Targeting the hedgehog pathway in medulloblastoma and advanced basal cell cancer therapy

Abstract

Patricia LoRusso, D.O., director of the Phase I Clinical Trials Program at the Barbara Ann Karmanos Cancer Institute and professor of Internal Medicine at the Wayne State University School of Medicine, recently contributed to two articles published in The New England Journal of Medicine. The New England Journal of Medicine is the oldest continuously published medical journal in the world and is one of the most popular and widely-read peer-reviewed general medical journals in the world. "Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma" was published in The New England Journal of Medicine on September 2, 2009. The study focused on basal-cell carcinoma, the most common skin cancer in the United States, and assessed the safety and pharmacokinetics of GDC-0449, a small-molecule inhibitor of smoothened homologue, and responses of metastatic or locally advanced basal-cell carcinoma to the drug. The study concluded that GDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal-cell carcinoma. The second article, "Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449," was also published on September 2, 2009 in The New England Journal of Medicine. This study focused on medulloblastoma, the most common malignant brain tumor in children, and the abnormal activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449, and treatment resulted in rapid, although temporary, regression of the tumor and reduction of symptoms. Molecular analyses of tumor specimens obtained before treatment suggested that there was activation of the hedgehog pathway, with loss of heterozygosity and somatic mutation of the gene encoding patched homologue 1 (PTCH1), a key negative regulator of hedgehog signaling. Dr. LoRusso developed the Phase I program at Karmanos, one of only 14 National Cancer Institute (NCI)-funded Phase I programs in the country, and the only such program in Michigan. For patients with advanced cancer who have exhausted conventional treatments, Dr. LoRusso's program brings them their last, best hope: tomorrow's drugs today. Dr. LoRusso has been integrally involved in the early clinical development of five of the last nine cancer drugs to become commercially available. Dr. LoRusso is recognized as an international expert in early phase clinical research. She has been awarded prestigious grants from the NCI and the Michigan Economic Development Corporation, and serves as Co-Chair of the NCI's Investigational Drug Steering Committee. She has also served on both the Education and Scientific committees of the American Society of Clinical Oncology, the Scientific Committee of the American Association for Cancer Research, and as a parent member of the NCI's Quick Trials Clinical Subcommittee. Dedicated to serving the community in which she was born, Dr. LoRusso gives cancer patients in Michigan access to as many novel agents as possible in hopes of granting them the best chance of improving their condition. Her goal is to make a difference in the lives of cancer patients. A member of the American Osteopathic Association and the American Association for Cancer Research, she has won numerous awards, including the 1999 Heroes of Breast Cancer and the 2004 Bennett J. Cohen Educational Leadership Award for Medical Research. Dr. LoRusso received her bachelor's degree from the University of Detroit and her doctor of osteopathy degree from Michigan State University. She completed her internship and residency in internal medicine at Riverside Osteopathic Hospital in Trenton, and completed a fellowship in hematology and oncology at Wayne State University and Harper Hospital.