Colorectal Cancer Immunotherapy by Pharmacological Suppression of Liver X Receptor Activity
Abstract
Fiscal Year 2015 Peer Reviewed Cancer Research Program Focus Area: Colorectal Cancer. Katherine Carpenter is a second year graduate student in the Department of Pharmacology and Physiology at Saint Louis University. She has extensive laboratory experience prior to starting her studies under Drs. Burris and Flaveny, but hopes to hone her current skills and develop new skills in the field of pharmacology and cancer immunotherapy during her studies. Both Dr. Burris and Dr. Flaveny have years of experience creating targeted drugs and working in the cancer cell biology field. In fact, Drs. Burris and Flaveny recently published a paper in Cancer Cell on their joint work looking at how targeted inhibition of cancer cell metabolism can be used to kill tumors in murine models of several different cancers. Along with guidance from both Dr. Burris and Dr. Flaveny, Mrs. Carpenter will be exposed to the full scope of drug discovery through conversations with medicinal chemists on faculty at Saint Louis University and through expert support of the research microscopy core and flow cytometry core facilities, both of which she will take full advantage of during this study. Mrs. Carpenter will be mentored equally by both professors and will have the opportunity to present her work at two conferences during the year. As a budding young scientist, this award would help push her in the right direction by allowing her to develop her skills early on in her career and to gain experience as an independent cancer researcher. The proposed project involves preclinical testing of a novel drug, SR9243, for use as a treatment of colorectal cancer. The lab has already tested the drug and has shown that it can inhibit cancer cell metabolism, but Mrs. Carpenter s project focuses on investigating the effects of SR9243 on the immune system. Colorectal cancer is the second and third leading cancer diagnosis for men and women, respectively, and there are one million new diagnosed patients every year. It has been shown previously that cancer cells secreted factors that prevent the immune system from responding to tumors by activating the liver X receptor a nuclear receptor. One of the immune cells affected by these factors is the dendritic cell. A healthy dendritic cell wanders throughout the body and looks for signs of diseased tissues or infection. Upon finding a diseased cell, the dendritic cell then navigates back to the lymph nodes where it activates naïve T cells. These T cells are able to find the diseased tissue or source of infection and destroy it. It has been shown previously that some tumors secrete molecules that prevent these dendritic cells from navigating back to the lymph node after they have found the tumor. This is called tumor "masking." It is well known that the liver X receptors are important for glucose, fat, cholesterol metabolism, and regulation of immune cell function in response to inflammation. The lab has developed a novel drug, SR9243, that can inhibit liver X receptor activity. We observed that SR9243 can reverse the effects of the factors that prevent dendritic cell movement back to the lymph node where they can alert T cells. This allows dendritic cells to activate the T cells needed to destroy the tumors that would otherwise go undetected and continue to grow and effectively clear the cancer from the body. This study will show that by inhibiting LXR activity, we can potently increase the immune system s response to the tumors and cause tumor destruction via the body s own immune system. Data from this study could substantially influence the landscape of colorectal cancer treatment overall and improve survival rates for patients suffering from the disease, all within the near future.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610333
Entities
People
- Katherine Carpenter
Organizations
- Saint Louis University
- United States Army