Director, Methodist Cancer Center
Professor, Weill Cornell Medical College
The Methodist Hospital Research Institute
Breast cancer is the second leading cause of cancer related death in the US. The subtypes of this 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 triple negative breast cancer (TNBCs), where there is a lack of expression of all three receptors, namely ER, PR and HER2. Fifteen to twenty percent 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 short interfering RNAs (siRNA) therapy is a new approach for Dr. Chang’s group to target novel non-druggable targets for which traditional therapies do not exist. With siRNA technology, it is possible to inhibit gene expression of specific genes. 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, They therefore are using a siRNA based approach to target these genes.
Dr. Chang and colleagues have packaged siRNAs in a liposome based delivery vehicle to specifically target the tumors. In this study, they demonstrate a significant reduction in tumor volume with a concomitant decrease in TIC markers in patient-derived human cancer xenograft tumors treated with siRNAs against the top two candidate genes alone or in combination with siRNA/chemotherapy. This was confirmed in two additional breast cancer cell lines. More importantly, Dr. Chang found a significant benefit in median survival in the laboratory models treated with combination of chemotherapy and siRNA against the candidate genes compared with those treated with chemotherapy alone. Next, her team showed a profound impact of lung metastases on silencing these genes. These results confirm the importance of the top candidate genes in tumor initiation and lung metastases. Dr. Chang thus hypothesizes that targeting these genes via siRNA therapy will provide novel methods to treat TNBCs in conjunction with standard chemotherapeutic regimens and also provide insights into the biology of the tumor initiation.
Dr. Chang’s team’s previous data have provided strong evidence documenting that breast cancer stem cells (BCSCs) are chemoresistant and associated with a more aggressive phenotype leading to metastasis and worse outcome. The researchers have identified two novel genes that promote invasiveness and metastases, and downregulation of these genes by small-interfering RNA (siRNA) approach decreased primary cancers, as well as lung metastases. Interestingly, mutations of these genes were found in half (50%) the lung metastases examined, suggesting additional damaging mutations might be present. On the basis of these observations they propose to firstly understand the signaling pathways that regulate these novel genes and confer chemoresistance and metastatic functions of these genes. Secondly, they propose to identify new candidate genes from their tumorigenic signature that may contribute to the progression of breast cancer stem cells to more malignant drug-resistant and metastatic phenotypes.
In their effort to identify signaling pathways that regulate these genes, the researchers performed microarray analysis of patient-derived human-cancer-in-models in which both RPL39 and MLF2 were silenced using siRNA approach. This was followed by Ingenuity Pathway analysis of the top signaling pathways common to both RPL39 and MLF2 siRNA-treated samples. Their recent results indicate that nitric oxide synthase (NOS) signaling pathway may be involved in regulating these novel genes. Their results would lay the foundation for the development of new gene silencing therapeutics in breast cancer patients with advanced disease who have failed conventional chemotherapy.
Dr. Jenny C. Chang is Director of the Cancer Center at the Methodist Hospital, Houston, Texas. She obtained her medical degree from Cambridge University in England and completed fellowship training in medical oncology at the Royal Marsden Hospital/Institute for Cancer Research. 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.
Breast cancer has been the focus of Dr. Chang’s research. She plans to improve the outcome of women with breast cancer by translating scientific discoveries directly into clinical practice and therapeutics. To this end, her most recent work has centered on identifying the mechanisms by which breast cancer stem cells, also known as tumor initiating cells, can survive chemotherapy, radiation, and hormonal therapy, leading to recurrences, relapses, and metastasis. 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.