Aggressive castration-resistant prostate cancer can persist after treatment with standard-of-care hormone therapies targeting the androgen receptor. Now a team led by Duke University scientists has identified a cell surface receptor that drives this resistance, as well as a Merck drug that inhibits prostate tumor growth in mice.
Resistance to hormonal therapy has been attributed to prostate cancer cells that lack the androgen receptor (AR). These cells harbor a different receptor called CXCR2 that contributes to their survival and progression, the researchers described in a study published in the journal Science Translational Medicine.
Pairing Merck’s investigational CXCR2 inhibitor navarixin (MK-7123) with Pfizer and Astellas’ anti-androgen drug Xtandi (enzalutamide) killed CRPC in a mouse model, the team showed. Merck was originally developing navarixin to treat chronic obstructive pulmonary disease (COPD).
Most primary prostate cancer is made up of a large number of AR-expressing luminal tumor cells plus a tiny population of neuroendocrine cells that do not express AR, the study’s senior author, Jiaoti Huang, chair of Duke’s Department of Pathology, explained in a statement. “Our hypothesis was that this minor population because they have the ability to survive, contribute to tumor recurrence,” he said. But what allows those neuroendocrine cells to resist treatment?
To answer that question, Huang and colleagues examined purified neuroendocrine cells from fresh human prostate cancer tissues and observed that CXCR2-positive cells make up 14% of the cells in CRPC. They're even more prevalent in metastatic disease (20%) and in a particularly lethal form of prostate cancer called small cell neuroendocrine carcinoma (74%).
Turns out, not only are hormone therapies unable to touch neuroendocrine tumor cells, they even help these malignant cells grow. When treated with Xtandi, prostate tumors in lab dishes did shrink, but at the same time, CXCR2-positive cell populations spiked, the team observed.
To determine whether CXCR2 is indeed a driver of resistance in neuroendocrine cells, the researchers over-expressed CXCR2 and found cells were resistant to Xtandi. After knocking CXCR2 out completely, the cells became sensitive to Xtandi again. What's more, the team found that CXCR2-positive cells somehow create an ideal tumor microenvironment that suppresses immune T cells and promotes tumor growth in other ways, as well.
During the study, Huang’s team combined navarixin with Xtandi and showed that the pair could shrink tumors better than either treatment alone in a mouse model of CRPC. Interestingly, a collaboration between Roche and the Paul Scherrer Institute recently found that navarixin may have additional anti-tumor metastasis effect by blocking a protein called CCR7.
CXCR2 is known to play a role in inflammatory responses. That’s why Merck originally developed navarixin for COPD. The company had initiated some studies in solid tumors, including one that pairs the drug with Merck’s PD-1 inhibitor Keytruda.
There have been several drugs approved to treat CRPC in recent years, including Xtandi, Johnson & Johnson’s Erleada and, most recently, Bayer’s Nubeqa, but scientists are still looking for new ways to crack the disease. Researchers at the MD Anderson Cancer Center, for example, found that inhibiting a protein called TGF-beta could boost checkpoint inhibitors’ efficacy in prostate cancer that had spread to the bone.
A team at the University of Pennsylvania’s Abramson Cancer Center discovered that blocking an enzyme called CDK7 could turn off AR’s “wingman,” Med-1, to achieve cell death in CRPC. Another group led by scientists at Cold Spring Harbor Laboratory showed that inhibiting a protein called PHLPP2 could reduce the cancer-related protein MYC and hence promote prostate cancer cell death.
The Duke University-led team now believes CXCR2 could be a therapeutic target for advanced and therapy-resistant prostate cancer.
“Because CXCR2 is ubiquitously expressed by neuroendocrine cells in prostate cancer of all stages, targeting CXCR2 may particularly benefit patients whose tumors are advanced, recurrent, and resistant to currently available therapies,” Huang said in the statement. And pairing CXCR2 inhibition with standard AR blockade could target both the luminal and neuroendocrine cells to achieve a durable therapeutic effect, the researchers argued in the study.
Editor's Note: A previous version of the story stated that a navarixin-Keytruda clinical trial is on hold. That is not the case, per clarification from Merck.