Siteman Investment Program Awards $2.24 Million for Cancer Research

Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine is pleased to announce $2.24 million in new funding for 11 new projects, including three clinical trials. Through this research, investigators aim to improve the understanding of tumor formation and growth, develop safer, more effective therapies, and remove barriers to precision medicine. The funded projects focus on a variety of cancers, including breast, colorectal, leukemia, lung, lymphoma, and skin cancer.

Provided through the Siteman Investment Program (SIP), the funding supports innovative, high-impact cancer research across the continuum of discovery, diagnosis, treatment and prevention. This program is designed to advance promising ideas with strong potential for future external funding and meaningful clinical or community impact.

These SIP Research Development Awards are supported by a variety of sources including: The Cancer Frontier Fund at The Foundation for Barnes-Jewish Hospital, which includes gifts from the Pedal the Cause annual bike challenge, the Foundation’s annual Illumination Gala and donations throughout the year; the Cancer Center Support Grant (CCSG) from the National Cancer Institute; the Alvin J. Siteman Cancer Research Fund; Swim Across America – St. Louis; and various philanthropic gifts via Siteman Cancer Center.

Please see below for more details on each funded project.

New Clinical Trial Category

Project Title: Phase II Trial Evaluating Trastuzumab Deruxtecan and Lovastatin in HER2-low and Ultralow Advanced or Metastatic Breast Cancer

Principal Investigator: Andrew Davis, MD

Co-PI: Patricia Ribeiro Pereira, PhD

Goal: To evaluate a new drug combination that could help improve outcomes without added toxicity in up to 75% of patients with metastatic breast cancer who are HER2-low or ultralow

Project Summary: Trastuzumab deruxtecan (T-DXd) is approved for patients with metastatic breast cancer whose tumors express various levels of the HER2 protein. However, how well T-DXd works and how long patients stay on this therapy is related to the level of HER2 protein. T-DXd is a treatment that uses an antibody to deliver chemotherapy directly to breast cancer cells in a targeted way. It has improved outcomes for many patients whose tumors have lower levels of the HER2 protein (HER2-low or ultralow). However, these patients do not benefit from T-DXd as much as patients with metastatic breast cancer whose tumors have higher HER2 levels. Based on studies in laboratory models that closely resemble human tumors, we have identified a new way to increase how much T-DXd accumulates in tumors and works in tumors with low HER2 levels using lovastatin, an inexpensive drug that is commonly prescribed to lower cholesterol. These studies suggest that the combination of T-DXd and lovastatin could be more effective than T-DXd alone and safe, as the lovastatin would only need to be given twice every three weeks.

 

Project Title: Cancer Immunotherapeutic (PCI) Strategy in Triple Negative Breast Cancer Patients

Principal Investigator: William Gillanders, MD

Co-PI: Katherine Clifton, MD

Goal: This is a phase 1 clinical trial to evaluate the safety, feasibility and effectiveness of a personalized cancer vaccine in combination with CD8-selective IL-2 in patients with newly diagnosed triple-negative breast cancer (TNBC) in the window before surgery.

Project Summary: TNBC is an aggressive subtype of breast cancer, accounting for about 15% of all breast cancers. TNBC is more likely to spread, has fewer treatment options and poor clinical outcomes. TNBC disproportionately impacts Black women. The researchers have completed two phase 1 clinical trials of DNA personalized cancer vaccines (PCV) in patients with TNBC (NCT02348320, NCT03199040). In NCT02348320, they demonstrated that DNA PCV can induce neoantigen-specific T cell responses and that patients treated with DNA PCV have improved progression-free survival when compared to institutional historical controls. In NCT03199040, the researchers combined DNA PCV +/- anti-PD-L1 and confirmed these findings, although the addition of anti-PD-L1 did not significantly improve correlative or clinical outcomes.

The focus of this application is a phase 1 clinical trial of a synthetic long peptide (SLP) PCV alone or in combination with CD8-selective IL-2 in patients with newly diagnosed TNBC in the window prior to surgery following neoadjuvant chemoimmunotherapy. Newly diagnosed TNBC patients being treated with chemoimmunotherapy before surgery are eligible to enroll. Patients undergoing standard-of-care neoadjuvant chemoimmunotherapy will be randomized into two treatment arms: SLP PCV alone (Arm 1) or SLP PCV + CD8-selective IL-2 (Arm 2). The primary objective is to evaluate the safety and feasibility of SLP PCV +/- CD8-selective IL-2. The secondary objective is to assess the neoantigen-specific T cell response. The researchers plan to recruit and treat patients at Siteman Cancer Center and satellite locations. To rigorously define the response to SLP PCV +/- CD8-selective IL-2, the researchers will perform state-of-the-art correlative studies focused on neoantigen-specific CD8 T cells in the peripheral blood (Aim 1), neoantigen-specific type 1 regulatory T cells (Tr1) in the peripheral blood (Aim 2), and neoantigen-specific CD8 and Tr1 cells in the tumor microenvironment (Aim 3). The hypothesis is that CD8-selective IL-2 will enhance neoantigen-specific CD8 T cell responses and abrogate neoantigen-specific Tr1 responses. The proposed correlative studies form the basis of an R01 application and will accelerate the clinical development of PCI for the treatment of TNBC.

 

Project Title: A Pilot Study of Golidocitinib, a JAK1 inhibitor, in Patients with Mycosis Fungoides/Sezary Syndrome and T-Cell Large Granular Lymphocytic Leukemia

Principal Investigator: Neha Mehta-Shah, MD, MSCI

Goal: To examine the safety, toxicity and efficacy of golidocitinib in advanced-stage cutaneous T-cell lymphomas and T-cell large granular lymphocytic leukemia (T-LGLL). The researchers will also collect blood and skin samples to help understand the mechanisms of response and resistance to golidocitinib and provide insight into the biology of these diseases using DNA, RNA analysis, measurement of how much the drug inhibits this pathway, and assessment of how gene expression is regulated by golidocitinib.

Project Summary: Cutaneous T-cell lymphomas (CTCL) and T-LGLL are a rare subset of T-cell non-Hodgkin lymphomas for which patients are treated to improve disease burden and improve quality and duration of life. Currently available therapies only work in 5% to 40% of patients, and each therapy has a limited duration of effectiveness and significant cumulative toxicity. Given the relatively meager response rates to currently available therapy, limited duration of response and their toxicity profile, there is a need to develop better-tolerated therapies for these rare diseases.

Golidocitinib is an oral, selective JAK1 inhibitor which is approved in China for the treatment of peripheral T-cell lymphomas. In international studies, it works to reduce the cancer in over half of patients and works for years with limited side effects. Through work done at Siteman Cancer Center and at other centers, the researchers have found that both CTCL and TLGLL cells have activation of the JAK-STAT pathway. Other less selective JAK inhibitors are effective in the treatment of these diseases. Given the known biology of these diseases, which is hinged on this pathway, the researchers are studying the use of golidocitinib in these rare T-cell lymphomas.

 

Pre-R01 Category

Project Title: Epigenetic Evolution of Cutaneous Squamous Cell Carcinoma

Principal Investigator: David Chen, MD, PhD

Goal: Cutaneous squamous cell carcinoma is a skin cancer with an estimated incidence of greater than 1 million cases per year and is a major driver of cancer-related death, disfigurement and healthcare costs. This study aims to develop a better understanding of the early initiating events in skin cancer development, which may potentially lead to novel therapeutic and preventive strategies for squamous skin cancer.

Project Summary: Squamous cell skin cancer is the second most common cancer in people, yet it remains relatively understudied because it can often be cured with surgery. However, given its prevalence — over 1 million estimated cases annually in the United States — squamous skin cancer is still a major cause of cancer-related mortality, disfigurement, and healthcare costs. Despite ongoing public health efforts promoting ultraviolet (UV) light avoidance, the incidence of cutaneous squamous cell carcinoma (cSCC) continues to rise, particularly among older age populations. The limited availability of robust cSCC animal models and human translational studies has impeded researchers’ ability to gain a detailed understanding of the molecular causes of cSCC. These resources are critically needed to identify new targets for therapy. In this proposal, the researchers will address these gaps by leveraging two critical resources they have established: a novel mouse model of spontaneous squamous cell carcinoma and a human skin cancer tumor bank. They will investigate how defects in the tumor suppressor gene KDM6A contribute to early stages of squamous skin cancer development. By validating their findings using both their mouse model and patient-derived samples, the researchers will ensure that the findings of this study are relevant to human disease. Ultimately, the insights gained from this study have the potential to inform new preventive and therapeutic approaches for squamous skin cancer.

 

Project Title: Stress-Activated Enteric Glia Reprogram Premalignant Epithelium to Promote Colorectal Cancer Onset

Principal Investigator: Xue-Yan He, PhD

Goal: To understand how chronic psychological stress changes enteric glial cells, which are the supporting cells of the gut’s nervous system, in a way that helps start colorectal cancer (CRC). The investigators hope this work will show how stress, acting through these glial cells, creates a tumor-permissive environment in the gut and could point to new ways to prevent stress-related colorectal cancer in high-risk individuals.

Project Summary: CRC is a leading cause of cancer-related mortality worldwide. While genetic mutations such as loss of the APC gene are known to initiate tumor formation, the factors that determine whether mutant intestinal stem cells progress toward malignancy remain poorly understood. Chronic psychological stress has long been suspected of influencing cancer development, yet the biological mechanisms linking stress to CRC initiation are largely unknown. Epidemiological studies using large population datasets, including the UK Biobank, have shown that individuals with psychiatric disorders such as depression, anxiety or stress-related conditions have a significantly increased risk of developing CRC. These findings raise an important question: Can chronic stress actively promote the early onset of CRC? Based on these findings, the researchers hypothesize that chronic stress promotes CRC initiation by activating enteric glial cells (EGCs) to create a protumorigenic niche that drives the malignant transformation of mutant intestinal stem cells. To test this hypothesis, the researchers will: 1) Determine how stress-activated EGCs promote the malignant transformation of mutant intestinal stem cells, and 2) Define the epithelial mechanisms that enable stress-induced malignant conversion. These studies will establish a new conceptual framework linking chronic stress to colorectal cancer onset and may identify novel opportunities for CRC prevention and early intervention.

 

Project Title: Rational Design of Enhanced CAR Signaling Domains Through Deep Learning

Principal Investigator: Alex Holehouse, PhD

Co-PI: Nathan Singh, MD, MS

Goal: To re-envision the design of cell-based immunotherapies by leveraging an emerging field that combines advanced protein engineering with machine learning. This approach has the potential to empower a new era of highly effective immunotherapies and lay the groundwork for future personalized medicine-based approaches against leukemia.

Project Summary: Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary treatment that re-engineers a patient’s own immune system to identify and destroy cancer cells. While this approach has achieved remarkable success in treating blood cancers, many patients still experience relapses because the engineered cells often fail to persist long enough in the body to fully eradicate the disease. This failure is largely due to current CAR designs relying on “copied and pasted” parts from natural receptors that evolved to fight temporary infections rather than to provide the sustained, synthetic immunity required to cure cancer. This project aims to overcome these limitations by redesigning the “engine” of the CAR T cell from the ground up. To do this, the researchers are taking two complementary strategies. First, they are taking existing machinery that underlies CAR T function and re-engineering it to work more efficiently. Second, they are using advanced computational modeling and artificial intelligence to “evolve” entirely new, synthetic signaling components that outperform anything found in nature. By discovering these new design principles, the researchers will deliver a more durable and potent generation of cell therapies specifically optimized to survive in the patient’s body until the cancer is permanently eliminated. Ultimately, this work shifts the field from simple trial-and-error engineering toward a predictable, chemistry-based framework that will provide more reliable and lasting cures for patients facing aggressive leukemias.

 

Project Title: Developing 5-year Risk Thresholds for the Initiation, Frequency, and Discontinuation of Supplemental Breast Cancer Screening MRIs

Principal Investigator: Ashley Housten, OTD, MSCI, OTR/L

Goal: To design and pilot a doctor- and patient-facing decision support tool about supplemental breast MRI screening for those with dense breasts. The central research question is to investigate if a decision support tool guided by expert consensus and designed with user-centered methods will be feasible,acceptable and improve well-informed decision-making for doctors and patients.

Project Summary: Almost half of all women in the U.S. have dense breast tissue, which is a breast cancer risk factor and makes it harder to spot tumors on mammograms. While federal law requires patients to be notified about their breast density, this often leaves both women and their doctors in a difficult situation, as there is no clear agreement on how often someone should get a supplemental MRI or when the benefits of extra testing outweigh the physical, psychological and financial costs. This research project aims to bridge that gap by creating a decision support tool designed for use during doctor visits to help doctors and patients make well-informed decisions together. To achieve this, the research team will first gather a panel of experts in oncology and radiology to establish clear, consensus-based guidelines on who should get an MRI and how frequently, based on specific risk levels. Next, the researchers will work directly with patients and doctors to design a tool that translates complex medical information into plain language, ensuring it effectively communicates the tradeoffs of extra screening. Finally, the research team will pilot this tool in real-world clinics to see if it is easy to use and if it helps women feel more confident and informed about their decisions. Ultimately, this study will provide the foundation for a larger trial, transforming an unclear notification process into a clear, evidence-informed approach.

 

Project Title: Modulating Host Myeloid Cells to Enhance CAR T Cell Activity

Principal Investigator: Miriam Kim, MD

Goal: To improve long-term survival for patients with cancer by using myeloid cells to help chimeric antigen receptor (CAR) T cells fight cancer more effectively

Project Summary: The researchers aim to mobilize the immune system to fight cancer and improve survival for patients. CAR T cells are immune cells that have been genetically engineered to attack cancer cells and have been very effective in treating certain types of cancers. In this project, the team will investigate how myeloid cells can aid CAR T cells in their fight against cancer. Myeloid cells are the most common type of white blood cell in our bodies and are the first line of defense against injury or infection. In addition to responding directly to threats, they play a key role in supporting the rest of the immune system to restore the body to health. The researchers’ preliminary work shows that CAR T cells perform much better when they receive support from myeloid cells. The team will study how different types of myeloid cells influence CAR T-cell behavior using both mouse models and samples from human patients treated with CAR T cells. The researchers will also test drugs that are known to activate myeloid cells and enhance their ability to stimulate CAR T cells.

 

Project Title: The Role of YTHDF1 and Acid Signaling in Colon Cancer

Principal Investigator: Christopher Maher, PhD

Goal: To understand how a modification to RNA affects both cancer cells and immune cells. In this case, cancer cells make the area around them more acidic, which weakens the immune system response to treatment and enables cancer cells to spread to other parts of the body. By studying this process in colorectal cancer, the researchers hope to better understand how colorectal cancer spreads and to find new ways to treat it.

Project Summary: Despite advances in the understanding of how a colon tumor progresses, the mechanisms by which the tumor spreads throughout the body remain poorly characterized. To address this knowledge gap, the research team studies how the primary tumor spreads and interacts with neighboring cells to reduce response rates and promote further tumor growth. This proposal focuses on a novel regulatory mechanism of a “vicious cycle” whereby tumor cells secrete acid to prevent nearby cells from mounting an immune response, further enabling tumor cells to metastasize and remain resistant to existing therapies. The long-term impact of this research is to significantly advance the understanding of colon cancer metastasis and reveal therapeutic vulnerabilities in these aggressive, treatment-resistant tumors to improve the dismal response rates to existing treatments.

 

Project Title: Evaluation of CD19 CAR-Modified Immune Cells as Novel Chronic GVHD Therapy

Principal Investigator: Melissa Mavers, MD, PhD

Goal: To test a method of engineering immune cells to target harmful B cells — a new treatment approach — with the goal of improving chronic graft-versus-host disease (GVHD) outcomes and making hematopoietic cell transplantation (HCT) safer for patients

Project Summary: Many patients with blood cancers must undergo a treatment called HCT, sometimes known as bone marrow transplantation. However, a serious complication called GVHD can occur. Chronic GVHD can significantly impact patients’ quality of life and even be deadly. Immune cells called B cells play an important harmful role in chronic GVHD, and mice without B cells do not develop this disease. Prior treatments targeting B cells did not work in most patients, likely because they were unable to fully eliminate B cells or stop their function. Other current treatments for chronic GVHD cause broad immune suppression (increasing the risk of infections) and other significant side effects, and do not work in many patients. Therefore, new treatments are needed. One promising approach involves engineering certain immune cells to target and kill B cells. This approach has been used previously in B cell cancers and can very effectively kill cancerous and healthy B cells. Therefore, in this project, the researchers will test whether targeting B cells more effectively with this new approach will lead to better treatment of chronic GVHD in a mouse model. They will engineer two different types of killer immune cells to target and kill B cells and monitor for survival and signs of disease in tissues. This project is very important to providing early data that will allow the team to get additional grant funding to study this novel treatment further. Ultimately, they aim to improve the management and outcomes of chronic GVHD, making HCT a safer and more effective treatment for blood cancers.

 

Project Title:Adenovirus-Targeted Expression of an Immune Checkpoint Stimulator in Pulmonary Endothelial Cells for Lung Cancer Immunotherapy

Principal Investigator: Haval Shirwan, PhD (University of Missouri-Columbia)

Co-PI: Zhi Hong Lu, PhD

Collaboration with University of Missouri-Columbia

Goal: To develop an effective immunotherapeutic approach to treating lung cancer. Pulmonary endothelial cells play a critical role in cancer development and the modulation of the immune system, often promoting cancer progression. The proposed immunotherapeutic approach directly targets both pulmonary endothelial cells and the immune system to generate a response that effectively destroys cancer cells.

Project Summary: This project aims to use a harmless virus to deliver a gene into cells in the lungs. That gene would make the lung cells produce a special immune-boosting molecule. The hypothesis is that these lung cells would begin producing large quantities of this molecule right where the lung tumor is growing. This should help the immune system attack the cancer more strongly, while causing fewer side effects throughout the rest of the body. Researchers will test this idea in mice with a type of lung cancer similar to human non-small cell lung cancer, which is often hard to treat.