Dosage and Timing may Improve Effectiveness of PI3K-inhibitors in Breast Cancer

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Citations American Association of Cancer Researchers conference

Newswise — (Lebanon, NH, 4/9/14) Researchers from the Geisel School of Medicine at Dartmouth will present a scientific poster on Wednesday, April 9, 2014 at the American Association of Cancer Researchers conference in San Diego, CA. Their study suggests that manipulation of drug dosage and schedules may improve anti-tumor effects of PI3K-inhibitors to target breast cancer tumors. These findings have implications for the optimal strategy to use such drugs in patients, and lay the groundwork for future development of anti-cancer therapeutics.

Sixty-five percent of all breast cancers are estrogen receptor positive (ER+), with tumors that can stop growing or die when treated with drugs that block estrogen signaling. Eighty percent of these ER+ breast cancers have mutations on the PI3K pathway, which regulates cell growth. Drugs that target the PI3K pathway have shown promise for the treatment of anti-estrogen-resistant breast cancers in early clinical trials.

The Dartmouth researchers noted that in clinical studies, novel drugs are often delivered in escalating doses until toxicities are observed in patients; this approach doesn’t provide information on target inhibition in tumors. Current PI3K inhibitor treatment regimens incompletely and temporarily inhibit the pathway in cancers, and are often accompanied by adverse effects in patients.

“We wanted to see if short-term, complete blocking of PI3K would have a greater impact on tumors, and also reduce the adverse effects,” said Todd Miller, principal investigator on the study and assistant professor of Pharmacology and Toxicology at Geisel. “Our findings indicate that optimization of rational drug doses and schedules early in the clinical development process may improve anti-tumor effects in larger, later-phase trials.”

The study suggests that short-term, complete inhibition of PI3K would have a greater anti-tumor effect than chronic, partial inhibition. The researchers will build on this study to test the anti-tumor efficacy of different treatment regimens of anti-estrogen and PI3K inhibition in different models of ER+/HER2- breast cancer.

This study is supported by the National Cancer Institute (R00CA142899; P30CA023108) and the American Cancer Society (#RSG-13-292-01-TBE). The research team for the project included Wei Yang, Jennifer R. Bean, Lloye Dillon, Laurent Salphati, Michelle A. Nannini, and Todd W. Miller

Poster #5512, “Pharmacodynamic analysis of PI3K inhibition in breast tumors: a model to improve early clinical investigation of novel agents,” will be in Hall A-E Section 33 from 8:00-12:00 pm PT on April 8, 2014 at the AACR Conference.

About Norris Cotton Cancer Center at Dartmouth-Hitchcock
Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 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 online at cancer.dartmouth.edu.

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