Therapeutic Targeting of CIMP+ Colorectal Cancers
Abstract
Colorectal cancer is the fourth leading cause of cancer-related death worldwide. One of the initiating cancer events for this particular human malignancy is the inactivation of tumor suppressor genes through a repressive epigenetic methylation event establishing a distinct subset of colorectal cancer termed “CIMP” (CpG Island Methylator Phenotype) colorectal cancer. This cancer model piques the interest of Principal Investigator (PI) Mahara due to its unique widespread dysregulated epigenetics event. During her previous Ph.D. candidature in Singapore, PI Mahara undertook a research study in epigenetic regulation in invasive breast cancer, and her work led to a recent publication in a lead journal of Proceedings of the National Academy of Sciences. She subsequently moved to Hudson Institute for her postdoctoral training under the supervision of Associate Professor Ron Firestein, a leader in the field of translational cancer research, where she developed a strong interest in the therapeutic targeting of epigenetic machinery of bowel cancer particularly in CIMP colorectal cancer. In her current postdoctoral study, she is given an opportunity to learn firsthand from Mentor Firestein of the latest genome editing technique, CRISPR/cas9. Mentor Firestein, with the support from both Monash University and Hudson Institute, not only provides conducive avenues for PI Mahara to further explore her research interest in epigenetic field, but also redefines her perspective of a scientific finding as a bridging tool to a clinical application. The Horizon Award offered through the Congressionally Directed Medical Research Programs will give her a funding opportunity to see through the completion of the project proposed for this award from a scientific finding obtained from laboratory bench to the development of therapeutic regime and biomarkers for early detection of colorectal cancer, which will bolster her career as a cancer researcher in both basic research and translational cancer research. The project proposed for this award is investigating the clinical application of restoring tumor suppressor genes often silenced in early onset of colorectal cancer disease, particularly the CIMP subset. Currently, there is a lack of clinical benefit in treating CIMP-positive patients with a cytotoxic chemotherapy. Furthermore, CIMP-positive patients are predisposed to early recurrence of metastatic colorectal cancer, which leads to poor patient outcomes. Hence, PI Mahara together with Mentor Firestein proposed an innovative approach of restoring the loss of tumor suppressor genes function through combination treatment of epigenetic inhibitors and standard chemotherapy to improve therapeutic response and subsequent patient outcomes. Moreover, several epigenetic inhibitors have been approved by U.S. Food and Drug Administration (FDA) for their use in cancer therapy with few side effects, e.g., 5-Azacytidine, Decitabine, Vorinostat, Valproic acid, etc. Hence, the clinical implementation for our proposed therapeutic regime will be rapid. In addition to the therapy, by harnessing the unique disease property, where the functional loss of tumor suppressor genes is a key cancer initiating event, we also propose develop a diagnostic kit to identify susceptible colorectal cancer patients even before the onset of the disease. The underlying non-genetic factors of CIMP-positive tumors suggest that the U.S. military population will be at risk due to their frequent exposures to cancer-associated risk factors. Moreover, colorectal cancer is the fourth most common form of cancer observed among active duty military personnel after testicular, prostate, and breast cancers. Interestingly, the risk of developing colorectal cancer is generally lower in active duty Service members compared to the general population, which could be attributed to the physically fitter, stricter compliance to cancer screening, and better access to health care in the former
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710553
Entities
People
- Sylvia Mahara
Organizations
- Monash University
- United States Army