American Cancer Society renews Siteman Cancer Center grant funding early-career scientists

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine has received a renewal of its Institutional Research Grant from the American Cancer Society. The $360,000 grant will support 12 pilot projects over the next three years, including the four new projects described below.

Washington University has funded early-career oncology researchers with this grant since 1958. Jason Weber, PhD, a Washington University professor of medicine at Siteman, has been principal investigator of the grant since 2011.

Title: Investigating the function of distinct myeloid-biased multipotent progenitor subsets in the pathogenesis of myeloid malignancies

Principal investigator: Yoon Kang, PhD

Description: Myeloproliferative neoplasms (MPNs) are a group of diseases characterized by too many white blood cells, red blood cells or platelets in the bone marrow. There are several well-known disease-causing mutations, and researchers try to develop treatments targeting those mutations. However, in many cases, several mutations are accumulated to develop disease phenotypes. Therefore, this study aims to find a treatment that is applicable to a broad range of MPNs independent of individual mutations. Dr. Kang’s previous work found there is a specific immature bone marrow population, which is expanded in various MPN mouse models regardless of their driver mutations. In this study, she will research distinct subsets of that specific population to understand how each subset contributes to disease development, and to control the production of each subset. The study will provide insights into the common mechanism underlying MPN development and clues to develop broadly applicable therapeutic interventions.

 

Title: Exploiting natural killer cells in immunotherapy-induced MHC-I tumor escape

Principal investigator: Sytse Piersma, PhD

Description: Cancer immunotherapy has been successful in inducing durable responses in a variety of cancers; however, not all patients are cured. Some patients relapse because the tumor manages to escape the immune system in response to therapy. An important escape mechanism is hiding flags that can be detected by so-called cytotoxic T lymphocytes, which are essential in eradicating the tumor. The absence of these flags should be detected by another immune cell, the natural killer cell. However, these natural killer cells are not efficient in clearing cancer in relapse patients. This project will investigate the process of tumor escape in response to cancer immunotherapy and the role of natural killer cells herein. Results from this project will help achieve the long-term goal of improving cancer immunotherapy by preventing tumor escape.

 

Title: Clicking antibodies on the cell surface to reverse drug resistance in cancer

Principal investigator: Patricia Ribeiro Pereira, PhD

Description: Antibody drugs kill cancer cells directly, and they have revolutionized the treatment of cancer. Antibodies that target the human epidermal growth factor receptor 2 (HER2), a protein with elevated levels in certain cancer cells, are approved as drugs for breast and gastric cancers. These drugs are also being evaluated for biliary tract cancers, colorectal, non-small-cell lung and bladder cancers. However, not all patients with high levels of HER2 in their tumors respond to these antibody therapies, and there is a dire need for methodologies that overcome drug resistance in cancers. Preliminary data show that nonresponder cancers contain high levels of another protein, caveolin-1 (CAV-1). Researchers will use whole-body antibody-imaging techniques to monitor the potential of clicking antibody-drug pairs at the cell surface of HER2/CAV-1 cancer cells, to convert cancers from nonresponders to responders.

 

Title: Mechanisms of immune checkpoint therapy resistance in STK11-mutant lung adenocarcinoma

Principal investigator: Jeffrey Ward, MD, PhD

Description: Immunotherapies that redirect a patient’s own immune system to control their cancer have provided much excitement for those affected by non-small cell lung cancer (NSCLC). One form of cancer immunotherapy, antibodies that block the inhibitory receptor PD-1 on T-cells, functions by activating T-cells that recognize mutant proteins formed only by cancer cells, called neoantigens, to destroy tumors. For unclear reasons, patients whose lung cancers contain mutations in STK11, a gene that senses cell stress, do not benefit from anti-PD-1 therapies, even when tumor cells make neoantigens. Using a mouse model of NSCLC, researchers will study how T cells from tumors containing normal STK11 differ from T cells in tumors containing mutant STK11, helping them to better understand how the immune system is manipulated by STK11-mutant lung cancer. The long-term goal is to develop better strategies to combat immunotherapy resistance in STK11-mutant tumors to bring forward into clinical trials to benefit patients.