Max S. Wicha, MD
Distinguished Professor of Oncology
2012-2013 BCRF Project:
Director, Comprehensive Cancer Center
University of Michigan
Ann Arbor, Michigan
The development of targeted therapeutics for breast cancers with an excess amount of HER2 protein (HER2 positive or HER2+) represents one of the greatest advances in clinical oncology over the past decade. When utilized to treat advanced breast cancers, HER2 targeted agents such as trastuzumab (Herceptin®) increase the response rate and patient survival. The beneficial effects of trastuzumab in this setting appear to be limited to the 20% of breast cancers that are HER2+. As a result of these studies, testing for HER2 protein has become part of the routine analyses for all women with newly diagnosed breast cancer.
Dr. Wicha's laboratory had previously demonstrated that HER2 plays an important role in the regulation of breast cancer stem cells in HER2 amplified breast cancer. They demonstrated that the molecular mechanism of this regulation was through Akt activation of Î²-catenin signaling. Dr. Wicha's team had extended their studies by examining the role that HER2 may play in the regulation of cancer stem cells (CSCs) in luminal breast cancers in a process that does not require HER2 amplification. They hypothesized that in these tumors, HER2 is selectively expressed in the cancer stem cell population and that this accounts for the clinical efficacy of trastuzumab when administered in the adjuvant setting in these patients. This benefit had previously been reported in retrospective analysis and forms the basis for a current, large-scale randomized clinical trial.
Over the upcoming year, Dr. Wicha's team plans to continue the previous studies by investigating the mechanisms of HER2 regulation by the bone microenvironment. In addition, they will pursue studies investigating the molecular mechanisms by which the PTEN tumor suppressor gene plays a role in mediating resistance in HER2+ breast cancers.
Mid-year Progress: Despite the clinical benefits of trastuzumab in improving progression free and overall survival, the majority of patients demonstrate "intrinsic" resistance or develop "acquired" resistance within one-to-two years. Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain to be investigated.
Dr. Wicha's laboratory generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrated that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell population. They and others previously demonstrated that cytokines including IL6 and IL8 regulates breast cancer stem cell self-renewal. Furthermore, elevated serum levels of these cytokines in breast cancer patients strongly correlated with metastatic disease and therapeutic resistance. They therefore hypothesized that activation of IL6 feedback loop may mediate trastuzumab resistance. Utilizing these models, Dr. Wicha's team has demonstrated that long-term trastuzumab treatment generates highly enriched cancer stem cells which display transition to a metastatic phenotype, which secretes over 100-fold more IL6 than parental cells. In combination, all of Dr. Wicha's studies have important clinical implications demonstrating that trastuzumab resistance may be mediated by an IL-6 inflammatory loop and suggest that blocking this loop represents a novel strategy to overcome trastuzumab resistance. Based on the pre-clinical studies supported by BCRF, Dr. Wicha is now designing a clinical trial that will test the efficacy a tociluzamab, an antibody to the IL6 receptor, in breast cancer patients with advanced trastuzumab refractory HER2+ breast cancer.
Dr. Wicha has been a major leader in the science of cancer stem cells. His group was part of the team that first identified breast cancer stem cells, the first such cells identified in solid tumors. His laboratory has identified a number of cancer stem cell markers and developed in vitro and mouse models to isolate and characterize these cells, models which have been widely utilized in the field. His group has subsequently elucidated a number of intrinsic and extrinsic pathways which regulate stem cell self-renewal and cell fate decisions. Most recently, his laboratory has focused on translating these laboratory findings into the development of clinical trials design to target breast cancer stem cells. According to the ISI citation index, Dr. Wicha is the most highly cited investigator in the field of cancer stem cells.