Siteman Investment Program awards $1.4 million in cancer research grants

Research focused on breast, gastric and pancreatic cancers, lymphoma, how to predict patient response to immunotherapy, and the development of evidence-based recommendations to strengthen support for families of individuals with advanced cancer are among the projects that will benefit from $1.4 million in new grants announced by Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

The money awarded comes from a variety of sources: Pedal the Cause annual bike challenge and Illumination gala, through the Cancer Frontier Fund at The Foundation for Barnes-Jewish Hospital; Swim Across America – St. Louis; Fashion Footwear Association of New York; National Cancer Institute; the Director’s Discovery Fund; and Barnard Trust.

The research projects are described below.

New Clinical Trial Mechanism

Project Title: Phase I Dose Escalation and Dose Expansion Study of Duvelisib Following Chimeric Antigen Receptor T Cell Therapy

Principal Investigator: Armin Ghobadi, MD

Goal: Our goal is to determine if adding the targeted oral drug duvelisib to standard treatment with genetically modified immune cells (chimeric antigen receptor or “CAR” T cells) will decrease cellular immunotherapy-related side effects and help CAR T cells to more effectively kill non-Hodgkin lymphoma.

Project Summary: Non-Hodgkin lymphoma is the most common blood cancer in adults. It develops from the lymphatic glands, which form an important part of the immune system. Currently, the first treatment patients receive for this cancer is high doses of chemotherapy, which can cure about half of patients. However, if the lymphoma does not disappear after chemotherapy or comes back after treatment, additional chemotherapy treatments are unlikely to provide a cure. Physicians are increasingly interested in harnessing the body’s own immune system to help fight cancer, including lymphoma. One promising approach is the collection and modification of the patient’s own immune cells to make a special type of anti-cancer treatment called chimeric antigen receptor T cells or “CAR T cells”. These cells are specifically designed to find and destroy lymphoma cells after recognizing a specific protein on their surface. In prior studies, the use of CAR T cells has been shown to cure about a third of patients with NHL who were not cured by chemotherapy. Unfortunately, this therapy can have significant side effects that require hospitalization or admission to the intensive care unit, including fevers, confusion, difficulty breathing and low blood pressure. Further, the majority of patients are still not cured by this approach and most treatments are ineffective if the lymphoma comes back after receiving CAR T cell therapy. Consequently, our study proposes to use duvelisib, a medicine that can be taken by mouth, to improve the function of CAR T cells during treatment. Based on work in the laboratory, we believe it will decrease the side effects of CAR T cell treatment while helping CAR T cells to last longer and kill cancer cells better. With this approach, we hope to increase the number of patients who can safely receive CAR T cells and provide better control of the cancer, ultimately leading to more patients with lymphoma being cured.

Project Title: Phase I trial of CA-4948 in Combination with FOLFOX/PD-1 Inhibitor +/- Trastuzumab for Untreated Unresectable Gastric and Esophageal Cancer 

Principal Investigator: Kian-Huat Lim, MD, PhD

Goal: Our goal is to improve the efficacy of treatment for patients with metastatic gastric and esophageal cancers by combining a new drug called CA-4948 with current chemo-immunotherapy treatments to activate killer T cells.

Project Summary: Chronic inflammation is an important risk factor that leads to the development of gastrointestinal cancers including gastric, esophageal, pancreatic, and colon cancers. Under the microscope, we can easily observe that these cancers are heavily surrounded by inflammatory cells. These inflammatory cells secrete soluble factors that not only fuel cancer cell growth, but also block our bodies’ main immune defense mechanism, particularly the killer T cells. We have recently identified IRAK4, an enzyme within cancer cells, as a key target that drives chronic inflammation in gastrointestinal cancers. We found that blocking IRAK4 using a new drug called CA-4948 can dramatically decrease inflammatory cells inside the cancer of experimental mouse models, causing the killer T cells to be partly activated. When we added an immunotherapy agent called anti-PD1 antibody, we observed a further boost in killer T cell activity and number, which led to complete elimination of cancers in more than half of the experimental mice. This is an exciting finding that led us to open a new clinical trial for patients with metastatic gastric and esophageal cancers, in which chemotherapy and immunotherapy are already part of the regimen. Our hope is that adding CA-4948 will make these therapies more effective and last longer in patients. To our best knowledge, this is the first clinical trial that combines CA-4948 with chemo-immunotherapy in cancer patients. If shown to be effective from this study, we will proceed to open this clinical trial in a larger scale in collaboration with other cancer centers in the future.

COE Supplement

Project Title: Centering Families in Advanced Cancer Care: A Group Concept Mapping Approach 

Principal Investigator: Karla Washington, PhD, LCSW

Goal: Our goal is to develop evidence-based recommendations to strengthen support for families of individuals with advanced cancer.

Project Summary: Family members of individuals with advanced cancer are increasingly recognized as “hidden patients” whose provision of around-the-clock, day-to-day care, coupled with the emotional distress of a family member’s serious illness, places them at heightened risk of anxiety, depression, physical illness, and compromised quality of life. Recognition of this reality has inspired calls for a more family-centered approach to advanced cancer care; however, there exists little consensus regarding what “family-centered” means in this context. This ambiguity impedes the development of concrete, actionable plans to enhance support services for families, increasing the likelihood of adverse outcomes for both family members and the patients who rely on their care. This application proposes a mixed-methods participatory research project in which a diverse subsample of family members of individuals with advanced cancer (n = 30) will collaboratively develop an operational definition of family-centered advanced cancer care via group concept mapping techniques. Researchers will: 1) engage family members of patients with advanced cancer in delineating a conceptual domain of family-centered care; 2) explore differences in the conceptualization of family-centered care based on family members’ race/ethnicity, rurality/urbanity, and degree of social/financial security; and 3) develop evidence-based recommendations to inform the provision of advanced cancer care that reflect an inclusive definition of family-centeredness and that are responsive to the needs of diverse family groups. The project will supplement an existing randomized clinical trial of a psychosocial intervention for family caregivers of individuals with cancer receiving outpatient palliative care (R01CA258311), leveraging existing resources to enable thorough, yet timely completion of the project.

Pre-R01 Mechanism: Made Possible by Pedal the Cause

Project Title: Advancing Breast Cancer Risk Assessment among White and Black Women Using Artificial Intelligence and Sequential Mammograms

Principal Investigator: Aimilia Gastounioti, PhD

Goal: Our goal is to discover novel imaging phenotypes of breast cancer risk from mammography and bring effective personalized breast cancer risk models to more racially diverse screening populations.

Project Summary: This is a study to learn whether a woman’s risk of developing breast cancer can be predicted by using computers to evaluate changes in her mammograms over time. Breast cancer risk is related to several factors, including having family members with breast cancer, certain changes in genes (mutations), and reproductive history (like number of children and breastfeeding history). Some previous studies have shown that a woman’s risk is associated with what her mammogram looks like when analyzed by a computer – looking at features of the image before a cancer is visible. However, most of these mammograms were from White women, and it is not known whether these same features can predict breast cancer risk in Black women. Because Black women are affected by more aggressive cancers that show up at younger ages, it would be particularly helpful to be able to predict breast cancer risk in this group of women. The previous studies have also looked only at features from a single mammogram. This study will look at changes in mammograms from year to year to find out whether risk can be better predicted from these changes. We will retrospectively analyze mammograms of both White and Black women in order to develop a computer program that will give a more accurate estimate of each woman’s individual risk of breast cancer, regardless of race. The ultimate goal is to improve our use of screening mammograms and lower risk of dying from breast cancer.

Project Title: The Role of Caveolin-1 in Gastric Cancer Response to Immunotherapy

Principal Investigator: Patricia Ribeiro Pereira, PhD

Goal: Our goal is to enhance the efficacy of immunotherapy treatments in gastric tumors. We aim to use molecular imaging techniques to investigate the mechanisms of cancer-cell surface protein regulation to enhance immune checkpoint blockade efficacy in gastric tumors.

Project Summary: Cancer cells can become invisible to monoclonal antibody drugs (i.e., a form of immunotherapy) by decreasing the availability of cancer-cell surface proteins, which are the ones targeted by these drugs. We have recently shown that proteins present in high quantities in gastric cancer cells are not always available at the cell surface for the effective binding of antibody drugs. The processes by which proteins are distributed throughout the cancer cell and internalized from the cell membrane could explain why immunotherapies only work in 30% of patients with gastric cancer. Thus, there is a critical need to understand the biological mechanisms of cancer-cell surface protein regulation and develop approaches that allow effective control of these processes.

The Disease Imaging and Therapy lab uses cutting-edge imaging technologies to visualize in the whole body and in real-time the biological processes by which proteins are internalized into the gastric cancer cell and away from the membrane where antibody drugs bind to them. We then develop pharmacologic approaches to control these processes in ways that enable the conversion of non-responder gastric cancers into responders. This proposal aims to use our imaging methodologies to discover the membrane trafficking mechanisms of PD-L1—an important membrane protein that prevents immune cells from destroying cancer cells—and determine whether PD-L1 trafficking can be modulated to enhance the efficacy of antibody drugs targeting PD-L1 in gastric cancers. These approaches will enhance antibody therapies targeting cell-surface receptors and increase the number of patients that benefit from them.

Project Title: Senescent Stromal Cells Sculpt the Tumor Microenvironment to Drive Breast Tumorigenesis

Principal Investigator: Sheila Stewart, PhD

Goal: Our goal is to develop smarter breast cancer therapies that have a more potent effect at limiting disease progression by interrogating how age-related changes in non-tumor cells contribute to increases in breast cancer.

Project Summary: Cancer is a disease of the aged. Indeed, there is a rapid increase in cancer rates after the 5th decade of life. While many components contribute to the development of cancer, we have found that normal cells in the vicinity of incipient cancer cells facilitate the formation of a tumor and its eventual metastasis to other organs in the body. We have found that age-related changes in one of these normal cells, referred to as fibroblasts, are capable of increasing tumor growth. Using specific systems that allow us to kill these normal cells in mouse models of breast cancer, we can significantly slow tumor growth. The focus of this proposal is to understand how these aged fibroblasts facilitate tumor growth and to develop and characterize additional experimental tools that will allow us to identify therapeutic approaches to inhibit the tumor-promoting activities of aged fibroblasts.

Project Title: Exploring Precision Oncology Opportunities Contributed by Transposable Elements

Principal Investigator: Ting Wang, PhD

Goal: Our goal is to improve the scalability and logistical feasibility of immunotherapy by developing a technology to help predict which patients will respond to the FDA-approved immunotherapy called checkpoint blockade and identifying vaccine targets shared by cancer patients.

Project Summary: Harnessing the immune system to fight cancer has ignited a revolution in oncology. Although these new immunotherapies have shown promise for certain patients with certain cancers, most patients with most cancers will unfortunately see little benefit from these treatments. Our proposal seeks to broaden the potential effectiveness of immunotherapy for most patients.

First, we will advance the development of vaccines to fight cancer. Vaccines are unique in their ability to precisely steer the immune system to recognize and attack predefined targets of interest, such as cancer cells. However, cancer vaccines can take a long time to produce and can be costly because they are personalized for each patient. To address these hurdles, we are identifying vaccine targets that are shared by most patients, thereby reducing the need for personalization. Achieving this goal will decrease the time and costs associated with cancer vaccination, expanding access to this promising treatment platform.

Next, we will develop a new technology to help doctors predict which patients will respond to a certain type of FDA-approved immunotherapy called checkpoint blockade. Checkpoint blockade works by “cutting the brakes” on the immune system, sending its natural cancer-fighting abilities into overdrive. However, for most cancer types, it is not clear which patients will respond to this therapy. Since these therapies can cause serious side effects, it is important to identify which patients have the best chance of responding to them. We hope this technology will improve patient outcomes by expediently matching patients to the treatments most likely to benefit them.