Novel combination therapeutic approach could increase survival of pancreatic cancer patients

A novel combination treatment approach extended survival in mice with pancreatic cancer, demonstrating a potential second-line therapy for patients, according to findings published in Proceedings of the National Academy of Sciences.

Chemotherapy is still a standard of care for pancreatic cancer, and it is unlikely to get replaced as first-line treatment anytime soon. But there is an urgent need to develop additional therapies for patients who progress on first-line combination chemotherapy."

Hidayatullah G. Munshi, MD, the Robert and Lora Lurie Professor of Medicine, member of the Robert H. Lurie Comprehensive Cancer Center and co-author of the study

Pancreatic cancer currently is the third-leading cause of cancer death in the US. Depending on the stage, the standard course of treatment is surgery, radiation and chemotherapy.

While these treatments can help extend patient survival, pancreatic cancer often progresses, underscoring the need for additional novel treatment strategies.

Pancreatic cancer is also associated with the dysregulation of certain epigenetic regulators, such as bromodomain and extraterminal motif (BET) proteins. These proteins read histone acetylation marks on chromatin while also facilitating the transcription of oncogenes that are essential for cancer cell survival and proliferation.

"That has been one of the reasons why BET proteins are very attractive and promising therapeutic targets. If you block these proteins, then you could block the transcription of certain oncogenes and therefore slow down or stop cancer cell proliferation," said Thao Nguyen Pham, PhD, a postdoctoral fellow in the Munshi laboratory and co-author of the study.

Unfortunately, BET inhibitors have demonstrated poor efficacy as single-agent therapy in recent clinical trials. However, when combined with other treatments, BET inhibitors exhibited greater efficacy in pancreatic cancer models, suggesting that a combined therapeutic approach could increase patient survival.

In the current study, investigators developed a novel compound called XP-524, which inhibits two proteins expressed in pancreatic cancer tissues and work together to enhance tumor formation: BET protein BRD4 and EP300/CBP.

First, the investigators tested the compound in pancreatic cancer cell lines and pancreatic tissue ex vivo, demonstrating increased potency and tumoricidal activity.

When tested in mice with pancreatic cancer, the investigators found the compound prevented neoplastic transformation induced by the oncogene KRAS and increased survival. The investigators also found that XP-524 increased the recruitment of cytotoxic T-cells to the tumor site but failed to promote an effective antitumor immune response due to T-cell exhaustion.

The investigators then combined XP-524 with an anti-PD-1 antibody, which has been shown to boost the body's immune response against cancer cells. They found the combination treatment helped elicit a cytotoxic immune response against tumor cells in vivo, extending overall survival beyond XP-524 alone.

According to Munshi, the team plans to eventually evaluate the safety and efficacy of the compound in clinical trials, as both a single-agent and in combination with other existing immunotherapies.

"You are killing two birds with one stone, which is good. But it could also be bad. If you inhibit multiple targets, you may have increased toxicity," Munshi said.

Source:
Journal reference:

Principe, D.R., et al. (2022) Elephant genotypes reveal the size and connectivity of transnational ivory traffickers. PNAS. doi.org/10.1073/pnas.2116764119.

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