10 Nov Breast Cancer: Overcoming Tumor Resistance With Combinatinon Therapy
MedicalResearch.com Interview with:
Ruth Keri, PhD, Professor and Vice Chair Department of Pharmacology
Case Western Reserve University School of Medicine, and Associate Director for Basic Research in the Case Comprehensive Cancer Center Case Western Reserve University
Medical Research: What is the background for this study?
Dr. Keri: Over the last several decades, the discovery of targeted therapies for certain types of breast cancer, and their use in the clinic, have greatly improved the long-term outcome of patients. Yet some breast cancers don’t respond to these therapies, and ones that do often become resistant over time, resulting in patient relapse and metastatic disease. Why does resistance occur? There are many tricks a tumor employs to evade death. When a drug targets a certain protein or pathway the cancer cell relies on for survival, one potential route of resistance is the cancer cell’s ability to adapt and find another pathway to maintain growth. We reasoned that targeting two separate proteins or pathways important for cancer cell growth may be more effective at preventing or delaying this adaptation.
Medical Research: What are the main findings?
Dr. Keri: The PI3K/AKT/mTOR pathway is a major regulator of cell survival, and frequently hyperactive in cancer. However, blocking this signal alone has shown limited clinical efficacy. The class of drugs known as mTOR inhibitors (including rapamycin (sirolimus), temsirolimus, everolimus) frequently result in increased signal to AKT (the survival protein) because the drug also blocks the feedback that normally tries to shut down this signal.
Another family of proteins, src-family kinases (SFKs), is also dysregulated in cancer cells. Using the drug dasatinib, an SFK inhibitor, we were able to block the increased survival signal that occurred with rapamycin treatment, essentially making the mTOR inhibitor a more effective drug. These studies were performed in several different breast cancer cell lines and mouse models of breast cancer.
What we ultimately found was that these proteins converged on the same pathway, and when they were both inhibited together, the effect was a profound reduction in tumor size and an increase in time to disease recurrence.
Medical Research: What should clinicians and patients take away from your report?
Dr. Keri: Interestingly, neither mTOR inhibitors nor dasatinib, when used alone, has been very effective for the treatment of breast cancer. Recent clinical trials have demonstrated their ability to overcome resistance to targeted therapies, such as in the case of HER2+ breast cancer, or hormone-dependent tumors. However, as mentioned earlier, there is another type of breast cancer, often referred to as triple negative breast cancer, for which there currently are no targeted therapies. Some of the breast cancer models we are using represent these types of tumors, and the combination of rapamycin and dasatinib appears to have similar effects in these models. While both of these drugs are already used clinically, the next step will be to test the safety and efficacy of this combination in patients with advanced disease, who have either failed or become resistant to prior standard-of-care therapies.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Keri: A major goal of our research has been to identify a combination therapy that is more successful in treating cancer than what is currently available — however, it is important to keep in mind that even within the same type of cancer, be it breast, ovarian, pancreatic or any other — each tumor is very unique. The success of this or any therapy depends on the ability of the unique tumor to respond. This will require a better understanding of each tumor’s “signature” in an attempt to discern whether it may be responsive to this combination therapy. This can be accomplished in the context of a clinical trial whereby genomic and proteomic assays are used to identify tumor markers that can distinguish tumors that respond to the dual therapy versus those that do not.
Yori JL, Lozada KL, Seachrist DD, Mosley JD, Abdul-Karim FW, Booth CN, Flask CA,
Cancer Res. 2014 Sep 1;74(17):4762-71. doi: 10.1158/0008-5472.CAN-13-3627. Epub 2014 Jul 14.
PMID: 25023728 [PubMed – in process]