New pancreatic cancer drug delivers life-changing results

A small molecule inhibitor that targets a hard-to-find cancer-causing gene mutation. RED, found in nearly 30 percent of all human tumors. (CREDIT: Creative Commons)

A small molecule inhibitor that targets a hard-to-find cancer-causing gene mutation. RED, found in nearly 30 percent of all human tumors, has successfully reduced the tumor or stopped cancer growth in preclinical models of pancreatic cancer, researchers at Penn Medicine’s Abramson Cancer Center have shown, suggesting the drug is a strong candidate for clinical trials. The study was published in Cancer discoveryJournal of the American Association for Cancer Research.

“The results of this study are in stark contrast to anything we’ve seen before for pancreatic cancer,” said co-author, senior author Ben Stanger, MD, Hannah Wise Professor of Cancer Research at the Perelman School of Medicine at UCLA. University of Pennsylvania and director of the Pennsylvania Center for Pancreatic Cancer Research. “Even in preclinical research models for this type of cancer, most of the drugs tested over the past decade, including newer immunotherapies, have had limited impact.”

Patients with pancreatic cancer have a generally poor prognosis with a five-year survival rate of 11 percent and limited treatment options. Nearly 90 percent of pancreatic cancers are caused by a mutation in RED gene, the most common oncogene among cancer types. First targeted therapy RED was approved last year for the treatment of non-small cell lung cancer with KRAS G12C mutations, but only 2 percent of pancreatic cancers show this type of mutation. About 36 percent of pancreatic cancers RED mutation KRAS G12D-mutant.

The small molecule inhibitor used in this study, MRTX1133 (developed by Mirati Therapeutics), specifically targets KRAS G12D, as the company first reported last month in natural medicine.

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Penn’s study now shows REDThe α-inhibitor not only directly affects cancer cells, but also surprisingly interacts with the immune system to cause a sustained response to treatment, which is important because cancer eventually finds a way to evade most targeted treatments.

“We know from KRAS G12C studies and other targeted therapy studies show that resistance can occur,” Stanger said. “Even before we start clinical trials, we are thinking about how to combine drugs so that the tumors do not return. Our results provide evidence to suggest immunotherapy as a partner with KRAS G12D inhibitors.”

The researchers were able to evaluate the effect of MRTX1133 on the immune system because the type of model used in the study allows the tumor to spontaneously develop after implantation in healthy mice, which allows the impact of the drug on the microenvironment surrounding the tumor to be determined. TME).

MRTX1133 selectively inhibits KRASG12D and downstream MAPK signaling in vitro. Dose-dependent response of MRTX1133 cells BxPC-3 (KRASWT), AsPC-1 (KRASG12D) and MIA PaCa-2 (KRASG12C) after 72 hours of treatment. Used 3-fold serial dilution and measured cell viability using CellTiter-Glo. IC50 values ​​are listed. (CREDIT: Cancer discovery)

The KPC immunocompetent model was developed by Penn Medicine nearly 20 years ago and is the gold standard used worldwide to evaluate potential treatments for pancreatic ductal adenocarcinoma (PDAC). PDAC is known for having a particularly dense TME, which contributes to therapy resistance.

The research team found that the drug caused an increase in the number of T cells in the TME, which improved the depth and duration of the response to MRTX1133. All complete remissions observed in the study were accompanied by T-cell mediated antitumor immunity.

MRTX1133 selectively inhibits KRASG12D and downstream MAPK signaling in vitro. Representative Western blot of cell lysates from 6419c5 (KRASG12D) cells treated with MRTX1133 or DMSO control for two hours. Representative Western blot of cell lysates from BxPC-3 (KRAS-WT) cells treated with MRTX1133 or DMSO control for two hours. Dose response of MRTX1133 for 4662-KRASG12D and 4662-KRASG12C after 72 hours of treatment. Used 5-fold serial dilutions. IC50 values ​​are listed (Credit: Cancer Discovery).

In mice without T cells, the effect of MRTX1133 was short-lived and tumors grew much faster. These results suggest that MRTX1133 can be combined with immunotherapy to improve long-term response to therapy and prevent cancer recurrence.

“After years of work to find much-needed new approaches to treating patients with pancreatic cancer, it’s exciting to see a new class of drugs on the horizon,” said co-author Robert Vonderheide, MD, director of Abramson Cancer. Center and John H. Glick Abramson Cancer Center Professor at Perelman School of Medicine, whose lab members worked with Stanger lab staff in a focused collaborative team on this study. “We are optimistic that KRAS G12D inhibitors will soon enter clinical trials. RED gives up, and now we know that the immune system sees it.”

MRTX1133 is selective for KRASG12D in immunocompetent implanted tumor models. Waterfall plot for tumors treated with vehicle and MRTX1133 (6419c5, SC) showing change in tumor volume after 7 days of treatment from baseline on day 0. Each band represents one tumor. n=10 mice/group. (CREDIT: Cancer discovery)

The study was supported by the National Institutes of Health (R01-CA229803, R01-CA252225, T32-CA009140 and P30-CA016520), Cancer Research Institute (CRI4097), Parker Cancer Institute.

Immunotherapy, Pennsylvania Pancreatic Cancer Research Center and Abramson Family Cancer Research Institute.

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Note. Materials provided above by UPenn School of Medicine. Content can be edited for style and length.

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