Research Spotlight: Howard Chang, M.D., Ph.D.
Katherine McKenzie, Ph.D.,
Research
Administrator and External
Relations Manager
Is Jane’s skinned knee related to breast cancer metastasis? Howard Chang, M.D., Ph.D., at Stanford University, is applying a scientific observation to further our understanding of breast cancer. For decades, scientists have observed similarities in cellular behavior of healing wounds, like skinned knees, to metastatic breast cancer. In both cases, the cells divide rapidly, move from one part of the body to another, build new tissue, and produce new blood vessels.
Dr. Chang chose a novel approach to explore this relationship by focusing on the biological effect of genes. He activated wound healing cells from different sites in the body cells by exposing them to serum (the signal that triggers wound healing) and compared their pattern of gene activation. By using a bioinformatics method, he determined that all activated wound healing cells had a similar molecular profile of 512 genes that characterize their behavior.
When he looked for this wound healing profile in a panel of 200 early human tumors, he found that 30 to 40 percent of early stage human breast tumors have this profile. He also found that patients with wound-like tumors have a three-fold higher risk of dying than those with non-woundlike tumors.
Having identified this sub-set of tumors, Dr. Chang secured funding from the CBCRP to pursue the possibility of exploiting the similarity and thereby find a way to diagnose and treat early stage breast cancers with the appropriate therapy.
Dr. Chang identified the protease inhibitor bortezomib (Velcade®), which is an FDA-approved chemotherapy drug that is used to treat some cases of multiple myeloma, as a likely candidate for specifically targeting wound-like tumors. This drug has already been tested for the treatment of a broad range of breast cancer with limited success. However, Dr. Chang’s team found that it specifically inhibits the proliferation of woundlike breast cancers in culture, without killing proliferating cells that don’t have the wound-like signature.
The team also made progress in identifying new molecular prognostic and treatment targets for wound-like breast cancer by genetically engineered mice to develop wound-like mammary tumors. They found that if they block CSN5, a gene that is amplified in the wound-like tumors, then they are also able to block the growth of tumors in these animals. This demonstrates that genes of wound healing profile are involved in tumor progression and can therefore be targeted for therapy.
By applying what he learned about the molecular biology of a skinned knee to the biology of breast cancer, Dr. Chang has uncovered new opportunities to diagnose and treat the disease. Because the wound healing molecular signatures are detectable in early breast tumors they could serve as excellent diagnostic tools for determining which patients should be treated with more aggressive therapy early in the course of disease. This work has also set a path for identifying drugs such as bortezomib that can specifically target wound-like tumors.
Howard Chang, M.D., Ph.D. is an assistant professor of dermatology at Stanford University. His work has been reported in mainstream media outlets. This study has been published in the journal Cancer Research (Cancer Res. 2008:68(2):506-15 and Cancer Res. 2008:68(2):369-78). It also won the Cornelius L. Hopper poster award for “Most Innovative Research” at the 2007 CBCRP “From Research to Action: Breaking New Ground” symposium.
