Siteman Investment Program Awards $1.89 Million in Cancer Research Grants

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine is pleased to announce funding for nine new projects. These include research focused on:

• Improving CAR T-cell therapy for lymphoma
• Identifying new treatment targets for leukemia
• Better understanding how myelodysplastic syndromes (MDS) develop
• Identifying a treatment for a broad range of myeloproliferative neoplasms (MPNs) independent of individual mutations
• Improving outcomes for brain tumors in children

The projects will benefit from $1.89 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: Pedal the Cause annual bike event and Illumination Gala through the Cancer Frontier Fund at The Foundation for Barnes-Jewish Hospital; the Cancer Center Support Grant (CCSG) from the National Cancer Institute; the Alvin J. Siteman Cancer Research Fund; the Siteman Discovery Fund; Swim Across America – St. Louis; and various philanthropic gifts via Siteman Cancer Center.

This grant cycle also includes a new clinical trial focused on a combination immunotherapy treatment for metastatic castrate-resistant prostate cancer that will expand the horizons for improved understanding of how the immune system responds to and may guide treatment of this disease.

The funded research projects are described below.

 

New Clinical Trial Category

Project Title: A Phase Ib Study Evaluating the Safety and Tolerability of Sipuleucel-T (Sip-T) in Combination with an N-803 in Patients with Metastatic Castrate-Resistant Prostate Cancer (mCRPC)

Principal Investigator (PI): Russell Pachynski, MD

Co-PI: Daniel Thorek, PhD

Goal: To determine the recommended phase 2 dose of an immunotherapy treatment for metastatic castrate-resistant prostate cancer that combines a protein called N-803 with a Food and Drug Administration (FDA)-approved cellular immunotherapy called sipuleucel-T (Provenge). Researchers hypothesize that the combination will have an acceptable safety profile and will be feasible to administer in this population.

Project Summary: Immunotherapy is an emerging treatment platform for cancer patients that can be highly effective. However, only a subset of patients demonstrates long-term responses. A persistent challenge has been how to identify patients that would benefit, and how to enhance immunological treatments to benefit more patients. This proposal addresses these critical issues by:

• Combining two immunotherapies that the researchers have shown work together in preclinical models
• Advancing a promising functional scanning technology to noninvasively characterize the immune response in these patients

Prostate cancer is the second most diagnosed cancer in males. Surgery or radiation can be curative when treated early and localized to the prostate; however, it is incurable once it has spread. Novel modes of treatment are needed. The researchers propose to combine Sipuleucel-T, an FDA-approved adoptive cell therapy for prostate cancer with modest outcomes, with N-803, an immunostimulatory engineered protein that binds to interleukin-15, a cytokine involved in activating immune cells. N803 has recently been FDA-approved for bladder cancer. The researchers will establish optimal dose and schedule for this new combination approach across three treatment cohorts. They will study the immune responses in blood, and use novel, functional noninvasive imaging of the active immune system using a novel radiotracer (specific for an immune mediator called granzyme-B). Together, this work is immediately impactful to men with prostate cancer and expands the horizons for the improved understanding of how the immune system responds to and may guide treatment.

 

Pre-R01 Category

Project Title: Mechanisms Driving Obesogenic Diet-accelerated Gliomagenesis in NF1

Principal Investigator: Nicole Brossier, MD, PhD

Goal: To improve the outcomes for brain tumors in children. This proposal aims to determine how different dietary components (fat and sugar) affect tumor formation, epidermal growth factor (EGF) levels and epidermal growth factor receptor (EGFR) signaling in a murine model of pediatric brain tumor formation, and then to determine whether inhibition of EGFR prevents diet-accelerated tumor formation in this model. This information will be used to improve dietary counseling in patients and to design subsequent studies testing the benefits of risk-adapted therapeutic strategies in children with brain tumors and poor dietary exposure.

Project Summary: As we enter into an era of precision pediatric oncology, it is becoming increasingly important to identify the factors that underlie the risk of brain tumor development. This challenge is particularly relevant for individuals with cancer predisposition syndromes like NF1, where 15-20% of children born with a germline NF1 gene mutation develop optic pathway gliomas (OPGs). Our inability to provide accurate risk assessment information for these young children leads to frequent sedated neuroimaging, suboptimal visual screening and delays in instituting treatment for those at greatest risk. The researchers recently performed pre-clinical studies that found exposure to an unhealthy, obesity-promoting diet (obesogenic diet, Ob) increased the likelihood of OPG development in NF1 mouse models. They also identified that these animals have much higher levels of epidermal growth factor (EGF) in their blood. Based on these observations, as well as findings that a high-fat diet drives tumor formation in other tumor types through activation of the EGF receptor (EGFR), the researchers hypothesize that high dietary fat intake drives NF1-OPG formation through increased EGFR signaling. In this grant, they propose to perform a detailed analysis of how different diets (high-fat, high-sugar or high-fat, high-sugar) affect NF1-OPG formation and how this correlates with circulating EGF levels. They will then inhibit EGFR through genetic and pharmacologic means in Ob-diet-driven NF1-OPG to determine whether this impairs tumor formation. Taken together, these experiments will determine how dietary composition affects tumor formation and the role of EGF in this process. This will provide a foundation for future investigations to determine whether EGF may be used as a biomarker to detect children at higher risk of NF1-OPG due to dietary exposure and to ascertain whether EGFR-directed therapy could be a useful addition to the existing treatment strategy of NF1-OPG in children with poor diets.

 

Project Title: Enhancing CAR T-cell Therapy for Diffuse Large B-cell Lymphoma

Principal Investigator: John DiPersio, MD, PhD

Goal: To improve anti-CD19 chimeric antigen receptor T cell (CART19) therapy for patients with relapsed or refractory large B-cell lymphoma (r/r LBCL). Currently, long-term disease-free survival with commercial CART19 in r/r LBCL is only about 40%, so more strategies to improve the efficacy of CART19 are warranted.

Project Summary: Diffuse large B-cell lymphoma (DLBCL) is a common type of fast-growing non-Hodgkin lymphoma. In about 33% of patients, DLBCL returns after the first treatment (relapsed DLBCL), or the first treatment is not effective and the patient is not cured (refractory DLBCL). The FDA has approved three chimeric antigen receptor T-cell (CAR-T) therapies for use in adults with relapse or refractory DLBCL. T cells are a part of the immune system and help protect the body from infection and cancer. CAR-T therapy involves engineering healthy T cells to attack cancer cells. Unfortunately, about 50% of patients treated with CAR-T cells will relapse again with DLBCL within eight months. Interleukins are a type of protein that help activate our immune system to fight infections and cancer. Three interleukins named IL-7, IL-15, and IL-21 are especially effective at helping T cells survive, proliferate and kill infected cells. In this proposal, the researchers are testing if IL-7, IL-15 and IL-21 can help CAR-T cells kill DLBCL. Since interleukins are very short-lived and only last for one to two hours, they are testing novel long-acting versions of IL-7, IL-15 or IL-21 that last two to three days in humans. In part 1 of their proposal, the researchers are performing a clinical trial to determine if a drug named NT-I7, which is a long-acting version of IL-7, is safe and effective in helping CAR-T cells kill DLBCL tumors. In part 2, they are testing a new compound named HCW9206 that merges IL-7, IL-15 and IL-21 into a single long-acting drug. Their studies with HCW9206 will test its safety and ability to help CAR-T cells kill DLBCL in mice.

 

 

Project Title: Targeting Myeloid-biased Multipotent Progenitor to Rebalance Lineage Output in MPNs

Principal Investigator: Yoon-A Kang, PhD

Goal: To identify a treatment for a broad range of myeloproliferative neoplasms (MPNs) independent of individual mutations. This project will focus on cells called multipotent progenitor 3 (MPP3), the expansion of which are common in a range of MPNs, and will investigate whether the process of controlling MPP3 blood cell production mechanisms can be targeted to regulate the excessive production of myeloid cells and form the foundation of a future therapy.

Project Summary: 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 have targeted these mutations to develop treatments. Although targeted therapies have revolutionized MPN treatment, they are not curative in most cases as the mutant cell population driving disease development and recurrence is usually not eradicated. However, their success in controlling disease development and progression has shown the clinical importance of normalizing blood production in disease contexts. Additionally, there are patients without known driver mutations, with no targetable driver mutations or who develop resistance to targeted therapies. Therefore, a better understanding of the mechanisms underlying myeloid cell expansion, a shared feature of various MPNs, is necessary to develop new treatments to be used in combination with current targeted therapies or as alternatives for patients who are ineligible for current therapies. The goal of this study is to find a treatment that is applicable to a broad range of MPNs independent of individual mutations. The researchers’ previous work found there is a specific immature bone marrow population, called multipotent progenitor 3 (MPP3), that can generate white blood cells, red blood cells and platelets. Importantly, MPP3 is expanded in various MPN mouse models regardless of their driver mutations. Interestingly, distinct MPP3 subsets are specifically increased corresponding to the overproduced mature cell types in MPNs. This indicates that controlling the production of different MPP3 subsets can regulate disease development and progression irrespective of disease-causing mutations. For this project, the researchers propose to study two commonly dysregulated pathways in human blood malignancies to control the production of distinct MPP3 subsets. Their study will provide insights into the common mechanism underlying MPN development and foundations to develop broadly applicable therapeutic interventions.

 

Project Title: Targeting HOXB13-mediated Immune Suppression of Prostate Cancer

Principal Investigator: Kiran Mahajan, PhD

Co-PI: Nupam Mahajan, PhD

Goal: To demonstrate that a protein called HOXB13 can be targeted to treat prostate cancer with novel combination therapies. The study will benefit African American patients expressing increased HOXB13 through genetic and epigenetic mechanisms.

Project Summary: Prostate cancer disproportionately affects African American men compared to white men. Recently, a HOXB13 variant (X285K) predisposing to prostate cancer in men of West African ancestry was reported in a large-scale germline genetic testing. HOXB13-X285K was significantly enriched in self-reported Black (1.01%;~21000 men screened) versus white (0.01%) patients. HOXB13-X285K carriers tended to have more aggressive disease, due to increased protein stability that resulted in an increase in cell proliferation. Besides germline mutations, gain-of-function modification in HOXB13 bump up HOXB13 RNA and protein levels. Thus, screening for HOXB13 expression and development of effective treatments is critical to improve clinical outcomes. Prostate-Specific Membrane Antigen-Targeted Imaging (PSMA-PET) imaging could be combined with molecular profiling of prostate biopsies for HOXB13 expression in white and African American patients for early detection and treatment of aggressive prostate cancers.

Results from this study will reveal previously unknown epigenetic regulation of immune suppression in prostate cancer. The researchers’ pre-clinical studies will advance the use of other checkpoint inhibitors alone or in combination with PD-L1/PD-1 axis to overcome poor response to immunotherapy. The results will provide the basis for combination therapies to improve treatment outcomes for prostate cancer patients.

 

Project Title: Regulation of Hematopoietic Stem Cell Metabolism by Stathmin 1

Principal Investigator: Laura Schuettpelz, MD, PhD

Goal: To determine how the gene called Stathmin 1 (Stmn1) regulates hematopoietic stem cell (HSC) metabolism and contributes to hematopoietic malignancies, especially leukemia. The researchers predict that high levels of Stmn1 support the needs of growing leukemic cells, and that it may be a new therapeutic target on which to focus.

Project Summary: The gene stathmin 1 (Stmn1) is expressed at high levels in normal blood stem cells and is overexpressed in blood cancer cells. The researchers’ preliminary studies suggest that Stmn1 is important for supporting various aspects of healthy blood stem cell metabolism, including maintaining healthy mitochondria and protein turnover in the cell. They predict that high levels of Stmn1 in leukemia cells are necessary to sustain the unique metabolic needs of leukemia cells. The proposed studies will determine the mechanisms by which Stmn1 influences blood stem cell metabolism, and in future studies researchers will determine whether inhibition of Stmn1 impairs the growth of leukemic blood cells. Ultimately, these studies will test Stmn1 as a novel therapeutic target to treat leukemia. As Stmn1 is overexpressed on multiple types of blood cancers, and loss of Stmn1 in mouse models has few effects outside of the blood system, the researchers predict that Stmn1-directed drugs could be useful to treat a wide variety of leukemias with limited side effects.

 

Project Title: Defining How the Role of DDIT4 in Mitochondrial Metabolism and Turnover Impacts Chemotherapy Responses in Acute Myeloid Leukemia

Stephen Sykes, PhDPrincipal Investigator: Stephen Sykes, PhD

Goal: To identify molecular pathways that support chemotherapy resistance in acute myeloid leukemia (AML) and utilize that information to identify potential new therapeutic targets. This proposal will specifically focus on a protein called DNA-Damage Induced Transcript 4 (DDIT4) that the researchers hypothesize supports AML cell survival and chemotherapy resistance and will establish that targeting this protein in a certain pathway will have therapeutic potential for leukemia patients.

Project Summary: Annually, approximately 1 in 12,500 Americans are diagnosed with acute myeloid leukemia (AML), and more than 12,000 die from the disease. The overall survival rate of AML patients is below 25% for adults and 70% for children, and these poor outcomes are largely due to high rates of resistance to the current standard-of-care treatments and disease relapse. The researchers have discovered that a protein called DDIT4 (DNA-Damage Induced Transcript 4) may play a central role in how AML cells evade current chemotherapies. This project will decipher the molecular mechanisms by which DDIT4 promotes chemotherapy resistance as well as test whether pharmacological targeting of DDIT4 enhances the anti-leukemia effects of current chemotherapies.

 

Project Title: Rescuing BRCA1 Haploinsufficieny and DNA Replication Fork Stability with Antisense Oligonucleotides

Principal Investigator: Alessandro Vindigni, PhD

Co-PI: Sergej Djuranovic, PhD

Goal: To study early detection strategies for breast and ovarian cancer in women with BRCA1 or BRCA2 gene mutations and research molecularly guided and nonsurgical interventions to prevent tumor development.

Project Summary: More than 1 in 500 women are affected by mutations in the breast cancer susceptibility genes BRCA1 or BRCA2. While it is known that these women have up to an 80% risk of developing breast and ovarian cancer in their lifetime, exactly why these cells become cancerous is unknown. The only preventive options currently available are risk-associated prophylactic surgeries of ovary/fallopian tube and breast removal, which result in surgical menopause and significant aesthetic consequences. Therefore, two major challenges that women with BRCA1 or BRCA2 gene mutations currently face are the lack of:

• Early detection strategies to identify which carriers will develop these malignancies
• Molecularly guided and nonsurgical strategies to prevent breast and ovarian tumor development

This project joins experts in DNA replication (Alessandro Vindigni, PhD), RNA processing (Sergej Djuranovic, PhD), and ovarian cancer (Mary Mullen, MD, MSCI) to tackle these challenges. The researchers know that BRCA1 is important for DNA replication and it helps protect the genome. Women with mutations in the BRCA1 gene have less BRCA1 protein in their cells. The researchers believe this lack of BRCA1 protein causes problems with DNA replication. These problems lead to more mutations in the genome, which can cause cells to become cancerous. They will test these new ideas using fallopian tube cells, new technologies from the Vindigni lab, and samples from patients. Next, they will use a technology developed by the Djuranovic lab called “antisense oligonucleotides” to increase BRCA1 protein levels. The researchers think that by increasing this protein, they can stop the unstable replication forks and prevent mutations that cause these cancers. Collectively, their studies will:

• Define the early changes that happen when normal fallopian tube cells with BRCA1 gene mutations turn into tumors
• Establish novel nonsurgical strategies to prevent ovarian cancer development in women with BRCA1 gene mutations

 

Project Title: Modulating TP53 Activity to Target Splicing Factor-mutant Blood Cancers

Principal Investigator: Matthew Walter, MD

Goal: To begin developing a new way to treat patients suffering from myelodysplastic syndrome, or MDS, by understanding how blood cells with mutations grow and expand. This project will test the safety and efficacy of selectively eliminating mutated blood cells by hyperactivating a pathway that reduces their growth, which could improve patients’ lives.

Project Summary: Myelodysplastic syndromes (MDS) are one of the most common types of blood cancer in adults. MDS patients suffer from problems related to low blood counts, including life-threatening infections and bleeding. Once MDS develops, the only cure is a bone marrow transplant. However, most patients are not eligible for a transplant due to their advanced age and other illnesses. Understanding how MDS develops may help researchers identify new ways to treat patients with MDS.

Up to half of MDS patients have mutations in genes in their blood cells that regulate how RNA is stitched together in a cell, called RNA splicing. A goal of this project is to understand how blood cells with a gene mutation that controls RNA splicing grow, expand and cause MDS. The researchers observed that early after a cell gets an RNA splicing gene mutation, mutant cells grow slower than normal cells. However, over time, a mutated cell changes and outgrows normal cells, causing MDS and other blood cancers. The researchers are studying what happens early after a mutation occurs in a blood cell so they can identify ways to kill cells with the mutation.

Their initial studies identified a pathway in mutant blood cells that they can hyperactivate to preferentially kill mutated cells in a culture dish. The researchers now want to test if they can kill mutant cells in preclinical models and see if it is safe. If this works, they could design a trial to test if a new approach could kill mutated MDS cells in patients and improve their lives.