Damon Runyon has announced its newest class of Fellows, seventeen remarkable postdoctoral scientists who will receive independent funding ($231,000 each) to support their training as they embark upon their research careers in the labs of leading senior investigators. The prestigious, four-year Fellowship Award encourages creative and high-risk projects dedicated to the search for cancer causes, mechanisms, therapies, and prevention.

“We are thrilled to be funding these innovative, young scientists with the brilliance and passion to push boundaries and make breakthroughs. They are committed to understanding the fundamental processes driving cancer, which may ultimately lead to new therapeutic approaches for patients. Damon Runyon Fellows are the future leaders of their respective fields,” said Yung S. Lie, PhD, President and CEO of the Damon Runyon Cancer Research Foundation.

Spring 2021 Damon Runyon Fellows:

Alain R. Bonny, PhD, with his sponsor Elaine V. Fuchs, PhD, at The Rockefeller University, New York, is studying the signal pathways and molecular cues that coordinate the transition from inflammation to tissue repair in response to acute skin injury. During wounding, cells collectively activate stress response programs to promote repair and survival. Dr. Bonny is adapting and developing novel tools to map how cells leverage signaling to enable precise coordination between several different cell types in the same area. Previous work has shown a striking similarity between these stress response programs and squamous cell carcinoma tumorigenesis, suggesting this skin cancer utilizes similar pathways. Understanding how healthy tissue implements this transition may shed light on how squamous cell carcinoma and other cancers hijack and ultimately exploit these signaling mechanisms.

Marco A. Catipovic, PhD [HHMI Fellow], with his sponsor Rachel Green, PhD, at Johns Hopkins University School of Medicine, Baltimore, focuses on the mechanisms governing the resolution of errors that arise during RNA translation in mammals. Ribosomes translating the same message can collide if they are damaged or encounter blockages. If not resolved quickly, these collisions activate cellular signaling pathways implicated in a number of cancers. Dr. Catipovic uses reconstituted translation systems, consisting of purified translation factors in vitro (or “in a test tube”), as a tool to study quality control pathways for ribosomes engaged in collisions. These pathways identify and recycle any damaged ribosomal components before the cell can mount more severe, oncogenic responses.

Ching-Ho Chang, PhD, with his sponsor Harmit S. Malik, PhD, at Fred Hutchinson Cancer Research Center, Seattle, is studying protamines—short, positively-charged proteins that condense DNA into chromatin and regulate gene expression in sperm nuclei. While eukaryotic cells use histones to package genomes in a way that allows access for transcription and replication, sperm cells must package their genomes more tightly. For this, many animals deploy protamines instead of histones. Despite sharing certain functions with highly conserved histones, protamines have independently arisen in evolution multiple times and are continuing to rapidly evolution. Using Drosophila fruit fly species as a model, Dr. Chang studies how sperm chromatin regulates gene expression and reproductive fitness. Additionally, although protamine expression is typically limited to testes, their misexpression has been observed in many cancers, indicating an opportunity for therapeutic intervention.

Madi Y. Cissé, PhD [Merck Fellow], with his sponsor Brendan D. Manning, PhD, at Harvard T. H. Chan School of Public Health, Boston, aims to define the functional importance of nutrient sensing within the tumor microenvironment. How cells sense and adapt to the availability of nutrients in their environment is incompletely understood, but one key pathway is the signaling system anchored by the mTORC1 kinase. The mTORC1 kinase regulates cell growth and metabolism in response to nutrients such as amino acids and glucose. Aberrant mTORC1 signaling is implicated in several cancers, including melanoma, known to be heavily influenced by factors in the microenvironment such as nutrient availability. Dr. Cissé aims to understand how tumor metabolism senses and responds to varying nutrient levels, which will be essential for developing novel therapeutic targets.

Edie I. Crosse, PhD [Illini 4000 Fellow], with her sponsors Lev Silberstein, MD, PhD, and Irwin D. Bernstein, MD, at Fred Hutchinson Cancer Research Center, Seattle, focuses on myelodysplastic syndromes (MDS), blood cancers that occur predominantly in the elderly. These cancers are initiated in the bone marrow when blood stem cells acquire a genetic mutation that causes them to divide and multiply uncontrollably. Through proliferation and acquisition of further mutations, the disease can evolve into acute myeloid leukemia, for which prognosis and survival rate are typically poor. Dr. Crosse aims to identify the specific blood stem cells that are most impacted by the mutation in the early stages of MDS and determine how they contribute to disease progression. The goal is to design therapies that inhibit these mechanisms and halt MDS cancer progression.

Elizabeth J. Culp, PhD [The Mark Foundation for Cancer Research Fellow], with her sponsor Andrew L. Goodman, PhD, at Yale University, New Haven, is exploring how the chemical components of food interact with the gut microbiome and how these interactions impact cancer risk. While diet is an important factor in cancer prevention, it is unclear how specific food components affect cancer risk in an individual. A key piece of information not currently understood is how dietary compounds are metabolized by the gut microbiome, and how these transformations alter the biological activity of the compound on the host. Dr. Culp is mapping the transformation of dietary compounds by bacterial members of the gut microbiome, deciphering the associated mechanisms, and testing their cancer-associated effects in mouse models. Together, these studies will provide a basis to inform intervention strategies addressing the link between the microbiome, diet, and cancer risk.

Karole N. D'Orazio, PhD [HHMI Fellow], with her sponsor Danesh Moazed, PhD, at Harvard Medical School, Boston, studies how epigenetically silenced regions of condensed DNA known as heterochromatin are maintained upon cell differentiation. In eukaryotes, heterochromatin is hallmarked by specific epigenetic modifications, e.g., the addition of methyl groups at specific sites. Two major protein complexes, Polycomb Repressive Complex 1 and 2, are essential for creating and maintaining these modification sites during development. Although RNA has been found to interact with and modulate (both positively and negatively) the activities of these two complexes, the need for RNA decay at the modification sites remains unclear. Dr. D’Orazio aims to understand how RNA turnover regulates heterochromatin and what factors are involved in these processes. These studies will provide insight into heterochromatin alteration in diseases such as cancer.

Catherine A. Freije, PhD [Berger Foundation Fellow], with her sponsor Charles M. Rice, PhD, at The Rockefeller University, New York, is studying how the genetic diversity of hepatitis B virus (HBV) is shaped by its need to replicate and interact with specific host genes. Current antiviral therapeutics for HBV merely suppress infection and do not cure disease; as a result, patients with chronic HBV infection are at risk of developing liver cancer. Dr. Freije plans to uncover essential genomic regions that HBV needs to survive and persist, as well as those that counteract host genes that function to restrict these activities. This approach could provide insight into the progression of disease and has the potential to identify new antiviral therapeutics and ultimately reduce the incidence of HBV-associated liver cancer.

Hannah A. Grunwald, PhD [Lallage Feazel Wall Fellow], with her sponsor Clifford J. Tabin, PhD, at Harvard Medical School, Boston, focuses on the disconnect between genotype and phenotype. Despite our wealth of knowledge about the human genome, we are often unable to accurately predict which individuals will suffer from genetic diseases, including cancers. It has been proposed that cells have mechanisms capable of buffering genetic variation, such that the phenotypic outcome of these genetic variants is sometimes obscured. When buffering systems, or “capacitors,” are de-stabilized or overwhelmed by genetic or environmental factors, “cryptic” genetic variants are exposed. Understanding the mechanism by which organisms buffer accumulated cryptic variants may illuminate the evolution of complex traits while providing vital insight into the heritability of genetic disease.

Bo Gu, PhD [Fraternal Order of Eagles Fellow], with his sponsor Michael B. Elowitz, PhD, at California Institute of Technology, Pasadena, is deciphering the combinatorial code of mammalian transcription regulation. The precise and robust regulation of gene expression is typically achieved through a combination of multiple transcription factors. However, we lack understanding of how a mammalian transcription system perceives, processes, and presents combinations of transcription factors. Dr. Gu will combine quantitative modeling and synthetic approaches to analyze the complex interactions among natural transcription regulatory proteins and apply the principles learned to engineer a programmable transcriptional platform with tunable logic. This work promises to deepen our understanding of mammalian transcription regulation and unlock new capabilities for emerging cell-based therapeutics.

Benjamin G. H. Guthrie, PhD [Connie and Bob Lurie Fellow], with his sponsor Peter J. Turnbaugh, PhD, at University of California, San Francisco, seeks to understand how the microbiome—the collection of bacteria, fungi, viruses, and other organisms that inhabit the body—affects patients’ response to chemotherapeutics. His research focuses on fluoropyrimidines, small molecules that are used to treat colorectal, head and neck, and breast cancers, but are not well tolerated by all patients. While it is known why some patients in that subset display adverse effects, the reason for poor tolerance in others is unclear. Dr. Guthrie will use molecular, ecological, and organismal approaches to understand how our microbiome might inadvertently degrade or prematurely activate fluoropyrimidines.

Jean-Benoît Lalanne, PhD, with his sponsor Jay A. Shendure, MD, PhD, at University of Washington, Seattle, investigates the biophysical determinants of gene expression. Dysregulation of the expression of select oncogenes and tumor suppressors in specific tissues is sufficient to initiate tumorigenesis. Such dysregulation can arise from small-scale genetic changes that alter the binding sites of transcription factors in otherwise inactive enhancers (the short, non-coding regions of DNA to which transcription factors bind, activating gene expression). Despite substantial efforts in functional genomics, the quantitative connection between DNA sequence and expression remains largely elusive. Using a combination of single-cell transcriptomics and reporter assays, Dr. Lalanne plans to decipher the underlying sequence determinants of cell type-specific gene regulation. His goal is to formulate predictive models of which mutations in the non-coding genome can perturb the gene expression program and ultimately lead to cancer development.

Georgia R. Squyres, PhD, with her sponsor Dianne K. Newman, PhD, at California Institute of Technology, Pasadena, is using quantitative microscopy and cell biology approaches to study how bacteria in biofilms coordinate their behavior in space and time. Biofilms are dense, multicellular communities of bacteria embedded in an extracellular matrix. Biofilms often form during bacterial infections, resulting in infections that are difficult to treat and resist antibiotics; cancer patients are at particular risk for these types of infections. Dr. Squyres is currently investigating how the release of extracellular DNA, a key component of the biofilm matrix, is coordinated during biofilm development. Greater understanding of how bacteria function in biofilms can lead to new approaches to target these treatment-resistant infections.

Jung-Shen Tai, PhD, with his sponsors Jing Yan, PhD, and Christopher Waters, PhD, at Yale University, New Haven, and Michigan State University, East Lansing, studies bacterial biofilms or aggregates of bacterial cells in an extracellular matrix. Biofilms play a critical role in many health and industry settings. Biofilm-forming bacteria and imbalance in patients’ gut microbiota have been found to correlate with cancer development, and cancer patients receiving therapy frequently suffer from bacterial infections. From the unique perspectives of microbiology, soft matter physics, and ecology, Dr. Tai aims to decipher how, at the single bacteria cell level, heterogeneities in cell shape, organization, and gene expression constitute the function and development of their collective communities: biofilms. His work is expected to deepen our understanding of bacterial biofilms and ultimately contribute to therapeutic strategies.

Akanksha Thawani, PhD [Merck Fellow], with her sponsors Eva Nogales, PhD, and Kathleen Collins, PhD, at University of California, Berkeley, studies selfish DNA sequences—so called because they copy and paste themselves within the human genome despite offering no specific fitness advantage. Dr. Thawani will utilize advanced methods such as cryo-electron microscopy to reveal the cellular machinery that assists these selfish elements and thus delineate their mechanism of mobility. She will use this insight to engineer new genome editing technologies to precisely insert large genes at user-specified sites in a variety of human cell types. This general technology will not only translate directly into new gene therapies, but also result in wide-ranging applications in synthetic biology. Ultimately, this work will contribute to treatment for many cancer types, including improved CAR-T therapies for blood cancers.

David M. Walter, PhD, with his sponsor Matthew L. Meyerson, MD, PhD, at Dana-Farber Cancer Institute, Boston, focuses on splicing factor genes, which carry out the RNA splicing process and are widely mutated in lung cancer. The splicing factor U2AF1 is mutated in 2% of lung cancer patients, but 80% of these mutations are identical, making it one of the most common missense mutations in lung cancer. Scientists do not have a good understanding of why this mutation occurs, or how it promotes cancer development. Dr. Walter will use a combination of cell and mouse model systems along with patient data to identify the unique molecular and genetic features of U2AF1-mutant cancer cells with the goal of identifying new therapeutic targets for lung cancer patients.

Qinheng Zheng, PhD [Connie and Bob Lurie Fellow], with his sponsor Kevan M. Shokat, PhD, at University of California, San Francisco, is developing small molecules that selectively inhibit the protein K-Ras(G12D). Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer due to the infrequency of early diagnosis and the lack of targeted or immune therapies. A high percentage (>90%) of PDAC patients harbor KRAS mutations, with the majority expressing the K-Ras(G12D) missense mutation. Despite extensive drug discovery efforts across academia and industry, there are no approved drugs directly targeting oncogenic K-Ras(G12D). K-Ras lacks an apparent surface topology for reversible small molecule binding, leading to its notorious characterization as “undruggable.” Dr. Zheng is searching for small molecules that form a permanent bond with the mutant protein at its missense site and inhibit its interaction with effector proteins.