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PanCAN Chief Scientific and Medical Officer Anna Berkenblit, MD, MMSc (left) with fellow advocacy organization representative Terri Conneran, founder of the KRAS Kickers and a survivor of lung cancer with a KRAS mutation.
For decades, one of the biggest challenges facing the cancer research community has been finding a way to therapeutically target RAS, the most common oncogene in human cancer. An oncogene is a gene that codes for a protein that is normally found in healthy cells that, when mutated or otherwise altered, contributes to the cells becoming cancerous. Approximately 30% of all solid tumors express a RAS mutation, with a staggering 95% of pancreatic tumors thought to be driven by mutations in a specific type of RAS, known as KRAS.
Following its discovery more than 40 years ago, RAS was considered “undruggable,” because researchers were not able to solve how to disrupt the structure of the protein or selectively attack the mutated version.
Within the past several years, the tide has turned tremendously.
This year, PanCAN Chief Scientific and Medical Officer Anna Berkenblit, MD, MMSc, attended the Fifth RAS Initiative Symposium, Oct. 8-10, in Frederick, MD, sponsored by the National Cancer Institute (NCI) RAS Initiative. Following years of unsuccessful attempts to target RAS, today there are many investigational drugs in preclinical and clinical development that target RAS. There are also two FDA-approved drugs that target a specific subset of KRAS mutations, known as KRAS G12C, in patients with lung cancer.
“It’s exciting for me to attend these prestigious meetings and see slides and poster presentations that cite PanCAN funding,” Dr. Berkenblit said. “The impact PanCAN has had in the research and clinical field is extraordinary, and we are at an inflection point in beginning to overcome the barriers to developing effective RAS-targeted therapies.”
RAS Symposium News and Updates
Presentations provided updates on the KRAS G12C-targeting drugs that were approved to treat lung cancer, with one of the drugs also approved as part of a combination approach for colorectal cancer. Although rare, the small subset of patients with pancreatic tumors that express KRAS G12C has also shown preliminary positive responses to these drugs. There were also discussions about the many drugs in scientific and clinical development that are designed to target additional specific mutations in KRAS, target all KRAS mutations, or even target all RAS mutations.
Several clinical trials are underway that are testing investigational drugs that aim to target KRAS mutations that occur more frequently in pancreatic tumors. The first Phase 3 clinical trial of a RAS inhibitor in pancreatic cancer opened to enrollment in October 2024. The trial, called RASolute 302, is testing an investigational RAS targeted therapy (RMC-6236) in patients with previously treated, metastatic pancreatic ductal adenocarcinoma (Clinicaltrials.gov NCT06625320). As researchers and clinicians continue to gather data about the different RAS-targeting drugs, they are also considering strategies to predict and overcome resistance to these investigational therapies.
Among the poster presenters at the meeting were PanCAN grantees Aaron Hobbs, PhD, and Kirsten Bryant, PhD, both proteges of Dr. Channing Der in their training. Dr. Der is a several-time PanCAN grantee and an emeritus member of our Scientific and Medical Advisory Board. He was involved in the initial discovery of RAS and has been making seminal discoveries in the field ever since.
Dr. Hobbs’ poster discussed compelling PanCAN-funded results related to a less studied form of mutated KRAS, G12R. Although researchers had previously believed that different mutated forms of KRAS would behave similarly in the cells, Dr. Hobbs and his team have shown that the signaling generated from KRAS G12R mutations differs from more common mutations like KRAS G12D. This information can help guide personalized treatment approaches for patients based on their tumor’s unique biology.
And Dr. Bryant showed data from her ongoing PanCAN Therapeutic Accelerator Collaborative Award-funded project that looks at blocking the activity of proteins that are directly activated by mutant KRAS. Set up alongside PanCAN’s inaugural Therapeutic Accelerator Award given to Verastem Oncology to launch an early-phase clinical trial, the Collaborative working group is a novel approach to translational research that takes place in parallel to a clinical trial, determining in real time why the treatment is effective for some patients and ineffective for others, and devising new combination therapies.
Overall, Dr. Berkenblit shared that the symposium highlighted our emerging understanding of the differences between different RAS mutations and the mechanisms of resistance, as well as data supporting combinations to overcome and prevent resistance.
A Brief History of the RAS Initiative, Pancreatic Cancer and PanCAN
The RAS Initiative was launched by the National Cancer Institute (NCI) at the Frederick National Laboratories in 2013 to establish research space, funding, and a concerted and collaborative effort to understand and devise strategies to target RAS. The passage of the Recalcitrant Cancer Research Act, spearheaded by PanCAN and our amazing advocates, led to the NCI devising a Scientific Framework that defined four key focus areas to improve outcomes for people with pancreatic cancer. One of the focus areas was KRAS, which contributed to the establishment of the RAS Initiative and renewed efforts to tackle RAS.
At the RAS Initiative Symposium, Dr. Berkenblit shared that they got to hear from W. Kimryn Rathmell, MD, PhD, and Douglas R. Lowy, MD, the Director and Principal Deputy Director of NCI, respectively. They spoke of the launch of the RAS Initiative, thanks to the idea from Nobel laureate Harold Varmus, MD, then-Director of the NCI, and progress made under the leadership of Frank McCormick, PhD, FRS, who’s a former PanCAN grantee and emeritus Scientific and Medical Advisory Board member.
Over the years, PanCAN partnered with the RAS Initiative to award several KRAS Fellowship and Travel Scholarship awards to promote collaboration between academic institutions and the NCI’s RAS Initiative and give early-career scientists the opportunity to visit the Frederick National Laboratories and receive mentorship from leaders in the KRAS field.
Around the same time as the establishment of the RAS Initiative, a research team at UC San Francisco identified a strategy to target KRAS G12C mutations. The two FDA-approved KRAS G12C-targeted drugs were based on this scientific insight. Patients with pancreatic cancer can learn about whether their tumor has a KRAS mutation and other features of their tumor biology through biomarker testing, offered free of charge through PanCAN’s Know Your Tumor® precision medicine service.
“We’re moving closer to a world where every patient with pancreatic cancer will be treated with a precision medicine approach – using genetics, biology, and other characteristics to determine the treatment rather than just the location of the tumor,” Dr. Berkenblit said.
“The upcoming emergence of RAS-targeted therapies into the clinic has the potential to revolutionize the treatment of patients with pancreatic cancer, and I’m excited to see results from the clinical trials and for PanCAN to play a role in supporting scientific and clinical research to help bring more effective treatment options to patients faster.”
