Max S. Wicha, MD
Distinguished Professor of Oncology
Director, Comprehensive Cancer Center
University of Michigan
Ann Arbor, Michigan
2013-2014 BCRF Project:
The development of HER2-targeted therapeutics represents one of the greatest advances in clinical oncology over the last decade. In work supported by BCRF, Dr. Wicha and his team have demonstrated that HER2 plays a pivotal role in the regulation of breast cancer stem cells (BCSCs) and that this may account for the remarkable clinical efficacy of HER2 blockade. Furthermore, they showed that HER2 regulation of BCSCs does not require HER2 gene amplification, providing a potential biological explanation for previous retrospective analysis suggesting that the clinical benefit of adjuvant trastuzumab (Herceptin) may extend to women whose breast cancers are “HER2-negative”. This strongly supports the NSABPB47 pivotal clinical trial to evaluate the efficacy of adjuvant trastuzumab in women whose tumors are currently classified as HER2-negative. The Wicha team has also demonstrated that resistance to HER2-targeted therapies may involve activation of an inflammatory loop involving the cytokine IL-6 which drives the BCSC population. In laboratory models, the IL-6 receptor blocking antibody tocilizumab blocks this inflammatory loop reducing BCSCs, inhibiting tumor growth and metastasis.
Based on their prior preclinical work, Dr. Wicha’s team plans in the coming year to initiate a phase I clinical trial of the IL6 receptor inhibitor tocilizumab in women with HER2-positive (HER2+) breast cancers refractory to HER2-targeting agents. In order to monitor the efficacy of this and other breast cancer stem cell targeting agents, these investigators are developing a novel strategy to isolate circulating breast cancer stem cells and to assess gene expression in these cells. To accomplish this, Dr. Wicha and his colleagues are collaborating with investigators in University of Michigan’s School of Engineering to develop microfluidic technology to isolate these cells, which then will be analyzed by multiplex PCR. This Fluidigm technology will permit simultaneous assessment of expression of 96 genes in up to 96 individual circulating tumor cells. If these researchers are successful in developing this novel technology, it may provide a reliable platform for monitoring treatment efficacy for women on this and other breast cancer clinical trials. Their ultimate goal is to demonstrate that successful targeting of breast cancer stem cells improves outcome for women with breast cancer.
Dr. Wicha’s team has made considerable progress toward their defined research aims in their study entitled “Molecular Analysis of Single CSCs using the C1 and BioMark HD Systems.” Based on prior preclinical findings, their goal is to initiate a phase I clinical trial of the IL6 receptor antibody Tocilizumab in women with breast cancers refractory to HER2-targeting agents. In order to monitor the efficacy of this stem cell targeting therapy (and that of other breast cancer stem cell treatment, or BCSC, regimens), the researchers are developing a novel strategy to isolate circulating BCSCs and to assess gene expression patterns in these cells. In preceding months they have developed the necessary upstream microfluidic technologies to isolate and characterize single cells from human tumor lines as well as spiked tumor cells separated from red and white blood cells of normal donors. They have validated the Fluidigm instrumentation which permits simultaneous assessment of over 9,200 cancer-related transcripts in circulating tumor cells. They are now starting to analyze single tumor cell gene expression profiles from tumor lines and patient samples. The researchers’ progress developing this novel technology provides a reliable platform for monitoring treatment efficacy for women on their envisioned clinical trial as well as many other oncology clinical trials. They plan to continue their investigations on patient blood samples in the coming months to better understand inherent BCSC genetic heterogeneity in order to define the criteria for successful targeting of stem cells for women with refractory breast cancers.
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.