Siteman Investment Program awards $2 million in cancer research grants

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine is pleased to announce funding for eight new projects, including research projects focused on prostate cancer, lymphoma, and breast cancer, as well as a team science project with a focus on myeloproliferative neoplasms, a blood malignancy that can develop into acute myeloid leukemia. Also included are two new clinical trials, one aiming to devise a more personalized treatment strategy for breast cancer in Black patients and another examining the efficacy of a novel drug treatment for patients with cutaneous T-cell lymphoma (CTCL).

All of these projects will benefit from over $2 million in new grants through the Siteman Investment Program. The goal of these grants is to support and accelerate the pace of innovation in cancer research.

The money awarded comes from a variety of sources: Pedal the Cause annual bike challenge; Illumination Gala, through the Cancer Frontier Fund at The Foundation for Barnes-Jewish Hospital; Swim Across America – St. Louis; National Cancer Institute Cancer Center Support Grant; Director’s Discovery Fund; Daniel E. Corbin, Jr. Lymphoma Research Fund; and Barnard Trust.

The research projects are described below.

 

New Clinical Trial Mechanism

Project Title: NeoTAILOR: A Phase II Biomarker-directed Approach to Guide Neoadjuvant Therapy for Patients with Stage II/III ER-positive, HER2-negative Breast Cancer

Principal Investigator: Nusayba Bagegni, MD

Goal: NeoTAILOR aims to utilize a novel biomarker-driven approach to guide neoadjuvant treatment selection. It is our hypothesis that this will improve clinical response for postmenopausal women with clinical stage II/III ER-positive, HER2-negative breast cancer and identify those who may not require neoadjuvant chemotherapy, with a primary focus on outcomes in Black patients.

Project Summary: Hormone-blocking therapy – called endocrine therapy (ET) – is the mainstay of treatment for hormone-receptor positive (HR+) breast cancer (BC). In patients with stage 2-3 BC, treatments may be given prior to surgery to help shrink the tumor and measure treatment effect. Some patients will have excellent response to ET, but others may require chemotherapy. Doctors decide who needs chemotherapy by estimating a patient’s risk based on tumor characteristics. Yet, standard tools used to assess risk and predict chemotherapy benefit remain inadequate, particularly in Black women. Ultimately, ~30% of patients’ cancers will return and some patients may suffer  chemotherapy side effects. The overarching goal is to better determine which patients will respond well to ET alone, and which patients have ET-resistant tumors who require escalation to chemotherapy to optimize response.

Testing the gene activity in tumors (using the PAM50 test) can subdivide BC into 5 subtypes. Luminal A subtype is associated with excellent ET response and is less likely to benefit from chemotherapy, whereas non-Luminal A subtypes are more variable. Studies show that measuring tumor cell growth response (called “Ki67”) after only one month of ET identifies ET-resistant BC with a higher risk for BC recurrence. Some data show higher incidence of ET-resistant subtypes in Black women, but since Black patients are under-represented in these trials, the genetic analysis data is extremely limited. BC mortality in Black women remains high in St Louis, and studies dedicated to understanding the biologic factors influencing BC treatment response are essential. In NeoTAILOR, we will utilize a novel approach of incorporating tumor subtype and “Ki67” analysis to personalize treatment strategy, with a prime focus on enrolling Black patients. If the trial is successful, we hope to be able to better tailor HR+ BC therapy, and ultimately impact BC treatment selection guidelines and enhance outcomes.

 

Project Title: Phase I Study with an Expansion Cohort of EZH2 Inhibitor CPI-0209 (Tulmimetostat) in Patients with

Mycosis Fungoides and Sézary Syndrome

Principal Investigator: Neha Mehta-Shah, MD, MSCI

Goal: The hypotheses of this study are that an oral drug known as tulmimetostat (CPI-0209) will be safe and well tolerated in patients with advanced (stage IB-IVB) Mycosis Fungoides and Sézary Syndrome who have had at least one prior systemic therapy, and that in these patients, tulmimetostat will demonstrate efficacy and be worthy of further study.

Project Summary: Mycosis Fungoides and Sézary Syndrome are both types of cutaneous T-cell lymphoma, a type of lymphoma that affects the skin. Cutaneous T-cell lymphomas are a rare subset of T-cell non-Hodgkin lymphomas for which patients are treated to improve disease burden and improve quality of life and improve duration of life. Currently available therapies only work in 5-40% of patients and each therapy has a limited duration of effectiveness. Furthermore, most therapies have significant cumulative toxicity. In advanced stage patients, 5-year survival remains 20%. Given the relatively meager response rates to currently available therapy, and their cumulative toxicity profile, there is a need to develop better tolerated therapies for this rare disease.

Tulmimetostat (CPI-0209) is an oral, second generation EZH2 inhibitor drug which has shown promise in a number of malignancies including T-cell lymphomas. In systemic or peripheral T-cell lymphomas, patients have had complete remissions to this agent by itself. Other EZH2 inhibitors have been shown to work in more than half of patients with peripheral T-cell lymphomas to lead to sustained remissions without cumulative toxicity. Additionally, responses have been seen in patients with skin involvement with lymphoma.

Given the favorable side effect profile of similar EZH2 inhibitors as well as its high rate of efficacy in T-cell lymphomas, we propose a single institution phase I study of single agent tulmimetostat with an expansion cohort. We will examine the safety, toxicity of this oral drug in advanced stage cutaneous T-cell lymphomas. We will also collect blood and skin samples to help us understand the mechanisms of response to tulmimetostat and provide insight into future therapies that would synergize with tulmimetostat. We will do this by doing both DNA, RNA analysis as well as assessment of how gene expression is regulated by tulmimetostat.

 

COE Supplement Mechanism

Project Title: Characterizing Rural Metastatic Breast Cancer Care: A Qualitative Analysis

Principal Investigator: Ashley Housten, OTD, MSCI

Goal: Our overall goal is to enhance cancer control research and the implementation of effective evidence-based interventions by gaining a more in- depth understanding of rural metastatic breast cancer care and facilitating partnerships with sites serving rural populations.

Project Summary: Metastatic breast cancer (MBC) care is complex and requires complex coordination to support patients and their needs, including: 1) clinical trial access and enrollment, 2) genomic testing to aid in decision making for next line therapies, and 3) diminishing patient burden (e.g., excess travel, unnecessary appointments). Furthermore, MBC patients often receive their care in either a community or an academic medical center, preventing patients’ from experiencing the distinct advantages that each setting has to offer. For patients living in rural settings, traveling long distances for care can contribute to patient burden. Not only do patients need to coordinate their transportation and lodging, but they also need to manage financial demands (e.g., direct costs from insurance related fees, indirect costs like missing work), opportunity costs (e.g., forgoing activities due to treatment), and a variety of other demands patients experience when they travel long distances for their care. The purpose of this proposal is to elucidate the determinants (i.e., barriers, facilitators) associated with rural MBC care coordination. We propose conducting qualitative interviews with hospital leaders, clinicians, and patients from the BJC Collaborative to gain a more in depth understanding of their referral and care experiences.

 

Pre-R01 Mechanism

Project Title: High Spatiotemporal Resolution Radioluminescent Dosimetry of Proton FLASH Radiotherapy for Pre-Clinical Studies

Principal Investigator: Arash Darafsheh, PhD

Goal: Develop accurate and precise systems for radiation dose measurement for FLASH radiotherapy (ultra-high dose-rate radiotherapy with great promise in sparing normal tissues) enabling us to robustly perform radiobiological studies paving the way to safely treat patients by FLASH radiotherapy. This project will positively impact public health by enabling more accurate and quantitative, but clinically practical, FLASH dose measurement, that is not achievable by currently available technologies.

Project Summary: Ultra-high dose rate FLASH radiotherapy is a promising emerging modality to improve the healthy tissue sparing during radiation therapy. Currently, there is no dosimeter available to reliably measure the radiation dose at such ultra-high dose rates. Our proposed radiation dosimeter technology based on radio-luminescent properties of fiber optics will support more objective and accurate preclinical assessment of its potential to improve radiotherapy by providing a solid scientific foundation for delivered dose assessment, thereby facilitating comparison of investigations performed in different institutions using diverse dose-delivery platforms, including real-time assessment of instantaneous and average dose rates in pulse-beam FLASH radiation delivery.

 

Project Title: Clinical Molecular Imaging of the Prostate Cancer Microenvironment

Principal Investigator: Joseph Ippolito, MD, PhD

Co-PI: Eric Kim, MD

Goal: Our overarching goal is to integrate a new, advanced, MR imaging tool (diffusion basis spectrum imaging or DBSI) with a new, advanced pathology imaging tool (mass spectrometry matrix assisted laser desorption ionization or MALDI) with existing imaging and genomic tools to predict PCa patient outcomes accurately.

Project Summary: Prostate cancer is the most common cancer among men in the United States. However, not all men with prostate cancer will die from it. In many cases, prostate cancer is very slow growing and the patient will ultimately die of another cause. However, there is a subset of men who undergo treatment for prostate cancer who develop recurrent, lethal metastatic disease. Right now, there are no robust tests that can be performed at initial diagnosis to predict who will ultimately die from prostate cancer.

Our group has advanced two novel technologies for early detection of lethal prostate cancer; diffusion basis spectrum imaging-magnetic resonance imaging (DBSI-MRI) and matrix associated laser desorption ionization imaging (MALDI) to identify molecular biomarkers that predict the development of lethal metastatic disease in the future. The goal of this proposal is to merge these technologies that will allow us to noninvasively image and detect the presence of these lethal molecular biomarkers in the patient’s prostate cancer prior to initial treatment. As these technologies are applicable to any tumor type, we anticipate that this could have the potential to advance the field of early detection.

 

Project Title: Understanding the Role of Mammogram Images in the Risk of Triple Negative Breast Cancer

Principal Investigator: Shu (Joy) Jiang, PhD

Goal: The successful completion of this study has the potential to offer valuable insights into the identification of novel targets for triple-negative breast cancer (TNBC). These findings could pave the way for innovative early prevention strategies, enhance future treatment options, and ultimately lead to improvements in the early detection of TNBC.

Project Summary: TNBC is an aggressive subtype of invasive breast cancer that disproportionately affects Black women relative to White women. Given that TNBC is more likely to occur between routine screening mammograms, it poses an urgent need for improved prevention and early detection years before the onset. While previous epidemiology studies fail to identify modifiable risk factors for TNBC, we hypothesize that the mammogram image may play a role in furthering our understanding of the TNBC pathway.

 

 

 

Project Title: A Novel Feed-Forward Cycle that Drives Tumor Progression and Immune Evasion

Principal Investigator: Jacqueline Payton, MD, PhD

Goal: We expect to define new paradigms of epigenetic-immune interaction that will be relevant for many cancers. These studies will advance our ongoing work and provide additional preliminary data needed for submission of an NCI R01 application.

Project Summary: Cutaneous T-cell lymphoma (CTCL) is a type of cancer in which the skin is invaded by cancerous white blood cells. The disease can take many forms, resembling a simple rash, solid tumors in the skin, or invading the blood and lymph nodes. These different forms can occur at different times or all at the same time in a patient. Patients also suffer from defects in immunity and opportunistic infections that can be life-threatening. CTCL patients with advanced disease have a 5-year overall survival of only 20%, and there is no curative drug therapy. While CTCL is relatively rare, it is a useful model for elucidating mechanisms of cancer progression and immune response that are relevant for all cancers.

Our studies over the last several years identified genetic factors that are associated with the progression of CTCL to more advanced disease. Three of these factors are also found in many other types of cancer. In the proposed studies, we will test these three factors in samples from patients with CTCL using cutting-edge DNA sequencing techniques and in animal models genetically engineered to recapitulate the disease. These approaches will enable us to test therapies that inhibit the genetic factors that we identified. These therapeutic inhibitors are safe in patients and if they are effective in our models, we will move to clinical trials upon completion of these studies (2 years). Because these genetic factors are found in other more common cancers, our results would support the use of these therapeutic inhibitors in other cancers and thus have broader implications for many cancer patients.

 

Team Science Mechanism

Project Title: Intrinsic and Extrinsic Factors Driving Clonal Evolution and Disease Progression in Myeloproliferative Neoplasms

Principal Investigator: Stephen Oh, MD, PhD

Project Leads: Grant Challen, PhD, Jorge Di Paola, MD, Daniel Link, MD

Goal: The overall objective of this proposal is to determine how inflammation drives MPN disease development and progression. Our proposed projects leverage established collaborations and incorporate state-of-the-art approaches to foster synergy beyond what could be achieved independently. These efforts are critical to establish the framework for a subsequent Program Project Grant (PPG) application focused on MPNs.

Project Summary: Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies that cause significant morbidity and have the propensity to transform to acute leukemia. Current treatment options for MPNs are limited. The studies proposed here will provide deeper insights in the pathogenesis of MPNs, and potentially lead to the development of more effective therapies for patients with MPNs.

 

Project 1: Mechanisms of DUSP6-RSK1 Signaling Driving MPN Progression (Oh, Stephen)

Project 2: Clonal Evolution of MPN to Secondary AML (Challen, Grant)

Project 3: TGF-β in the clonal expansion of JAK2-mutated HSCs (Link, Daniel)

Project 4: Role of TNFɑ in MPN disease development and clonal expansion (Di Paola, Jorge)