Probing new targets for treating the most lethal form of pancreatic cancer

Pancreatic Cancer Ribbon
Disrupting the metabolism of cancer cells is one strategy being investigated to treat pancreatic ductal adenocarcinoma. (Photo by ThitareeSarmkasat/iStock/Getty Images Plus)

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and also one of the most difficult cancers to treat, because the tumors evolve to evade chemotherapy, and they often spread rapidly throughout the body.

Two new studies are reporting progress in the ongoing effort to find new targets for treating PDAC. One seeks to disrupt the metabolism of cancer cells, while the other blocks a key protein that PDAC cells need to grow.

Monday, Tyme Technologies presented data from a small phase 2 study of its lead drug candidate, SM-88 (racemetyrosine), which is designed to kill cancer cells by exposing them to oxidative stress. During the study, the investigators tracked an 80% decline in circulating tumor cells and observed a correlation between that decline and overall survival. The median overall survival rate among the 38 patients who were evaluated was six months.

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The results prompted Tyme to announce that it will launch a pivotal phase 3 trial of SM-88 this quarter. The company discussed the results of the phase 2 trial at the American Association for Cancer Research (AACR) Special Conference on pancreatic cancer in Boston.

Treating pancreatic cancer by disrupting metabolic pathways is a popular idea. France’s Erytech Pharma was cleared by the FDA in June to start a phase 3 trial of its drug, eryaspase, in pancreatic cancer. Eryaspase is designed to break down asparagine, an amino acid that serves as a nutrient for cancer cells.

Another amino acid, glutamine, could also be a tangible target in pancreatic cancer, scientists from Sanford Burnham Prebys (SBP) Medical Discovery Institute suggested earlier this summer. They analyzed cell lines from patients with PDAC and discovered depleting the cancer cells of glutamine made them more sensitive to some drugs used to treat pancreatic cancer.

Metabolism-targeted drugs are also being investigated in other cancers. Tyme has charted responses to SM-88 in 15 tumor types, including breast and prostate cancers, the company said.

RELATED: Treating pancreatic cancer by starving tumor cells

Last week, a team at MD Anderson Cancer Center reported progress in their efforts to thwart the growth of pancreatic cancer via a different mechanism: starving the cells of ubiquitin specific protease 21 (UPS21). The gene that makes the protein is frequently amplified in PDAC, they reported in the journal Genes & Development.

“This overexpression correlated with cancer progression in PDAC patient samples, drove malignant transformation of human pancreas cells, and promoted mouse tumor growth,” said Ronald DePinho, M.D., professor of cancer biology at MD Anderson, in a statement.

The MD Anderson researchers depleted UPS21 in mouse models of pancreatic cancer and observed impaired tumor growth. They suggested that UPS21 stabilizes a transcription factor that in turn promotes the “stemness” of cancer cells, or their ability to proliferate.

Several biotech companies are investigating the potential of targeting the stability of cancer-driving proteins including Cedilla Therapeutics and Nutrix, which formed a $45 million research pact with Gilead Sciences in June.

To validate UPS21 as a target, the MD Anderson team consulted an “atlas” of genetic aberrations that have been found to drive PDAC. DePinho believes that by further probing these genes, his team will find new therapeutic strategies for treating pancreatic cancer.

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