A team at the University of Michigan Rogel Cancer Center has discovered that targeting the lipid kinase PIKfyve may be an effective treatment strategy alone—or in combination with immunotherapies—against the most challenging type of prostate cancer.
The study is published in Nature Cancer in the paper, “Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer.”
“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, MD, PhD, director of the Michigan Center for Translational Pathology and S.P. Hicks professor of pathology at Michigan Medicine.
Chinnaiyan and colleagues screened a library of 167 inhibitors against prostate cancer cells. They found one, ESK981, had the most impact. ESK981 is a multi-tyrosine kinase inhibitor—designed to hit multiple targets. Originally developed to check blood vessel growth, ESK981 has already been tested in Phase I 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. “The response was intriguing, but we wanted to understand the mechanism at play with ESK981 in prostate cancer cells,” Chinnaiyan said.
The researchers discovered several cellular processes were occurring. 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.
Mechanistically, the team identified the lipid kinase PIKfyve as the direct target of ESK981. The researchers confirmed this by knocking down PIKfyve in cell lines and mice. The PIKfyve knockdown “recapitulated ESK981’s antitumor activity and enhanced the therapeutic benefit of immune checkpoint blockade,” the authors wrote. 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.
The authors noted that their findings reveal that, “targeting PIKfyve via ESK981 turns tumors from cold into hot through inhibition of autophagy, which may prime the tumor immune microenvironment in patients with advanced prostate cancer and be an effective treatment strategy alone or in combination with immunotherapies.”
“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 II clinical trials using ESK981 alone or in combination with the immunotherapy nivolumab for metastatic castration-resistant prostate cancer.