Thus, they discovered that tumor cells can eliminate the oncogene identified by drugs that specifically target them, and regain the oncogene after treatment is stopped. Importantly, the tumor cells’ dynamic ability to reacquire this oncogene makes them vulnerable to the original therapy.
“Now that we know that tumor cells have the surprising capacity to lose this oncogene during treatment and then reverse the process after drug removal, we may be able to exploit this phenomenon in the clinic,” Nathanson said.
Glioblastoma is the most common and deadliest form of brain cancer. Drugs have been designed to find and kill glioblastoma cells by targeting telltale mutations on the cell surface that accelerate tumor growth. The JCCC team, led by first author David Nathanson, assistant professor of Molecular and Medical Pharmacology, and former UCLA professor Paul Mischel, now at the Ludwig Institute for Cancer Research at UCSD, found that the tumor cells are able to eliminate the gene mutation, essentially removing the target while the drug is present and allowing the tumor to become drug resistant.
Remarkably, Nathanson and Mischel’s study, co-led by JCCC professors Harley Kornblum (UCLA), James Heath (UCLA and Caltech) in close collaboration with Dr. Timothy Cloughesy (UCLA), and Nagesh Rao (UCLA), also found that after the drug is removed, the tumor cells reacquire the gene mutation (called an oncogene) that helps the tumor cells grow more robustly.
Another exciting aspect of this discovery is that it is potentially applicable to other cancers that are susceptible to oncogene elimination. This is the first study to show reversible loss of an oncogene causing drug resistance, and could lead to different and more effective approaches to treat these cancers.
This research was supported by The Ben and Catherine Ivy Foundation Fund, the National Institutes of Health, the Ziering Family Foundation, Art of the Brain Fund, the James S. McDonnell Foundation, The European Commission, the Ruth L. Kirschstein Institutional National Research Service Award, the UCLA Scholars in Oncologic Molecular Imaging Program and the Ludwig Institute for Cancer Research.
Dr. Caius Radu, fellow senior author on the recently published IFN study and primary investigator for the second NIH grant, is a Professor of Molecular and Medical Pharmacology and Co-Director of the JCCC Cancer Molecular Imaging, Nanotechnology and Theranostics Program. Dr. Radu’s NIH grant, titled Targeting KRAS and adenosine mediated immunosuppression in pancreatic cancer will work in collaboration with Drs. Donahue and Wainberg to better understand the immunobiology of pancreatic tumors.
Immunotherapy has had great success for the treatment of other tumors such as melanoma and lung cancer but pancreatic tumors show an intrinsic resistance to immunotherapy. This immunosuppressive tumor microenvironment, along with KRAS mutations and altered metabolism, are all hallmarks that make pancreatic ductal adenocarcinoma (PDAC) so difficult to treat.
Research teams at UCLA have received two grants from the National Institutes of Health (NIH), totaling over $6 million dollars to study the immunobiology of pancreatic tumors and develop a series of immunotherapy clinical trials. Our Seed Grant Program funded the early stages of these research projects and provided the preliminary data used to secure this substantial NIH funding.
The complicated nature of the pancreatic cancer microenvironment has led to difficulties in treatment options but Stimulator of interferon genes (STING) agonists are a promising new avenue being explored in this study. This multiyear research seeks to understand the interplay between STING signaling, nucleotide/NAD metabolism and replication stress response in pancreatic ductal adenocarcinoma (PDAC) with the ultimate goal of developing new therapeutic treatments.
Research by 2019 Seed Grant award recipient, Thuc Le, PhD, furthered understanding of how mutant KRAS impacts nucleotide metabolism, as nucleotides play a critical role in tumor cell growth. The recent groundbreaking discovery of KRASG12C-specific inhibitors has proved hopeful for KRAS targeted therapies and open further exploration of immunotherapy for pancreatic tumors. There is also mounting evidence that the therapeutic potential of mutant KRAS inhibitors can only be fully realized when administered with immune-priming combination therapies. Dr. Radu’s project seeks to understand the interrelationships between KRASG12C inhibition, nucleotide metabolism, adenosine signaling, and immunosuppression in order to bring to clinical trial a new immunotherapeutic strategy that combines drugs across several therapeutic classes.
Through collaborative research, Dr. Donahue’s team continues to investigate the targetable vulnerabilities in pancreatic tumors to develop novel immunotherapy treatments for this disease. Dr. Donahue wrote us to say, “We are thrilled that the Hirshberg Foundation has supported both of our laboratories with Seed Grants that generated data specifically for these awards.”
One of the studies, led by Dr. Timothy Donahue will further the recently published research into interferon (IFN) signaling that triggers a decrease in the level of NAD and NADH in pancreatic cancer cells, crucial cofactors for cell function. Dr. Donahue’s NIH project titled Leveraging vulnerabilities induced by interferon signaling in pancreatic cancer, also builds on earlier IFN and NAD metabolism research from 2018 Seed Grant recipient Shili Xu, PhD.