Dr. Lin [Walter Isaacson Fellow] is studying how hepatitis C virus (HCV) rewires cell biology and causes liver cancer. Modern HCV antiviral therapies are effective in curing hepatitis, but puzzlingly, recovered patients sometimes still develop cancer. This suggests that infection and subsequent inflammation permanently alter liver cells, but how this leads to cancer remains unclear. Dr. Lin is developing a CRISPR-based molecular "recorder" to determine whether cells that become more cancer-like have a history of infection and inflammation. This technology could identify genes that predispose healthy liver cells to infection, chronic immune stimulation, and transformation to cancer cells, which could point to potential therapeutic targets to interrupt the development of liver and other cancers.

While immunotherapies such as anti-PD-1 therapy have provided an important treatment option for bladder cancer, the majority of patients do not respond to these regimens. This may reflect the distinct activation requirements of other immune T-cells besides CD8+ T-cells. In recent work, Dr. Oh and colleagues have identified cytotoxic (cancer cell-killing) CD4+ T-cells in human bladder cancer that are associated with immunotherapy responses. However, the regulation of cytotoxic CD4+ T-cells and how these mechanisms compare with CD8+ T-cells is not understood. Dr. Oh proposes to identify and validate surface receptors that enhance or inhibit the activity of cytotoxic CD4+ T cells in human bladder cancer, and the tumor antigens that are recognized specifically by these cells. He will also compare which of these regulatory mechanisms are unique to cytotoxic CD4+ T-cells relative to their CD8+ T-cell counterparts from the same patients. This work has the potential to increase both the proportion of bladder cancer patients who respond to immunotherapy as well as the quality of their response.

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.

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.

The exploration of human tumors in their native environment is challenging, precluding a deeper understanding of how cancer and important therapeutics work.  Dr. Puleston is developing new ways to investigate human cancer by keeping tumor-bearing organs alive outside of the body, allowing for the experimental study of tumors within human tissues. Employing this approach to study hepatocellular carcinoma (HCC), one of the most lethal forms of liver cancer, Dr. Puleston will expose HCC-laden livers to immunotherapy drugs and metabolic tracers to reveal the metabolic landscape of HCC cancers and how tumor metabolism is shaped following drug treatment. Through the study of tumors and anti-cancer agents in situ, Dr. Puleston hopes to elucidate new pathways with therapeutic potential and novel strategies to optimize existing therapeutics.

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.

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.

Many viruses that have devastating results in humans, such as SARS-CoV-2, HIV, and influenza, originate from pathogens in non-human animal species. These 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.

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.

Dr. Zhang [Timmerman Traverse Fellow] aims to engineer T cells with synthetic cell adhesion molecules (synCAMs) to augment current approaches for immunotherapy. This project represents a fundamentally new strategy for CAR T cell engineering that could overcome tumor escape from immunotherapy across multiple forms of cancer. Understanding how synCAMs contribute to CAR T cell efficacy will provide insights beyond cytotoxic CAR T cell therapy; this work could lead to the application of synCAMs in other engineered immune cell therapies under investigation, such as CAR macrophages, CAR natural killer cells, and CAR T regulatory cells. Overall, this approach could lead to CAR T cells that are much more robust to tumor evasion and target antigen expression, and thus much more effective therapeutically. Dr. Zhang received his PhD from University of Chinese Academy of Sciences, Shanghai and his BS from Wuhan University, Wuhan.