A research team from Huntsman Cancer Institute at the University of Utah (the U) reports that a groundbreaking pathway-targeted therapy could be an effective treatment for certain melanoma patients and fill an unmet clinical need for patients with advanced disease.
Martin McMahon, PhD, senior director of preclinical translation at Huntsman Cancer Institute and professor of dermatology at the U, evaluated an investigative compound of the drug daraxonrasib in NRAS-driven melanoma. NRAS-driven melanoma is an aggressive type of skin cancer driven by mutations in the NRAS gene. Daraxonrasib, developed by Revolution Medicines, targets and inhibits RAS, a protein that drives cancer when altered. NRAS is a subtype of RAS that is mutated in roughly a quarter of melanoma cases.
The results of daraxonrasib as a treatment for metastatic pancreatic cancer-in which it doubled patients' life expectancy in a Phase 3 clinical trial-recently received a standing ovation from thousands of physicians at the American Society of Clinical Oncology Annual Meeting. Huntsman Cancer Institute was one of just 60 hospitals worldwide who offered that trial (RASolute 302).
"The remarkable success of daraxonrasib in the treatment of pancreatic cancer indicates that we are in an era where even the most recalcitrant RAS-driven cancers can be treated," says McMahon. "Our data strongly supports the potential future clinical utility of treating patients with NRAS-driven melanoma with daraxonrasib."
McMahon and his team evaluated the effectiveness of the RAS inhibitor in numerous preclinical models, including melanoma samples from patients. The results of the study have been published in Cancer Research, a journal of the American Association for Cancer Research.
"All our NRAS-driven models were very responsive to this RAS inhibitor. It's actually quite rare that we see shrinkage of NRAS-driven tumors," says Mona Foth, PhD, research scientist at Huntsman Cancer Institute and first author of the publication. "It's inspiring to think that these results could potentially lead to a new patient therapy that will help them overcome their disease."
Melanoma is the deadliest form of skin cancer, and their research aims to help fulfill an unmet clinical need in patients with metastatic disease. These patients usually receive immunotherapy, the harnessing of a patient's own immune system, as the earliest form of treatment. Immunotherapy has revolutionized metastatic melanoma care. Foth says the treatment is effective in about half of melanoma patients, sometimes with deep and durable responses.
If immunotherapy fails or becomes less effective, physicians switch to targeted therapies as a secondary line of treatment. Targeted therapies attack oncoproteins and their effectors to kill cancer cells or slow their growth.
"Patients with other mutations like BRAF have access to clinically approved secondary lines of treatment. But patients with NRAS-driven melanoma do not have effective targeted therapies to treat their cancer," says McMahon. "Daraxonrasib is a targeted therapy that may provide another path for treatment and hope for patients affected by this devastating disease."
The team also observed that some of the models became resistant to the drug, as often happens in patients taking pathway-targeted therapies. Resistance to daraxonrasib was tied to mutations in the mitogen-activated protein kinase (MEK1), a protein downstream of RAS, or to loss of expression of cyclophilin A, a chaperone protein required for the inhibitory action of daraxonrasib toward RAS proteins.
"We will need to do more research to find drug combinations, based on a backbone of daraxonrasib, that will increase the depth and durability of melanoma patient responses," says McMahon.
McMahon and Foth hope the drug will move into a clinical trial for patients who are either ineligible for immunotherapy or whose immunotherapy did not work.
"This research reflects the power of Huntsman Cancer Institute's integrated approach, where laboratory discovery, translational research, and clinical trials come together to accelerate progress for patients," says Neli Ulrich, PhD, MS, executive director of the Comprehensive Cancer Center and chief scientific officer at Huntsman Cancer Institute, Jon and Karen Huntsman Presidential Professor in Cancer Research, and professor of population health sciences at the U. "We are proud to contribute to advances that have the potential to change treatment options for our patients with melanoma. This is of utmost importance in Utah and the Mountain West, where melanoma is a very common cancer."
The critical research happening every day at Huntsman Cancer Institute is supported by the National Institutes of Health/National Cancer Institute, including Cancer Center Support Grant P30 CA042014, as well as Huntsman Cancer Foundation.
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