Jenny C. Chang, MD
Director, Methodist Cancer Center
2012-2013 BCRF Project:
(made possible by generous support from The Housewares Charity Foundation)
Professor, Weill Cornell Medical College
The Methodist Hospital Research Institute
Systemic therapies are initially effective in controlling and reversing tumor growth; however, residual cancers will invariably re-grow despite this initial response. Dr. Chang's group has published data from human breast cancer samples showing that standard therapy every three weeks kills dividing daughter cells but not "cancer stem" or "tumor-initiating" cells (TICs). These TICs have the ability to self-renew in mammosphere cultures, and to give rise to tumors upon transplantation into immune-deficient laboratory models.
Dr. Chang and colleagues have recent data in human breast tumors indicating these TICs may in fact be initially chemosensitive, with a decrease in TICs observed within two days of chemotherapy treatment. These results indicate TICs were initially responsive to chemotherapy but became chemoresistant, or even activated by chemotherapy. The researchers have carried out a series of preclinical studies to further define the timing of this transition and to directly test the hypothesis that breast cancer TICs may be eliminated by repeat frequent doses of docetaxel. Their current efforts are focused on identifying the underlying mechanisms that regulate this transition and designing optimal treatment regimens in laboratory studies.
Mid-year Progress: Subtypes of breast cancer are primarily defined by the presence or absence of three markers estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The most aggressive form of breast cancer is the "triple negative breast cancer" (TNBCs), where there is a lack of expression of all three receptors, namely ER, PR and HER2. Approximately 15-20% of all breast cancers are TNBCs, and studies have shown that the patients with this type of cancer have the worst outcomes and are more likely to relapse than their non-TNBC counterparts. There are no defined targeted therapies for this disease, leaving the patients with only the option of conventional chemotherapy and a high possibility of relapse. Thus it is imperative to identify and pursue novel therapies against triple negative breast cancer. Use of liposome mediated nanoparticles in order to mediate siRNA/shRNA therapy is a new approach for Dr. Chang's group to target novel non-druggable targets for which traditional therapies do not exist. One of the prevailing theories suggests that breast cancer relapse is caused because conventional chemotherapies do not target the sub-population of tumor initiating cells (TICs), which are the roots of the cancer and allow it to initiate again and metastasize.
Dr. Chang's team has identified novel gene targets of TICs using a lentiviral shRNA screen, for which no established small molecule inhibitors exist; therefore they are using a siRNA based approach to target these genes. The investigators have packaged siRNAs in a liposome based delivery vehicle to specifically target the tumors. Selective siRNA knockdown of two top candidate genes in human breast cancer xenografts showed reduced tumor volume with a concomitant decrease in BCSC markers. They hypothesize that targeting these genes via siRNA therapy will provide novel methods to treat TNBCs in conjunction with standard chemotherapeutic regimens and also give insights into the biology of the tumor initiation.
Dr. Jenny C. Chang is Director of the Cancer Center at The Methodist Hospital, Houston, Texas, USA. She obtained her medical degree at Cambridge University in England, following which she completed fellowship training in medical oncology at the Royal Marsden Hospital/Institute for Cancer Research in the United Kingdom. She was also awarded a research doctorate from the University of London. There, she developed an interest in breast cancer, particularly in the area of prognostic and predictive markers. She used the clinical situation of locally advanced breast cancer, in which patients are traditionally treated with pre-operative therapy, to assess the use of such markers in predicting treatment response. Her recent work has focused on the intrinsic therapy resistance of cancer stem cells, resulting in several publications and international presentations. In addition, she holds several federal grants evaluating novel biologic agents and patents on new technological advances, especially in the area of high throughput molecular profiling.