Colleagues: Recently Tenured

Meet your recently tenured colleagues: Clint T. Allen (NIDCD), John Brognard (NCI-CCR), Jonathan Hofmann (NCI-DCEG), Yuichi Machida (NCI-CCR), and Quan Yuan (NINDS).

CLINT T. ALLEN, M.D., NIDCD

Senior Investigator and Chief, Section on Translational Tumor Immunology, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders

Education: Texas A&M University, College Station, Texas (B.S. in biochemistry); Clinical Research Training Program (CRTP), Head and Neck Surgery Branch, NIDCD (fellowship); Texas A&M University Health Science Center College of Medicine, Bryan, Texas (M.D.)

Training: Surgical internship and resident in Otolaryngology–Head and Neck Surgery, Washington University in St. Louis (St. Louis, Missouri); surgical fellow in laryngology, University of Washington (Seattle)

Came to NIH: In 2006 for CRTP fellowship in NIDCD; returned to NIDCD 2013 as an investigator

Outside interests: Running; woodworking; traveling

Website: https://www.nidcd.nih.gov/about/staff/clint-t-allen-md

Research interests: I am interested in the immunologic aspects of neoplastic development and progression, with a focus on head and neck epithelial neoplasms. My lab is studying different combinations of immunotherapy for human papillomavirus (HPV)–positive or –negative head and neck cancer. We explore mechanisms of resistance to immunotherapy mediated by genetic and microenvironment factors and translate these finding into novel phase 1 and phase 2 studies that are performed at the NIH Clinical Center. My being a surgeon–scientist facilitates my access to clinical specimens for study in the laboratory and rapid translation of new findings into the clinic in collaboration with several intramural medical oncology groups.

In our study of head and neck cancer, we are trying to understand 1) how tumor heterogeneity can be overcome with combination immunotherapy approaches using both T cells and natural killer cells to maximize response and clinical benefit (J Immunother Cancer 9:e002128, 2021); and 2) how the immunosuppressive tumor microenvironment can be overcome to unleash the potential benefit of existing or new immunotherapies. Ultimately, our findings could lead to better ways of safely combining immunotherapies based on rational, mechanism-driven approaches.

Several of our studies focus on neoadjuvant administration of immunotherapy with the goal of improving recurrence-free survival in patients with newly diagnosed, advanced-stage head and neck cancer.

Our program also translates many important findings learned in our study of cancer to the examination of a rare disorder called recurrent respiratory papillomatosis (a disease characterized by recurrent wartlike growths on or around the vocal cords). We are one of the few programs worldwide to study this devastating disease and have completed several clinical trials investigating both repurposed and novel, first-in-human immunotherapies. Our current work involves the study of a therapeutic vaccine designed to activate T-cell immunity against existing HPV infection (NPJ Vaccines 6:article 86, 2021). Promising early clinical results have been observed.

JOHN BROGNARD, PH.D., NCI-CCR

Senior Investigator, Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute

Education: James Madison University, Harrisonburg, Virginia (B.Sc. in chemistry); Johns Hopkins University, Baltimore (M.Sc. in biotechnology); University of California at San Diego, San Diego, California (Ph.D. in biomedical sciences)

Training: Postdoctoral fellow, Salk Institute for Biological Studies (San Diego)

Before coming to NIH: Group leader, Cancer Research UK Manchester Institute, University of Manchester (Didsbury, England)

Came to NIH: First as a summer intern with an NCI basic-research program (1993–1995), then as a research technician at the NCI-affiliated SAIC-Frederick, and later as a research associate in NCI (1999–2002); returned in 2016 as a tenure-track Stadtman Investigator

Outside interests: Spending time outdoors with his sons playing soccer and tennis; hiking; fishing; skiing

Website: https://irp.nih.gov/pi/john-brognard

Research interests: I investigate genetic and molecular pathways that contribute to the development of cancers. The major focus of my lab is elucidating cancer-associated kinases in the unexplored human kinome (complete set of protein kinases encoded in the genome). Of the 538 kinases in the human kinome, approximately 300 have not been explored in depth, but we know—from cancer genomic-sequencing studies—that they are implicated in cancer. We hope to identify novel kinase drivers and develop new drugs targeting these kinases so that we can expand the number of cancer patients who can benefit from precision-medicine-based therapies. Collectively, our research should identify new genetic drivers, targets for therapeutic intervention, and novel mechanisms of tumorigenesis.

We use bioinformatics and functional genomic approaches to initially identify novel cancer-associated kinases. We then proceed to decipher the molecular mechanisms by which these kinases promote tumorigenesis. We then develop compounds (small molecule catalytic inhibitors or proteolysis-targeting chimeras) to target our most promising kinase drivers. We use in vivo patient-derived xenograft mouse models to assess the efficacy of these new drugs, with the overall goal of bringing new therapies to the clinic for cancer patients.

Specifically, we are defining novel kinase drivers in squamous cell carcinomas and exploring the mechanisms by which these kinases promote cancer. For example, we identified the protein kinase TNIK as a promising therapeutic target in lung squamous-cell carcinoma, the second most prevalent type of lung cancer, and defined a novel mechanism in which TNIK regulates the Merlin protein to promote lung tumorigenesis (Cancer Discov 11:411–1423, 2021).

JONATHAN HOFMANN, P.H.D., M.P.H., NCI-DCEG

Senior Investigator, Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute

Education: Carleton College, Northfield, Minnesota (B.A. in English); School of Public Health, University of Washington, Seattle (M.P.H. in environmental and occupational health; Ph.D. in epidemiology)

Training: Postdoctoral fellow (2009–2011), then research fellow (2011–2015), Occupational and Environmental Epidemiology Branch, NCI-DCEG

Came to NIH: In 2009 for training; became an investigator in 2015 in Occupational and Environmental Epidemiology Branch, NCI-DCEG

Outside interests: Running; gardening; spending time outdoors with his family and their dog Evie

Website: https://dceg.cancer.gov/about/staff-directory/hofmann-jonathan

Research interests: The goal of my research program is to advance our understanding of the role of agricultural exposures, per- and polyfluoroalkyl substances (PFAS), and other risk factors in the development of various cancers. In particular, I focus on multiple myeloma and renal cell carcinoma (RCC), the most common form of kidney cancer. I am also using molecular epidemiologic approaches to investigate the biological mechanisms that influence the development of multiple myeloma and progression from its precursor, monoclonal gammopathy of undetermined significance (MGUS).

Pesticides, endotoxins, and other agricultural exposures have been associated with risk of various cancers, although the biological mechanisms underlying these associations are not well understood. I am the principal investigator of the Biomarkers of Exposure and Effect in Agriculture (BEEA) study within the Agricultural Health Study. Field work for the BEEA study ended in 2018; we collected biospecimens (including blood, urine, buccal cells, and house dust) and updated information about pesticide use and other agricultural exposures of more than 1,600 farmers in Iowa and North Carolina. In a recent investigation in BEEA, we confirmed an excess of the myeloma precursor MGUS in farmers and identified novel associations with several pesticides, including permethrin, a widely used pyrethroid insecticide previously linked to an increased risk of multiple myeloma (Environ Health Perspect 129:17003, 2021).

I am also investigating the risk of RCC and other cancers in relation to exposure to PFAS, a diverse class of synthetic chemicals that are highly persistent in the environment. In a recent investigation in a cohort with PFAS exposures comparable to that of the general population, we found that elevated levels of perfluorooctanoic acid, a commonly detected and widely studied PFAS, were associated with an increased risk of RCC (J Natl Cancer Inst 113:580–587, 2021).

YUICHI MACHIDA, PH.D., NCI-CCR

Senior Investigator, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute

Education: Nagoya University, Nagoya, Japan (B.S., M.S., and Ph.D. in biotechnology)

Training: Postdoctoral fellowship, Brigham and Women's Hospital, Harvard Medical School (Boston); research associate, University of Virginia (Charlottesville, Virginia)

Before coming to NIH: Associate professor of pharmacology, Mayo Clinic College of Medicine and Science (Rochester, Minnesota); senior associate consultant II–research, Division of Oncology Research, Department of Oncology, Mayo Clinic (Rochester, Minnesota)

Came to NIH: In January 2022

Outside interests: Skiing; playing tennis; listening to music

Website: https://irp.nih.gov/pi/yuichi-machida

Research interests: DNA damage is the major source of mutations and genomic instability, which are the hallmarks of cancer. I am studying the proteases involved in DNA repair and their roles in maintaining genomic stability.

My lab and I are examining how cells resolve replication conflicts with DNA-protein crosslinks (DPCs) to prevent genomic instability and tumorigenesis. My group at the Mayo Clinic was one of the laboratories that contributed to the discovery of SprT-like N-terminal domain (SPRTN), a nuclear metalloprotease that is important for repairing DPCs at DNA replication forks (Cell Cycle 11:3395–3402, 2012).

Mutations in the SPRTN gene cause Ruijs-Aalfs syndrome, a rare genetic disease characterized by genomic instability, progeria, and early onset of liver cancer. We generated a mouse model with reduced expression of the Sprtn gene that not only recapitulated the phenotypes of Ruijs-Aalfs syndrome but also exhibited accumulation of DPCs in the liver, in which tumors were later formed (Nat Commun 5:5744, 2014). Our findings demonstrated that spontaneous DPCs are produced frequently yet removed efficiently by a mechanism involving SPRTN (Nucleic Acids Res 45:4564–4576, 2017).

We are also investigating the effect of DPC repair inhibition on chemotherapies in order to develop strategies to sensitize tumors to chemotherapeutic drugs and identify types of tumors that are susceptible to DPC-inducing or protein-trapping drugs. Our study showed that SPRTN-deficient cells are hypersensitive to the topoisomerase I inhibitor camptothecin, suggesting that inhibition of DPC repair mechanisms could enhance the toxicity of DPC-inducing chemotherapeutic drugs (Nucleic Acids Res 45:4564–4576, 2017). More recently, one of our studies showed that a protein called FAM111A plays an important role in mitigating the effects of protein obstacles on DNA replication forks and thereby influences sensitivities to chemotherapeutic drugs (Nat Commun 11:1318, 2020). Using molecular and cell biology techniques, we are currently investigating the function and regulation of these DPC proteases.

QUAN YUAN, PH.D, NINDS

Senior Investigator, Dendrite Morphogenesis and Plasticity Unit, National Institute of Neurological Disorders and Stroke

Education: Lanzhou University, Lanzhou, China (B.S. in biology); University of Pennsylvania, Philadelphia (Ph.D. in biology)

Training: Postdoctoral training in developmental and behavioral neurobiology, University of California at San Francisco (San Francisco); Howard Hughes Medical Institute

Came to NIH: In 2013 as an Earl Stadtman Tenure Track Investigator

Outside interests: Traveling; hiking; slowly building up a rock and fossil collection

Website: https://irp.nih.gov/pi/quan-yuan

Research interests: My lab and I are trying to understand how experience and genetic programming interact to shape the structural and functional connectivity of neuronal circuits during brain development. We use Drosophila melanogaster (the fruit fly) as a simple model system to untangle the complex molecular inner workings of neural development.

We are interested in neuronal dendrites, the branchlike structures that receive sensory signals from the surrounding environment or synaptic input from connected partner cells. The elaborate dendritic arborizations are genetically controlled, often unique to the specific neuronal type, and sensitive to experience and activity. Although neuroscientists have been captivated by dendrite morphogenesis and plasticity for decades, we are still trying to figure out what the cell- and context-specific mechanisms are.

Previously, I established a genetic model in Drosophila larvae for performing systematic in vivo analyses on dendrite plasticity. I identified homeostatic structural plasticity as a major contributor to neurons’ compensatory responses toward alterations in synaptic inputs. My group has been digging deeper into the cellular and molecular mechanisms of this phenomenon.

Our work has revealed visual-experience-induced homeostatic plasticity targeting dendritic filopodia (thin protrusions in neurons at early developmental stages) regulates synapse number and dendrite size in the developing Drosophila larval visual circuit (Nat Commun 9:3362, 2018). We also isolated molecular signatures associated with the neuronal adaptive responses (Cell Reports 25:1181–1192.e4, 2018). Our follow-up studies uncovered a pair of carriers mediating neuron-glia lipid trafficking and offered molecular insight into how glia-derived factors help regulate brain lipid homeostasis, which is closely linked to human neurodevelopmental disorders and neurodegenerative diseases (Nat Commun 12:article number 2408, 2021).

We conducted another study to help us understand how cholinergic neurotransmission (linked to many neuropsychiatric disorders in humans) in the central nervous system contributes to neural plasticity. We demonstrated that the temporal regulation of nicotinic acetylcholine receptor (nAchR) subunits during development is critical for the structural and functional maturation of cholinergic synapse in the Drosophila central nervous system (Proc Natl Acad Sci USA 118:e2004685118, 2021). These findings offer us opportunities to further explore the complex organization of the nAchR receptor complex, discover the key factors modulating cholinergic transmission, and better model related human psychiatric disorders.