Researchers from the University of Illinois Cancer Center have developed a compound that more than doubles mean survival time in animal models of pancreatic cancer. Survival time was further extended when immune therapy was added.
Their findings, published in PNAS, show that the experimental compound XP-524 redirects two different proteins involved in pancreatic cancer and can help reactivate the immune response to pancreatic ductal adenocarcinoma. The novel compound was tested in test tubes, animal models of the disease, and human tissue samples.
XP-524 alters bromodomain and extra-terminal motif (BET) proteins and the histone acetyltransferase EP300/CBP, both present in pancreatic cancer. The two proteins interact to promote the formation of several types of tumors, including lung cancer. Researchers found XP-524 reshapes the tumor microenvironment and sensitizes it to immune checkpoint therapy.
The study was led by Cancer Center translational oncology group leader and endowed professor Ajay Rana, PhD, director of research in the Department of Surgery, and two equal co-first authors, Daniel Principe, an MD/PhD student in Rana’s lab, and Rui Xiong, PhD, UIC research assistant professor of pharmaceutical sciences.
No effective treatments for pancreatic cancer currently exist. The disease, which is resistant to chemotherapy, radiation therapy, and immunotherapy, has the lowest five-year survival rate of almost all cancers – 11% for all stages combined and less than 5% for distant disease. In studies, XP-524 appears to reprogram the pancreatic tumor microenvironment to extend survival, Rana explained.
“BET inhibitors show promise for treating pancreatic cancer, but so far that hasn’t translated to improving outcomes for patients. By simultaneously targeting two aspects of the disease process, we see the potential for a clinically effective treatment,” he said.
Due to high toxicity and limited clinical efficacy, clinical trials involving other BET inhibitors were stopped. The data suggested that BET inhibitors may be more effective when combined with other treatments, which led researchers to investigate a combination approach.
“In addition to extending survival in laboratory models of the disease, we also found XP-524 turned on the immune response and, when used in combination with an anti-PD1 antibody, more than doubled the median survival time in mouse models,” he added. “It could be a useful strategy to sensitize pancreatic tumors to immune checkpoint inhibition, though the approach warrants caution if it is explored in clinical trials.”
This work was largely supported by Veterans Affairs Merit Award I01BX004903 and Career Scientist Award IK6 BX004855 to Ajay Rana, by Chicago Biomedical Consortium Accelerator Award and NIH UL1TR002003 provided via the UICentre to Gregory Thatcher and Rui Xiong.