Current standard-of-care hormone therapy can only go so far in treating metastatic prostate cancer until the body develops resistance, but new research from the Cleveland Clinic suggests a new pathway that could make tumors respond to treatments once again.
Cleveland Clinic has discovered a new drug target that reduced the size of tumors and improved survival in mice with drug-resistant prostate cancer. The findings, published today in Science Translational Medicine, also suggest potential for use in humans after research was conducted on biopsied patient tumors.
The current standard of care for this type of prostate cancer is Xtandi, made by Astellas and Pfizer. The drug, also known as enzalutamide, blocks the proteins that help drive cancer cells known as androgen receptors. This is effective at first, but most patients eventually form resistance to the treatment because cancer cells adapt and get a boost from the glucocorticoid receptor, a similar receptor to androgen.
These glucocorticoid receptors bind to and interact with cortisol, the stress hormone, causing an increase in tumor cortisol levels that has been linked to Xtandi resistance. When the protein 11β-HSD2 is inhibited in some tumors, cancer cells take advantage of the cortisol and glucocorticoid receptors.
Coupled with the decreased expression of 11β-HSD2, resistant tumors increase levels of the protein H6PD. The team at Cleveland Clinic, led by Nima Sharifi, M.D., of the Lerner Research Institute, found that by inhibiting H6PD, they could reinstate anti-cortisol effects, which prevents the cancer cells from dipping into a “backup fuel supply” of cortisol and glucocorticoid receptors.
“When we block this pathway, tumors begin to become responsive to standard treatments again,” said Sharifi, director of Cleveland Clinic’s Genitourinary Malignancies Research Center, in a statement announcing the findings.
Paired with a 2017 study conducted by Sharifi that linked Xtandi resistance to increased tumor cortisol levels, the new findings suggest inhibiting the H6PD protein can reverse drug resistance in prostate cancer cells, Sharifi said.
The researchers used Clovis Oncology’s FDA-approved drug Rubraca, or rucaparib, to target H6PD. The mice were given Xtandi, and when H6PD was blocked in some of the models, they showed significantly smaller tumors and survival without disease progression.
“These findings hold promise for novel precision medicine approaches in the management of men with aggressive prostate cancer,” said Eric Klein, M.D., chair of Cleveland Clinic’s Urology & Kidney Institute and Sharifi’s clinical collaborator and study co-author. Grants from the National Cancer Institute and the Prostate Cancer Foundation helped fund the research, which was submitted in September.
The Cleveland Clinic research comes amid other updates in the field of treating prostate cancer.
Researchers at Sidney Kimmel Cancer – Jefferson Health found a circadian clock gene, dubbed CRY1, that plays a major part in prostate cancer progression. The researchers now believe new treatments could target CRY1, which helps regulate circadian rhythms, according to a January report in the journal Nature Communications.
Last month, a Cedars-Sinai Cancer Institute team showed in preclinical models that blocking the protein EZH2, either genetically or with Epizyme’s FDA-approved inhibitor Tazverik, leads to a reduction in resistance to immune-boosting checkpoint inhibitors. Regeneron is currently testing a bispecific antibody as a solo therapy and in combination with the company’s PD-1 inhibitor Libtayo in a phase 1/2 clinical trial.