2024 Accelerator Impact Report
Letter from
Accelerator Leadership
We are delighted to present the 2024 Dana-FarberAccelerator Impact Report, a testament to the progress and innovation achieved over the past year. The Dana-FarberAccelerator is dedicated to transforming groundbreaking scientific discoveries into therapies and diagnostics that improve the lives of patients and their families worldwide.
Since its founding in 2010, with a catalytic gift from Bud and Barbara Herzstein, the Dana-FarberAccelerator has dispersed a total of $9 million in non-dilutive funding in support of 31 projects and four clinical trials. This financial support has led to over $24 million in follow-on funding, 17 licenses to pharma or biotech partners and four new companies.
2024 FUNDED TECHNOLOGIES
New Therapies Focus on “Undruggable” Targets in Intrinsically Disordered Regions in Cancer
Membrane Protein Degraders: A New Therapeutic Strategy for Autoimmune Disease
Mary Tolikas, PhD, MBA SVP & Chief Innovations Officer
Christiana Iyasere, MD, MBA Senior Director, Accelerator
Our approach to technology development integrates cutting-edge science with business and intellectual property strategy, allowing us to navigate the rapidly evolving oncology landscape with agility. By leveraging the diverse expertise within Dana-Farber and fostering partnerships with industry, venture capital, and government, we look to accelerate impact in cancer research and treatment.
This report highlights the innovative projects funded by the Dana-FarberAccelerator in the 2024 cycle and includes our development pipeline with projects that are reaching patients or are on the cusp of significant clinical impact. These achievements are a direct result of the unwavering commitment and collaboration among our researchers, clinicians, and partners across various sectors and areas of expertise.
We extend our gratitude to the Dana-Farber community and our generous donors, whose support has been instrumental in our success. What we do here at Dana-Farber changes lives everywhere, and, as we look to the future, we remain steadfast in our mission to advance technologies to the patient and excited about the opportunities that lie ahead.
Thank you for your continued support and partnership.
Sincerely,
MaryTolikas ChristianaIyasere
Innovative Inhibitors of Creatine Kinase Pathway Metabolism Offer New Hope for Colon Cancer Therapy
Natural Killer Cell Clinical Trial Aims to Eradicate Residual Disease in Leukemia Patients
Funding the Technology Pipeline
One of the challenges in the development of novel technologies for academic investigators is their advancement along the preclinical stages, pushing scientific inquiry from a series of observations made in the lab to a set of goals and experiments focused on creating a technology with potential clinical utility. In early therapeutic development, these next steps often involve target validation, high-throughput screening for potential compounds of interest, and testing the technology in a preclinical model – known as in vivo proof of concept. For diagnostics, moving from an identified biomarker with predictive ability to a diagnostic tool with both analytic and clinical validity is a significant challenge, both in determining the necessary experiments to demonstrate the technology works and in understanding the clinical paradigm in which the diagnostic will impact clinical care.
The Dana-FarberAccelerator program provides financial support and requisite expertise to help achieve crucially important junctures of technology development, an area where traditional funding sources often fall short. SPARK awards fund up to 12 months focused on testing whether high risk ideas can be validated through early-stage experiments. LEAP awards provide larger financial support over a 18-24 month timeline to help bring promising technologies to key inflection points to demonstrate their value and commercial potential.
Since 2010 the Accelerator has funded 31 projects, all of which our team closely follows to understand their outcomes. Projects that are partnered with external parties are closed out of the portfolio, although we continue to track their progress. Given the early stage of many of these efforts, some projects are not further supported due to lack of scientific results that would support commercialization and clinical potential. Importantly, for all open projects in the portfolio we continue to work closely with the project teams to support their evolution towards success.
Accelerator Projects: 2010-2024
DISCOVERY PRECLINICAL
Validation/Lead Optimization
2010 Bromodomaininhibitors forcancer therapy
2013 Targetingnovel oncogenic kinases, in breast cancer
DUB Inhibitors in cancer therapy
2015 Novel inhibitors of the deubiquitinatingenzymes to target leukemiaoncogenes
2016 Targetedinhibitors forbreast and ovariancancers
2017 Small molecule degraders for thetreatment of mantle cell lymphomas
Development of anovel p300/CBP inhibitor targeting oncogenic transcription
2019 Chromatinreader protein inhibitor as novel therapy in B cell neoplasms
2020 Chemical manipulation of “undruggable” proteins to treat obesity and cancer
2020 Discovery of mutant-selective allosteric inhibitors of cancertargets
Development of next generationallosteric EGFR
TargetingTIRR dependency in p53heterozygous
Small molecules targetingchromatin regulatory complexes
Targetingcreatine kinase in colon cancer
molecule targetingoncogenic driver
CAR T Cell factories to achieve B-CLL
cells as as CAR
CD4+ cytotoxic T lymphocyte(CTL) therapy to cure refractory B-cell malignancies
Dual-targeted CAR to cure Multiple Myeloma
Antibody discovery platform inovarian and pancreatic cancer Engineered NKCARs forenhanced immunotherapy
for targetedproteindegradation
Memory like NK cells to eradicateMRD cells in high-risk
StabilizedmRNA for improved gene therapy and vaccines
Predicting disease by immune andcirculating tumor cell profiling
More
Investment for Impact
$9 million of philanthropic and Institute funding to the Accelerator since 2010 has enabled four new companies, four clinical trials and more than $24 million in follow-on funding.
31 Projects Funded
4 Clinical Trials
29 IP Filings
Accelerator Technology Moving Towards the Clinic
New Genomic and Immune Profiling Platform Predicts Treatment for Patients with Multiple Myeloma
This condition, driven by genetic mutations that turn plasma cells in the bone marrow into malignant forces, is notoriously difficult to diagnose and treat. Traditional diagnostic methods, such as bone marrow biopsies and FISH (fluorescence in situ hybridization), are invasive and often lack precision. However, a new liquid biopsy diagnostic platform developed in the laboratory of Dana-Farber’s Irene Ghobrial, MD, aims to better profile patients with hematological cancers, like multiple myeloma. The technology taps into the immune system as a sensor for detecting these cancers to improve clinical decisionmaking and patient outcomes.
Multiple myeloma is marked by its complexity and variability in symptoms, making it a formidable adversary for both patients and clinicians. Despite the availability of over 20 approved treatments, selecting the optimal therapy for each patient remains a daunting task. "Current diagnostic procedures can be difficult for patients to tolerate and are not always accurate," explains Ghobrial, Director of the Center for Early Detection and Interception of Blood Cancers and Co-Leader of the Lymphoma/Myeloma Cancer Center Program, both at Dana-Farber. "This often leads to patients experiencing toxic side effects without the desired therapeutic benefits."
The frequent relapses and variable survival rates associated with multiple myeloma underscore the urgent need for more precise diagnostic tools and personalized treatment strategies. This need catalyzed Prof. Ghobrial's pursuit of innovative solutions to bridge the existing gaps in patient care
The Birth of GenoPredicta
In collaboration with Kenneth Anderson, MD Dana-Farber Professor of Medicine, Romanos Sklavenitis-Pistofidis, MD, PhD, Department of Medical Oncology at DanaFarber, and Gad Getz, PhD of Massachusetts General Hospital and the Broad Institute, Ghobrial developed GenoPredicta, a technique based on whole genome sequencing (WGS) of circulating
2023 Accelerator Project Update
tumor cells and single-cell sequencing of immune cells isolated from blood samples to predict patient responses to specific therapies. Papers describing the platform and potential uses were published in Nature1 and Cancer Discovery2
"Sequencing this breadth of blood samples will provide physicians with the chance to discover any characteristics on the cancer cells that are not on the healthy cells, which can lead to the development of new therapeutic targets that we can bring into patient care," says Anderson. These efforts culminated by the founding of Predicta Biosciences in early 2024 to bring GenoPredicta’s liquid biopsy platform from the lab to the clinic.
Milestones and Impact
GenoPredicta represents a significant leap forward in blood cancer diagnostics. By analyzing a simple blood sample, this technology can identify genomic abnormalities indicative of disease progression, replacing the need for invasive bone marrow biopsies. "WGS provides important details that FISH misses," notes Ghobrial. "The characteristics detected in the immune cells can also be used to understand how a person will respond to different treatments, identifying the one with the
The potential benefits of GenoPredicta extend beyond multiple myeloma to other hematological cancers.
The integration ofAI capabilities further enhances its utility, enabling the identification of novel therapeutic targets and facilitating minimal residual disease monitoring.
Ghobrial is optimistic about the future of GenoPredicta and its impact on patient care. "While it’s great that approaches like singlecell sequencing exist today, what really matters is being able to actually bring them into the clinic so we can use them with patients to improve their experience and outcomes," she emphasizes. Predicta Biosciences aims to make GenoPredicta available to patients by the summer of 2025, marking a significant milestone in the journey from bench to bedside. best potential for their specific situation."
1
Project Lead
Irene Ghobrial, MD Professor, Harvard Medical School, DanaFarber, Senior Vice President for Experimental Medicine Dana-Farber
Project Collaborators
Kenneth Anderson, MD, PhD Program Director, Jerome Lipper Multiple Myeloma Center, DanaFarber, Professor, Harvard Medical School
Gad Getz, PhD Director, Cancer Genome Computational Analysis Group, Broad Institute, Professor, Harvard Medical School
Romanos SklavenitisPistofidis, MD, PhD Instructor of Medicine, Harvard Medical School, Dana-Farber
Membrane Protein Degraders: A New Therapeutic Strategy for Auto Immune Disease
Xin Zhou, PhD, Assistant Professor of Cancer Biology at Dana-Farber and Biological Chemistry and Molecular Pharmacology at Harvard Medical School, focuses on cellular signal perception in cancer and immunological diseases. Her lab is developing novel technologies to degrade cell surface proteins involved in these conditions and applying these new therapeutic approaches to address unmet biomedical needs. Initially designed for targeting cancer cells, Zhou’s membrane protein degradation technology is now being adapted to immune modulation and autoimmune diseases, for which she has received Dana-FarberAccelerator funding.
Targeted Proteins are Captured then Destroyed
Zhou’s technology, Transferrin Receptor
Targeting Chimera (TransTAC), offers a novel cancer-targeting approach by directing cancer-driver membrane proteins for degradation. Membrane proteins play crucial roles in cellular activities, including signal transduction and cell communication. Misregulation of membrane proteins are drivers of many diseases. However, some of these proteins are considered "undruggable" due to their complex structures and functions. TransTAC circumvents these challenges by
inducing the internalization of target proteins with bifunctional antibodies and their degradation in lysosomes.
As described in a recent Nature1 paper, in cancer, TransTAC exploits the high expression of Transferrin Receptor 1 (TfR1) on cancer cells to degrade its target. Zhou's team is now adapting a novel membrane protein degradation technology for targeting immune cells and addressing autoimmune conditions.
Focus on a Key Autoimmune Receptor
Developing this technology to target the immune system is a natural extension of its earlier success in cancer. By leveraging a protein expressed in immune cells and specifically
1
2024 Accelerator Project
degrading key surface receptors that regulate immune signaling, this new approach could highly effectively inhibit receptors that were previously difficult to block. This targeted approach promises to both enhance efficacy and avoid the side effects associated with broad immune suppressive therapies, offering patients a safer and more effective treatment option.
Zhou’s first target is a well-validated drug target in various autoimmune conditions and has been extensively explored in drug discovery; however, both small molecule and antibody approaches have failed in the past due to either limited efficacy or toxicity issues. This makes it an ideal candidate for Zhou’s targeted degradation approach. Early experiments have shown promising results, with significant downregulation of the receptor and complete inhibition of its functional activity. The Dana-FarberAccelerator funding is providing critical support for the team to fully establish the method and build intellectual property around this technology.
The team's work on its initial target is just the beginning, and future studies will explore other targets that have been considered "undruggable" proteins. Zhou’s vision extends beyond autoimmune diseases. The platform's versatility suggests potential
applications in other fields, such as immunotherapy for targeting cancer, or other non-oncology indications such as pain management and rare diseases. In addition to Dana-FarberAccelerator funding, Zhou’s lab research is supported by a National Institutes of Health Director’s New Innovator Award, a National Institute of Biomedical Imaging and Bioengineering R00 Award, and a Dana-Farber Helen Gurley Brown Presidential Initiative Helen Trailblazer Award.
Project Collaborators
Jhoely Duque-Jimenez
Former Research Technician/Lab Manager, Zhou Lab, Dana-Farber
Current MD Student, BU
Kaitlin Rhee
Graduate Student, Zhou Lab, DanaFarber
Aoxing Cheng, PhD
Postdoctoral Fellow, Zhou Lab, Dana-Farber
Project Lead
Xin Zhou, PhD
Assistant Professor, Harvard Medical School, Dana-Farber
Jun Huh, PhD
Associate Professor, Harvard Medical School
Lawrence Shue
Graduate Student, Zhou Lab, Dana-Farber
Dingjingyu Zhou
Research Technician/Lab Manager, Zhou Lab, DanaFarber
Itay Algov, PhD
Postdoctoral Fellow, Zhou Lab, Dana-Farber
New Therapies Focus on “Undruggable” Targets in Intrinsically Disordered Regions in Cancer
Cigall Kadoch, PhD, Associate Professor of Pediatric Oncology at Dana-Farber and Harvard Medical School, is spearheading a transformative project to understand and target intrinsically disordered regions (IDRs) of chromatin regulatory proteins that control the opening and closing of chromatin, the 3D structure of DNA wrapped around proteins in a cell’s nucleus. Her team’s innovative approach brings together multiple methodologies to probe the very factors that are frequently mutated and known to uphold cancer growth.
Newly supported by the Dana-Farber Project Lead
Cigall Kadoch, PhD
Associate Professor, Harvard Medical School, Dana-Farber, Co-Director,
Epigenomics Program, Broad Institute of MIT and Harvard
Project Collaborator
Whitney Lieberman Graduate Student, Kadoch Lab, Dana-Farber
Accelerator, this project has the potential to redefine drug discovery for "undruggable" targets.
Chromatin regulatory proteins have emerged as among the top-mutated and involved factors in cancer biology. “Such nuclear proteins are particularly enriched in disordered sequences that lack
defined 3D structure, and because of that, we need to both understand their diverse
functions and define new ways to alter their biochemical properties and interactions,” says Kadoch, explaining the goal of her current work.
Over 40% of a cell’s protein content (cellular proteome) consists of IDRs, which are
challenging to target therapeutically due to their
lack of defined structure. These regions arecrucial in numerous biological processes, yet their roles remain poorly understood. Kadoch's lab has identified that IDRs play a pivotal role in the function of key chromatin regulatory complexes known as mammalian SWI/SNF (mSWI/SNF or BAF) complexes, which are heavily implicated in cancer. "These complexes are the most frequently mutated entities in all of human cancer, second only to the wellknown tumor suppressor, TP53, and represent top vulnerabilities across a range of disease states", she explains.
1 Cell 186 (22): 4936 - 4955.e26 (2023)
Identifying First-in-Class IDR Engagers
Kadoch’s recent work published in Cell 1 in 2023 demonstrated that specific amino acid sequences, or "sequence grammars," are crucial for IDR function. "We learned that specific grammars, or strings of amino acids, are required to enable cell type- and cancerspecific interactions," Kadoch emphasizes. By understanding these grammars, the team hopes to alter the function of various chromatin regulatory IDRs selectively.
"If we can develop new proof-of-concept approaches on a few top cancer targets, our approaches could open the floodgates for efforts across a broader range of factors that have been historically recalcitrant to small molecule targeting," Kadoch states. By targeting these IDRs and their interfaces, the research could lead to more effective treatments for cancers that currently lack targeted therapies.
Applications Beyond Cancer
Beyond cancer, the insights gained from this research could have far-reaching implications for drug discovery across various human diseases. The ability to target IDRs could unlock new therapeutic possibilities for immune conditions, neurodevelopmental disorders and other diseases involving targets that currently lack conventional small molecules. The Dana-FarberAccelerator funding is key in establishing a platform to interrogate IDRs of chromatin regulatory proteins and subject them to chemical intervention. This support allows the team to explore new strategies for understanding and targeting disordered regions.
Innovative Inhibitors of Creatine Kinase Pathway Metabolism Offer New Hope for Colon Cancer Therapy
Colorectal cancer remains a formidable challenge, particularly in its metastatic form, which is often resistant to current treatments. Addressing this critical need, a groundbreaking research project led by Edward Chouchani, PhD, Professor of the Department of Cancer Biology Program at Dana-Farber, explores innovative approaches to target cancer metabolism. This project, newly funded by the Dana-FarberAccelerator, targets the metabolic dependencies of cancer cells on
Project Lead
Ed
Chouchani,
PhD
Professor, Harvard Medical School, DanaFarber
creatine energetics, particularly the creatine kinase pathway, which plays a crucial role in cellular energy management.
An Already De-Risked Pathway
Cancer cells, particularly those in aggressive forms like metastatic colorectal cancer, have been shown to depend
heavily on creatine metabolism. This pathway involves the conversion of creatine into creatine phosphate, an energy reserve that supports rapid cell proliferation.
“In the last eight years or so, a lot of preclinical and clinical findings have shown that creatine metabolism appears to be an important dependency for this type of cancer,” Chouchani says, whose lab has long studied this pathway. But historically, researchers have been a bit hesitant to attempt to manipulate metabolism pathways like creatine simply because it is needed for normal bodily function.
But Chouchani believes this strategy of require extremely high dosing.
pharmacokinetics of the compound inhibiting creatine energetics has
already been de-risked. For decades, scientists have used the molecule βGuanidinopropionic acid (β -GPA) successfully to poison the creatine pathway yet it is extremely well-tolerated by mice and early clinical work shows preliminary efficacy in humans for colorectal cancer. However, the
2024 Accelerator Project
Encouraged by these findings, Chouchani’s team set out to develop next-generation creatine inhibitors with nanomolar potency to disrupt the cancer cells' energy supply. “We wanted to make a more efficacious therapy for colorectal cancer targeting creatine energetics, especially considering how the pathway has been de-risked,” Chouchani adds.
The Chouchani team recognized that the creatine kinase has an active site cysteine residue that is critical for activity. Using a platform in their lab to screen small molecules as covalent ligands for cysteines, they identified a covalent inhibitor. Their discovery was published in a 2023 Nature Chemical Biology1 paper as a first-in-class creatine kinase inhibitor. However, the pharmacokinetics were poor.
Moving forward with Dana-FarberAccelerator funding, Chouchani plans on screening, identifying, and synthesizing drug-like molecules that target the same cysteine residue. To date, the team has identified a series of molecules that are much more stable and potent in animal studies than the first-generation compound.
“We are ready now to scale up the synthesis of lead molecules and ultimately put them head-to-head with the current standard of care for treating metastatic colorectal cancer in mouse models,” says Chouchani. The potential benefits of this technology are significant. By selectively targeting cancer cells' metabolic pathways, this treatment could offer a more precise and less toxic alternative to traditional chemotherapy. "If successful, this could lead to a new class of therapeutics that are not only more effective but also better tolerated by patients, improving their quality of life during treatment," Chouchani emphasizes.
Collaborations with other scientists have been instrumental in advancing this research, notably with Profs. Nathanael Gray and Tinghu Zhang at Stanford University, and Prof. Jianwei (John) Che of the Computational Chemistry Core at Pat Dana-Farber.
1 Nat Chem Biol. 19(7):815–824 (2023)
Project Collaborators
Nathanael Gray, PhD
Professor of Chemical and Systems Biology at Stanford University
Tinghu Zhang, PhD
Senior Scientist, Cancer Institute of Stanford University
Jianwei Che, PhD
Director, Computational Chemistry Core, Dana-Farber
Emma Fink, MD, PhD
Postdoctoral Fellow, Chouchani Lab, Dana-Farber
Natural Killer Cell Clinical Trial Aims to Eradicate Residual Disease in Leukemia Patients
For many patients with hematologic malignancies like Acute Myelogenous Leukemia (AML), Myelodysplastic Syndrome (MDS), or Myeloproliferative Neoplasms (MPN), the only curative option is stem cell transplant (SCT). However, for patients with residual disease after chemotherapy but before transplantation, more than 60 percent of them will relapse and do extremely poorly, according to Rizwan Romee, MD, Director, Haploidentical Donor Transplantation Program at Dana-Farber and Associate Professor of Medicine, Harvard Medical School. “And on top of that, if people have TP53 gene mutations, the most commonly mutated cancer gene, relapse is almost a certainty.”
Mopping Up Residual Disease
A new clinical trial1 led by Romee, supported by the Leukemia & Lymphoma Society (LLS) and the Dana-FarberAccelerator, seeks to change this grim prognosis by leveraging the unique properties of natural killer (NK) immune cells. Romee and his team have discovered that these cells can be trained to enter a "memory-like" state, enhancing their anti-leukemia properties. "We hypothesized that if we give these memory-like NK cells from the same donor who provides the stem cell graft, those patients may have a better chance of curing their disease," he explains. "These NK cells can clear or mop away the residual leukemia cells, significantly increasing the odds of success with the transplant."
All manufacturing of the NK cells occurs at the Connell and O'Reilly Families Cell Manipulation Core Facility at Dana-Farber, with advanced immune monitoring methods employed to track the cells' interactions within the body. "We hope to learn not only how to help patients but also to gain scientific insights into cell interactions and persistence.”
Project Lead
Rizwan Romee, MD
Associate Professor, Harvard Medical School,Dana-Faber, Director, Haploidentical Donor Transplantation Program
The potential benefits of this trial for patients significant impact on the prognosis of these patients," he asserts. "It's a huge unmet need,
are immense. For those leukemia patients at high risk for post-allogeneic SCT relapse, the odds of relapse are dauntingly high, with traditional transplants offering less than a 20% chance of cure.
Romee's approach could dramatically alter this landscape. "We are hoping to make a
and we believe our trial can address it."
Understanding The Relapse Process
The trial was recently activated and is now enrolling patients, with funding from LLS covering the costs of the cells and the trial itself.A Dana-FarberAccelerator Award supports the deep dive into the biology and interaction of the cells, a critical component of the research. "Without this type of collaboration and funding, which is a great example of how clinical and bench research
Project Collaborator
Roman Shapiro, MD Instructor in Medicine, DanaFarber Cancer Institute and Harvard Medical School
The trial's success could pave the way for the next generation of therapies, offering hope to patients who currently face limited options. "We want to maximize how much we learn," Romee says. "This is not standard treatment. It's about understanding the immune escape mechanisms and why some patients still relapse. This trial is a critical piece of the puzzle." inform each other, no discovery would happen," Romee emphasizes. "These are highly complex, manipulative cells, and we need to know what they are doing in the body. Are they safe? Where are they going? How long are they persisting? These are critical questions."
1 Leukemia& Lymphoma
Classification Tool for Diffuse Large B Cell Lymphoma to Guide Treatment and Improve Prognostic
Accuracy
Diffuse Large B-cell Lymphoma (DLBCL), the most common adult lymphoid malignancy, is known for its molecular heterogeneity, despite being a single diagnosis under the microscope. While over 60% of patients respond well to standard R-CHOP immunochemotherapy, the remainder either fail to respond or experience recurrence. The molecular heterogeneity of the cancer complicates treatment, necessitating a robust molecular classifier to better inform prognosis and therapeutic decisions. Toward that goal, a project led by Margaret Shipp, MD, Chair, Division of Hematologic Neoplasia at DanaFarber, has developed a new diagnostic tool aimed at improving DLBCL’s molecular diagnosis, prognostic accuracy, and treatment strategy for the disease. The project received funding from the Dana-FarberAccelerator Program in the 2024 cycle.
Focusing on Five Genetic Subtypes
Project Lead
Margaret Shipp, MD Professor, Harvard Medical School, DanaFarber, Chief, Division of Hematologic Neoplasia
Project Collaborators
Gad Getz, PhD Director, Cancer Genome Computational Analysis Group, Broad Institute; Professor, Harvard Medical School
Björn Chapuy, MD, PhD Department of Hematology, Oncology and Tumorimmunology
Charité Universitätsmedizin Berlin
Chip Stewart, PhD
Associate Director, Scientific Projects, Getz Lab, Broad Institute
In earlier research, Shipp and her team in Nature Medicine1 in 2018, laid the
collaborated with colleagues from the lab of Gad Getz, PhD, director of the Cancer Genome ComputationalAnalysis Group at the Broad Institute, to define five distinct genetic subtypes of DLBCL, each with unique biological characteristics and varying responses to standard chemotherapy. This framework, published
Tim Woods LabAlumnus, Associate Computational Biologist, Getz Lab, Broad Institute
Eleonora Calabretta, MD Research Fellow, Shipp Lab, Dana-Farber
Sumbul Khan, PhD Research Associate, Shipp Lab, Dana-Farber
2024 Accelerator Project
foundation for the development of a robust molecular classifier known as DLBclass by characterizing genetic alterations in DLBCL and identifying five distinct subtypes that could provide physicians with crucial insights into overall prognosis and treatment strategies.
As described in a recent paper in Blood 2, the team further validated the DLBclass taxonomy and developed a probabilistic molecular classifier, using a dataset of 699 primary DLBCL samples. They employed machine learning models to achieve high accuracy in classifying these subtypes, demonstrating 91% accuracy in training/validation sets and 89% in independent test sets. The classifier has potential for widespread clinical application, positioning it as a best-in-class diagnostic tool for DLBCL.
Outperforms Existing Classification Tools
The benefits of DLBclass a significant portion of
are substantial. It enables precise classification of DLBCL subtypes, critical for enrolling patients in genetically guided clinical trials and optimizing treatment strategies. This classifier outperforms existing tools like the NIH’s LymphGen, which only classified 58% of cases into
patients without clear subtype identification. In contrast, DLBclass successfully classified all samples, providing actionable genetic information for a larger number of patients.
The Accelerator award recognizes a pivotal moment for the project, enabling the team to transition from research to clinical application. The goal of the project is to develop the test under CLIA guidelines, ensuring that it produces consistent and accurate results across different conditions and equipment. Achieving CLIA certification would allow the classifier to be used in translational research and prospective clinical trials and practice, enabling oncologists to make informed treatment decisions based on a patient's specific genetic subtype.
The DLBclass project has been a testament to the power of sustained collaboration. The Shipp team worked closely with the Getz group at the Broad Institute, building on their previous work to define the genetic framework of DLBCL. Key contributors included Björn Chapuy, a former member of Dr. Shipp's group now leading a lymphoma program at Charité – Berlin University Medicine, Getz lab members, Chip Stewart and Tim Woods, and additional Shipp group participants, Eleonora Calabretta and Sumbul Khan.
1 Nat Med. May;24(5):679-690. 2018.
2 Blood 2024; 2024025652.
Beyond the ACCELERATOR
Beyond funding innovative technologies emerging from Dana-Farber research labs, the Dana-Farber Accelerator contributes to the business development and marketing efforts for the entire Dana-Farber intellectual property portfolio. Working closely with the Institute's faculty, the Belfer Office for Dana-Farber Innovations and Office of General Council's IP team, the Accelerator team helps develop strategy for dozens of technology programs in multiple modalities such as small molecules, cell therapies, vaccines, and antibody-drug conjugates, as well as novel diagnostics and digital platforms. The examples below are just a fraction of the innovations ready for partnering and commercialization. We invite collaborators to join us in transforming the future of cancer treatment and diagnosis.
A Vaccine Prompts a Dual Attack Against Resistant Tumors
A novel cancer vaccine developed by Kai Wucherpfennig, MD, PhD, Chair, Cancer Immunology and Virology at Dana-Farber, seeks to overcome common challenges in cancer treatment. Unlike traditional vaccines that require personalization, his team’s approach targets MICA and MICB
stress proteins found on many cancer cells. These proteins activate T cells and
natural killer (NK) cells, but tumors often evade detection by shedding them. The new vaccine increases the presence of MICA/B on tumor surfaces, enhancing immune response, and maintaining effectiveness even against tumors that resist typical T cell attacks. It also shows promise in preventing metastasis after surgery, offering a broad protective immunity against diverse cancer types.
Manipulating the Immuno-peptidome for Rapid Tumor Elimination
A team of researchers led by Ellis Reinherz, MD, Chief, Laboratory of Immunobiology, Dana-Farber, has developed a comprehensive immuno-oncology technology platform to understand and manipulate immune recognition of cancer cells by cytotoxic CD8 T lymphocytes (CTLs). The team has identified druggable pockets in target proteins that can be exploited to change the cellular immuno-peptidome of cancer cells, enhancing their sensitivity to CTL destruction.
Primary targeted indications include prostate, lung, breast, brain, and pancreatic cancers, with additional HLA-type specific applications.
ALLoRIGHT: An AI-Tool for ALLograft Risk Prediction of GvHD after Hematopoietic Transplant
Dana-Farber researchers led by Nicoletta Cieri, MD, PhD, of the Department of Medical Oncology, a member of the laboratory of Catherine Wu, MD, Chief, Division of Stem Cell Transplantation and Cellular Therapies, have created a method to predict detrimental graft versus host disease GvHD) in blood
(cancers after hematopoietic transplant. Allogeneic hematopoietic cell transplantation (allo-HCT) has transformed leukemia and lymphoma care by identifying minor histocompatibility antigens (mHAgs) from genetic differences between patients and donors to improve patient outcomes. These mHAgs influence both beneficial graft-versus-leukemia (GvL) and harmful GvHD effects. The team has developed a clinically validated analytical pipeline that systematically discovers mHAgs by integrating whole exome sequencing, single-cell datasets, and computational methods to minimize false positives. This AI-tool would help clinicians to better match donors and recipients for allo-HCT, tailor prophylaxis, and identify targets for post-transplant immunotherapy.
Beyond the ACCELERATOR
Targeting BFL-1 Reactivates Cancer Cell Death
Dana-Farber researchers, led
by Loren Walensky, MD, PhD, Principal Investigator, Department of Pediatric Oncology,
have developed the first known selective inhibitors targeting BFL-1,a protein that inhibits apoptosis and contributes to cancer progression and treatment resistance. BFL-1 is implicated in various cancers, including leukemia, lymphoma,
melanoma, and breast cancer. The team has identified a unique cysteine residue within BFL-1's BH3-binding groove, enabling the design of cysteine-reactive compounds to target this previously undruggable protein. These inhibitors aim to reactivate apoptosis in BFL-1-driven cancers and could be used as monotherapy or in combination with other treatments to overcome resistance.
Targeting DDX5 in AML, Colorectal Cancer, and Other Malignancies
Dana-Farber researchers have identified DDX5 as a key therapeutic enzymatic target in acute myeloid leukemia (AML) and other cancers. DDX5 activates beta-catenin, a critical cancer pathway that has been challenging to target. Current AML treatments involve intensive chemotherapy with high toxicity, and targeted therapies benefit only a few patients.
By inhibiting DDX5 which induces cancer cell death, researchers led by James Griffin, MD, Professor of Medical Oncology, have demonstrated significant efficacy in AML across diverse genetic backgrounds, using cell lines, patient samples, and in vivo models.
CRISPR-Based Rapid Molecular Diagnostic Tests for Fusion-Driven Leukemias
A project led by Professor R. Coleman Lindsley, MD, PhD of Dana-Farber aims to rapidly diagnose fusion driven leukemias using a CRISPR-based method, called the SHERLOCK diagnostic assay. The fusion oncogenes PML-RARA and BCR-ABL are crucial markers in acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL), and require timely and targeted treatment. Routine diagnostics in central labs are often inaccessible, causing delays and higher mortality rates. The SHERLOCK assay offers a rapid (under two hours), affordable, and userfriendly point-of-care diagnostic solution for these leukemias. This patented technology enables prompt treatment and better patient outcomes.
Beyond the ACCELERATOR
Small Molecule Inhibitors for the Treatment of VEXAS Syndrome
Dana-Farber scientists have
developed a promising approach to treat VEXAS syndrome, a severe inflammatory blood disorder caused by mutations in the UBA1 gene. This condition, which primarily affects males over 50, currently has limited treatment options, with allogeneic
hematopoietic stem cell transplantation being the only potential cure. Led by Roger Belizaire, MD, PhD, Assistant Professor of Pathology, DanaFarber Cancer Institute and Harvard Medical School, the research team has created a model system that accurately mimics the disease, enabling the study of its pathogenesis. This model has demonstrated that small molecule inhibitors targeting the UBA1 mutation can effectively induce apoptosis in disease-causing cells.
RNA
Surveillance
Tracks Down and Degrades CancerCausing Molecules
Dana-Farber researchers, led by Megan Insco, MD, PhD, Principal Investigator, Molecular and Cellular Oncology Department, have uncovered a novel approach to cancer treatment by targeting RNA surveillance mechanisms. RNA surveillance is crucial for maintaining RNA integrity and preventing the translation of defective proteins.
Mutations in this RNA surveillance system, particularly in cyclin-dependent kinase 13 (CDK13), can lead to the accumulation of aberrant RNAs, driving cancer progression. The Insco lab has demonstrated that restoring RNA surveillance can suppress tumor growth, particularly in melanoma. They are conducting small molecule screens to identify compounds that modulate RNA surveillance and target CDK13-mutant cells.
Small Molecule-Binding Proteins Improve Treatment Efficiency
A team led by Nicholas Polizzi, PhD, Principal Investigator, Department of Cancer Biology at Dana-Farber, has developed a novel approach to design proteins that can specifically bind to small molecules, addressing a critical need in various applications such as drug detection, delivery, and detoxification. Known as Convergent Motifs for Binding Sites (COMBS), his computational method starts with small-molecule fragments coupled with machine learning to create high-affinity drug-binding proteins with predictable binding energy and specificity.
By rapidly binding excess free small molecules, these proteins can help reduce off-target activity and improve the therapeutic index so patients can be given small molecule treatment longer. This method has successfully produced proteins that bind to poly(ADPribose) polymerase inhibitors (PARPi) with affinities as low as 5 nM. This advancement highlights the potential of de novo protein design to generate effective drug-binding proteins without extensive experimental screening.
Translating Scientific Discovery Accelerator Model: How We Work
• Fund high potential technologies
• Aim funding to achieve key development inflection points
• Mentor faculty and staff
• Expand network to enable collaborations
ACCELERATOR
• Align technical / IP / Business strategies
• De-risk technologies within Dana-Farber
• Strategically partner with industry to move technologies to the clinic
The Accelerator is focused on the translation of scientific discovery from Dana-Farber investigators into first in class technologies with the potential to create significant impact for patients worldwide. We identify investigators taking on high risk science who with earlystage funding and mentorship can efficiently move their project along towards further derisking and eventuallly, commercialization. Accelerator funding is focused on key development inflection points, aiming to pressure test assumptions and answer critical questions about the technology's potential to translate into a therapeutic or diagnostic for patients with cancer or related diseases. We align technical, business and intellectual property strategies to enable subsequent collaboration with the best partner to further the next stage of development. Our work is just one step in a long journey from translational science to improved diagnosic and therapy.
An Integrated Strategy
Successful development of nascent technologies requires a multidisciplinary approach that takes into account the unique opportunity presented by the technology, integrating in-depth understanding of the science, the relevant competitive landscape into which the technology will be introduced, and an intellectual property strategy that strengthens the business case, all with a focus on maximizing the potential impact of the technology. To be able to do such work, the Accelerator draws upon the diverse expertise of the Dana-Farber community.
IMPACT
Importantly, the Accelerator team operates out of the Belfer Office of Dana-Farber Innovation (BODFI), a group of business development, licensing, and contracts professionals whose collective mission is to expedite the translation of discoveries made in the labs at Dana-Farber. To make this all work requires a dedicated collaboration between the primary investigator, the Accelerator team, the larger BODFI Office, and the DanaFarber Office of General Council to create and hone an effective strategy for technology development.
The Team
Operations
• Christiana Iyasere, MD, MBA, Senior Director, Business Development
• Harry Rogoff, PhD, Director, Business Development – Therapeutics
• Shankar Parajuli, PhD, Business Development Director – Startups
• Linda Van Weele, PhD, Business Development Specialist
• Javi Vinals Camallonga, PhD, Business Development Data Analyst
• Alice McCarthy, MBA, Editorial Content Manager
• Liz Robinson, Accelerator Pipeline Marketing Manager
• Steven Caltrider, Esq., Vice President and Chief Intellectual Property Officer, Dana-Farber
• Emy Chen, PhD, Vice President of Innovation, Dana-Farber
• Benjamin Ebert, MD, PhD, President and Chief Executive Officer, Dana-Farber
• Lee Greenberger, PhD, President, LMG Bio1 Consulting, Former Chief Science Officer, The Leukemia & Lymphoma Society
• William Hahn, MD, PhD, Executive Vice President and Chief Operating and Transformation Officer, Dana-Farber
• Kevin Haigis, PhD, Chief Scientific Officer, Dana-Farber
• Kostas Kaloulis, PhD, Chief Executive Officer and Board Member, EpiCure Biotechnologies
• Hillary Mankin-Kufe, Senior Counsel, Dana-Farber
• Christopher Mirabelli, Chairman, Leap Therapeutics
• Steven Neier, PhD, Principal at Binney Street Capital
• Martin Seidel, PhD, Chief Executive Officer, IFM Therapeutics
• Alice Shaw MD, PhD, Chief, Strategic Partnerships, Dana-Farber
• Mary Tolikas, Senior Vice President and Chief Innovation Officer, Dana-Farber
Business Development Council Scientific Review Committee
• David Barbie, MD, Associate Professor, Harvard Medical School, Dana-Farber
• Myles Brown, MD, Professor, Harvard Medical School, Dana-Farber
• Sara Burhlage, PhD, Associate Professor, Harvard Medical School, Dana-Farber
• Kathleen Burns, MD, PhD, Professor, Harvard Medical School, Dana-Farber
• Edward Chouchani, PhD, Professor, Harvard Medical School, Dana-Farber
• Michael Eck MD, PhD, Professor, Harvard Medical School, Dana-Farber
• Eric Fischer PhD, Professor, Harvard Medical School, Dana-Farber
• Irene Ghobrial MD, Professor, Harvard Medical School, Dana-Farber
• Rudolf Hulspas PhD, Director Process Development, Dana-Farber
• Jeffrey Meyehardt, MD, MPH, Professor, Harvard Medical School, Dana-Farber
• Jerome Ritz, MD, Professor, Harvard Medical School, Dana-Farber
• David Scott, PhD, Principal Scientist, Director of Medicinal Chemistry Core, Dana-Farber
• Eric Smith, MD, PhD, Assistant Professor, Harvard Medical School, Dana-Farber
How to Get Involved
INTERACT
Want to learn more about how to work with the Accelerator?
Accelerator support is open to all Dana-Farber faculty engaged in translational science who are looking for mentorship and support towards pursuing a commercial opportunity. We hold biannual requests for proposals in the fall and spring, focused independently on therapeutics and diagnostics. Individuals may engage with the Accelerator team at any time; we are always eager and interested to hear how we can help enable the important work of Dana-Farber investigators.
Email: DFCI_Accelerator@dfci.harvard.edu
PARTNER
Interested in the science behind some of these projects?
Accelerator funding is one small step in part of a long pathway toward the creation of successful technologies and impact; our goal is to demonstrate the potential of the science as a solution to elicit follow-on funding for the next stage of development. Please reach out if you are interested in hearing more about the science or want to learn about other opportunities in Dana-Farber’s technology portfolio. Here we have highlighted only a small fraction of the exciting science that is part of the Accelerator and the larger technology landscape of Dana-Farber.
Email: DFCI_Accelerator@dfci.harvard.edu
DONATE
Looking to support the Accelerator with the potential to change cancer care?
Generous philanthropy created and continuous to support the DFCI Accelerator and the projects we fund. We are interested in high-risk, high-reward translational science that can change the face of cancer therapy. Please contact our team.
Email: Christiana_Iyasere@dfci.harvard.edu or Mark_Veligor@dfci.harvard.edu
NOTES
“
I have never accepted the incurability of cancer. And, I have remained hopeful, not because of wishful thinking — that's not progress — but because of the factual evidence of progress. ”
Sidney Farber, MD
Thank you to our donors for enabling our mission and making the work of the DanaFarber Accelerator program possible.