AACR: Attacking pancreatic cancer by thwarting its survival strategies

Pancreatic cancer
New tactics for treating pancreatic cancer seek to prevent tumors from using common escape mechanisms to evade therapies. (Manu 5 via Wikimedia Commons)

Pancreatic tumors employ multiple strategies for evading treatment, making them quick to spread and difficult to treat effectively. At this week’s virtual meeting of the American Association for Cancer Research (AACR), several research groups are presenting new therapeutic tactics aimed at interrupting survival pathways in pancreatic cancer.

A research team led by the University of Minnesota is investigating a combination of blocking both the immune checkpoint PD-L1 and CD40, a cell-surface molecule that also moderates the immune response to cancer. In mouse models of pancreatic cancer, either therapy alone prolonged survival—but the tumors recurred in 100% of the animals. The researchers found tumor “escape variants” in key genes.

When the team tested a combination of PD-L1 and CD40 blockade, 60% of the mice were cured, the researchers reported at AACR.

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They went on study gene expression in the tumors of the animals that received the combination treatment. They discovered an accumulation of tumor-specific T cells capable of eradicating pancreatic tumors. What’s more, the anti-PD-L1 and anti-CD40 combination prompted an accumulation of “memory” T cells in the pancreas—cells that could be critical for preventing recurrences. They plan to discuss the findings in detail on Wednesday.

CD40 is a popular target for researchers investigating cancer combination treatments. Roche, for example, is testing its CD40 drug, selicrelumab, in combination with its PD-L1 blocker Tecentriq in solid tumors.

RELATED: An immuno-oncology triplet from Roche shows promise in mouse models of several tumors

Tyme Technologies is pursuing a different strategy for preventing tumor escape—one that hinges on cancer metabolism. Its drug, SM-88 (racemetyrosine), is designed to alter protein synthesis, increase oxidative stress and change other metabolic factors in ways that hamper the ability of the cancer cells to survive.

Tyme used cell lines and mouse models to characterize the anti-cancer effects of SM-88, which is currently being tested in a pivotal clinical trial in metastatic pancreatic cancer.

At the AACR virtual conference, Tyme reported that SM-88 disrupted “autophagy” in two types of pancreatic cancer cells. Autophagy is the process by which cells recycle waste products so they can survive.

In mouse models of pancreatic cancer, the drug reduced levels of regulatory T lymphocytes and M2 macrophages—cells that suppress the immune response to cancer—Tyme showed in a poster presentation (PDF).

Tyme has started a phase 2/3 trial that will combine SM-88 with three other treatments in patients with metastatic pancreatic cancer who have failed two previous lines of therapy.

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