Sept. 14, 2020
In his previous role at Moffitt Cancer Center, Said Sebti, Ph.D., and his colleagues discovered a novel drug that overcomes a major hurdle in halting the growth of malignant tumors driven by the cancer-causing KRAS protein, including in pancreatic cancer. Now Sebti, the associate director for basic research at VCU Massey Cancer Center and a professor of pharmacology and toxicology at the VCU School of Medicine, is working with Massey researchers and the Medicines for All Institute at VCU to further develop this drug, called FGTI-2734, in an effort to eventually gain Food and Drug Administration approval for testing in clinical trials.
Pancreatic cancers are the fourth-leading cause of cancer-related deaths in the United States, and KRAS is mutated in 90% of pancreatic cancers. Cancer patients with KRAS mutations have more aggressive tumors, respond poorly to chemotherapy and targeted therapies and tend to have a worse prognosis. Targeting KRAS and developing KRAS-specific therapies is a high priority for the National Cancer Institute.
A protein called farnesyltransferase (FT) is behind the cancer-causing activity of KRAS. Previous clinical approaches have revolved around the development of drugs to inhibit this protein, but these therapeutics have been mostly ineffective because KRAS can be alternatively activated by another protein.
“At present, there are no FDA-approved drugs to directly target mutant KRAS-driven human cancers, and novel drugs are urgently needed for the large number of afflicted patients,” said Sebti, the Lacy Family Chair in Cancer Research and a member of the Developmental Therapeutics research program at Massey. “We developed a small molecule that overcomes the major hurdle of mutant KRAS-dependent resistance to FT [inhibitors], thwarting growth in primary and metastatic tumor samples.”
Through previous research, published in Clinical Cancer Research and supported by a National Cancer Institute grant, Sebti and collaborators discovered the FGTI-2734 drug can inhibit KRAS membrane localization, which is required for its cancer-causing activity. The drug proved effective when applied to human pancreatic, lung and colon tumors. It also prevented growth in tissue samples from four pancreatic cancer patients with mutant KRAS tumors and suppressed the viability of KRAS tumor cells in eight pancreatic cancer patients, some of whom were resistant to chemotherapy.
Finally, the research also showed that the drug blocked cancer-causing pathways while increasing the levels of the body’s own cancer-suppressing protein.
“We demonstrated FGTI-2734’s therapeutic efficacy in clinical samples from 12 pancreatic cancer patients with mutant KRAS tumors,” Sebti said. “This discovery opens new avenues to target mutant KRAS-dependent cancers and warrants further advanced preclinical and clinical studies.”
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