Targeting KRAS Mutations in Pancreatic Cancer

Trial Investigates Novel Approach to Targeting KRAS Mutations in Pancreatic Cancer; Researchers Identify Early Sign of the Disease

Medical oncologists in the Pancreaticobiliary Tumor Center, part of the Center for Gastrointestinal Oncology and the Robert T. and Judith B. Hale Center for Pancreatic Cancer at Dana-Farber/Brigham and Women’s Cancer Center, are leading a novel clinical trial for pancreatic cancer and have recently discovered a new sign of early development of the disease.

Identifying Key Genes Downstream of KRAS

The trial is based on pioneering research performed by David Barbie, MD, a medical oncologist in the Lowe Center for Thoracic Oncology, and William C. Hahn, MD, PhD, Deputy Chief Scientific Officer and Director, Center for Genome Discovery. After conducting systematic screens of genes in KRAS mutant and wild-type cell lines, they discovered that the kinase TBK1 was selectively essential in cells that harbor mutant KRAS (Nature. 2009 November 5; 462(7269):  108-112.). Through further testing in human and murine lung cancers, they confirmed that tumors that depend on oncogenic KRAS require TBK1 activity and inhibition of this activity leads to tumor regression.

“Finding drugs that effectively target KRAS, which is mutated in a wide range of cancers, has been an extremely difficult challenge,” said Dr. Barbie. “We developed a novel approach to targeting KRAS mutant tumors by examining signaling downstream from KRAS.”

Building on these earlier findings, researchers in the Pancreaticobiliary Tumor Center are now conducting studies to investigate a novel approach to target KRAS mutations.

Combination Trial for Advanced Pancreatic Ductal Adenocarcinoma

The Gemcitabine and Nab-paclitaxel Combined with Momelotinib in Participants with Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma trial is a two-phase study evaluating a combination therapy that is designed to interrupt TBK1 signaling in KRAS mutant pancreatic tumors. Following a lead-in phase to evaluate safety and define the maximum tolerated dose, participants are being randomized to receive nab-paclitaxel and gemcitabine, the standard-of-care for advanced pancreatic cancer, with either momelotinib or placebo. The study, which will measure overall survival, progression-free survival, and response rate, could lead to expedited review and approval of the therapy, if it is shown to be effective. For more information regarding this trial, please contact Principal Investigator Kimmie Ng, MD, MPH, at (617) 632-4150 or kng4@partners.org.

“With KRAS mutations present in up to 90 percent of all pancreatic tumors, this approach has the potential to benefit many patients,” said Kimmie Ng, MD, MPH, a medical oncologist in the Pancreaticobiliary Center.

Early Sign of Pancreatic Cancer

Dana-Farber/Brigham and Women’s Cancer Center medical oncologist Brian Wolpin, MD, MPH, recently led a study examining metabolic changes that occur before pancreatic cancer is diagnosed. Using prediagnostic plasma samples from individuals with pancreatic cancer, derived from the Brigham and Women’s Hospital Nurses’ Health Study and other large studies, the researchers profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer, along with matched controls. They found that elevated plasma levels of branched-chain amino acids (BCAAs) were associated with a greater than two-fold increased risk of future pancreatic cancer diagnosis, with the strongest association observed two-to-five years before diagnosis. (Nat Med. 2014 Oct;20(10):1193-8.)

“The majority of patients with pancreatic ductal adenocarcinoma are diagnosed in an advanced stage of the disease and survive less than 12 months following diagnosis,” said Dr. Wolpin. “Our findings suggest that, together with genetic and other risk factors, elevated levels of branched-chain amino acids may serve as a useful marker for diagnosing pancreatic cancer earlier in the disease process.”

Using pre-clinical models in collaboration with Matthew Vander Heiden, MD, PhD, a medical oncologist in the Center for Genitourinary Oncology, the researchers also showed that plasma BCAAs were elevated in early-stage pancreatic cancers driven by mutant KRAS expression (but not in KRAS-driven tumors in other tissues) and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. These findings point to increased whole-body protein breakdown as an early event in development of pancreatic cancer, similar to what is seen in cancer cachexia.

“By uncovering key elements in the underlying biology of pancreatic cancer, our team is introducing new approaches to the treatment and earlier detection of this disease,” said Charles S. Fuchs, MD, MPH, Director of the Center for Gastrointestinal Oncology and the Robert T. and Judith B. Hale Chair in Pancreatic Cancer.

  • William C. Hahn, MD, PhD
    Deputy Chief Scientific Officer, Director, Center for Genome Discovery, Dana-Farber Cancer Institute
    Medical Oncologist, Center for Genitourinary Oncology, Dana-Farber/Brigham and Women’s Cancer Center
  • Charles S. Fuchs, MD, MPH
    Director, Center for Gastrointestinal Oncology, Robert T. and Judith B. Hale Chair in Pancreatic Cancer, Dana-Farber/Brigham and Women’s Cancer Center
  • David Barbie, MD
    Medical Oncologist, Lowe Center for Thoracic Oncology, Dana-Farber/Brigham and Women’s Cancer Center
  • Kimmie Ng, MD, MPH
    Medical Oncologist, Pancreaticobiliary Tumor Center, Center for Gastrointestinal Oncology, Dana-Farber/Brigham and Women’s Cancer Center
  • Brian Wolpin, MD, MPH
    Medical Oncologist, Pancreaticobiliary Tumor Center, Center for Gastrointestinal Oncology, Dana-Farber/Brigham and Women’s Cancer Center

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