Posted May 15, 2013
Dennis J. Slamon, M.D., Ph.D., University of California, Los Angeles (UCLA)
Research into the molecular diversity of breast cancer has led to an understanding of this cancer as a spectrum of diseases that can be classified into subtypes. Although some treatments, such as trastuzumab (Herceptin) and aromatase inhibitors (AI), have provided benefit to certain subtypes of breast cancer, there are some subtypes for which no targeted treatment has been identified. In addition, some breast cancer subtypes that initially respond to a treatment may subsequently acquire resistance, leading to progression of the disease.
In Fiscal Year 2004 (FY04), Dr. Slamon received a Breast Cancer Research Program (BCRP) Innovator Award to develop new targeted treatments in breast cancer using an integrated approach to translational research. Under this BCRP award, Dr. Slamon used complex, coordinated analyses of breast cancer cell lines, animal models, and human tissue banks to unravel the mechanisms and biological pathways that underlie breast cancer progression and resistance to therapy. This research was designed to study all of the molecular subtypes of breast malignancies including ER+ disease, which represents 50%-65% of breast cancers. One of the mechanistic targets identified was the family of cyclin-dependent kinases (CDKs), a group of proteins that play a key role in regulating cell replication. Experiments in a spectrum of human breast cancer cell lines demonstrated that estrogen receptor-positive (ER+) breast cancer, a subtype that can develop resistance to hormonal therapies such as tamoxifen, is sensitive to a CDK inhibitor, PD-0332991. PD-0332991 works by inhibiting CDK4 and CDK6. Additional preclinical studies showed that PD-0332991 worked synergistically when combined with tamoxifen, supporting the advancement of this CDK inhibitor into a Phase I study at UCLA and sponsored by the manufacturer Pfizer that was designed to test safety and establish a dose for combination with the AI, letrozole. This study was followed by two multi-institutional Phase II trials led by the UCLA investigators and again sponsored by Pfizer. The interim Phase II clinical trial results, presented at the 2012 San Antonio Breast Cancer Symposium, showed that patients with ER+ breast cancer treated with PD-0332991 in combination with the aromatase inhibitor letrozole demonstrate an increase in median progression-free survival from 7.5 months using letrozole alone to over 26 months with combination therapy. These findings provide a promising outlook for women with ER+ breast cancer.
In July 2012, the Food and Drug Administration Safety and Innovation Act was approved. Under this legislation, the U.S. Food and Drug Administration is allowed to expedite the development and approval of drugs that show a potential for significant advancement over existing treatments for serious or life-threatening conditions. As of March 31, 2013, only 10 drugs had been granted "Breakthrough Therapy" status. Thanks to the promising clinical trial results demonstrating that PD-0332991 provides substantial improvement in progression-free survival over current treatment for ER+ breast cancer, PD-0332991 (under the manufactured name palbociclib), was given "Breakthrough Therapy" status on April 10, 2013.
Dr. Slamon is continuing to advance this BCRP-supported clinical translational work as part of the Innovator Award funding he received in FY10. A Phase III clinical trial of palbociclib combined with letrozole was recently initiated in February 2013 by Pfizer. Dr. Slamon plans to perform molecular analysis and correlative studies on tumor tissues from the patients who participated in the Phase II studies as well as those participating in this trial. The goal is to identify what characteristics may best determine sensitivity to this combination treatment and any potential mechanisms of resistance to this new form of targeted therapy. With this knowledge, palbociclib can be administered to patients who will benefit most from its use.
Dr. Slamon explained, "We are very gratified that the preclinical studies supported by the Innovator Award have translated so significantly into the early clinical results we have now seen in patients with ER+ metastatic breast cancer. We are also very excited about our previous and continued collaboration with Pfizer in taking this drug forward into formal Phase III clinical testing. Our hope is that this translational research will ultimately result in a new treatment approach for women challenged with ER+ breast cancers. "
Public and Technical Abstracts: An Integrated Program in Translational Research in Human Breast Cancer