Identifying and Validating Oncogene-Induced Mechanisms of Immunosuppression Downstream of the ESRP1/FGFR2/KRAS Axis to Improve Immunotherapy
Abstract
The current CDCRP Ideas grant application addresses the FY21 PRCRP Topic Area of Endometrial Cancer (EC). EC is increasing in incidence and mortality, due partly to increased societal obesity, and is underfunded based on disease burden. In 2021 EC is predicted to occur in 66,570 American women with 12,940 women estimated to die (American Cancer Society). Rationale: There are four well recognized subtypes of EC that differ in the genetic mistakes that give rise to each subtype and there is evidence from clinical trials that some subtypes respond better to chemotherapies while others respond better to immunotherapies. This Ideas grant proposal is focused on improving responses and long-term survival to immunotherapy in the second most common subtype of EC with respect to both incidence and mortality. This EC subtype is characterized by defective mismatch repair (dMMR) and a high mutational load (mistakes in the DNA sequence) and is responsible for ~25% of EC deaths. New immunotherapy treatments for cancer are now approved for the treatment of dMMR EC after failure of standard of care. While some patients show a complete response to these drugs, most have a partial response and ~50% of patients have no benefit. We believe we have identified a novel pathway involving a new gene (ESRP1) as well as two genes already known to be important in EC (FGFR2 and KRAS). Although the latter two genes have been previously shown to cause EC cells to grow uncontrollably and be more resistant to killing, we believe that this pathway also plays another important role in cancer – to change the types and activity of the immune cells in the tumours to be growth promoting rather than tumour killing. Scientific objective: This grant proposal has two main Aims, the first is to do detailed laboratory studies to understand more about how mutations that turn off the ESRP1 gene contribute to the initiation and progression of EC. All genes are made up of small fragments of DNA (exons) that are stitched together (spliced) to form one long protein. Which fragments get stitched together can drastically alter a proteins function. The ESRP1 gene encodes a special protein involved in choosing which fragments (exons) to stitch together (splice). It plays a crucial role in normal epithelial cells to bind to special places along the DNA to stop the wrong fragments being stitched together. Mutations that turn off ESRP1 then lead to the wrong fragments being stitched together for hundreds of genes. This gene has been studied in detail in several mouse tissues (ear, kidney, palate) but because different genes are expressed in different tissues, we need to determine the effect of losing ESRP1 in EC cells and which genes now include the wrong fragments. We hypothesize that the primary way ESRP1 drives EC is through the incorrect stitching together of FGFR2 to make the wrong FGFR2c version which is stuck in the on position. The second aim of this proposal is focused on implanting small fragments of patient tumours into special mice that have undergone irradiation (much like a human prior to a bone marrow transplant) then injected with human stem cells from fetal cord blood so that the immune cells that regrow in the mouse are made up of human immune cells as well. This lets us treat these mice with anticancer drugs and then measure how these drugs change the human immune cells within the tumour from those that promote tumour growth to those that recognize and kill the tumour cells. Collecting this evidence with these specialized models will provide key data to support the design of a new clinical trial testing this combination in patients with dMMR EC. If we can show our hypotheses are correct, the combination of an immunotherapy drug (e.g. pembrolizumab) with a drug targeting this pathway (e.g infigratinib) can be expected to improve the outcomes for ~50% of dMMR EC patients (~8300 patients/year diagnosed and ~1600 patients that
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210432
Entities
People
- Pamela Pollock
Organizations
- Queensland University of Technology
- United States Army