Michael F. Clarke, MD

2007-2008 BCRF Project:
Dr. Clarke's laboratory has recently found that a minority of the cancer cells within a breast tumor, called breast cancer stem cells, are responsible for the maintenance of a tumor. Only breast cancer stem cells can disseminate from the original breast tumor to form new tumors in distant organs such as the brain, liver and lungs. It is these distant tumors that ultimately lead to the death of patients. Thus, understanding how breast cancer stem cells spread to distant organs may give insights into ways to prevent this fatal event.

In the first portion of this grant, the researchers have discovered a possible mechanism that regulates the spread of the breast cancer stem cells. They recently found that a gene fingerprint obtained from breast cancer stem cells could be used to identify patients with early stage breast cancer at risk for relapse of their disease. This information is likely to lead to new clinical tests that will identify patients who do or do not need adjuvant therapies. This would minimize the toxicity of unnecessary cytotoxic therapies to which many women are exposed. In the coming year, Dr. Clarke plans to build upon results from the previous year�s funding. The major goal of this proposal is to identify women at risk for relapse from early stage breast cancer.

Mid-Year Progress Report:
During the first part of funding, Dr. Clarke’s team has made three important findings that may eventually result in decreased mortality from breast cancer. First, using a fingerprint derived from breast cancer stem cells they have identified a new way to identify women with early stage breast cancer who are at increased risk of relapse. This may allow them to better identify women who do, or just as importantly do not, need adjuvant therapies. Next, the researchers have identified a new way in which cancer stem cells escape specific treatments. This may allow one to better tailor treatments to an individual patient. It also gives insights into the development of new drugs that more effectively treat cancer. Finally, they have potentially identified a novel mechanism by which breast cancer stem cells maintain themselves and spread to distant organs. Again, this may lead to new therapeutic strategies.

Bio:
After receiving his MD degree from Indiana University, Dr. Clarke was an Oncology Fellow at the National Cancer Institute. In 1986, he joined the faculty at the University of Michigan where he was a Professor of Internal Medicine and a Professor of Cell and Developmental Biology. In the fall of 2005 Dr. Clarke will move to Stanford University where he will direct the solid tumor cancer stem cell program and serve as Deputy Director of the Stem and Regenerative Medicine Institute.

While a post-doctoral fellow at the NCI, Dr. Clarke was the first to demonstrate that enforced expression of a normal proto-oncogene (c-sis) could lead to transformation (Clarke, et al. Nature , 308: 1984). While at the University of Michigan, Dr. Clarke has made several discoveries relevant to cancer. He was the first to demonstrate that an alternatively spliced proto-oncogene mRNA (mbm2) could function as a dominant-negative inhibitor of the proto-oncogene (Weber, et al. Science, 249: 1990). He was also the first to demonstrate that inhibition of programmed cell death (PCD) was essential for the survival of human breast cancer cells (Clarke, et al. PNAS, 92: 1995).

Most recently, Dr. Clarke's laboratory has made two important findings. He was the first to identify a molecular pathway that regulates the essential process of adult stem cell self-renewal (Park, et al. Nature. 43: 2003). Next, he has found that not all cancer cells found in solid tumors have the capacity to self-renew and form new tumors. His laboratory has developed methods to prospectively identify this "cancer stem cell" population in breast cancer (Al-Hajj, et al. PNAS 7: 2003). These findings have linked the process of self-renewal in normal stem cells to cancer. These observations have implications for the treatment and diagnosis of human cancers. The focus of the laboratories research efforts are directed at the identification and eradication of breast cancer stem cells, the cells that drive the growth and metastasis of these tumors.