All Cancers

Current Projects
Joshua B. Sheetz, PhD

Cancer cells adapt their metabolism to achieve rapid growth and proliferation. Much of their metabolic malleability hinges on mitochondria, subcellular hubs for energy transformation and biosynthesis. As a key means to control mitochondrial composition and meet metabolic demands, cells mark mitochondrial proteins for degradation by a process called ubiquitylation. How both cancerous and healthy cells direct and monitor mitochondrial ubiquitylation remains poorly understood. Dr. Sheetz [HHMI Fellow] aims to dissect the cellular machinery that performs mitochondrial ubiquitylation and determine how this process promotes metabolic adaptability in cancer cells. A major translational goal is to identify approaches for tuning the levels of mitochondrial ubiquitylation in tumors and in metabolic disorders that put patients at risk for cancer. Dr. Sheetz received his PhD from Yale University, New Haven and his BS from the University of North Carolina, Chapel Hill. 

 

Project title: "Mitochondrial ubiquitylation mechanisms to exploit metabolic vulnerabilities in cancer"
Institution: University of California, Berkeley
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Michael Rape, PhD
Cancer Type: All Cancers
Research Area: Cell Biology
Youngmu (Nick) Shin, PhD

Cells in our body communicate with each other in a highly selective manner. These cell-cell interactions form the basis of numerous physiological functions, such as neuronal wiring and immune recognition. Dr. Shin plans to explore the general principles of cell-cell communication by constructing a synthetic synapse and studying its organization and functional diversity. His findings will elucidate the mechanisms that organize cell-cell interfaces involved in immune cell recognition of cancer and in the cell-type transitions associated with cancer and metastasis. This work will also provide a platform for engineering highly customized cell-cell interfaces, which may prove useful in engineering immune cell therapeutics.

This project employs the stickers-and-spacers model adapted from polymer physics. Macromolecules such as proteins and nucleic acids are described as a sequence of attractive domains called "stickers" and flexible, non-interacting domains called "spacers." Dr. Shin will  use his lab's Monte Carlo simulation engine LaSSI (Lattice simulation engine for Sticker and Spacer Interactions) to calculate the average interactions between macromolecules and analyze their mesoscopic organization and phase properties.

Project title: "Exploring phase condensation as a general mechanism for organizing cell-cell communication assemblies"
Institution: University of California, San Francisco / Washington University
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Wendell A. Lim, PhD (University of California, San Francisco), and Rohit V. Pappu, PhD (Washington University)
Cancer Type: All Cancers
Research Area: Cell Biology
Sukrit Singh, PhD

Kinase proteins, which regulate the activity of other proteins, are a major class of cancer therapy targets, with over 65 FDA-approved drugs targeted against them. However, tumors can evolve resistance to kinase-targeting therapies, and it remains difficult to predict whether a specific tumor will resist a particular kinase-targeting drug. Dr. Singh will use protein structural models and biophysical predictions to analyze how kinase mutations cause cancers to resist therapy. As these computationally intensive calculations could require decades on a single desktop computer, he will use a computing platform called Folding@home, which harnesses idle computer time donated by citizen scientists around the world to run the calculations. By developing new algorithms to predict whether a known mutation will resist a kinase-targeting drug, Dr. Singh hopes to advance precision oncology to allow clinicians to predict a treatment's chance of success given a patient's tumor profile. While his work primarily focuses on resistance to the drug crizotinib, used to treat non-small-cell lung carcinomas, his approaches can be extrapolated to other tumors and cancer targets. Dr. Singh received his BA and his PhD in computational and molecular biophysics from Washington University in St. Louis.

Molecular dynamics (MD) simulations are computational microscopes that model and capture atomically detailed protein motions. To analyze MD simulations, Dr. Singh will construct Markov State Models, network representations of a protein's conformational landscape, and couple them with information theoretic measures of communication between mutated residues and drug binding sites. Alchemical Free Energy calculations will predict the impact of mutation on a drug's binding energy using artificial "alchemical" intermediates to measure the energetic cost of mutating a residue.

Project title: "Physics-driven prediction of drug-resistant clinical mutations to improve precision oncology"
Institution: Memorial Sloan Kettering Cancer Center / Stony Brook University
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): John D. Chodera, PhD (Memorial Sloan Kettering Cancer Center), and Markus A. Seeliger, PhD (Stony Brook University)
Cancer Type: Blood, Kidney and Bladder, Lung, All Cancers
Research Area: Biophysics
Marie R. Siwicki, PhD

Neutrophils are important anti-microbial cells within the innate immune system. Recently, it has been shown that neutrophils can perform diverse functions, taking on both pro-inflammatory and pro-healing roles in response to tissue injury or insult. Dr. Siwicki's [Dale F. and Betty Ann Frey Fellow] goal is to understand how different neutrophil subtypes or states function to balance inflammatory versus regenerative processes, ultimately influencing tissue health and cancer. This work has the potential to uncover the basis of neutrophils' pro-tumor versus anti-tumor functions and could open the door to therapeutic targeting of specific neutrophil behaviors in order to improve clinical outcomes in cancer. Dr. Siwicki received her PhD from Harvard Medical School, Boston and ScB from Brown University, Providence.

 

Project title: "Investigating neutrophil functional heterogeneity in wound healing and cancer"
Institution: University of Calgary
Named Award: Dale F. and Betty Ann Frey Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Paul Kubes, PhD
Cancer Type: Other Cancer, Colorectal, All Cancers
Research Area: Basic Immunology
Jamie B. Spangler, PhD

Groundbreaking advances in immunotherapy have revolutionized the treatment of cancer. In particular, new antibody drugs that block immunosuppressive pathways have achieved remarkable success in reawakening the immune system to clear tumor cells, leading to lasting cures in patients whose cancers do not respond to any other therapies. Unfortunately, the majority of patients (>70%) do not respond to immunotherapy treatment. It is difficult to predict which patients will benefit, creating an urgent demand for novel immunotherapy drugs that act through alternative mechanisms. Dr. Spangler is working to develop a class of antibody therapeutics that target cancer-promoting pathways in a different way than all current immunotherapies, with the goal of drastically expanding the percentage of cancer patients who benefit from them.

Project title: "Engineered multispecific antibody-drug conjugates as novel cancer immunotherapeutics"
Institution: Johns Hopkins University
Award Program: Innovator
Cancer Type: Breast, Colorectal, Skin, All Cancers
Research Area: Immunotherapy
Georgia R. Squyres, PhD

Dr. Squyres [National Mah Jongg League Fellow] 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.

Project title: "Spatiotemporal regulation of eDNA release in Pseudomonas aeruginosa biofilms"
Institution: California Institute of Technology
Named Award: National Mah Jongg League Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Dianne K. Newman, PhD
Cancer Type: All Cancers
Research Area: Microbiology
Benjamin M. Stinson, PhD

Our DNA is constantly subjected to damage, and our cells must repair this damage to ensure survival. Breaks in DNA that completely sever DNA molecules are particularly toxic, and failure to repair these breaks can lead to genetic alterations that drive cancer initiation and progression. Dr. Stinson studies the two main cellular pathways that repair these DNA breaks: non-homologous end joining (NHEJ) and homologous recombination (HR). Defects in these pathways are linked to predisposition to many cancers, including leukemia, breast, ovarian, and prostate cancers. His prior work has demonstrated how NHEJ minimizes genetic alterations during DNA break repair. Ongoing work will elucidate fundamental mechanisms of HR that suppress cancer and seek to identify new HR factors. This work has important clinical implications for identifying patients that may benefit from treatments that target HR-defective tumors and for discovering potential mechanisms of resistance to treatment.

Project title: "Mechanism of DNA processing during non-homologous end joining"
Institution: Dana-Farber Cancer Institute
Award Program: Dale Frey Scientist
Cancer Type: All Cancers
Research Area: Biochemistry
Mark R. Sullivan, PhD

Many types of cancer, chemotherapy, and numerous other underlying conditions can leave patients vulnerable to infection by bacteria that would normally be unable to survive in the body. These opportunistic infections are challenging to treat, as antibiotics are often ineffective against these pathogens or have serious side effects not well-tolerated by individuals with underlying conditions. Dr. Sullivan studies how opportunistic infections occur, with a particular focus on lung infection. His ongoing work is centered on identifying bacterial adaptations that enable pathogens to survive both the host defense systems present in the lung as well as antibiotic treatment. His work will help deepen our understanding of opportunistic infection and may provide novel avenues for more effective and tolerable treatment of these pathogens.

Project title: “Identifying determinants of pathogenesis and drug resistance in opportunistic lung infection”
Institution: Harvard T.H. Chan School of Public Health
Award Program: Dale Frey Scientist
Cancer Type: All Cancers
Research Area: Infectious Disease
James C. Taggart, PhD

Antimicrobial resistance is a growing crisis that imperils our ability to protect patients immunocompromised by cancer treatment. Despite this, the few new antibiotics currently in clinical trials primarily use established mechanisms of action. Identification of new targets for antimicrobial drugs is thus an urgent clinical need. Recent work has shown that bacteria can tolerate substantial inhibition of many proteins thought to be essential for growth, rendering them poor drug targets. The mechanisms that cause this robustness are poorly understood. By combining cutting-edge microfluidic technologies with methods for controlled gene repression, Dr. Taggart will systematically identify mechanisms that allow bacterial cells to tolerate inhibition of genes critical for cellular growth. This work will guide the selection of targets for future antibiotic development and may reveal mechanisms by which to sensitize bacterial cells to existing drugs. Dr. Taggart received his PhD from Massachusetts Institute of Technology, Cambridge and his BS from Haverford College, Haverford.

Project title: "Mechanistic interrogation of robustness and vulnerability in a bacterial essential gene network"
Institution: Harvard Medical School
Award Program: Fellow
Sponsor(s) / Mentor(s): Allon M. Klein, PhD, and Johan Paulsson, PhD
Cancer Type: All Cancers
Research Area: Systems Biology
Jung-Shen Benny Tai, PhD

Dr. Tai 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.

Project title: "From form to function: Cell shape, cell ordering, and gene regulation in bacterial biofilm"
Institution: Yale University / Michigan State University
Award Program: Fellow
Sponsor(s) / Mentor(s): Jing Yan, PhD (Yale University), and Christopher Waters, PhD (Michigan State University)
Cancer Type: All Cancers
Research Area: Microbiology
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