Research we fund

A proportion of follicular lymphoma patients will experience early treatment failure and premature death. We will delineate the molecular features that underlie treatment failure from a recent randomized trial (BIONIC) & Canadian cohort via 3 aims: 1) confirm the prognostic significance of prior reported biomarkers (eg, m7-FLIPI, etc); 2) establish the genetic taxonomy of FL via integrated genomic analyses and consensus clustering; and 3) determine the prognostic value of circulating tumor DNA.

Project Term: July 1, 2019 - June 30, 2022

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.

Project Term: April 1, 2021 - March 31, 2026

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Project Term: July 1, 2021 - June 30, 2024

The objective of this project is to decipher mechanisms driving transformation of myeloproliferative neoplasms (MPNs) to secondary acute leukemia (sAML). We have identified increased expression of DUSP6 and RSK1 in sAML patient cells. Genetic/pharmacologic targeting suggest a role for DUSP6 and RSK1 in MPN development. We thus propose studies to determine how DUSP6 and RSK1 contribute to MPN pathogenesis, and to evaluate the therapeutic potential of DUSP6 and/or RSK1 inhibition for MPN patients.

Project Term: October 1, 2021 - September 30, 2024

Dr. Orlowski assembled an experienced, collaborative group of researchers who work in a multidisciplinary manner on projects focusing on basic, translational, and clinical aspects of smoldering multiple myeloma (SMM) and multiple myeloma (MM). Both high risk SMM and MM represent important and urgent unmet medical needs for the development of novel, more effective therapies.

Project Term: October 1, 2017 - September 30, 2022

Multiple myeloma remains largely incurable and there is consensus that the pathway to cure cancer involves treating patients earlier. Thus, there is an unmet need to develop methods for early detection of pre-malignant disease and to help tailoring treatment for patients with smoldering myeloma. We aim to develop new methods for minimally invasive characterization of patients with smoldering myeloma in order to treat disease causation instead of symptomatology and increase curability rates.

Project Term: October 1, 2021 - September 30, 2024

Acute myeloid leukemia (AML) is an aggressive blood cancer that still lacks effective therapies. Our goal is to identify therapeutic vulnerabilities for long-lasting remission or cure of AML by targeting the leukemia stem cells (LSCs), the cells that maintain the disease and re-grow it upon relapse. To this end, we leverage unique model systems of AML LSCs that we have developed using induced pluripotent stem cell (iPSC) technology. Our study may open new avenues for the therapy of AML.

Project Term: July 1, 2018 - June 30, 2023

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).

Project Term: June 1, 2021 - December 31, 2021

Defining mechanisms of dysregulated gene control are central to understanding cancer and the development of effective therapies. Our research is focused on the mechanisms of gene control dysregulation in acute myeloid leukemia (AML), a refractory form of blood cancer that affects both children and adults. Using new methods for manipulating proteins, we are defining essential mechanisms by which AML cells enable cancer-causing gene expression. This work also allowed us to develop new drugs to specifically block this in cancer, but not healthy cells. Ongoing work aims to define precise mechanisms of cancerous gene control and develop definitive treatments for its control.

Project Term: July 1, 2019 - June 30, 2024

SARS-Cov-2 infections may be prolonged in cancer patients and may enable intrahost development of virulent viral variants. Adoptive immunotherapy with virus-specific T-cells has been an effective treatment for refractory viral infections in immunocompromised patients following HSCT. We propose to study the functionality of coronavirus-specific T-cells (CSTs) from healthy donors, and utilize CSTs as preventative therapy for patients undergoing bone marrow transplant in a phase I study.

Project Term: July 1, 2021 - June 30, 2024

We have identified the multi-domain protein DCAF1 as a genetic dependency in multiple myeloma and developed a series of potent on-target DCAF1 inhibitors that have a unique mode of action compared with existing therapies. In this proposal we will continue the detailed molecular characterization of our lead compound Vpr8. In parallel, using Vpr8 as the scaffold, we will develop a new series of PROTAC drugs that engage the ubiquitin ligase activity of DCAF1-containing E3 complexes.

Project Term: October 1, 2021 - September 30, 2024

The goal of this study is to selectively eradicate blood cancer cells carrying mutations in a gene called calreticulin. Genes and corresponding proteins required for cancer cell survival but not for the survival of healthy cells will first be targeted in mice, both genetically and by using drugs. Validated drugs will then be tested on patient samples. This study will lay the foundation to the development of tailored treatments for patients with calreticulin-mutated blood cancer.

Project Term: October 1, 2021 - September 30, 2024