Siteman Cancer Center Announces 2023 American Cancer Society Funded Pilot Projects

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine is excited to announce the next cohort of pilot projects funded by the Institutional Research Grant from the American Cancer Society. The $480,000 grant will support a total of 12 pilot projects from 2022-2024, including the four new projects for 2023 described below.

Under the leadership of Jason Weber, PHD, who has been the principal investigator of the grant since 2011, these awards support independent, self-directed investigators early in their careers and enable them to conduct research in areas of special interest to the American Cancer Society.

Washington University has funded early-career oncology researchers with this grant since 1958. To see past funded projects through this grant, click here: 2022 ACS IRG Awardees

 

Project Title: Contribution of Myeloid Cells to the Post-Radiation Immune Response

Principal Investigator: Mai Dang, MD, PhD

Project Summary: Brain tumors are the leading cause of death by cancer in the pediatric population; thus there is a great need for novel therapies. Radiation is an important part of therapy for many high-grade tumors including medulloblastoma, the most common malignant pediatric brain tumor, but it is rarely curative and comes with significant side effects.

This project aims to identify reversible causes of immune suppression in medulloblastomas treated with radiation so that we can leverage the benefits of immunotherapy to achieve long-term remission for patients with treatment-resistant tumors.

Project Title: PD-1 and CD40 Combination Immunotherapy Reshapes the Cardiac Immune Landscape

Principal Investigator: Jesus Jimenez, MD, PhD

Project Summary: Immunotherapies including immune checkpoint inhibitors have revolutionized cancer treatment and are a cornerstone of standard clinical practice and clinical trials. To expand their therapeutic benefit, combining immunotherapies is increasingly investigated. However, combining agents that regulate critical checkpoints of autoimmunity can impart life threating cardiac events including myocarditis.

The basis for cardiac injury from checkpoint inhibitors is unknown but recent evidence suggests that immune cells such as macrophages and T-cells infiltrate the heart, resulting in an overwhelming inflammatory response. Checkpoint inhibitors target interactions between immune cells including T-cells and macrophages or target (cancer) cells. While combining established checkpoint inhibitors like PD-1 with CD40 agonists increases the efficacy against previously untreatable cancer, little is known regarding how combining treatments impacts the heart. In this proposal, I will test the hypothesis that combining PD-1 blockade with a CD40 agonist reshapes the immune landscape of the heart, priming inflammatory responses to cardiac injury.

Project Title: Investigate the Tumor Suppressive Role of ARID Homologs in Melanoma

Principal Investigator: George Souroullas, PhD

Project Summary: Recent cancer studies have identified errors in proteins that chemically modify the genetic code (DNA). Modifications to the DNA affect many of its functions, such as how more copies are made and how genes are expressed. These modifications to the DNA are referred to as the “epigenome”. Identification of errors in genes and proteins that modify the epigenome presents us with a great opportunity in cancer therapeutics because unlike the DNA, which cannot be corrected in patients, the epigenome can be modified by using small molecules (drugs). Melanoma patients exhibit frequent errors in a group of proteins that regulate the epigenome. In preliminary studies, we found that when we delete a specific group of these genes, melanomas grow faster and are more sensitive to a specific drug that inhibits a different protein. In this proposal, we will further explore these interactions in order to help develop improved therapeutic strategies.

 

Project Title: Connecting Metabolism with PARP Inhibitor Responses in BRCA-Mutant Cancers

Principal Investigator: Priyanka Verma, PhD

Project Summary: Breast and ovarian cancers with mutations in BReast CAncer (BRCA)-dependent DNA repair genes represent approximately 70% of triple-negative breast cancers and 50% of high-grade serious ovarian carcinoma. These two cancer types are the most aggressive and difficult malignancies to treat. Precision medicine approaches based on Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated promising clinical efficacy, but there is variability in patient response, the basis for which remains enigmatic. Therefore, there is a pressing unmet clinical need for identifying cancer cell intrinsic mechanisms that dictate PARPi response. We have recently made an exciting discovery that depletion of a metabolic enzyme, fumarate hydratase, can enhance PARPi sensitivity of BRCA-mutant breast and ovarian cancer cells. Here, we will identify the basis of this enhanced sensitivity. Our results can establish an innovative and promising biomarker for this high-risk group of women with BRCA-mutations who have limited chemotherapeutic options.