuses on Hippo signaling pathway as critical link between fibrosis, vascular dysfunction, and sex bias in systemic sclerosis
Headshot of Anne Draelos
Research News
U-M's Anne Draelos named a 2024 Sloan Research Fellow in neuroscience
Anne Draelos, Ph.D., Assistant Professor of Biomedical Engineering and Computational Medicine & Bioinformatics, has been named a 2024 Sloan Research Fellow in Neuroscience.
Woman in pink shirt lifts kettleball in an outdoor exercise class
Health Lab
How to make cancer prevention more equitable
Expert explains six behavioral risk factors for cancer and why current programs don’t always meet the needs of people from racially and ethnically minoritized groups and other vulnerable populations.