Developing Biomarkers of Response to Chemoradiation Therapy in Rectal Carcinoma: Toward Precision Medicine
Abstract
Rectal cancer is growing in incidence in the United States (39,910 cases in 2017), especially an increased incidence has been observed in younger people (<50 years of age). This application proposes to addresses the gaps in treatment of individuals with rectal cancer (both military and civilian population) that prevent them from becoming better (such as improved survival, reduced chances of tumor recurrence). Most (~60%) rectal cancer cases are identified at the advanced stages, which means that the primary tumor has spread to the lymph nodes or even further in the individual’s body. In such a scenario, the individual is treated with chemotherapy drugs and radiation prior to surgical removal of their tumor. This is called neoadjuvant chemoradiation therapy (nCRT) and is the standard of care. When an individual achieves a complete benefit from this therapy, i.e., no more advanced tumor in lymph node and other areas of the body, this is called a complete response. A complete response leads to improved survival and prevents recurrence of the tumor. However, this happens in only 20%-30% of cases. In 70%-80% of cases, patients either have a poor response or no response to nCRT. Thus, there is a huge gap in treatment of rectal cancer patients as there is no biological marker – biomarker – that can identify which individuals with rectal cancer will or will not benefit from the standard of care (nCRT). This gap is a critical problem in the Fiscal Year 2017 Peer Reviewed Cancer Research Program topic area of colorectal cancer (CRC). In this proposal, we will address this critical treatment gap by identifying biomarkers that can help predict who will benefit or not benefit from nCRT among individuals with rectal cancer. As nCRT works by causing damage to DNA, we reasoned that the ability of the individual (coded in their DNA and reflected in all their cells, such as blood cells) to “deal” with DNA damage can help predict response to nCRT. This ability to deal with DNA damage, i.e., to recognize damage and repair it is called DNA-DRR capacity. We will study this DNA-DRR capacity by using blood cells and DNA donated by rectal cancer patient at our institute, Fox Chase Cancer Center (FCCC). We will prepare a profile of DNA-DRR capacity for each individual in our study. We will do this by studying expression of proteins that regulate DNA-DRR capacity and changes (variants) in DNA sequence in genes related to DNA-DRR capacity. Both the proteins and the DNA variants will be alterations that occur inherently in the person with cancer, i.e., changes that are not caused by the cancer. We will compare these changes between complete and poor responder patients to determine which changes correlate with which clinical outcome. Finally, we will combine the protein expression data and the DNA variant data into a hybrid DNA-DRR capacity signature. This hybrid signature will serve as a biomarker that can predict response to therapy. Because other patient-specific factors, e.g., age, sex, smoking history, might also affect response to nCRT, we will test if combining such data with the hybrid signature improves the biomarker. My career goal is to lead an independent research program, where basic science researchers and clinicians work together to understand why individuals respond differently to cancer therapy. This would allow personalized treatments and improve clinical outcomes in CRC. My career development plan includes conducting the proposed research project and training in multivariate analysis and in structural and computational analysis of DNA variants. This Career Development Award will provide me with support to carry out this study during the first years of my faculty position. I will work closely with my mentors, who are both at FCCC. My primary mentor, Dr. Margie L. Clapper, a Senior Investigator (Professor) and an expert in CRC biology and genetics. My secondary mentor, Dr. Joshua E. Meyer (Associate Professo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810148
Entities
People
- Sanjeevani Arora
Organizations
- United States Army