2018 NCI Outstanding Investigator Award Recipients

Smita Bhatia, M.D., M.P.H.
Title: Director of the Institute for Cancer Outcomes and Survivorship
Institution: University of Alabama at Birmingham
Research: The two leading causes of premature mortality in childhood cancer survivors are radiation-related subsequent neoplasms (SNs) and anthracycline-related cardiac dysfunction (CD). Bhatia seeks to develop a risk prediction model for radiation-related SN and anthracycline-related CD in childhood cancer survivors, replicate the optimized model in an independent cohort of childhood cancer survivors, apply the model to newly-diagnosed children with cancer to predict the risk of incident SN/CD, and determine the functional relevance of the genetic signatures. Findings from this application will help reduce the burden of morbidity in this population.

Xandra O. Breakefield, Ph.D.
Title: Professor, Neurology, Harvard Medical School; Geneticist in Radiology at Massachusetts General Hospital
Institution: Massachusetts General Hospital
Research: Glioblastoma releases extracellular vesicles containing nucleic acids and proteins that convert normal brain cells to tumor supportive cells. Breakefield will explore how tumor extracellular vesicles participate in changing the phenotype of microglia, macrophages and astrocytes in the tumor microenvirons and analyze the microenvironment which sustains the tumor. This research is designed to increase sensitivity and reveal clinical correlates of RNA and protein in extracellular vesicle biomarkers from serum/plasma with the goals of early detection, informing therapeutic decisions and longitudinal evaluation.

Timothy A. Chan, M.D., Ph.D.
Title: PaineWebber Chair in Cancer Genetics; Member/Professor, Human Oncology and Pathogenesis Program; Director, Immunogenomics and Precision Oncology Platform; Vice Chair, Department of Radiation Oncology
Institution: Memorial Sloan Kettering Cancer Center
Research: Treatment with antibodies against CTLA4, PD-1, or PD-L1 can result in promising tumor control. Chan’s team will explore how tumor and patient genetics/genomics affect tumor immune phenotypes and influence the response to immunotherapies. The team will analyze how the diversity of mutational landscapes and densities, and DNA damage repair (DDR) deficiencies affect immunotherapy response in cancers treated with immune checkpoint blockade (ICB anti-PD1 or anti-CTLA4). Then, they will use pre-clinical models and patient samples to evaluate how driver mutations in critical DDR mutations influence tumor immunity, ICB response, and acquired resistance. Lastly, the team will characterize how the patient germline genotype influences response to ICB.

David Cheresh, Ph.D.
Title: Distinguished Professor and Vice Chair in the Department of Pathology
Institution: University of California, San Diego
Research: Integrin αvβ3 expression can be induced by stress to reprogram tumor cells toward a stress-tolerant, drug-resistant, stem-like state that is associated with tumor progression and metastasis for many cancers. The goal of Cheresh’s research is to understand how such tumors use integrin αvβ3 to gain stress tolerance and devise ways to attack this process therapeutically. His research will explore how tumors adapt to therapy or microenvironmental stress and identify new druggable targets to limit cancer progression by preventing or overcoming tumor cell drug resistance and stress tolerance.

Arul M. Chinnaiyan, M.D., Ph.D.
Title: Director of the Michigan Center for Translational Pathology
Institution: University of Michigan at Ann Arbor
Research: Chinnaiyan’s research will include creation of new bioinformatic resources, high throughput single cell sequencing analysis of patient samples, and creation of cancer-specific lncRNA panels. Therapeutic targeting will be explored using antisense oligos to lncRNAs and studies on the efficacy of peptidomimetics for gene fusions and “undruggable” targets. This research will provide new community resources, identify novel biomarkers, explore the therapeutic targeting of nominated molecular players, and add to the knowledge-base of cancer development mechanisms.

Benjamin Cravatt, Ph.D.
Title: Professor in the Department of Chemistry
Institution: Scripps Research Institute
Research: Many oncogenes code for proteins that lack chemical probes and are even considered undruggable. Cravatt hopes to characterize the functional relevance of protein targets in cancer and cancer-related immunology. He will use the activity-based protein profiling (ABPP) technology to discover chemical probes that perturb the function of genetically-defined human cancer targets, as well as produce advanced chemical libraries for ABPP to further increase the druggable fraction of the human cancer proteome, including E3 ligases for ligand-induced protein degradation and post-translationally modified forms of cancer-relevant proteins.

Channing J. Der, Ph.D.
Title: Sarah Graham Kenan Distinguished Professor of Pharmacology
Institution: University of North Carolina at Chapel Hill
Research: Der focuses on pancreatic ductal adenocarcinoma (PDAC), a cancer where effective therapies remain to be found. His research will focus on exploiting novel protein kinases that regulate MYC protein stability to cause MYC loss, determining key ERK substrates that are critical for ERK-dependent KRAS-mutant PDAC growth, applying experimental approaches to define YAP1–independent mechanisms, and pursuing outlier mutations in PDAC to identify mutation-specific vulnerabilities as the basis for the development of mutation-selective therapies. These findings will help develop anti-KRAS therapies and achieve breakthroughs needed for development of anti-RAS oncogene therapies that can impair growth of PDAC.

Robert N. Eisenman, Ph.D.
Title: Member, Basic Sciences Division
Institution: Fred Hutchinson Cancer Research Center
Research: Research in the Eisenman lab is focused on the MYC transcription factor network, whose interacting components comprise a broadly acting gene regulatory system. The MYC network is essential for normal cellular functions but, when dysregulated, drives formation of multiple tumor types. Work in the lab is directed towards three areas: role of the MLXIP protein in alleviating cellular stress upon MYC-induced metabolic reprograming in cancer; mechanism of tumor suppression by Mga, another member of the MYC network; and point mutations within MYC that activate its oncogenic functions.

Jennifer Grandis, M.D.
Title: Professor, Otolaryngology-Head and Neck Surgery
Institution: University of California, San Francisco
Research: There is an emerging epidemic of head and neck cancer caused by human papillomavirus (HPV) among both smokers and nonsmokers. We want to research the key genetic alterations that mediate HPV+ HNC growth, determine the mechanisms of each target, and its role in HPV+ HNC. The findings will contribute to new treatments for HPV+ HNC. Grandis will focus on alterations that activate phosphatidylinositol 3- kinase (PI3K) signaling including changes in PIK3CA, or PTEN loss, and activation of the EGFR family member HER3. These results may relate to other HPV+ cancers including cervical and anal cancers.

Douglas R. Green, Ph.D.
Title: Peter C. Doherty Endowed Chair of Immunology
Institution: St. Jude Children's Research Hospital
Research: Green’s research explores the processes of regulated cell death in the forms of apoptosis and necroptosis and seeks to understand how they are tied to other cellular physiologies. His team’s goals are to find what the mechanisms of cell survival in apoptosis/necroptosis are, how these integrate with cell life, and how diverse processes of cellular life integrate with the core mechanisms of apoptosis and necroptosis. Green will continue his studies into the activation and regulation of necroptosis in relation to cellular physiology and develop tools to probe its activation in relation to cancer and other pathologies.

Christine A. Iacobuzio-Donahue, M.D., Ph.D.
Title: Attending and Member
Institution: Memorial Sloan Kettering Cancer Center
Research: Pancreatic ductal adenocarcinoma (PDAC) is the most common neoplasm of the pancreas and soon the second most common cancer in the U.S. Iacobuzio-Donahue will research features of intratumoral heterogeneity at the genetic level, what cellular factors influence the evolution of PDA, and if therapies influence PDA evolution. Using whole exome/whole genome sequencing of pancreatic cancer tissues, single cell technologies for copy number alterations and RNA expression, long-term evolution experiments, mouse models and computational models, this research will help with identification of optimal agents and timing of administration based on the evolutionary context of the patients' PDA.

Pasi A. Jänne, M.D., Ph.D.
Title: Director, Lowe Center for Thoracic Oncology; Director, Belfer Center for Applied Cancer Science
Institution: Dana-Farber Cancer Institute
Research: Genotype directed precision therapies to combat EGFR mutant or ALK rearranged non- small cell lung cancer show favorable response rates and progression free survival compared to chemotherapy. Significant improvements in treatment using precision therapies involve using combination therapies. Jänne will develop combination therapies using dual targeting of EGFR, vertical pathway inhibition and parallel pathway inhibition. He will focus on improving therapies for EGFR inhibitor naïve cancers. The research will inform preclinical approaches to refine treatments and make improvements in the outcome of EGFR mutant and other lung cancer patients.

Alec Kimmelman, M.D., Ph.D.
Title: Professor and Chair, Department of Radiation Oncology
Institution: Perlmutter Cancer Center NYU Langone Medical Center
Research: Kimmelman’s team has been studying how pancreatic ductal adenocarcinoma (PDAC) rewires the metabolism to proliferate and survive in nutrient poor microenvironments. Integration of PDAC’s metabolic adaptations and how they influence the tumor’s metabolism in vivo is not yet known. Kimmelman will use syngeneic models of pancreatic cancer to assess metabolic dependencies, use co-culture systems to identify metabolic cross-talk in the microenvironment and dissect nutrient scavenging pathways. From this information robust metabolic targets will be tested in vivo.

David Lyden, M.D., Ph.D.
Title: Professor of Pediatrics
Institution: Weill Medical College of Cornell University
Research: Dr. Lyden will explore the possibility that inhibition of specific exosomal cargo or their targets in hematopoietic cells could reverse immunosuppression, pre-metastatic niche formation and the systemic effects of cancer. He will study the mechanisms through which exosome subpopulations and exomeres (the most prominent tumor-secreted particles) regulate immune system mobilization, metabolic changes and plasticity of pre-metastatic and metastatic niches in cancer models and patients.

Ari M. Melnick, M.D.
Title: Gebroe Professor of Hematology and Oncology; Chair, Hematologic Malignancies Program
Institution: Weill Medical College of Cornell University
Research: Melnick will elucidate how B-cell lymphomas arise through disruption of an intricate network of epigenetic mechanisms that regulate and control the humoral immune response. He proposes that malignant transformation occurs in a different way in the germinal center (GC) B-cells that give rise to follicular lymphoma and diffuse large B-cell lymphomas. For this study, Melnick has assembled technologies such as GC organoids that allow observation of immune synapse signaling, genetically engineered mouse models, and extensive libraries of epigenomic profiles in primary human and murine lymphomas. This information will be leveraged to design clinical trials of novel epigenetic targeted therapies.

Carol Prives, Ph.D.
Title: Da Costa Professor of Biological Sciences
Institution: Columbia University
Research: There are few effective treatments that prevent oncogenic activities of mutant p53 protein, a major suppressor of cancer. Prives’ research will focus on a novel mechanism by which Mdm2 degrades p53, a series of CRISPR-derived cell lines harboring Li-Fraumeni-Syndrome p53 mutations, p53- independent roles of Mdm2 and MdmX, long non-coding RNAs that are p53 targets, new approaches to understand how p53 identifies its sites in vitro and in vivo and examination at single molecule resolution the localization of wild-type and mutant forms of p53 and Mdm2 after different stimuli. This will help diagnosis and treatment of sporadic and inherited cancers.

John Quackenbush, Ph.D.
Title: Chair, Department of Biostatistics
Institution: Harvard T.H. Chan School of Public Health
Research: Biological systems operate through the action of complex networks of genes, proteins, and other molecules working together. But deducing these networks from “snapshots” of a cell’s mutations, or gene expression, or any set of single measurements is like trying to learn the rules of football armed only with still photographs of a game. We have developed methods that use our existing understanding of biology to guess a cell’s networks, and then to use data to refine those models to better fit the data. Quackenbush’s team will develop systems-based modeling in cancer with the goal of understanding how the disease develops, to explore potential treatment options, and to study sex differences in cancer risk and response to therapy.

John A. Tainer, Ph.D.
Title: Professor in the Department of Molecular and Cellular Oncology
Institution: The University of Texas MD Anderson Cancer Center
Research: Cancer is linked to almost every human DNA repair (DR) pathway. Yet, the effects of DNA damage depend on poorly understood DR complexes that are targets for treatments. Tainer seeks to define and test DR changes that will inform BRCA protein essentiality in cells and synthetic lethality in tumors, as well as strategies to control the abscopal effect (where ionizing radiation is immunosuppressive yet can activate an immune response to kill tumors distant from the radiation site). Results will produce data to combine measurements from molecules to cells, help design dissection-of-function mutations and inhibitor tools, and predict biological outcomes.

Cheryl Lyn Walker, Ph.D.
Title: Director of the Center for Precision Environmental Health; Alkek Presidential Chair in Environmental Health; Professor, Departments of Molecular and Cellular Biology, Medicine and Genetics
Institution: Baylor College of Medicine
Research: The cell’s methylation machinery serves two coding functions, one on chromatin and one on the cytoskeleton. Walker’s team seeks to understand how cells utilize and regulate one machinery with two distinct, but equally important, remodeling functions on chromatin and the cytoskeleton. As a result, defects in chromatin remodeler genes can directly impact the cytoskeleton, which in cancer, can drive genomic instability and cause cytoskeletal defects that alter mobility to promote metastasis. This research will help inform understanding the role of chromatin remodelers in cancer, and the development of therapies with efficacy against both the chromatin and cytoskeletal alterations caused by defects in genes encoding dual-function chromatin-cytoskeleton remodelers.

Lihong Wang, Ph.D.
Title: Bren Professor of Medical Engineering and Electrical Engineering
Institution: California Institute of Technology
Research: There remains an imperative need for more advanced breast imaging technologies. Wang will work to develop two innovative high-speed 3D photoacoustic computed tomography (PACT) systems to diagnose breast lesions. One is a single-breath-hold 3D breast imaging system with nearly isotropic 3D resolutions and dual-wavelength contrasts, and the second is a snapshot 3D breast PACT system. Wang’s team will test the PACT for the diagnosis of lesions by comparing with the gold standard of tissue pathology — leading to a more streamlined and accurate workup that reduces unnecessary follow-up imaging and benign breast biopsies.