Siteman Investment Program Awards $2.42 Million for Cancer Research

Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine is pleased to announce funding for 12 new projects, including four clinical trials. Through this research, investigators aim to improve the understanding of tumor formation and growth, develop safer, more effective therapies, and explore new cancer screening strategies.

The projects will benefit from $2.42 million in new grants awarded through the Siteman Investment Program. The goal of the grants is to support and accelerate the pace of innovation in cancer research. The money awarded comes from a variety of sources, including The Cancer Frontier Fund at The Foundation for Barnes-Jewish Hospital, which includes gifts from Pedal the Cause’s 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.

Please see below for more details on each funded project.

New Clinical Trial Category

Project Title: Phase II Study of Stereotactic Body Radiotherapy plus FAK and RAF/MEK inhibition in Advanced Pancreas Adenocarcinoma

Principal Investigator: Hyun Kim, MD

Co-PIs: Patrick Grierson, MD, PhD, and David DeNardo, PhD

Goal: This is a phase II, single-institution, open-label trial treating patients with borderline resectable (difficult to remove surgically) or locally advanced (cannot be removed by surgery) pancreatic cancer. The hypothesis is that advanced pancreatic cancer patients receiving treatment of adaptive (change the plan each day to adapt to patient’s anatomical changes in bowel and tumor position) stereotactic body radiotherapy (SBRT) plus defactinib + avutometinib at the same time will have more time after treatment during which the cancer will not progress (otherwise known as increased progression-free survival, or PFS) compared to historical PFS rates for patients receiving adaptive SBRT alone.

Project Summary: Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of 12%. The only potential for a cure is surgical removal of the tumor (resection). However, despite 48% of patients presenting with advanced non-metastatic disease, only 10-15% of these patients are surgically resectable. Current standard of care for these locally advanced PDAC (LAPC) patients who are surgically unresectable is chemotherapy followed by consolidation stereotactic body radiation therapy (SBRT). However, more than half of these patients will progress to metastatic disease in one year. Current SBRT strategies infrequently generate sufficient tumor regression to enable a surgical option in LAPC patients. Thus, more effective treatment strategies for LAPC that lead to greater prevention of metastatic disease would directly improve PDAC patient survival. This application seeks to build on exceptional scientific, pre-clinical, clinical and biomarker findings. We will conduct a phase I/II study of SBRT plus FAK inhibition (Defactinib) and a RAK-MEK inhibitor (Avutametinib) in advanced pancreatic cancer patients. Our hypothesis is that this combination will be safe and lead long-term survival through modulation of tumor-intrinsic and immune pathways.

 

Project Title: Therapeutic RSK1 Targeting in Myeloid Malignancies

Principal Investigator: Stephen Oh, MD, PhD

Goal: This study investigates a new approach to treating certain types of blood cancers. Currently available treatments for these blood cancers are only partially effective. Thus, there is a desperate need to develop more effective treatments for these diseases. The proposed study involves the repurposing of a treatment that is currently in development for breast cancer. This would be the first study of this treatment in blood cancers. This study hypothesizes that PMD-026, an oral inhibitor of ribosomal protein S6 kinase A1 (RSK1), is safe and well tolerated in participants with MF and MDS/MPN and will improve spleen response, symptom response and bone marrow histopathological response.

Project Summary: Myelofibrosis is a chronic myeloproliferative neoplasm (MPN) characterized by anemia, enlargement of the spleen, bone marrow fibrosis, fever, night sweats, fatigue and weight loss. Life expectancy with MF is limited, with a median survival of only five years. MF exhibits a propensity for transformation to post-MPN secondary acute myeloid leukemia (sAML), for which the prognosis is dismal (median survival < 6 months). Despite vigorous research, therapies capable of effectively treating MF and preventing progression to sAML remain elusive. Thus, there is a pressing need to develop novel therapeutic strategies for patients with these diseases. We initially identified aberrantly increased expression of the phosphatase DUSP6 in CD34+ hematopoietic stem/progenitor cells (HSPCs) from patients with MPNs transformed to sAML. Genetic and pharmacologic inhibition of DUSP6 inhibited MPN cell proliferation and suppressed downstream signaling effectors including phosphorylated RSK1 (pRSK1). To further understand the role of RSK1 (encoded by RPS6KA1), we performed patient-derived xenograft (PDX) experiments with sAML patient CD34+ HSPCs subjected to RPS6KA1 shRNA knockdown. Remarkably, RPS6KA1 knockdown led to near complete elimination of human CD45+ cells in the peripheral blood and bone marrow of engrafted mice. Our clinical trial challenges current treatment paradigms by investigating therapeutic targeting of a novel signaling pathway in myeloid malignancies. This investigator-sponsored study will be the first study with PMD-026 in blood cancers. The study additionally incorporates laboratory correlative studies (RNA-sequencing, mass cytometry, multiplex cytokine profiling, molecular genomics) to characterize how treatment with PMD-026 impacts downstream signaling effectors, inflammatory markers, and molecular response. This proposal leverages novel scientific concepts to address important unmet needs for patients with myeloid malignancies.

 

Project Title: Phase II Trial of Surgery followed by Risk-Directed Post-Operative Adjuvant Therapy for HPV-Related Oropharynx Squamous Cell Carcinoma: “The Minimalist Trial-2 (MINT-2)”

Principal Investigator: Sidharth Puram, MD, PhD

Co-PI: Douglas Adkins, MD

Goal: To reduce the dose of radiation and chemotherapy a patient receives after undergoing surgery for human papillomavirus (HPV)-related oropharynx squamous cell carcinoma (throat cancer)

Project Summary:

Despite improvements in operative techniques (e.g. transoral robotic surgery, or TORS), which have reduced short-term surgical morbidity for HPV+ oropharyngeal squamous cell carcinoma (OPSCC), otherwise known as throat or tonsil cancer, radiation and chemo after surgery remain a cause of significant long-term morbidity. While surgery is well-tolerated, post-surgery therapy often causes serious acute and chronic adverse events (AEs), including debilitating inflammation of the mucous membranes that line your mouth and GI tract, severe dry mouth, taste disorders and neck fibrosis/scarring among others, potentially resulting in long-term dependence on a feeding tube. Given the overall high rates of cure for HPV+ throat or tonsil cancer, there has been a strong focus on de-escalation of chemoradiation therapy (POACRT) in these patients to improve long-term morbidity. Our prior MINT trial (MINT-1) was a major step forward in de-escalation of HPV+ OPSCC patients. We believe this new proposal will significantly alter the standard of care adjuvant therapy of HPV+ throat and cancer patients and improve the therapeutic potential of current treatments. Importantly, MINT-1 was a non-randomized study; thus, at a minimum, confirming and extending the results of that study through MINT-2 represents a critical advance that is likely to yield adoption of this approach nationally and change the standard of care.

 

Project Title: A Multicenter Phase II Study of Propranolol for the Treatment of Kaposi Sarcoma in Adults

Principal Investigator: Lee Ratner, MD, PhD

Co-PI: Thomas Odeny, MD, MPH, PhD

Goal: This is a phase II, open-label, multicenter, single-arm treatment trial evaluating the use of propranolol (a beta blocker) to treat Kaposi sarcoma (KS), a disease in which cancer cells are found in the skin or lymphatic or visceral sites in the body. The hypothesis of this study is that an overall response rate (ORR = CR + PR rate) of at least 45% (as assessed by the AMC KS response criteria) will be achieved in participants, and that propranolol will be safe and well-tolerated by patients with KS. Our goals are to determine: 1) the safety and response of propranolol for KS, and 2) the effect on KS-associated gene expression.

Project Summary: Infectious agents cause 20% of cancers worldwide. Kaposi sarcoma (KS) is caused by the KS γ-herpesvirus (KSHV). KSHV is also associated with primary effusion lymphoma, a B cell lymphoproliferative, preneoplastic disease, multicentric Castleman’s disease (MCD), and KS inflammatory cytokine syndrome (KICS). Treatment of KS involves immune reconstitution and/or systemic liposomal anthracyclines, taxanes, pomalidomide, or immune checkpoint inhibitors, but most of these therapies are not available low-income countries, and KS is one of the most common cancers in sub-Saharan Africa in HIV-negative or positive individuals.

Although remissions are obtained in most patients, complete remissions are rare, and continuous therapy is required. Propranolol is an inexpensive, globally available beta blocker, which is highly effective therapy for infantile hemangioma, and other vascular lesions and anecdotal reports describe successful treatment of KS with oral propranolol. Therefore, it is logical to assess the safety and activity of propranolol in a prospective clinical trial, and identify biomarkers of response. Single cell transcriptomics (scRNAseq) provides in-depth data about KS interactions with the tumor microenvironment, which will be utilized with baseline and on-treatment biopsies. We are uniquely qualified for this project given our extensive KS biological, pathological, epidemiological, translational and clinical experience.

Up to 25 eligible patients will be enrolled in a 2-stage phase 2 clinical study (18 at Washington University and 7 at the Kenya Medical Research Institute), with different KS subtypes, and treated with up to 20 weeks of propranolol. Successful completion of this study trial may provide a new, inexpensive, well-tolerated, globally available therapy for KS, and identification of biomarkers of response. This should prompt an assessment of beta blockers in other malignancies.

Team Science

Project Title: Elucidating Mechanisms and Translational Strategies to Enhance Therapeutic Anti-Tumor Immunity

Principal Investigator: Todd Fehniger, MD, PhD

Project Leads: Carl DeSelm, MD, PhD; Robert Schreiber, PhD; Nathan Singh MD, MS

Goal: The Cancer Immunity Team Science group is a translational, interdisciplinary research program with the overarching goal to develop new forms of immunotherapy that enhance a patients’ anti-tumor T cell immunity by design and thereby improve clinical outcomes or achieve cure.

Project Summary: The Cancer Immunity program is a group of physicians and scientists united in the goal of discovering new strategies that initiate or promote a patient’s own T cells to destroy their cancer. These discoveries will then be translated into multiple novel treatment strategies that may have a broad impact on multiple cancer types. The projects utilize solid tumor (sarcoma) and blood cancer (lymphoma) immunocompetent mouse models to evaluate these new ideas, with translational relevance enhanced by confirming findings within lymphoma patient samples. The first project established these two cancer models in mice, defined key cancer cell proteins (neoantigens) targeted by T cells, developed neoantigen vaccines to initiate cancer immunity, and discovered a new CD4+ Tr1 cell that suppresses effective CD8+ T cell responses to these malignancies. This project serves as an integrative hub for the other projects. A second project investigates how chimeric antigen receptor (CAR) T cells bring about cancer immunity, and correlates key findings in samples from patients undergoing CAR T cell therapy. The third project defines the ability of CAR natural killer (NK) cells to increase anti-tumor immunity by enhancing neoantigen release via direct killing, dendritic cell localization and maturation, antigen presentation and T cell localization. Concepts discovered will be confirmed in humanized mouse models. The fourth project advances CAR dendritic cells, evaluating mechanisms to promote robust cancer immunity through epitope spreading, and combining with strategies that target suppressive cells, including Tr1 cells. The projects are highly integrated by evaluating Tr1 cells in each strategy, performance of inter-project experiments to address resistance to a single immunotherapy, and have shared model profiling that evaluates Tr1, T cells, NK cells and DCs across projects. The projects will be supported by research cores that facilitate uniform immunology and informatics analysis, biostatistics and shared mouse modeling, in a planned extramural team science program application.

 

 

Pre-R01 Category

Project Title: Optimizing Targeted Alpha-Emitter Radiopharmaceutical Therapy for Intraperitoneal Carcinomatosis

Principal Investigator: Remco Bastiaannet, PhD

Co-PI: David Bauer, PhD (MU)

Collaboration with University of Missouri – Columbia

Goal: This proposal aims to develop a safer, more effective radiotherapy treatment for patients with advanced colorectal cancer that has spread to the abdomen — helping improve both survival and quality of life.

Project Summary: Colorectal cancer often spreads to the lining of the abdomen, forming small tumors called peritoneal metastases. These tumors are especially hard to detect and treat and current therapies like systemic chemotherapy offer only limited benefit. There is a critical need for more effective and targeted treatments. This project explores a promising new strategy called intraperitoneal targeted alpha therapy (IP TAT). This approach delivers powerful cancer-killing radiation — known as alpha particles — directly into the abdominal cavity, where it can precisely target cancer cells while minimizing damage to healthy tissue. Alpha-emitters deliver extremely potent radiation and are increasingly being used in cancer patients, often successfully treating tumors for which other therapies have failed.

In the first part of this study, we will test a group of specially designed radioactive drugs that are made to seek out and attach to colorectal cancer cells. These agents are developed by our collaborators at the University of Missouri, who bring expertise in radiochemistry and tumor biology. By comparing different versions, we aim to find the one that most effectively reaches and sticks to tumors and stays in place long enough to be effective. In the second part of the project, we will use advanced imaging techniques and computer modeling—developed by the physicists and radiobiologists of the Washington University team — to precisely measure where the radiation accumulates and how much radiation the tumors receive. This will help us determine how best to eliminate cancer cells while avoiding harmful side effects.

 

Project Title: Diet-Related Therapies to Enhance Radiation Anti-Tumor Responses and Minimize Toxicity

Principal Investigator: Carmen Bergom, MD

Goal: The primary objective of this proposal is to investigate how cellular processes, such as autophagy and the activation of specific metabolic pathways, may enhance the effects of radiation therapy on tumors and protect the heart from radiation-induced damage. Our goal is to develop treatments that improve radiation’s helpful effects on cancer and reduce its harmful effects on the heart.

Project Summary: Radiation therapy (RT) is an important component of modern cancer treatment; it is received by over half of all patients with cancer. Despite recent advances, RT does not cure all patients, and some experience harmful side effects — especially to the heart when the chest is treated. This highlights the need for new strategies to improve RT. We recently demonstrated that intermittent fasting (IF), a dietary approach that alternates periods of fasting with normal eating, enhances RT’s ability to kill tumors and also protects against RT-induced heart damage in animal models. IF can cause a wide range of effects, including increased cycling of a process called autophagy, which is linked to health and aging, as well as altered tumor metabolism. Our preliminary data from pre-clinical laboratory models suggest that IF and RT alter autophagy in tumors and the heart, which may lead to the favorable effects of combining IF and RT. Our metabolomics and other data from pre-clinical models suggest that regulation of branched-chain amino acid metabolism may also mediate the enhanced anti-tumor effects of IF on radiation. Our objective in this proposal is to use innovative preclinical techniques to determine how IF and RT impact autophagy and branched-chain amino acid metabolism in preclinical models of cancer and heart damage using RT. Our findings have the potential to identify translatable interventions that replicate the beneficial effects of IF, thereby enhancing radiation outcomes in patients with cancer. For instance, approved drugs used for other conditions may mimic IF, potentially improving RT efficacy in patients. These studies may lead to clinical trials and ultimately improved outcomes for patients with cancer.

 

Project Title: Bacteria to Treat Brain Tumors

Principal Investigator: Paul de Figueiredo, PhD (MU)

Co-PI: Milan G. Chheda, MD

Collaboration with University of Missouri – Columbia

Goal: The long-term goal of this project is to develop a new treatment for glioblastoma (GBM) by leveraging the immune-boosting effects of a safe and weakened version of a bacterium, Brucella melitensis, which we call SPIKE1.0.

Project Summary: A major challenge in the treatment of patients with GBM is that patients’ immune systems do not attack the tumor. The tumor suppresses the number and function of immune cells around it. Researchers from the laboratories of Drs. de Figueiredo (University of Missouri) and Chheda (Siteman Cancer Center/Washington University) are working together on a new strategy using a safe, genetically modified bacterium that carries activating molecules, to lure and unleash anti-tumor defenses to attack and clear the tumor. Before moving to treatment in humans, they will rigorously test the hypothesis that this new treatment will improve the anti-tumor immune response in mice bearing brain tumors and significantly increase their survival. Upon successful completion of the specific aims of the project, the investigators will have the necessary preliminary data for an R01 proposal in which they will delve deeper into how this treatment works and develop even better therapeutic interventions. If successful, this research will eventually lead to a new treatment for glioblastoma patients that will improve their quality of life and help them live longer.

 

Project Title: Adapting a Multi-Level Intervention to Increase Lung Cancer Screening and Reduce Rural Cancer Disparities

Principal Investigator: Aimee James, PhD, MPH

Goal: To change practice, increase lung screening, and reduce the elevated rates of lung cancer mortality in rural southern Illinois

Project Summary: Many rural communities, including those in the Siteman catchment area, experience persistently elevated rates of cancer and cancer mortality compared to more urban areas. This holds true for lung cancer. Low-dose CT (LDCT) scans are recommended for adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Less than 1 in 5 eligible adults are up to date with lung cancer screening, and rates are lower in rural areas. Rural southern Illinois is no exception to this trend and has areas that are health professional shortage areas and experience longer distances to care, persistent poverty and higher rates of tobacco use. We must find effective ways to increase lung cancer screening rates. Our team collaborated with Southern Illinois Healthcare, a rural health system, to develop, implement, and test a bundle of multi-level interventions (a “toolkit”) to increase colon cancer screening. We successfully partnered with providers to distribute patient education, deliver provider nudges, make systems changes and, and provide community awareness. In clinics that participated in the intervention, the likelihood of patients being screened for colon cancer was increased. We now propose to collaborate similarly to increase lung cancer screening. To transition this work to a successful NCI R01 trial, our toolkit must be substantially revised. As such, for this pre-R01 Siteman Investment Program study, we propose: Aim 1 — Identify primary care providers’ challenges in lung screening and preferences for intervention support. We will conduct interviews and site visits at primary and specialty care, to examine the context and challenges of lung cancer screening and identify provider-proposed strategies to increase screening. We will interview patients to identify potential areas of hesitance or needs for support. Aim 2 — Build on prior work and Aim 1 findings to create a toolkit to help primary care providers increase lung cancer screening. We will adapt our existing materials, while bringing in new LDCT specific elements. Aim 3 — Prepare for successful R01 by completing two key foundational steps: (1) Begin adaptation of health maintenance page in EHR to make screening easier to find and (2) add lung cancer screening materials to SIH’s community outreach. We will observe and investigate perceptions of these materials for improvement in our trial. This work is necessary for our future R01 and will directly lead to a stronger NCI application. Our likelihood of success with NCI funding is better if we have developed these components, which we feel we can do with this SIP research. We plan to submit the R01 in 2026.

 

Project Title: Characterizing Hepatocellular Carcinoma (HCC) Tumor Immune Microenvironments to Inform Rationale Combination of Y-90 Radioembolization and Immune Checkpoint Inhibitors through Spatial Transcriptomics

Principal Investigator: Christopher Malone, MD

Goal: To identify predictive biomarkers of treatment response and resistance, supporting future precision strategies to optimize the use of Y-90-RE and ICIs in early and intermediate stage hepatocellular carcinoma, a type of liver cancer

Project Summary: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally, with increasing incidence in the United States driven by metabolic-associated steatotic liver disease (MASLD, or fatty liver disease) and alcohol-related liver disease. While Yttrium-90 radioembolization (Y-90-RE) is a highly effective liver-directed therapy capable of achieving complete tumor response in early-stage HCC, a substantial proportion of patients, particularly those with more advanced disease, experience recurrence due to minimal residual disease (MRD). This failure to eradicate all viable tumor cells is likely driven by underlying differences between tumor cells, such as the presence of treatment-resistant cancer cells and the ability to avoid detection by the immune system. Although immune checkpoint inhibitors (ICIs) have shown promise in advanced-stage HCC, their use in early and intermediate HCC stages in combination with Y-90-RE is currently empirical and lacks molecular guidance. This proposal aims to identify molecular and tumor immune microenvironment (TME) features associated with response or resistance to Y-90-RE, and to determine which patients may benefit from the addition of ICIs. Using a unique biobank of pre-treatment biopsies and explant specimens from HCC patients treated with Y-90-RE with or without ICIs, we will analyze how genes are active in different parts of the tumor using advanced spatial mapping technology called Xenium.

 

Project Title: Targeting c-Myc Transcriptional Stress in Cancer

Principal Investigator: Nima Mosammaparast, MD, PhD

Co-PI: Hani Zaher, PhD

Goal: To understand the workings of a specific pathway (RNF113A-ASCC) that maintains genome stability and is lethal to cells with the c-Myc oncogene, a gene that plays a crucial role in cell growth and cancer proliferation

Project Summary: The main goal of this proposal is to understand the mechanism of a specific pathway that maintains genome stability and is lethal to cells with the c-Myc oncogene, a gene that plays a crucial role in cell growth, proliferation, and cancer metabolism. Our team discovered a new signaling pathway that starts when cells face damage to their DNA and RNA bases, a common effect of cancer treatments. This pathway involves two key proteins, RNF113A and SMYD3, which help bring repair enzymes to the damaged DNA. We’ve found that RNA signaling is crucial for activating this repair pathway. Our findings suggest that a certain protein (known as ASCC3 helicase) helps separate the spliceosome from the DNA, which is important when there’s increased stress from high c-Myc activity. We believe this pathway works during active RNA transcription and processing, which makes targeting it in tumors with high c-Myc levels a promising strategy. In this proposal, we plan to inhibit the RNF113A-ASCC pathway using genetic tools and existing drugs that act as inhibitors of SMYD3 to see if it can effectively fight small cell lung cancer (SCLC), a deadly cancer often linked to c-Myc amplification. We will also study how this pathway helps manage stress from high transcription to prevent harmful DNA-RNA structures and replication issues (Aim 2). This research aims to enhance our understanding of genome stability and its application in cancer treatment.

 

Project Title: Functional Impact and Clinical Application of DNA Methylation Epimutations in Acute Myeloid Leukemia

Principal Investigator: David Spencer, MD, PhD

Goal: To define the changes in DNA methylation (chemical changes in DNA) that occur in acute myeloid leukemia and leverage these insights to improve our understanding of the way the disease forms and our ability to predict its potential return after treatment

Project Summary: Acute myeloid leukemia (AML) is a lethal hematologic malignancy characterized by mutations in hematopoietic (blood) stem cells. Prior research has shown that AML can develop from pre-existing clonal bone marrow diseases, including clonal hematopoiesis (CH) and myelodysplastic syndromes (MDS), and there is extensive overlap in the mutational spectrum across these conditions. In some CH and MDS patients, transformation to AML can occur with little change in the genetic composition of the cancerous cells, indicating a role for other contributing factors. DNA methylation is a chemical change in DNA that is essential for normal tissue development and is universally abnormal in AML patients. Recent studies by our lab have used new methods to directly sequence native DNA molecules without modifying them first, which improves our ability investigate changes in DNA methylation as a potential source of novel contributing factors to AML development. This approach identified specific regions in the DNA of patients with AML where DNA methylation was different between the maternal and paternal copies of specific genes that are important for blood cell function. These methylation patterns stayed the same in samples from the same patients at the start of their illness as when the illness came back, and they were also seen in these patients when they did not have active disease but still had signs of cancer cells based on genetic tests. Many of these “methylation spots” were recurrent across multiple patients and affected how easily parts of the DNA could be accessed, and they affected genes that control how stem cells grow and renew themselves, including a gene called GATA2 that is known to be very important for blood cell development.

Based on this evidence, we hypothesize that specific changes in DNA methylation represent clonal “epimutations” that can disrupt normal gene regulation and be selected for during the formation of leukemia. We further hypothesize that epimutations create a unique pattern in leukemia cell populations, which means they could help detect leftover leukemia cells when patients are in remission. In this proposal, we will study how DNA methylation epimutations affect the GATA2 gene by closely examining the structure of the chromatin in leukemia cells. After that, we will create a new testing method to detect both genetic mutations and these epimutations. This test will help us find remaining leukemia cells in patients who seem cured after chemotherapy. Overall, these studies will help us understand how DNA methylation epimutations impact the GATA2 gene in leukemia and offe