Max S. Wicha, MD

2009-2010 BCRF Project:
There is evidence that many malignancies, including breast cancer, are driven by a cellular subcomponent that displays stem cell properties. Although it is clear that the tumor microenvironment effects tumor growth and metastasis, the role that this microenvironment plays in the regulation of cancer stem cells is not known. In work supported by BCRF, Dr. Wicha demonstrated that bone marrow-derived mesenchymal stem cells are able to traffic to sites of developing breast tumors where they associate with and regulate the cancer stem cell population. This interaction defines a "cancer stem cell niche" regulated by cytokine loops. This work formed the basis for strategies to directly interfere with cytokine signaling to target cancer stem cells.

There is increasing evidence from the Wicha lab and others that breast cancers are driven by a small subset of cells that display properties of stem cells. These "cancer stem cells" may also be responsible for mediating tumor metastasis and resistive to cancer treatments. Recently, several new cancer therapies targeting angiogenesis have been developed and investigated in clinical trials. These agents include the VEGFR antibody bevaczumab and the multi-kinase inhibitors sunitinib and sorafenib. In metastatic breast cancer, addition of bevaczumab delays tumor progression but has not been shown to affect patient survival. In other tumor types sunitinib and sorafenib have only modest effects on patient survival. Recent reports have suggested that in laboratory models, angiogenesis inhibitors may, in fact, promote tumor invasiveness and metastasis which likely results from the generation of tumor hypoxia by these agents.

Based on previous studies demonstrating an hypoxic environment in normal stem cell niches and Dr. Wicha's previous work suggesting a role for cancer stem cells in mediating tumor invasion and metastasis, he hypothesizes that increased tissue hypoxia produced by anti-angiogenic agents may accelerate tumor growth and metastasis via their effects on the cancer stem cell population. The Wicha group proposes to test this hypothesis utilizing both in vitro systems and xenograft models. They will determine whether hypoxia increases cancer stem cell self-renewal and survival in vitro and whether anti-angiogenic agents increase the breast cancer stem cell population in tumor xenografts. Finally, they will develop novel strategies for inducing pro-oxidants in breast tumors to specifically target the cancer stem cell population. These studies should help to elucidate the mechanisms accounting for the limited clinical utility of anti-angiogenesis agents as well as suggesting new approaches to overcome resistance to these agents by targeting the cancer stem cell population.

Mid-Year Progress Report:
Support from BCRF enabled Dr. Wicha to make significant progress into two related, yet distinct research areas. First, his team completed studies which demonstrate that an important link between inflammation and breast cancer is mediated by IL-8/CXCR1 signaling. They demonstrated that normal and malignant breast stem cells express the IL-8 receptor CXCR1. CXCR1 blockade utilizing either a CXCR1-specific blocking antibody or repertaxin, a small-molecule CXCR1 inhibitor, selectively depleted the CXC population in human breast cancer cell lines and primary xenografts. Their data suggests that CXCR1 blockade may provide a novel means of targeting and eliminating breast cancer stem cells.

The second area in which they made interesting progress with BCRF funding relates to how hypoxia regulates the breast cancer stem/progenitor cell population. There is increasing evidence from the Wicha lab and others supporting the "cancer stem cell" hypothesis in breast cancer, which deems that tumors are driven a small population of cells exhibiting stem cell properties. These cancer stem/progenitor cells may be responsible for mediating tumor metastasis and resistance. Recently, several therapies targeting tumor angiogenesis have been developed and validated including VEGFR inhibitors like Sunitinib. Recent reports have found that these angiogenesis inhibitors promote tumor invasiveness and metastasis in rodent breast cancer models. Dr. Wicha and colleagues hypothesize that the tumor stem/progenitor cell population increases in response to hypoxia in anti-angiogenic treated cancers, leading to increased tumor aggressiveness. They are using in vitro and in vivo assays to study the possible role of hypoxia in regulating mammary cancer stem/progenitor cells. These findings may help to explain resistance to angiogenesis inhibitors and reveal that therapies targeting tumor angiogenesis should be combined with treatments targeting the cancer stem cell population.

Bio:
Dr. Wicha is the founding and current Director of the University of Michigan Comprehensive Cancer Center and distinguished professor of oncology. His lab was part of the team that first discovered stem cells in breast cancer, the first described in any human solid tumor. He is a leading expert in normal and malignant breast stem cells.

In addition to his research, and administrative roles, Dr. Wicha is also active as a clinician, specializing in the treatment of breast cancer. His laboratory demonstrated an important connection between hereditary and sporadic breast cancers by showing that both may be initiated by description of stem cell self-renewal pathologic. His group is developing novel breast cancer therapies that target breast cancer stem cells.

Dr. Wicha received his medical degree from Stanford University and trained in internal medicine at the University of Chicago. He then went on to the National Cancer Institute, where he trained in clinical oncology and cancer biology. He joined the University of Michigan Medical Center in 1980 and has served as Director of the Comprehensive Cancer Center since 1988.