Dana-Farber Cancer Institute
Boston Children's Hospital
The General Hospital Corporation
Principal Investigators
Andrew A. Lane, MD, PhD
Chief, Division of Hematologic Neoplasia
Dana-Farber Cancer Institute
450 Brookline Ave, Mayer Building 413
Boston, MA 02215
617-632-4589
Richard M. Stone, M.D.
Director, Translational Research, Adult Leukemia Program
Harvard School of Medicine
Dana-Farber Cancer Institute
Department of Medicine
44 Binney Street
Boston, MA 02115
617-632-3940
Overview:
The Harvard Cancer Consortium (HCC) Specialized Program of Research Excellence (SPORE) in Leukemia aims to improve understanding of the genetic and molecular basis of leukemia and acquired treatment resistance, and to translate these insights into novel, effective therapeutic strategies. The Leukemia SPORE leverages HCC's extensive scientific and clinical resources, spanning genetics, immunology, biostatistics, murine models, and clinical trial development, to improve outcomes for patients with leukemia.
Each of the three Projects builds on recent findings from HCC laboratories, combining pre-clinical testing, mechanistic studies of therapeutic activity, and innovative clinical trials, with the Cores providing support to accelerate their success.
● Project 1: Overcoming resistance to Menin inhibition in acute myeloid leukemia (AML)
● Project 2: Therapeutic efficacy of PI3 kinase gamma PI3K inhibition in AML
● Project 3: Targeting the mSWI/SNF chromatin remodeling complex in AML
These three projects build on recent advances in targeted AML therapies.
Project 1 assesses mechanisms of resistance to Menin inhibitor treatment, identifies therapeutic targets likely to synergize with Menin inhibition, and will test immunomodulatory imide drugs (IMiDs) in combination with Menin inhibition in clinical trials.
Project 2 investigates the efficacy and predictors of response to PI3Kgamma inhibition, uses mechanistic analyses to optimize combination therapies, and will assess PI3Kgamma inhibition in an early-phase clinical trial.
Project 3 defines the gene regulatory functions of the mammalian SWI/SNF complex in primary leukemias, evaluates pharmacologic SMARCA4/2 ATPase inhibition, and tests mSWI/SNF ATPase inhibitor combinations in a phase 1b trial.
These research projects are supported by three highly interactive Cores and an Administrative Core. The Biospecimens Core provides biospecimen banking, a data repository, and support for data access and study design, with samples and data available to all Project PIs.
The Functional Precision Medicine Core supports correlative studies across clinical trials, including serial genetic analysis of patient samples and generation of apoptotic BH3 priming scores linked to clinical response.
The Biostatistics and Bioinformatics Core provides statistical and computational biology guidance for experimental design and interpretation of laboratory and clinical results.
The Administrative Core monitors research progress and planning, fosters collaboration, integrates the SPORE within the HCC structure, and administers the Career Enhancement Program (CEP) and Developmental Research Program (DRP), from recruitment through award selection.
Project 1: Project Title: Targeting Menin in Leukemia
Project 1 Co-Leaders:
- Scott A. Armstrong, MD, PhD (Basic Leader);
- Amir Fathi, MD (Clinical Leader)
Specific Aims:
A protein called Menin partners with another protein, KMT2A, to switch on genes that drive certain forms of acute myeloid leukemia (AML), especially cases with a KMT2A gene rearrangement or an NPM1 mutation. Blocking this Menin-KMT2A partnership with small-molecule drugs reverses this abnormal gene activity and slows tumor growth. These Menin inhibitors are now being tested in patients, and the AUGMENT-101 clinical trial showed that one such drug, revumenib, produced remission in about 30 percent of patients with these leukemia subtypes.
As with many targeted cancer drugs, some patients' leukemia becomes resistant to Menin inhibitors over time. Our team found that 40 percent of patients on the AUGMENT-101 trial developed new mutations in the MEN1 gene that weaken the drug's effect. We also identified patients whose leukemia became resistant without any MEN1 mutation, pointing to other, less understood mechanisms.
Aim 1. Identify the biological mechanisms that allow AML cells to adapt and resist Menin inhibitor treatment, using patient samples and laboratory models.
Aim 2. Study leukemia cells that survive treatment at very low levels, known as minimal residual disease (MRD), to understand how they differ from fully resistant cells and how they might be eliminated.
Aim 3. Conduct a phase 1 clinical trial combining the Menin inhibitor ziftomenib with a second drug, mezigdomide, to test whether the combination is safe and more effective than either drug alone.
Our team has extensive experience moving cancer therapies from the laboratory into human clinical trials. Members of this group helped develop several Menin inhibitors now being tested in patients, including revumenib and ziftomenib. This project is expected to improve our understanding of how resistance to Menin inhibitors develops, clarify the relationship between drug-resistant leukemia cells and minimal residual disease, and advance a new combination therapy toward clinical use for patients with these hard-to-treat forms of AML.
Project 2: Project Title: Targeting PI3Kγ in Acute Myeloid Leukemia
Project Co-Leaders:
- Andrew Lane, MD, PhD (Basic Leader)
- Jacqueline Garcia, MD (Clinical Leader)
Specific Aims:
Some genetically defined types of acute myeloid leukemia (AML) now have targeted treatment options, but many patients still have no genotype-specific therapy available to them. Certain AML subtypes are especially hard to treat: leukemias with monocytic features respond poorly to standard venetoclax-based regimens, and monocytic leukemia cells often drive disease relapse. We hypothesized that identifying shared vulnerabilities across these high-risk, treatment-resistant AML subtypes could reveal new treatment approaches and biomarkers for patients with few options.
Using genome-wide functional screening and validation in leukemia models and patient samples, we discovered that this high-risk group of AML depends on an enzyme called PI3K gamma (PI3Kγ) to survive, particularly in leukemias with monocytic or dendritic features. PI3Kγ inhibitors are already being tested in other cancers and have been well tolerated in early clinical trials. In our preliminary studies, leukemias that depend on PI3Kγ showed elevated levels of a PI3Kγ complex protein, PIK3R5, which was linked to poorer survival in AML patients. We also found that PI3Kγ inhibition worked well alongside standard AML therapies, including chemotherapy and venetoclax. A PI3Kγ inhibitor called eganelisib extended survival in preclinical models, even when combined with chemotherapy in leukemias that would otherwise resist treatment.
This Project aims to advance PI3Kγ inhibition toward clinical use in AML patients through three aims:
Aim 1. Identify biological markers that predict which AML cells are vulnerable to PI3Kγ inhibition and clarify the mechanisms behind that sensitivity.
Aim 2. Determine the best timing and drug combinations for using PI3Kγ inhibition alongside standard frontline AML therapies, and test whether leukemia cells that survive treatment become more dependent on PI3Kγ.
Aim 3. Conduct a phase 1/2 clinical trial testing the PI3Kγ inhibitor eganelisib in combination with standard therapy in patients with relapsed or high-risk AML and identify features that predict patient response.
This project is expected to deliver a new treatment strategy for high-risk AML along with a clearer understanding of why certain leukemias depend on PI3Kγ, and early clinical safety and effectiveness data to support its continued development.
Project 3: Targeting mSWI/SNF in AML
Project Co-Leaders:
- Cigall Kadoch, PhD (Basic Leader)
- Richard Stone, MD (Clinical Leader)
Specific Aims:
Acute myeloid leukemia (AML) is a diverse blood cancer marked by a buildup of immature blood cells that crowd out healthy bone marrow function, and fewer than 40 percent of patients are cured with current treatments. Recent genetic screens have shown that many AML subtypes depend on a group of proteins called mSWI/SNF, which help control how genes turn on and off. Studies in other cancers suggest that blocking mSWI/SNF activity can also help overcome resistance to certain targeted drugs.
A small-molecule drug called FHD-286, which blocks key components of the mSWI/SNF complex, has been shown to push AML cells toward normal maturation and slow their growth in laboratory and animal models. An early-phase clinical trial in patients with relapsed or treatment-resistant AML confirmed that FHD-286 causes this same maturation effect, though lasting clinical benefit was limited when the drug was used alone. This project will study how mSWI/SNF disruption changes gene activity in AML cells and test whether combining FHD-286 with other approved AML drugs improves and sustains its effectiveness.
Aim 1. Define how FHD-286 changes gene activity and chromatin structure in AML cells and patient tumor samples. Identify markers that predict which patients are likely to respond.
Aim 2. Test whether combining FHD-286 with the drugs venetoclax or FLT3 inhibitors improves treatment of AML in cell, animal, and patient-derived models. Determine how this combination affects gene activity and drug resistance.
Aim 3. Conduct a phase 1 clinical trial testing FHD-286 combined with decitabine and venetoclax in patients newly diagnosed with AML who cannot tolerate intensive chemotherapy. Measure the treatment's effects on bone marrow and blood samples over time.
This project brings together the laboratory research of Dr. Kadoch with the clinical leadership of Dr. Stone and the Dana-Farber Cancer Institute Leukemia service. The work is expected to clarify how mSWI/SNF inhibitors affect cancer-driving gene activity, cell growth, and maturation when combined with standard AML therapies, and to define their potential role in frontline AML treatment.
Administrative Core
Core Co-Directors:
Specific Aims:
The Administrative Core provides oversight and leadership for the scientific, administrative, and fiscal operations of the Harvard Cancer Consortium (HCC) SPORE in Leukemia. It coordinates SPORE activities and meetings to maximize collaboration, accelerate the translation of laboratory findings into clinical trials, and ensure that clinical observations continue to inform basic research. The Core draws on HCC's administrative infrastructure to direct resources toward the projects most likely to produce clinical results. An annual Leukemia SPORE retreat with investigators from the Washington University, Memorial Sloan Kettering, and MD Anderson Leukemia SPOREs is organized by this Core.
Dr. Lane and Dr. Stone, the SPORE Co-Directors, oversee the progress of all Projects and Cores, along with the Career Enhancement Program and Developmental Research Program. A monthly Governance Committee provides guidance and decision-making support. The Internal Advisory Board of senior Harvard Medical School leaders and an External Advisory Board of leaders from partner leukemia SPOREs and other leukemia experts meet regularly to guide planning and promote collaboration across institutions.
The Core's aims are to:
(1) monitor research progress,
(2) foster collaboration within and beyond HCC,
(3) integrate the SPORE into the HCC structure,
(4) provide fiscal oversight, and
(5) promote rapid dissemination of research findings.
Biospecimens Core
Core Co-Directors:
Specific Aims
The mission of the Biospecimen Core is to provide the infrastructure and expertise needed to collect, bank, characterize, and distribute primary myeloid leukemia samples and clinical data to SPORE investigators. Patient samples are collected prospectively through established tissue banking protocols and clinical trials, then characterized using genetic and functional testing before serving as key research materials for each Project. The Core also maintains a data repository combining clinical and genetic information for patients with myeloid cancers.
Dr. Ritz has worked in leukemia and transplant research for more than 40 years and founded the Connell and Pasquarello Tissue Bank in 2001, which has collected over 10,000 bone marrow samples from more than 3,700 patients with AML and MDS. Dr. Lindsley directs the DFCI Hematologic Malignancy Data Repository, created in 2016, which holds data on more than 27,000 patients and has supported over 120 research projects.
The Core's aims are to collect and preserve viable cells, DNA, and plasma from patients with myeloid malignancies, and to maintain a database of clinical, pathologic, and genetic information. This work supports the success of every SPORE Project and advances the diagnosis and treatment of myeloid cancers.
Biostatistics and Bioinformatics Core
Core Director:
Specific Aims
The goal of Biostatistics and Bioinformatics Core is to provide reliable statistical and computational support for every study conducted through the SPORE in Leukemia. Core members work directly with investigators to offer statistical consultation and collaboration. These services are available to everyone connected to the SPORE, whether through the Research Projects, the Developmental Research Program, the Career Enhancement Program, or the other Cores.
The Biostatistics and Bioinformatics Core provides biostatistics and bioinformatics expertise for the planning, design, execution, analysis, and reporting of laboratory, genomic, animal, translational, and clinical studies, including their associated correlative research. The Core also advises on data management and integrity, covering how data is collected, stored, transferred, shared, and quality-checked. The Core provides guidance on statistical and computational software, and on aligning laboratory findings with outcomes from clinical studies and research databases.
In addition to long-term Project support, the Biostatistics and Bioinformatics Core offers short-term biostatistics and computational biology consultation to the entire community of SPORE researchers. This is to ensure that every investigator, regardless of project size or duration, has access to rigorous statistical guidance throughout their research.
Functional Precision Medicine Core
Core Directors:
Specific Aims:
The Functional Precision Medicine Core provides validated genetic testing and correlative diagnostic services to support all SPORE Projects. The Core runs a clinically validated DNA-based next-generation sequencing (NGS) assay that:
(1) profiles patient samples at diagnosis,
(2) monitors residual disease down to very low levels,
(3) tracks how leukemia clones evolve at relapse,
(4) detects emerging drug-resistant mutations, and
(5) identifies clonal hematopoiesis.
A companion RNA-based NGS assay helps classify samples that lack a clear molecular subtype from DNA sequencing or standard cytogenetics and can detect gene fusions relevant to residual disease monitoring, drug resistance, and gene expression signatures used in Project trials.
The Functional Precision Medicine Core develops and validates new diagnostic tests based on BH3 profiling. BH3 profiling is a technique that measures how "primed" leukemia cells are for programmed cell death; to help predict which patients will respond to specific therapies. The Functional Precision Medicine Core works closely with Project leaders to identify new testing needs. This Core continues expanding its capabilities through genome-wide technologies such as optical genome mapping, total RNA sequencing, and methylation profiling which can help clarify unusual or ambiguous cases.
Across all of its assays, the Functional Precision Medicine Core is committed to delivering accurate, quantitative results to SPORE Projects quickly enough to support real-time treatment decisions and ongoing correlative research.
Developmental Research Program
Program Co-Directors:
Specific Aims:
The Developmental Research Program (DRP) provides a continuous flow of new ideas and seed funding to stimulate innovative leukemia research within the HCC SPORE in Leukemia. The program encourages new research directions, facilitates collaboration, and provides initial support to pilot projects. This Program helps translate promising early-stage findings into full research projects given the long, uncertain path to clinical development for new leukemia therapies. The DRP also gives the SPORE an opportunity to recruit talented investigators from a broad range of backgrounds and institutions. The Program is widely advertised through web postings and email announcements across HCC institutions to attract high-quality applications.
The DRP is led by SPORE Directors, Dr. Andrew Lane and Dr. Richard Stone, who monitor the progress of funded projects. Project selection is guided by the SPORE DRP Review Committee, which includes internal SPORE members and external reviewers to ensure funded projects have strong scientific merit and translational potential.
The DRP's goals are to:
(1) solicit and identify novel leukemia research projects,
(2) evaluate candidates for funding,
(3) fund the most innovative proposals,
(4) reassess funded projects for progress and potential promotion to full project status, and
(5) evaluate the success of the program overall.
Career Enhancement Program
Program Co-Directors:
Specific Aims:
The goal of the Career Enhancement Program (CEP) is to increase the number of investigators engaged in translational leukemia research and strengthen their training. The program recruits promising candidates, including advanced postdoctoral researchers, junior faculty, and established faculty new to the field. The CEP provides funding, mentoring, and access to didactic training. The CEP also recruits from other disciplines to broaden the range and quality of translational leukemia research, drawing on Harvard's large faculty base with strong track records in mentorship and its deep pool of talented trainees.
Each year, the CEP issues a Request for Applications through multiple channels to reach a wide range of candidates. A committee of SPORE leadership and Harvard faculty selects awardees based on their qualifications, mentoring plan, scientific approach, and alignment with the program's translational mission.
The program has received commitments for matching institutional funds to support two investigators per year for up to two years each. Awardees receive research supervision, help with manuscripts and grant applications, access to core facilities, and networking opportunities through an exchange program with other leukemia SPOREs.
CEP Directors monitor awardee progress, gather feedback from SPORE leadership and past awardees, and track research productivity and career advancement to continually refine the program.