Cancer Center Researchers Find New Cancer-Fighting Drug Combination
March 29, 2012
Treatment targets DNA to arrest tumor growth
Researchers at Dartmouth-Hitchcock Norris Cotton Cancer Center have found that combinations of certain cancer-fighting drugs significantly increase their cancer-killing ability compared to their individual effectiveness. Cytotoxicity was dramatically increased by a novel and selective Chk1 inhibitor (SCH900776) when combined with hydroxyurea, according to a study published in Molecular Cancer Therapeutics (Mol Cancer Ther February 2012 11;427).
"These results are exciting as they provide the foundation for a novel clinical trial. The results define an optimum drug combination and schedule, and demonstrate a dramatic sensitivity of some tumor cell lines," said Alan Eastman, PhD, professor of pharmacology and toxicology at Dartmouth Medical School and co-director of the Molecular Therapeutics Research Program at the Cancer Center, who was the lead investigator on the study. "We believe this combination may be effective in some patients without eliciting unnecessary toxicity."
Many established cancer-fighting drugs damage a tumor's DNA. But a tumor's cells usually respond by activating checkpoints that arrest cell cycle progression and permit time for repair of the damage to the DNA, allowing the tumor to survive. A critical checkpoint protein in this pathway is Chk1. The drug SCH900776 (recently renamed MK-8776), currently in Phase I clinical trials, inhibits Chk1, thereby reducing time for repair and increasing the other anti-cancer drug's efficacy. Dr. Eastman's team screened several different anti-cancer agents and discovered a 100-fold sensitization when SCH900776 was combined with hydroxyurea. Other potent combinations involved cytarabine and gemcitabine.
The research revealed two very important factors to consider when developing a clinical trial of this drug combination. First, the schedule of drug administration is critical, with maximum sensitivity occurring when SCH900776 is administered 18 hours after the hydroxyurea is administered. Second, some cell lines were found to be highly sensitive to SCH900776 alone and this enhanced their efficacy when combined with hydroxyurea. Dr. Eastman's group hypothesizes that this sensitivity will also be seen in some patients' tumors, and ongoing research will identify which tumors are most sensitive. Other studies are already confirming the efficacy of the SCH900776/hydroxyurea combination and therapy schedule in animal models, and a Phase 1 clinical trial has been approved that will begin to assess the potential toxicities and efficacy in human cancer patients.
The paper, "Preclinical Development of Novel Chk1 Inhibitor SCH900776 in Combination with DNA Damaging Agents and Antimetabolites," appeared in the February 2012 issue of the peer-reviewed journal Molecular Cancer Therapeutics. Other authors of the paper who are affiliated with Norris Cotton Cancer Center include Ryan Montano and Kristen Garner. The research was funded by a grant from the National Cancer Institute.
About Dartmouth-Hitchcock Norris Cotton Cancer Center
Norris Cotton Cancer Center combines advanced cancer research at Dartmouth College and Dartmouth Medical School with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center, at Dartmouth-Hitchcock regional locations in Manchester and Keene, N.H., and St. Johnsbury, Vt., and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 40 centers nationwide to earn the National Cancer Institute's "Comprehensive Cancer Center" designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials at cancer.dartmouth.edu.