Life-changing new drug revolutionizes pancreatic cancer treatment
The inhibitor targets the KRAS gene mutation, which is responsible for almost 90 percent of pancreatic cancers.
[June 17, 2023: Staff Writer, The Brighter Side of News]
A small molecule inhibitor that attacks the difficult to target, cancer-causing gene mutation KRAS, found in nearly 30 percent of all human tumors. (CREDIT: Creative Commons)
Researchers from Penn Medicine’s Abramson Cancer Center have made a breakthrough in the fight against pancreatic cancer with the discovery of a small molecule inhibitor that has been shown to shrink tumors or halt cancer growth in preclinical models of the disease. The inhibitor targets the KRAS gene mutation, which is found in almost 30 percent of all human tumors and is responsible for almost 90 percent of pancreatic cancers.
The study, which was published in the journal Cancer Discovery, was led by co-corresponding senior authors Ben Stanger, MD, PhD, the Hanna Wise Professor in Cancer Research in the Perelman School of Medicine at the University of Pennsylvania and director of the Penn Pancreatic Cancer Research Center, and Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center and the John H. Glick Abramson Cancer Center Professor in the Perelman School of Medicine.
The team used a small molecule inhibitor called MRTX1133, which was developed by Mirati Therapeutics, to specifically target the KRAS G12D mutation. The drug was found to not only directly target cancer cells but also unexpectedly cooperate with the immune system to produce a durable response to treatment. This is important because cancer eventually finds a way to evade most targeted therapies.
“The results of this study are in stark contrast to anything we’ve seen before in pancreatic cancer,” said Stanger. “Even in preclinical research models for this cancer type, most drugs tested within the last decade – including novel immunotherapies – have had limited impact.”
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Pancreatic cancer has an overall poor prognosis, with a five-year survival rate of only 11 percent and limited treatment options. The KRAS gene mutation is the most common oncogene across cancer types and the first targeted therapy for KRAS was approved last year for non-small cell lung cancer with KRAS G12C mutations, but only 2 percent of pancreatic cancers express that type of mutation. Around 36 percent of pancreatic cancers with a KRAS mutation are KRAS G12D-mutant.
The research team was able to assess the impact of MRTX1133 on the immune system by using a type of model that allows the tumor to spontaneously evolve after implantation in otherwise healthy mice, making it possible to discern the drug’s impact on the surrounding tumor microenvironment (TME).
The immunocompetent KPC model was developed by Penn Medicine nearly 20 years ago and is the gold standard used worldwide to assess potential therapies for pancreatic ductal adenocarcinoma (PDAC). PDAC is known for having a particularly dense TME, which contributes to resistance to therapy.
MRTX1133 selectively inhibits KRASG12D and downstream MAPK signaling in vitro. MRTX1133 dose response of BxPC-3 (KRASWT), AsPC-1 (KRASG12D), and MIA PaCa-2 (KRASG12C) cells after 72h of treatment. 3-fold serial dilutions were used, and cell viability was measured with CellTiter-Glo. IC50 values are listed. (CREDIT: Cancer Discovery)
The team found that the drug prompted an increase of T cells in the TME, which improved the depth and duration of response to MRTX1133. All complete remissions observed in the study were accompanied by T cell-mediated anti-tumor immunity. In mice without T cells, the effect of MRTX1133 was brief, and tumors grew back much more quickly. These results suggest that MRTX1133 could be combined with immunotherapy to improve the long-term response to therapy and keep the cancer from returning.
“After many years of work to find much-needed new approaches for patients with pancreatic cancer, it’s exciting to have a new class of drugs on the horizon,” said Vonderheide. “We’re optimistic that KRAS G12D inhibitors will make their way into clinical trials soon. KRAS is surrendering, and now we know the immune system can see it.”
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. MRTX1133 dose response of 4662-KRASG12D and 4662-KRASG12C after 72h of treatment. 5-fold serial dilutions were used. IC50 values are listed (CREDIT: Cancer Discovery)
Clinical trials are a crucial step in the drug development process, as they allow researchers to evaluate the safety and efficacy of new treatments. Before a drug can be approved for use by the FDA, it must go through several phases of clinical trials.
Pancreatic cancer is one of the deadliest forms of cancer, with a 5-year survival rate of just 11%. The majority of pancreatic cancers are driven by mutations in the KRAS gene, which makes it an attractive target for researchers looking to develop new treatments.
The first targeted therapy for KRAS, sotorasib, was approved by the US Food and Drug Administration (FDA) in 2021 for the treatment of non-small cell lung cancer with KRAS G12C mutations. However, only a small percentage of pancreatic cancers have this type of mutation, so there is a need for new treatments that target other KRAS mutations.
MRTX1133 is selective for KRASG12D in immunocompetent implantation tumor models. Waterfall plot of vehicle and MRTX1133 treated tumors (6419c5, subcutaneous) showing change in tumor volume after 7d of treatment compared to baseline at day 0. Each bar represents a single tumor. n=10 mice/group. (CREDIT: Cancer Discovery)
The researchers note that while the results are promising, there is still much work to be done. The next step will be to move the treatment into clinical trials and test it on human patients. However, the success of the preclinical models provides hope that this new approach could be a breakthrough for pancreatic cancer treatment.
Symptoms of Pancreatic Cancer
According to the Mayo Clinic, signs and symptoms of pancreatic cancer often don't occur until the disease is advanced. They may include:
Abdominal pain that radiates to your back
Loss of appetite or unintended weight loss
Yellowing of your skin and the whites of your eyes (jaundice)
Light-colored stools
Dark-colored urine
Itchy skin
New diagnosis of diabetes or existing diabetes that's becoming more difficult to control
Blood clots
Fatigue
The study was supported by the National Institutes of Health (R01-CA229803, R01-CA252225, T32-CA009140 and P30-CA016520), the Cancer Research Institute (CRI4097), the Parker Institute for Cancer Immunotherapy, the Penn Pancreatic Cancer Research Center and The Abramson Family Cancer Research Institute.
The study was supported by the National Institutes of Health (R01-CA229803, R01-CA252225, T32-CA009140 and P30-CA016520), the Cancer Research Institute (CRI4097), the Parker Institute for Cancer Immunotherapy, the Penn Pancreatic Cancer Research Center and The Abramson Family Cancer Research Institute.
For more science and technology stories check out our New Discoveries section at The Brighter Side of News.
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