UCLA Jonsson Comprehensive Cancer Center researchers have been awarded two research grants, bringing $6 million from the National Institutes of Health to identify new ways to treat pancreatic cancer. A seriously deadly disease, pancreatic cancer is the third leading cause of cancer-related death in America with over 47,000 deaths annually. The survival rate is low—only one in ten people diagnosed with the disease make it beyond five years and most therapies have been unsuccessful beating the cancer. The lack of effective treatments to pancreatic cancer must be overcome, but the way to date has been “…an inadequate understanding of the biologic complexity of the disease and the mechanisms behind its resistance to therapies that work treating other cancers,” quotes co-principal investigator Dr. Caius Radu, professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA. The other co-investigator is Dr Timothy Donahue, a professor of surgery and chief of surgical oncology at the Geffen School of Medicine. The duo and their support seek to untangle those complexities as well as identify possible new immunotherapeutic approaches for the breakthrough pancreatic cancer patients and their loved ones seek.
The studies will focus on two areas of investigation, including 1) KRAS gene mutations and 2) interferon signaling in pancreatic cancer. What follows is a brief summary via the UCLA Jonsson Comprehensive Cancer Center news room.
KRAS: Genetic mutations and pancreatic cancer
The first grant project will focus on mutations to the KRAS gene, which are implicated in nearly all pancreatic cancer cases. Mutated KRAS genes drive tumor growth in the pancreas in much the same way mutations to BRCA genes drive the development of breast cancer.
Working with Dr. Zev Wainberg, an associate professor of medicine at the Geffen School of Medicine and co-director of UCLA Health’s gastrointestinal oncology program, the team will specifically target these KRAS oncogenes. In addition, they will investigate the mechanisms behind pancreatic cancer cells’ overproduction of adenosine, a metabolite that can suppress the body’s cancer-killing T cells, which play a crucial role in most immunotherapies.
“Immunotherapy has revolutionized the way we treat a number of malignancies, but to date, its impact in pancreatic cancer has been disappointing,” said Donahue, who is also the surgical director of the UCLA Agi Hirshberg Center for Pancreatic Diseases. “Conventional immune checkpoint inhibitors approved for use in melanoma, lung cancer and other solid tumors show little or no benefit for the vast majority of pancreatic cancer patients, indicating that additional priming of the immune system will be absolutely necessary to overcome the intrinsic resistance of pancreatic tumors to immunotherapy.”
In addition to studying preclinical models of pancreatic cancer, the researchers will use some of the support from the grant to open a clinical trial investigating new immunotherapeutic strategies that combine drugs across several therapeutic classes.
Interferon signaling: Looking for Vulnerabilities
The second project will focus on interferon signaling in pancreatic cancer. The team will seek to identify vulnerabilities in tumor cells’ interferon signaling process that can be leveraged for effective therapeutic strategies.
The researchers have already identified that interferon signaling is upregulated in a subset of human pancreatic cancer cells and functions to deplete nucleotides, which are essential for DNA replication and repair. They will continue to examine the mechanisms these tumor cells have in place to counterbalance the nucleotide-depleting and potentially deleterious effects of interferon signaling and will explore the potential therapeutic benefits of inhibiting the signaling process.
The information gleaned from these grant-funded experiments will provide the scientific basis for upcoming investigator-initiated clinical trials to evaluate novel immunotherapies against pancreatic cancer.
Dr. Caius Radu, professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA
Dr Timothy Donahue, a professor of surgery and chief of surgical oncology at the Geffen School of Medicine
Dr. Zev Wainberg, an associate professor of medicine at the Geffen School of Medicine and co-director of UCLA Health’s gastrointestinal oncology program
Call to Action: Note the hope is that these two grant-funded studies will generate the scientific basis for forthcoming investigator-initiated clinical trials to evaluate novel immunotherapies against pancreatic cancer. With TrialSite’s new Patient Communities, we hope to set up a pancreatic cancer group and provide ongoing news and intelligence for that patient group—including the tracking of this UCLA-based preclinical and clinical research, the investigators themselves—true global experts as well as other studies focused on this deadly form of cancer. Join TrialSite Communities and check out TrialSite Patient Centers.