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Investigators Named to Stand Up 2 Cancer’s Colorectal Dream Team

Weill Cornell Medicine and NewYork-Presbyterian have been named to the nonprofit Stand Up 2 Cancer’s Colorectal Dream Team to drive new advances in colorectal cancer research and treatment.

The interdisciplinary team, funded by a grant worth up to $12 million, brings together researchers from six institutions who will focus on three complementary areas of research that have the potential to affect all stages of colorectal cancer, from the pre-malignant lesion to patients diagnosed with metastatic disease. SU2C announced the grant, which also involves investigators from Memorial Sloan Kettering Cancer Center, Johns Hopkins University, Yale University and Case Western Reserve University, on April 3 at the American Association for Cancer Research’s annual meeting in Washington, D.C.

Dr. Lewis Cantley, the Meyer Director of the Sandra and Edward Meyer Cancer Center, will co-lead the dream team and head Weill Cornell Medicine and NewYork-Presbyterian’s nine-member cohort. His team will develop clinical trials in an effort to validate a 2015 discovery that a subset of colorectal cancers is sensitive to vitamin C therapy.

Colorectal cancer is the third most-common cancer diagnosed in the United States, with about 93,000 new cases each year. Around half of those cases harbor mutations in the KRAS and BRAF genes; these forms of the disease are more aggressive and don’t respond well to current therapies or chemotherapy. KRAS mutations are also found in 95 percent of pancreatic cancer cases and up to 25 percent of non-small cell lung cancer cases.

In a 2015 study in Science, Dr. Cantley and his team found in pre-clinical models that high doses of vitamin C — roughly equivalent to the levels found in 300 oranges — impaired the growth of KRAS and BRAF mutant colorectal tumors. 

The SU2C grant will now empower investigators to confirm their findings in human trials, with patients split into two groups. In the first, patients scheduled for surgery to treat their colon, pancreatic or lung cancer will receive regular vitamin C infusions in the four weeks leading up to their operation, with scans taken throughout this period. Physicians will collect tumor samples during the surgery, conducting genetic sequencing tests and growing pieces of the tumors into organoids for further study. The precise genetic mutation driving the disease, not known to researchers before the trial commences, will be used to evaluate how patients with the KRAS and BRAF subtypes responded compared to those without the mutations.

“We would expect and hope to see some tumor shrinkage among those with KRAS and BRAF mutations,” said Dr. Cantley, who serves on Agios Pharmaceuticals’s Board of Directors and Enlibrium’s Scientific Advisory Board — companies that develop drugs targeting cancer metabolism. He is also founder of Petra Pharma Corporation, a company developing small molecule inhibitors for treating cancer. “Increased time to progression or quantified stable disease would also be considered a good response.”

The second group will comprise previously treated patients known to have KRAS or BRAF mutations whose tumors did not respond to traditional therapies or whose diseases had metastasized. They will receive the same infusions, for up to six months, with a three-month check to see disease response. If there appears to be a clinical benefit, additional trials could be designed to determine optimal efficacy and dosage, and to compare therapeutic results against other treatments, such as current chemotherapy-based standard of care or combination therapy. 

The dream team’s other investigators will study the molecular underpinnings of treatment resistance, particularly to immunotherapy and other targeted treatments. They hope their findings will lead to new therapeutic strategies that can overcome the resistance, and inform the development of new treatment approaches for early-stage colorectal cancer.

 

 

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