Thursday, April 25, 2024
4/25/2024
Despite important advances in detection, surgery and chemotherapy, colorectal cancer (CRC) is the second cause of cancer death in the U.S. Most of these deaths are due to cancer progression and the subsequent development of metastatic disease and therapy resistance. New targets, ideally targets whose inhibition could suppress tumor growth, metastasis and therapy resistance, are still sorely needed. Accumulating data on usage of non-steroidal anti-inflammatory drugs reveals that inhibition of inflammation remarkably lowers the risk of cancer death, especially in CRC, indicating that inflammation may be a critical driver of cancer progression and metastasis beyond rare cases of colitis-associated cancer. We postulated that many apparently “non- inflammatory” solid tumors have a surprising ability to recruit immune cells and upregulate inflammatory mediators- a phenomenon named “tumor-elicited inflammation” (TEI). However, the exact molecular and cellular mechanisms of how inflammation regulates cancer progression, metastasis and therapy resistance are not fully understood, delaying identification and validation of new targets in cancer. In our preliminary studies, we specifically identified the IL-17B, and its receptor IL-17RB, pathway as: 1) upregulated in inflammation, CAC and CRC; 2) correlated with poor prognosis in human patients, and with expression of immune checkpoints that are required for inhibition of specific anti-tumor immune responses; 3) essential for CAC and CRC progression and inflammation 4) a molecular pathway whose inactivation reduced CAC and CRC, while other known inflammatory mediators are still present 5) a pathway, which controls both cancer cells and myeloid cell of microenvironment. This suggested that IL-17B/RB signaling is a key regulator of TEI and CRC tumorigenesis. Here we will test this hypothesis by defining the contribution of IL-17B/RB signaling to CRC progression, metastasis and response to therapy, and evaluting its mechanism of action, using multi-allele composite genetic murine models that mimic human CAC and CRC disease. As IL-17RB is expressed by both epithelial (cancer) cells and myeloid cells, we developed novel, conditional models of IL- 17RB deficiency in each cell type to allow us to dissect the cell-type-specific roles of IL-17RB signaling in TEI. Specific Aims for this project are the following: (1) Define the contribution for IL-17RB signaling and its mechanism action in CRC tumorigenesis. (2) Delineate the role of IL-17RB in CRC progression and metastasis. (3). Evaluate therapeutic targeting of IL-17RB to curb inflammation and CRC tumorigenesis. Overall these studies will establish a rationale for the specific inhibition of inflammation by targeting the IL- 17RB pathway as a strategy to halt CRC growth, progression and metastasis. Our long-term goal is to better understand the components of the inflammatory milieu in CRC progression, and thus define molecular predictors of primary and recurrent metastasis, leading to improved prevention and treatment of CRC.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
