Other Cancers

Current Projects
Tristan Wold Owens, PhD

Dr. Owens [Suzanne and Bob Wright Fellow] focuses on heat shock proteins (HSPs) and their “master regulator” called heat shock transcription factor 1 (HSF1). The transformation and growth of cancers causes a wide array of cellular stresses including metabolic changes, genomic instability, and protein misfolding that would halt the growth of a normal cell. Tumor cells, however, depend on cellular stress response machinery, like HSPs, for their survival. HSF1 is critical to tumor development and progression, and HSF1 activity is strongly correlated with poor prognosis in many common cancers. For decades, efforts to develop cancer therapies targeting HSPs have failed. Dr. Owens aims to understand how HSPs and HSF1 interact to regulate activity, and how this regulation is co-opted to promote tumor growth and progression.

Project title: "Molecular mechanisms of heat shock transcription factor 1 in cancer"
Institution: University of California, San Francisco
Named Award: Suzanne and Bob Wright Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): David A. Agard, PhD
Cancer Type: Other Cancer, Breast, Prostate, All Cancers
Research Area: Biochemistry
Phillip L. Palmbos, MD, PhD

Although immunotherapy results in improved survival for some patients with advanced bladder cancer, most tumors do not respond, and the molecular drivers of this resistance to immunotherapy are poorly understood. Dr. Palmbos' goal is to use advanced bladder cancer models and patient data to identify the molecular drivers of resistance to bladder cancer therapy and to develop therapeutic strategies to reverse therapy resistance. His group has identified a gene, TRIM29, which is expressed in 70% of bladder cancers and is associated with immunotherapy resistance. TRIM29 is a protein that promotes degradation of STING and other innate immune proteins that drive anti-tumor immune response. He is currently investigating the regulation of the TRIM29-STING pathway and developing strategies to sensitize bladder and other cancer types to immunotherapy.

Project title: "Targeting TRIM29 to reverse immune checkpoint inhibitor resistance in bladder cancer"
Institution: University of Michigan
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Joshi J. Alumkal, MD
Cancer Type: Kidney and Bladder
Research Area: Immunotherapy
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
Tyler Starr, PhD

Many viruses that have devastating results in humans, such as SARS-CoV-2, HIV, and influenza, originate from pathogens in non-human animal speciesThese viruses can play a direct role in enabling the progression of viral-specific cancer etiologies (e.g., HIV and AIDS-defining cancers). Additionally results from the SARS-CoV-2 pandemic illustrate the measurable delays in cancer diagnosis, treatment, and research that arise from pandemic-driven upheavals. Dr. Starr studies how and why animal viruses evolve the molecular traits that enable spillover into humans, aiding efforts in surveillance and prediction of viral zoonotic threats. Dr. Starr also studies the molecular evolutionary forces that drive the development of antibodies that can broadly inhibit viruses across families of known spillover potential, contributing to the development of antibody and vaccine candidates that can prepare for or even prevent future viral zoonoses.

Project title: "Protein evolution at the host-virus interface"
Institution: University of Utah
Award Program: Dale Frey Scientist
Cancer Type: Other Cancer
Research Area: Evolution
Srinivas R. Viswanathan, MD, PhD

Epidemiologic studies have revealed that many cancer types display differences in incidence or outcomes between the sexes. In most cases, these differences are only partially explained by non-genetic factors such as hormonal differences, carcinogen exposure, lifestyle, and access to health care. Our understanding of how genetic factors contribute to differences in cancer incidence between the sexes remains incomplete. A fundamental genetic difference between the sexes is in chromosome composition. Relative to male somatic cells, female somatic cells have an extra X chromosome. Most genes on the second copy of chromosome X in females are inactivated via a process known as X-chromosome inactivation, which approximately equalizes the dosage of X-linked genes between males and females. Dr. Viswanathan's project tests the hypothesis that genetic alterations to the X chromosome in cancer may perturb this carefully regulated process and thereby contribute to differences in cancer incidence or pathogenic mechanisms between males and females.

Project title: "X marks the spot: exploring how X-chromosome alterations drive sex differences in cancer"
Institution: Dana-Farber Cancer Institute
Award Program: Innovator
Cancer Type: Kidney and Bladder, All Cancers
Research Area: Cancer Genetics
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