Research We Fund
With hundreds of projects currently underway, we fund scientists through our academic grant programs and biotech partners through our strategic venture philanthropy initiative. Use the filters below to find an LLS-funded project.
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Todd Fehniger, MD PhD
Washington University in St. Louis
St. Louis, WashingtonDeveloping Novel Immunotherapies for Challenging Lymphomas
This team science program from Washington University will develop new immunotherapy treatments for patients with hard to treat or incurable lymphomas. The team includes physicians and scientists who have developed new ideas in the laboratory for immune-based treatment, and will translate these to clinical trial testing. These include engineered natural kill cells, healthy donors T cell engineered to attack a T cell lymphoma, and lymphoma-patient specific mutations as vaccine targets.
Program: Specialized Center of Research ProgramProject Term: Start Date: October 1, 2023 End Date: September 30, 2028
Jianguo Tao, MD PhD
University of Virginia
Charlottesville, VirginiaUnderstanding Resistance Mechanism to Enhance CAR-T Immunotherapy for MCL
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by resistance to standard treatments and short survival. For the 2023 LLS MCLII Synergistic Team Award, we have assembled a team of leaders in basic, translational, and clinical research in MCL to tackle the current significant obstacles in understanding and treating MCL. In the last decade, we investigated the therapy resistance mechanism of MCL, and pioneered clinical trials for targeted therapies (ibrutinib, lenalidomide) and chimeric antigen receptor T-cell (CAR-T) therapy. However, despite these dramatic advancements, resistance to these newer therapies, including targeted therapy and CAR-T cells, is seen in over 50% of patients. Thus, it remains an unmet need to better define the mechanisms of resistance and then develop rationally designed strategies to overcome resistance. The overall goal of this Synergistic Team Award is to develop improved curative therapies for patients with MCL at relapse. The goals will be addressed in three highly focused, independent but highly integrated projects that utilize state-of-the-art genomic technologies, patient-derived xenograft models, clinical data and primary MCL samples. With the joint effort of our laboratories, highly interactive and accomplished scientists, and physician researchers from multiple institutions with expertise in MCL and therapy, we are uniquely poised to develop improved next-generation of combination therapy for relapsed MCL patients.
Program: Mantle Cell Lymphoma Research InitiativeProject Term: Start Date: July 1, 2023 End Date: June 30, 2027
Martin Dreyling, MD
Ludwig Maximilian University of Munich
MunichMULTIlayer Predictive models for relapsed MCL after ibrutinib as first line therapY (MULTIPLY)
The MULTIPLY is a large multi-institutional project aimed at characterization of a variety of clinical predictors, both baseline and at relapse through three interconnected Work Packages (WP) with the following objectives: I) Identification of clinical factors affecting prognosis and characterization of relapses; II) Identification of lymph node biomarkers III) characterization of liquid tissue associated biomarkers. All parameters will be integrated through biostatistical and artificial intelligence tools to establish a comprehensive model of relapse prediction and optimal salvage treatment. The proposal is conducted by the Eu-MCL-Network which is the largest group conducting clinical and translational research worldwide in MCL including the largest phase III trials ever conducted. MULTIPLY will exploit the extensive dataset and tissue bank of the TRIANGLE trial that will be presented as abstract #1 at the ASH plenary session. This study will establish a novel standard by the addition of ibrutinib to first-line treatment, but will also raise relevant issues for prediction and management of disease relapse in first-line BTK-era. The expected results will be the generation of comprehensive integrated models for relapse prediction MCL and development of an effective platform to develop rational chemotherapy-free strategies based on genetic alterations of the malignant cell and innovative biomarker-driven strategies.
Program: Mantle Cell Lymphoma Research InitiativeProject Term: Start Date: July 1, 2023 End Date: June 30, 2027
Matthew Frank, MD PhD
Stanford University
Palo Alto, CaliforniaAutologous CD22 CAR T cell Therapy for the Treatment of non-Hodgkin Lymphoma
CD19 targeting chimeric antigen receptor (CAR) T cell therapies (CAR19) are effective treatments for patients with non-Hodgkin Lymphoma (NHL), however, the majority of these patients will relapse. We have now evaluated a CD22 targeting CAR T cell therapy (CAR22) in patients who have large B cell lymphoma who have relapsed after CAR19 therapy and found that this therapy is both safe and effective resulting in a high rate of durable complete responses. We will now test this promising CAR22 for the first time in patients with other non-Hodgkin Lymphoma subtypes including mantle cell lymphoma, follicular lymphoma, and other CD22-expressing lymphomas.
Program: Academic Clinical Trials Program (ACT)Project Term: Start Date: July 1, 2023 End Date: August 31, 2026
Michael Wang, MD
MD Anderson Cancer Center
Houston, TexasDevelopment of novel BTK-MALT1 dual inhibitors to treat MCL
Most patients respond well to drugs that inhibit an important MCL target named BTK. However, almost all of them will eventually relapse and then do very poorly. Inhibition of MALT1, a target which is biochemically downstream of BTK, may rescue many of these patients, and inhibiting both BTK and MALT1 may be better still. Developing a drug that inhibits both targets at the same time, from the beginning of treatment, will avoid some complications and likely be best of all; we will find out.
Program: Mantle Cell Lymphoma Research InitiativeProject Term: Start Date: July 1, 2023 End Date: June 30, 2026
Christopher Flowers, MD
The University of Texas MD Anderson Cancer Center
Houston, TexasResearch Infrastructure to Promote Enrollment of Underserved Patients on Clinical Trials
The goal of the Clinical Trial Network of South Texas is to expand access to high quality clinical trials for under-represented minority (African American and Hispanic) patients with lymphoid cancers who receives care at the UT San Antonio Mays Cancer Center (MCC) and community oncology centers in South Texas. To achieve this goal, we will leverage the existing partnership between MD Anderson Cancer Center (MDACC) and its robust clinical trial infrastructure to identify and deploy suitable clinical trials. We also will strengthen the research infrastructure at MCC and community sites, including providing equipment, clinical trial navigation support, and oversight to successfully deploy trials. By establishing MDACC/MCC as a hub for clinical trials, developing the necessary research infrastructure at community oncology centers, and allowing patients to participate in clinical trials at their local oncology centers, this IMPACT program has the potential to improve clinical outcomes.
Program: IMPACTProject Term: Start Date: October 1, 2022 End Date: September 30, 2027
Tanya Siddiqi, MD
City of Hope National Medical Center
Duarte, CaliforniaEstablishing Hematology Clinical Trial Hubs within the City of Hope Community and Affiliate Network
City of Hope (COH) has embarked on a strategic initiative to optimize our clinical network and increase research capacity at our Community and Affiliate Network (CAN) sites in Southern California. I would like to spearhead this endeavor for the Hematology program at our new Irvine campus in Orange county, which is set to open in August 2022. We are employing a hub-and-spokes model, in which the Duarte main campus is the main research center, with 3-5 multi-disciplinary CAN sites ultimately designated as research hubs. These CAN sites (hubs) will serve geographically proximal practice sites (spokes), which will refer patients for treatment on clinical trials at either the CAN site itself or at the main Duarte campus. Following a 6-month pilot for optimizing staffing, investigational pharmacy setup, specimen and data collection in Irvine, an additional CAN site will be initiated each year over a 5-year period to allow a wider area of Southern California residents to have access to high quality and impactful clinical trials in Hematology. Our ultimate goal is to accrue 20-50 patients per year from the community, depending on the number of sites activated each year.
Program: IMPACTProject Term: Start Date: October 1, 2022 End Date: September 30, 2027
Markus Muschen, PhD, MD
Yale University
New Haven, ConnecticutTargeting SYK:ZAP70 coexpression in refractory B-cell malignancies
The B-cell kinase SYK and its T-cell homolog ZAP70 have almost identical functions but are strictly segregated to B- and T-cells. We recently discovered that B-cell malignancies frequently coexpress ZAP70 and that only SYK but not ZAP70 can trigger negative B-cell selection and cell death. Here we test the hypothesis that ZAP70 enables malignant B-cell transformation, test pharmacological SYK-hyperactivation and validate ZAP70 as biomarker of patients who benefit from this approach.
Program: Translational Research ProgramProject Term: Start Date: July 1, 2022 End Date: June 30, 2025
Tycel Phillips, MD
Beckman Research Institute of the City of Hope
Duarte, CaliforniaStratified treatment of newly diagnosed MCL based on the presence or absence of high risk features utilizing non-cytotoxic agents.
We believe that regimens without chemotherapy can induce significant and durable remissions in patients with Mantle cell lymphoma (MCL). We will confirm this hypothesis by conducting two clinical trials stratified by the presence or absence of high risk features. We will utilize BH3 profiling and MRD testing to assist with predicting treatment response and remission. Our goal is to verify the efficacy of our regimen and prove the utility of BH3 profiling and MRD testing in outcome prediction.
Program: Career Development ProgramProject Term: Start Date: July 1, 2022 End Date: September 30, 2027
John Leonard, MD
Weill Cornell Medicine
New York, New YorkBRIDGE (Blood cancer Research Initiative Developing Greater Engagement) with community patients
The Weill Cornell Medicine (WCM) Meyer Cancer Center (MCC) has an internationally recognized, clinical/translational blood cancer research program focused at its Manhattan campus. Elsewhere in New York City, the borough of Queens has 2.3 million and the borough of Brooklyn has 2.5 million residents. Both are among the most ethnically diverse urban areas in the world, and each separately ranks just behind Los Angeles and Chicago in population. Over 50% of patients diagnosed with blood cancers in New York City live in Brooklyn or Queens, and half of those are non-white. Involvement of academic cancer centers with a hematologic malignancy clinical trials program physically located in Brooklyn or Queens has previously been limited. New York Presbyterian Hospital and WCM have now integrated with New York Presbyterian-Queens (NYP-Q) and New York Presbyterian-Brooklyn Methodist Hospital (NYP-BMH) to provide access to outstanding cancer care and research for these populations. The community outreach and engagement core of the MCC (led by Dr. Erica Phillips) partners with a robust network of affiliated ambulatory care practices in Brooklyn and Queens. The core has hosted roundtables with over 120 stakeholders (cancer advocacy groups, community physicians, social service organizations) around barriers to diagnosis and treatment in solid tumors, and we will capitalize on this program to expand to blood cancer trials. Other workshops will be targeted directly to diverse groups of patients. Additionally, WCM-MCC cross-campus Hematologic Malignancy Disease Management teams are led locally by Dr. Perry Cook (NYP-BMH) and Dr. Gina Villani (NYP-Q). Clinical trials infrastructure and staffing, a joint IRB, training and oversight are being implemented. This foundation is ideal to synergize with this proposal (BRIDGE) to accelerate access and support for clinical trial participation of blood cancer patients in Brooklyn and Queens who have been previously underserved.
Program: IMPACTProject Term: Start Date: April 1, 2021 End Date: March 31, 2026
Larry Kwak, PhD, MD
Beckman Research Institute of the City of Hope
Duarte, CaliforniaDelivering unique immunotherapeutics for treatment of mantle cell lymphoma
City of Hope has a reputation for innovative translational research, and multiple researchers in the proposed application are prominent in the lymphoma field. The institutional commitment to translational science is evident in City of Hope’s investment in research support/regulatory affairs infrastructure and campus GMP manufacturing facilities. Since patients with mantle cell lymphoma (MCL) have poor outcomes after autologous transplantation, our researchers have been developing new immunotherapeutic strategies to combat this disease. This RFA was timely, as our team was preparing several innovative projects specifically focused on MCL. Our projects are unified by a focus on specific cell and pathway targeting, and antibody-based biologic agents. In fact, 3 of the proposed agents to be tested in this grant were developed here and will be manufactured at City of Hope. The immunotherapies proposed here target a range of antigens, including a unique MCL-specific antigen, and employ novel mechanisms of action, including B-cell receptor (BCR) feedback control, T cell killing and antibody-dependent cytotoxicity. Tumor target specificity is crucial to the safety and tolerability of any immunotherapy. However even with perfect specificity, targeting a single antigen or pathway is frequently insufficient due to antigen- and immune-escape mechanisms. Therefore we are exploring combining our antibody-based agents with inhibitors of B cell signaling (BTK, PI3K, Akt), as well as combining them between projects, in order to cut off tumor escape routes. Developing therapeutics with both high specificity and high potency against MCL is a lofty goal, but one that we aim to achieve. Project 1: Development of a unique tumor-specific, antibody therapy against mantle cell lymphoma (L Kwak, H Qin, L Chen). We have utilized a live cell-based phage display platform to target low-abundance, unique cell markers, discovering an antibody light chain binding domain specific to human MCL. We have further engineered a light chain antibody that binds highly specifically to MCL (MCLC-Ab), with no binding to other subtypes of B-cell lymphomas, nor to normal blood cells. This MCLC-Ab shows potent anti-tumor activity in xenograft MCL models. In Project 1, we will identify the MCLC-Ab target and confirm the antibody specificity for MCL by immunohistochemistry and flow cytometry (SA1). The MCLC-Ab will then undergo preclinical development as both an MCL diagnostic antibody (SA2) and as a potent, MCL-specific therapeutic (SA3). Project 2: Combining CAR T cells with signaling modulators for treatment of relapsed/refractory mantle cell lymphoma (S Forman, X Wang, E Budde, S Blanchard). CD19 chimeric antigen receptor (CAR) T cell therapy is limited by suboptimal response rates in non-Hodgkin lymphoma (NHL), persistent B cell aplasia, and a high risk of cytokine release syndrome (CRS). To improve the remission rates for patients with MCL, we propose combining CAR T cells with 3 oral agents that modulate B and T cell signaling: the BTK inhibitor ibrutinib, the Akt inhibitor MK-2206, and the PI3K inhibitor TGR-1202. First we propose a clinical trial of ibrutinib for relapsed MCL, followed by CD19CAR T cell infusion (SA1). We expect that ibrutinib will enhance response rates to CAR T cell therapy and may also decrease cytokine production, reducing severe CRS. This trial is built on our established clinical platform for CD19CAR T cell therapy for NHL. We will also optimize and pre-clinically develop the MCLC-Ab from Project 1 as a CAR, with the potential to avoid persistent B cell aplasia (SA2). Finally, we plan to test the use of Akt and PI3K inhibitors as part of CAR T cell manufacturing to improve T cell persistence and potency, and in vivo as combined therapy with CAR T cells (SA3). Project 3: Targeting oncogenic B cell receptor (BCR)-feedback control in refractory mantle cell lymphoma (M Muschen, V Ngo, R Chen, L Chen). Project 3 proposes to target the CD25 surface antigen present on both regulatory T cells (Tregs) and MCL cells, using a new CD25 antibody-pyrrolobenzodiazepine conjugate (ADCT-301). In SA1, in a humanized mouse model, we will use the CD25-ADC to pre-deplete immunosuppressive Tregs and enhance the activity of Project 1’s MCLC-Ab and Project 2’s CD19 CAR T cells. We have discovered that MCL cell surface CD25 recruits inhibitory SHIP1, attenuating oncogenic BCR signaling strength. CD25 normally cycles from cytoplasm to surface of MCL cells, but can be forced to remain on the cell surface via CD19 engagement or PI3K/Akt inhibition. In SA2, we will combine CD19 antibody or CD19 CAR T cells with CD25-ADC to force CD25 surface expression, enhancing ADCT-301 targeting. In SA3, we will stimulate CD25 surface accumulation using Akt and PI3K inhibitors to maximize targeting. Core A: Pathology and Tissue Bank Core (WC Chan, J Song). Core A will provide tissue bank services, screen MCLC-Ab to validate its specificity (FFPE sections, flow cytometry) and diagnostic utility (Project 1), provide MRD and residual tumor assessment for the clinical trial (Project 2), and assess immune reconstitution in humanized mice (Project 3). Core B: Translational Core (S Thomas, C Matsumoto). Core B will provide project management, clinical trial design, clinical protocol development, IND preparation, scientific writing and regulatory support services. Synergy: Our researchers are extremely collaborative as evidenced by the interactions that weave the individual projects into a cohesive team-science program. Project 1 + Project 2: Development of MCLC-CAR T cells. Project 2 + Project 3: CD19 stimulation of CD25 surface expression prior to ADC therapy, PI3K/Akt inhibition studies. Project 3 + Project 2 + Project 1: Regulatory T cell depletion with CD25-ADC prior to CAR T cell therapy or MCLC-Ab. Core A and Core B will provide services for all 3 projects as described above.
Program: Mantle Cell Lymphoma Research InitiativeProject Term: Start Date: January 1, 2018 End Date: December 31, 2022
Grzegorz Nowakowski, MD
Mayo Clinic, Rochester
Rochester, MinnesotaREACH: Recruitment Expansion through community Access to Clinical trials in Hematologic malignancies
Mayo Clinic Rochester (MCR) is a tertiary center with 35,000 blood cancer visits annually. Circa 70% of patients referred to MCR come from 5 states: MN, WI, IA, SD and ND inhabited by 10,483,946 people living primarily in a rural setting. To improve local care access, MCR has developed the Mayo Clinic Health System (MCHS), a network of 17 community sites of which 7 have oncology care. In 2018, the MCR joined with the University of Minnesota to establish the Minnesota Cancer Clinical Trials Network (MCCTN) that includes 18 sites. These 2 networks encompass large areas of rural, economically disadvantaged populations and unrepresented minorities, including Native Americans, Latinos and African Americans. The MCR is actively supporting clinical research at MCHN sites, including access to clinical trials (CTs) portfolio. Oncology CTs are open in some of MCHS sites but of the 25 currently open, only 2 CTs target blood cancers. The University of Iowa/Mayo Clinic Lymphoma SPORE has opened epidemiological trials in the MCHS. The MCCTN is new and none of the 3 open CTs are hematologic. Lymphoma study accruals from the MCHS include 42 patients (1 therapeutic; 41 lymphoma epidemiology). The robust epidemiology trial accrual demonstrates that these new lymphoma patients are being seen at these sites and are willing to consent. While many patients from rural communities are seen at MCR for initial diagnosis, these patients often are unable to enroll into trials due to distance from MCR. Feedback from providers from both Networks identified barriers to accrual to lymphoma CTs: i) lack of local lymphoma trials; ii) competition with the more common solid tumor CTs for scarce resources; iii) very busy clinical practices that limits dedicated time for enrollment of intensive complex hematology patients. The practice pressure particularly affects patients requiring language or financial assistance. In this proposal, we outline our plans to address the 3 barriers identified.
Program: IMPACTProject Term: Start Date: April 1, 2021 End Date: March 31, 2026
Sameer Parikh, MBBS
Mayo Clinic, Rochester
Rochester, MinnesotaImmunogenicity and safety of commercially available vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with hematologic malignancies and associated precursor conditions
Mass immunization campaigns are underway in the US after the emergency use authorization of highly effective vaccines against SARS-CoV-2. Despite the efficacy of these measures, patients with B cell malignancies and associated precursor conditions remain at a high risk of adverse outcomes due to COVID-19 infection. These patients were excluded from pivotal vaccination trials that tested the efficacy in the general population. Historically, patients with hematologic malignancies have a 20-50% rate of immunogenicity to routine vaccinations – either due to the underlying malignancy itself or due to immunosuppressive therapies. We are currently enrolling patients in an observational study (NCT04748185) to assess the immunogenicity and safety of commercially available vaccines against SARS-CoV-2 in patients with B cell malignancies and associated precursor conditions such as monoclonal B cell lymphocytosis (MBL). Eligible patients who those with a diagnosis of a B cell malignancy (without regard to treatment status of the underlying malignancy). In collaboration with the Mayo Vaccine Center, we will determine immunogenicity of SARS-CoV-2 vaccination by: a) measuring antibody response (including anti-spike antibody, anti-nucleocapsid antibody, and blocking antibody titers); and b) measuring cell mediated immune response (including T cell ELISpot assay).
Program: Special GrantsProject Term: Start Date: June 1, 2021 End Date: December 31, 2021
Alexey Danilov, PhD, MD
Beckman Research Institute of the City of Hope
Duarte, CaliforniaOvercoming ibrutinib resistance in mantle cell lymphoma
Mantle cell lymphoma (MCL) is an aggressive blood cancer which affects about 3,000 individuals in the United States annually. Despite advances of novel therapies in blood cancers, MCL remains incurable, and patients ultimately succumb to disease. We seek to evaluate longitudinal samples from patients with MCL treated with novel therapies to understand the mechanisms of drug resistance. We identify novel targets, with a particular focus on protein turnover pathways, to overcome drug resistance and improve survival of patients with MCL.
Program: Career Development ProgramProject Term: Start Date: July 1, 2018 End Date: June 30, 2023
Selina Chen-Kiang, PhD
Weill Cornell Medicine
New York, New YorkLongitudinal functional genomics in mantle cell lymphoma therapy and drug resistance
Overview Title: Longitudinal functional genomics in mantle cell lymphoma therapy and drug resistance Weill Cornell Medicine and Ohio State University PI: Selina Chen-Kiang, Ph.D. co-PI: Peter Martin, M.D. Despite the plethora of therapies available for mantle cell lymphoma (MCL), it remains incurable due to the development of drug resistance. Moreover, each successive treatment failure is associated with a more rapidly proliferating disease and fewer practical treatment options. For example, the BTK inhibitor (BTKi) ibrutinib has unprecedented activity but failure is virtually universal and is associated with dismal outcomes. Understanding the genomic basis and mechanisms for drug resistance in MCL is therefore urgently needed. Our goal is to develop superior therapies for MCL that are practical, well tolerated and amenable to patient stratification, by defining the genomic and the molecular and immunological mechanisms for drug resistance in the context of rationally designed clinical trials with targeted agents. Targeting the cell cycle represents a rational approach to MCL therapy, as dysregulation of CDK4 and aberrant cyclin D1 expression underlie unrestrained proliferation in disease progression. We have demonstrated that induction of prolonged early G1 arrest (pG1) by inhibiting CDK4 with palbociclib not only prevented proliferation of primary MCL cells but also reprogrammed them for killing by clinically relevant targeting agents including ibrutinib and PI3K inhibitors (PI3Ki)s. By longitudinal functional genomics of serial biopsies from MCL patients treated with either palbociclib or ibrutinib we discovered a close association of clinical response with inactivation of PI3K and activation of the tumor suppressor transcription factor FOXO1. Moreover, chromatin remodeling appeared to be the proximal event that reprograms MCL cells in response to CDK4 inhibition. Collectively, our findings suggest that through regulation of PI3K and FOXO1 and the epigenome, induction of pG1 by CDK4 inhibition reprograms MCL for a deeper and more durable clinical response to BTKi and PI3Ki. Supporting this hypothesis, in our phase 1 clinical trial of palbociclib + ibrutinib (PALIBR) in recurrent MCL (N=27) the overall response rate was 67% with 43% complete responses. The responses were rapid and durable; only 2 responding patients have progressed in the 32 months since the trial opened. To further accelerate the development of targeted MCL therapies, we have developed a novel inhibitor for protein arginine methyl transferase 5 (PRMT5), which is dysregulated in MCL and many other human cancers. Inhibition of PRMT5 reverses PRMT5 catalyzed epigenetic marks, restores regulatory pathways and enhances survival of preclinical models of MCL and kills ibrutinib-resistant primary MCL cells. Building on these novel findings and capitalizing on the upcoming multi-center phase 2 PALIBR in recurrent MCL, we propose to investigate drug resistance and develop new strategies that circumvent drug resistance in three integrated projects. Project 1: Development of rational treatment strategies for new and recurrent MCL (PI: Peter Martin, M.D.; co-PI: Jia Ruan, M.D., Ph.D., and Kami Maddocks, M.D.). We aim to develop regimens that can be targeted to the appropriate patient subset, are well tolerated, and can be administered in the community. We will conduct a multicenter feasibility trial of lenalidomide + rituximab (R2)+ durvalumab in untreated MCL with real-time monitoring of MRD. We will explore whether durvalumab can overcome immune-mediated resistance to R2 and whether using MRD to modify therapy improves tolerability and practicality without compromising efficacy. We will also conduct a multicenter phase 2 trial of PALIBR in previously treated MCL to better define patients most likely to benefit from this therapy while providing information on mechanisms of resistance in collaboration with Project 2 and 3. Project 2: Functional genomics and mechanism of drug resistance in MCL (PI: Selina Chen-Kiang, Ph.D.; co-PI: Olivier Elemento, Ph.D., and Lewis Cantley, Ph.D.) The clinical response from the phase 1 clinical trial of PALIBR supports our hypothesis that induction of pG1 by CDK4 inhibition reprograms MCL for a deeper and more durable clinical response. To understand the underlying mechanism, we aim to identify the genomic resistance biomarkers by longitudinal functional genomics in the context of the clinical response to PALIBR in the phase 2 clinical trial in collaboration with Project 1. We will further elucidate the mechanism of pG1 reprograming for ibrutinib vulnerability, and target the therapy vulnerability conferred by the genomic resistance biomarkers discovered in this study, such as targeting PRMT5 in collaboration with Project 3. Project 3: Targeting the epigenome in MCL (PI: Jihye Paik, Ph.D., co-PI: Robert Baiocchi, M.D., Ph.D.). Based on our collective evidence, we hypothesize that dysregulation of PRMT5 and FOXO1 causes epigenetic and gene expression changes promoting MCL proliferation and survival. Thus, targeting PRMT5-regulated epigenome may restore FOXO1-mediated cytotoxic gene expression and induce MCL killing. Our goal is to characterize the epigenetic recruitment of PRMT5 and FOXO1 for mechanism-based targeting of MCL epigenome. We aim to identify direct targets of PRMT5 necessary for MCL proliferation and survival, and to define the role of FOXO1 in killing of MCL cells by targeting the epigenome, in collaboration with Projects 1 and 2. These innovative studies are supported by the Administrative Core, Pathology Core and Genomics, Bioinformatics & Biostatistics Core (organization table appended). In addition, WCM has pledged a match of 1.7 million for the proposed studies as indicated in the letters from Drs. Augustine Choi, Dean of WCM, John Leonard, Interim Chairman of Medicine and Lewis Cantley, Director of the Meyer Cancer Center (appended).
Program: Mantle Cell Lymphoma Research InitiativeProject Term: Start Date: January 1, 2018 End Date: December 31, 2022