Zhigang Charles Wang, MD, PhD

2012-2013 BCRF Projects:

1) (made possible by generous support from Play for P.I.N.K.)

Co-Investigators: Ross Berkowitz, MD and Ursula Matulonis, MD, Dana-Farber Cancer Institute and Brigham & Women's Hospital/Harvard Medical School, Boston, MA

The goal of this research team at the Dana-Farber Cancer Institute and Brigham and Women's Hospital is to discover genomic predictors for response to therapy and potential therapeutic target(s) shared by high-grade serous ovarian tumors and triple-negative breast cancer. In the past year, Drs. Berkowitz, Matulonis, and Wang investigated mutations in a dataset using a genome-wide assay in a group of ovarian cancer patients treated in Boston, and they extended their analyses to a publically available genome sequencing dataset. The results suggest that the number of genome-wide gene mutations may reflect the degree of genomic instability and may also be useful to predict sensitivity to platinum-based chemotherapy in high-grade serous ovarian cancer. This genomic feature may also be applicable to triple negative breast cancer since these cancers possess DNA repair deficiencies that are observed in high-grade serous ovarian cancer. Drs. Berkowitz, Matulonis, and Wang generated a genomic dataset of the new genome-wide assay from ovarian cancer tissues from ongoing clinical trials with PARP inhibitors, which are drugs that stop repair of DNA in tumor. They have also included genome sequencing for mutation analysis in these studies.

Mid-year Progress: This team continues to work on the discovery of predictors for response to therapy and potential therapeutic targets shared by high-grade serous ovarian tumors and triple negative breast cancer. Recently, a mutation analysis was done using a publically available set of data from the National Cancer Institute. This dataset contains a large amount of genetic information, which was scrutinized with the hypothesis that the number of genetic mutations predicts response to treatment and the outcome of patients with breast and ovarian cancer. This group found that total mutation number in tumor genomes reflects the amount of genomic instability in both ovarian and breast cancers. As the mutation burden increases, so does the sensitivity to ovarian cancer chemotherapy, and patient survival increases as well. Surprisingly, this measure seems to predict chemotherapy response and survival in the subset of ovarian cancer patients with deficiency in one of the two key DNA repair genes called BRCA1 and BRCA2. These two genes are also the inherited causes of breast and ovarian cancer. Drs. Berkowitz, Matulonis, and Wang are analyzing data from breast cancer patients to see if the same relationship between good outcome and higher mutation burden is maintained. The working hypothesis is mutation burden reflects fidelity of DNA repair, which in turn predicts the outcome of certain chemotherapies and new agents like PARP inhibitors in both breast and ovarian cancer. The breast and ovarian group in Boston published an influential manuscript describing some of their work in ovarian cancer, acknowledging BCRF support, and already is talking to industrial partners about using their findings in upcoming clinical trials.

2) (made possible by generous support from Price Chopper Supermarkets/Golub Corporation)
Co-Investigators: J. Dirk Iglehart, MD and Andrea Richardson, MD, PhD, Dana-Farber Cancer Institute and Brigham and Women's Hospital/Harvard Medical School, Boston, MA

In 2012, this research group published several articles on their studies funded by The Breast Cancer Research Foundation. In the Cancer Research journal, Drs. Iglehart, Richardson, and Wang reported that LAPTM4B promotes cell survival during stress and faster tumor growth by inducing autophagy, a scavenger-like process allowing tumor cells to conserve nutrients when external nutrient supply is low. They found that knocking down expression of LAPTM4B reduces tumor growth in a laboratory tumor model.

Also, they published in the Cancer Discovery journal their work reporting that triple negative breast cancers that carry a high level of chromosome rearrangement resulting from improperly repaired DNA strand breaks are more sensitive to cisplatin treatment. They have recently found that overexpression of two genes, BLM and FANCI, is also associated with cisplatin sensitivity and reducing expression of these genes makes tumors more resistant to cisplatin. In addition, this team has continued work on altered expression of microRNAs (regulatory RNA molecules). They reported their results on microRNA expression profiling of breast cancers in a poster at the 2011 San Antonio Breast Cancer Symposium where they found that the miR-17-92 cluster as significantly overexpressed in triple negative breast cancers and that these tumors may be addicted to high miR17-92 for cell survival. Furthermore, these researchers have recently identified miR-218 as a potential regulator of BRCA1. In 2012-2013, this group will continue the projects described above as well as continue to participate in the cisplatin trial jointly conducted among several BCRF-funded teams at Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, and University of Pennsylvania Abramson Family Cancer Center.

Bio:
Zhigang Charles Wang received his MD from Shanghai Second Medical University in Shanghai, China and his PhD in Microbiology and Immunology from New York Medical College. His resident training in pathology was completed at Rie-Jing Hospital in China and his post-doctoral training occurred at the Center for Blood Research at Harvard Medical School and at the National Institute for Dental Research. At the latter, he served as Senior Staff Fellow. Dr. Wang is an active member of the American Association for Cancer Research and currently an Assistant Professor of Surgery at Harvard Medical School, Dana-Farber Cancer Institute and Brigham & Women's Hospital.

Dr. Wang's research is interested in the genetics of breast cancer, with a particular focus on the heterogeneity of the disease which he studies through detailed mapping of chromosomal lesions and analysis of genes critical for its pathogenesis. He has worked closely with other BCRF grantees, Drs. Andrea Richardson and James D. Iglehart, to discover the high genetic instability and signature chromosomal alterations of a highly malignant subtype of breast cancer (the basal-like tumor). He has also discovered a significant association between copy gain of chromosome 8q22 and distant metastasis in breast cancer patients that received post-surgery chemotherapy. Furthermore, studies are underway to identify critical genes in this chromosomal region as therapeutic targets and prognostic markers.

Recently, he became interested in the genetic similarities between serous ovarian cancer and basal-like breast tumors. In collaboration with Drs. Ross Berkowitz and Ursula Matulonis at the Brigham and Women's Hospital and Dana-Farber Cancer Institute, he has begun a comprehensive genomic analysis of breast and serous ovarian cancer to discover the common chromosomal alterations and genes critical for the pathogenesis of both diseases.