Among the six recipients of the Damon Runyon-Dale F. Frey Award, Dr. Fangtao Chi of MIT is delving into the nuanced interplay between dietary nutrients and cellular metabolism as they influence intestinal regeneration and tumorigenesis. His work focuses on how the intestine’s rapid self-renewal, mediated by intestinal stem cells, is affected by metabolic signals derived from diet. While these metabolic pathways promote tissue repair after damage such as inflammation or cancer therapy, Dr. Chi’s groundbreaking investigations also reveal that the same regenerative mechanisms can be subverted to fuel abnormal cellular growth, leading to tumors. By systematically dissecting these nutrient-metabolism pathways, Dr. Chi aims to establish dietary strategies that optimize tissue repair while mitigating colorectal and other intestinal cancers.

Dr. Cayla E. Jewett at the University of Colorado, Denver Anschutz Medical Campus is tackling an intriguing paradox presented by multiciliated cells. These specialized cells generate an abundance of centrioles—cellular organelles ordinarily tightly regulated to prevent cancerous transformation. Surprisingly, multiciliated cells manage to safely increase centriole numbers and use the DNA damage response pathway normally associated with oncogenic stress as part of their development. Dr. Jewett’s research seeks to decode how such cells reconcile these contradictory features, hoping to uncover novel molecular checkpoints that prevent tumorigenesis. Insights from this research may identify new therapeutic targets that inhibit abnormal centriole amplification in cancer cells while sparing normal tissue.

At Princeton University, Dr. Titas Sengupta investigates how epigenetic modifications of histones—proteins around which DNA is wrapped—influence gene regulation in neurons, especially regarding aging and environmental responses. Her work has unveiled mechanisms by which rapid histone modifications modulate neuronal functions such as short-term memory, highlighting that dynamic gene expression changes rather than static protein reserves underlie these cognitive processes. This line of inquiry is highly relevant to understanding the epigenetic dysregulation often observed in cancers affecting nervous tissues, providing a potential framework for uncovering how altered chromatin landscapes contribute to cancer progression and neurological dysfunction.

Dr. Dylan M. Parker of the University of Colorado, Boulder studies stress granules—membraneless molecular condensates that form within cells under stress conditions, impacting gene expression and cell survival. Stress granules are garnering attention for their roles in cancer, particularly in how their dynamics could promote tumor progression and resistance to chemotherapy. Dr. Parker aims to elucidate the molecular controls governing stress granule assembly and disassembly, advancing our understanding of how cancer cells adapt to treatment. Such knowledge might open avenues for developing drugs that disrupt granule formation, thereby sensitizing resistant tumors to existing therapies.

At the University of Pennsylvania, Dr. Catherine Triandafillou explores error correction mechanisms during early development using gastruloids, three-dimensional stem cell clusters that mimic embryonic patterning. Her microscopy-enabled lineage-tracing studies assess how deviations in cellular behavior impact developmental outcomes and the capacity of tissues to correct aberrations. Understanding how these processes fail in cancer could illuminate why tumors contain abnormal cellular compositions and proliferate unchecked. Dr. Triandafillou’s work aims to uncover cellular and tissue-level responses to early developmental errors, potentially revealing new approaches to target cancer’s root defects.

Dr. Youngmu (Nick) Shin from UCSF is pioneering the engineering of scaffold proteins to reconstruct and probe cell-cell communication interfaces known as synapses. By building synthetic synapses through designed protein condensates, he strives to elucidate the physical principles governing synaptic organization and strength. Insights from this synthetic biology approach have profound implications for immunotherapy, including engineering immune cells like T cells to form precise, robust connections with cancer cells, enhancing their ability to target malignancies while minimizing damage to healthy tissues.

The November 2025 cohort of Damon Runyon Fellows also exemplifies the breadth and depth of current cancer research. Dr. Duaa H. Al-Rawi at Memorial Sloan Kettering focuses on the earliest genetic disruptions in high-grade serous ovarian cancer, particularly alterations in the p53 tumor suppressor pathway and chromosomal instability in fallopian tube cells. By modeling these initial events, her research aims to inform early detection and prevention strategies for this deadly cancer subtype.

Dr. Tatsat Banerjee from the Whitehead Institute investigates the fundamental signaling architecture within CAR T cells—immune cells genetically reprogrammed for cancer therapy—seeking to enhance their ability to recognize and persist against solid tumors like melanoma. His innovative melding of molecular genetics and biophysics targets improvements in the immunological synapse’s function, essential for T cell-mediated tumor eradication.

Leukemia translation regulation is the focus for Dr. Elizabeth Black, also at the Whitehead Institute. Her research zeroes in on translation start site selection, a nuanced control point of protein synthesis that is dysregulated in blood cancers but overlooked due to experimental challenges. Understanding how cancer cells manipulate translation initiation could herald novel therapeutic interventions.

At UCSF, Dr. Sarah W. Cai investigates how TRP ion channel receptors, key mediators of pain, form nanoscale clusters in sensory neurons during cancer-associated pain and chemotherapy-induced neuropathy. Her work employs advanced microscopy to parse receptor organization changes that amplify pain signaling, with prospects for designing better pain management approaches for cancer patients.

The interplay between diet-derived xenobiotics and inflammation in cancer progression forms the basis of Dr. Esther J. Han’s work at Yale University. She studies how gut microbes and host cells chemically modify these plant-derived molecules, influencing cancer risk and inflammation, potentially guiding nutritional interventions to prevent or mitigate disease.

Dr. Qixiang He at Columbia University explores a novel bacterial antiviral defense that synthesizes DNA rather than cleaving it. By deciphering this system’s mechanisms, his research aims to develop innovative gene therapy delivery methods that circumvent immune reactions, potentially enhancing gene- and immunotherapies in cancer treatment.

Dr. King L. Hung at The Scripps Research Institute employs the regenerating flatworm as a model to study how chemical and mechanical signals integrate to maintain tissue integrity, a property lost in cancer. His live imaging approaches seek to untangle the multicellular circuitry that prevents unchecked proliferation and invasion.

Protein complexes essential for lung cancer progression are the subject of Dr. Jinho D. Jeong’s research at Massachusetts General Hospital. Using Molecular COUPLrs, a novel chemical biology technology, he aims to selectively disrupt complexes driving non-small cell lung cancers and brain metastases, potentially revealing new drug targets for these lethal diseases.

At the Broad Institute, Dr. Wenbin Mei studies the influence of inherited genetics on the development and aggressiveness of ERBB2-driven cancers, such as breast and lung cancers. His work aims to integrate germline and tumor genomic data to personalize risk prediction and therapy.

Dr. Rishi Kumar Mishra at the University of Michigan focuses on how the motor protein dynein localizes at microtubule plus-ends during cell migration, a process critical for cancer metastasis. Understanding this mechanism may identify vulnerabilities to inhibit cancer spread.

Dr. Christian G. Peace from Princeton University has developed novel in vivo technology for tracking nutrient utilization by cancer and immune cells within the tumor microenvironment. His work sheds light on the metabolic competition in tumors influencing immunotherapy efficacy.

Dr. Juntao Yu at Whitehead Institute investigates chromatin-based mechanisms guiding asymmetric cell division in stem cells, fundamental for tissue homeostasis and cancer prevention. Dissecting chromosome inheritance patterns may reveal how cancer cells bypass these controls.

Finally, Dr. Ming M. Zheng at the Broad Institute integrates large-scale genetics, single-molecule imaging, and AI to create dynamic maps of oncogene behavior in living cells, aiming to guide the creation of precise and long-lasting cancer therapies with minimal side effects.

Together, these fellows and awardees represent a vanguard of cancer research, tackling fundamental questions with cutting-edge tools across genetics, cell biology, immunology, and bioengineering. Their combined efforts underscore the Damon Runyon Cancer Research Foundation’s commitment to nurturing innovative science that holds promise for transformative advances in cancer prevention, diagnosis, and treatment worldwide.

Subject of Research: Cancer research focusing on fundamental mechanisms of tumorigenesis, metastasis, immunotherapy, epigenetics, and cellular communication.

Article Title: Damon Runyon Foundation Announces 2026 Fellows and Breakthrough Scientists Driving Cancer Research Innovation

News Publication Date: 2025-11

Web References: http://damonrunyon.org/

Keywords: Cancer research, postdoctoral fellows, tumorigenesis, immunotherapy, epigenetics, cellular metabolism, stem cells, DNA damage, translation regulation, tumor microenvironment, cancer genetics, synthetic biology

Historically, the molecular landscape of cancer has posed enormous challenges, particularly in AML. This aggressive blood cancer exhibits a complex network of pathways essential not only to malignant cells but also to normal hematopoietic stem cells, thus creating a precarious therapeutic balance. Conventional drugs, albeit somewhat effective, often falter due to their inability to distinguish thoroughly between malignant and normal cells, resulting in substantial toxicity and poor patient tolerance. This scientific impasse has sustained an urgent demand for selective molecular targets—biomarkers that are expressed predominantly or exclusively on cancerous cells.

The Flynn group’s discovery capitalizes on an unusual feature: the ectopic localization of the RNA-binding protein NPM1 to the exterior of AML cells. While NPM1 traditionally functions within the nucleolus as a chaperone for ribosomal biogenesis and genomic stability, its aberrant expression on the cell surface of cancer cells marks a profound departure from its canonical role. Detailed investigations revealed that cell-surface NPM1 is dramatically upregulated in leukemic cells, with expression levels exceeding those found on healthy blood stem cells by over 100-fold. This significant differential creates a therapeutically exploitable target that, until now, remained concealed within the interior of the cell.

The team elucidated the mechanistic underpinnings of this phenomenon in the context of glycoRNAs—an emerging class of glycoconjugated RNA molecules residing on the cell exterior, which form organized clusters with RNA-binding proteins including NPM1. Prior foundational work has characterized these glycoRNA-protein complexes as novel signaling platforms modulating cellular communication with the microenvironment. This groundbreaking concept redefines the understanding of cell-surface biology, highlighting an uncharted molecular landscape ripe for targeted intervention.

Leveraging this insight, Flynn and colleagues engineered monoclonal antibodies specifically directed against NPM1 presented on the surface of AML cells. These antibodies demonstrated potent anti-leukemic efficacy across multiple preclinical in vivo models, selectively eliminating malignant cells while sparing normal hematopoietic populations. Such specificity is crucial as it addresses one of the most stubborn obstacles in AML treatment—the preservation of healthy bone marrow function during therapy. Notably, the antibodies also effectively targeted leukemic stem cells, the elusive subpopulation responsible for disease initiation, persistence, and relapse.

The impact of targeting leukemic stem cells cannot be overstated. These cells exhibit remarkable resistance to conventional chemotherapies and are often responsible for the clinical recurrence of AML. By attacking these cells head-on through a uniquely surfaced antigen like NPM1, the therapeutic paradigm shifts from merely controlling disease to potentially achieving durable remission or cure. In murine models, this strategy extended survival and markedly reduced disease burden, with no observed off-target toxicity, emphasizing the treatment’s clinical promise.

Beyond leukemia, the research explored the broader oncological relevance of cell-surface NPM1. Screening an extensive panel of 47 human and murine solid tumor models unveiled variable but significant expression of cell-surface NPM1 across many tumor types, including prostate and colorectal carcinomas. These findings suggest a wider applicability of NPM1-targeting antibodies, potentially expanding immunotherapy’s arsenal against notoriously treatment-resistant solid tumors.

The identification of NPM1 as a cell-surface antigen in solid tumors is particularly compelling given the historical difficulty of finding cancer-selective surface markers for these malignancies. Cancers like colorectal carcinoma have long evaded effective immune targeting due to the scarcity of unique markers distinguishable from normal tissue. The cell-surface presentation of NPM1 thus represents a potential ‘molecular handle’ for immune system engagement, a prospect that could reinvigorate therapeutic strategies for multiple cancers.

Crucially, the research underscores the newly appreciated biology of glycoRNAs and RNA-binding proteins as a rich source of tumor-associated antigens. The clustering of these molecules on the cell surface appears not to be a random occurrence but an orchestrated phenomenon potentially advantageous to tumor survival and immune evasion. The team’s future investigations aim to decode the biological imperatives underpinning the externalization of NPM1 and to identify additional molecular candidates within these clusters that could serve as targets or biomarkers.

The discovery that malignant cells co-opt an RNA-binding protein, traditionally intracellular, and mobilize it to the cell membrane hints at a novel tumor strategy that may confer advantages such as altered signaling, adhesion, or immune modulation. Understanding these dynamics will be critical to refining antibody-based therapeutics and possibly integrating them with other modalities, including cellular therapies and immune checkpoint inhibitors.

To translate these foundational findings into clinical impact, Boston Children’s Hospital has already pursued intellectual property protections domestically and internationally. This strategic move paves the way for the development of antibody therapies targeting NPM1, with the potential to enter early-phase clinical trials and ultimately offer new hope to patients with aggressive hematologic and solid malignancies.

The collaboration among interdisciplinary teams spanning molecular biology, oncology, immunotherapy, and structural biochemistry highlights the power of cross-sector partnerships in unearthing novel therapeutic targets. The convergence of expertise in glycoRNA biology, stem cell research, and antibody engineering illustrates a modern scientific approach to solving intractable problems in medicine.

In summary, Dr. Ryan Flynn’s team has illuminated a captivating facet of cancer biology—the aberrant cell-surface expression of an RNA-binding protein—and harnessed it into an actionable therapeutic target. By shifting the paradigm toward precision targeting of cancer stem cells with minimal collateral damage, their work charts a course for next-generation cancer therapies. As future studies delve deeper into the mechanisms and clinical translation, this discovery holds transformative potential for millions battling AML and other formidable cancers, marking a true milestone in the quest for safer, more effective treatments.

Subject of Research: Treatment of acute myeloid leukemia and solid tumors through targeting cell-surface RNA-binding proteins, specifically NPM1.

Article Title: Treatment of acute myeloid leukemia models by targeting a cell-surface RNA-binding protein

News Publication Date: 23-Apr-2025

Web References:
DOI: 10.1038/s41587-025-02648-2
Flynn Lab at Boston Children’s Hospital
Cambridge Stem Cell Institute

Keywords:
Cancer stem cells, RNA binding proteins, Myeloid leukemia, Gene targeting, Molecular targets, Stem cell therapy, Antibody therapy, Monoclonal antibodies, Cell surface receptors