2021 NCI Outstanding Investigator Award Recipients
NCI’s Outstanding Investigator Award supports accomplished leaders in cancer research, who are providing significant contributions toward understanding cancer and developing applications that may lead to a breakthrough in biomedical, behavioral, or clinical cancer research. Below are profiles of the most recent NCI Outstanding Investigator Award recipients.
Title: Director, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Professor of Biophysics and Biophysical Chemistry
Institution: Johns Hopkins University
Research: The appropriate control of DNA topology has a major impact on the stability and flow of genetic information. Type II DNA topoisomerases are molecular machines that modulate DNA supercoiling and remove chromosome entanglements by catalyzing the ATP-dependent transport of one DNA duplex through another. This research will deliver groundbreaking solutions to key problems in the field, including how certain classes of anti-topo II drugs act on the enzyme, how topo II is localized to key sites of action where it resolves potentially deleterious chromosomal topologies, and how aberrant topo II activity can promote DNA damage and genetic instability. The Berger Lab’s approach is distinguished by a comprehensive blend of biochemical, structural, computational, cell-based, and chemical biology methodologies.
Title: Member, St. Jude Faculty, Robert G. Webster Endowed Chair in Immunology
Institution: St. Jude Children’s Research Hospital
Research: The goal of the Chi Lab’s research program is to discover the mechanisms linking the metabolic state of immune cells with tissue homeostasis and antitumor immunity, and to use these insights for development of better cancer treatments. They approach these questions by integrating hypothesis-driven and systems immunology approaches. Their work has produced innovation in three main areas including the principle of metabolic reprogramming for T cell fate, state, and tolerance; mechanisms of nutrient and immune signaling; and the discovery of ‘hidden drivers’ and immuno-oncology targets via systems immunology and functional screening approaches. Their experience in the application of multidisciplinary approaches, combined with their development of novel disease models for cancer immunotherapy, make them uniquely positioned to produce fundamental discoveries in immunometabolism and clinical translation for cancer treatments by reprogramming metabolic pathways.
Title: Member, St. Jude Faculty, Director, Division of Experimental Hematology, The Wall Street Committee Endowed Chair
Institution: St. Jude Children’s Research Hospital
Research: Since Dr. Crispino’s laboratory discovered GATA1 mutations in all cases of acute megakaryocytic leukemia in children with Down syndrome, Dr. Crispino and his team have been at the forefront of defining the specific genetic events that promote leukemia. The Crispino lab wants to spend the next seven years and beyond on understanding the mechanisms of leukemia progression from clonal hematopoietic disorders. Specifically, they will identify and compare the ways that pediatric and adult disorders progress to acute myeloid leukemia. Through their research, they hope to answer three main questions: 1) What are the similar and disparate events that promote malignant progression of pediatric versus adult blood disorders? 2) How does dysregulation of pathways downstream of identified tumor suppressor genes promote malignant progression? 3) Which investigational or approved therapies can prevent progression or treat the tumors? The answers to these questions will increase their basic understanding of cancer, reveal new therapeutic targets, and possibly shed light on chemoprevention strategies.
Title: Efim Guzik Distinguished Professor in Cancer Biology; Leader, Program; and Co-Leader, Cancer Immunology & Immunotherapy Program, UCSF Helen Diller Family Comprehensive Cancer Center
Institution: University of California, San Francisco
Research: While immunotherapy is transforming cancer treatment, the majority of patients do not achieve durable responses. Dr. Fong’s group is studying mechanisms of response and resistance to different immune checkpoint inhibitors through dissecting immune states and pathways triggered by immunotherapies. The lab will use multi-omic single cell approaches to identify and track immunotherapy-induced immune states in cytotoxic T cells and non-canonical immune effectors. The Fong Lab’s proposal is based on bench-to-bedside and bedside-to-bench mechanistic studies with the goal of advancing cancer immunotherapy. By leveraging multiple clinical trials of different immunotherapies and mouse models, their group will define treatment induced resistance mechanism that can be co-targeted to enhance anti-tumor efficacy.
Title: Abraham and Mildred Goldstein Professor of Pathology and Cell Biology (in the Institute for Cancer Genetics)
Institution: Institute for Cancer Genetics, Columbia University Medical Center
Research: Inactivation of the p53 tumor suppressor is a pivotal event in the formation of most human cancers. The main issue in targeting this pathway for cancer therapy is whether activation of p53 function in vivo leads to significant tumor regression without causing serious toxicity in normal tissues. Cancer cells rewire cellular metabolism to meet the energetic and substrate demands of tumor development, but this rewiring also creates metabolic vulnerabilities specific for cancer cells. By taking advantage of these metabolic vulnerabilities, the Gu Lab’s preliminary studies showed that specific activation of the tumor suppression function of p53 through metabolic targets can be effective in suppressing tumor growth but apparently does not cause severe harm to normal tissues. The goal of the research plan is to comprehensively define a p53-mediated metabolic regulation program that is required for its tumor suppression as a means to identify new targets/pathways for therapy. They expect to identify specific targets to suppress tumor growth that have minimal or at least manageable toxicity in normal tissues.
Title: Senior Vice President and Director, Human Biology Division, Fred Hutch, Director, Seattle Translational Tumor Research, Fred Hutch and UW Medicine
Institution: Fred Hutchinson Cancer Research Center
Research: The Holland Lab has developed a suite of genetically engineered mouse models that are demonstrably representative of human gliomas and other tumor types. These models have been used to inform treatment options for clinical agents, and this now enables the lab to propose these models are suitable for testing potential major improvements to how these diseases are treated. Dr. Holland and his team are now working on three primary activities: to understand the central role of specific splice variants of TrkB in embryonic development and oncogenesis throughout the body; to use the modeling system developed for glioma to address the biology of rare tumors driven by gene fusions; and to use these mouse models to study therapeutic response and identify therapeutic strategies for these fusion-driven tumors including identification of FDA approved drugs that would intervene downstream of the action of the gene fusion.
Title: Professor of Neurology, Professor of Pathology and Cell Biology (in the Institute for Cancer Genetics)
Institution: Columbia University Health Sciences
Research: Dr. Iavarone and his team combine innovative computational tools and state-of-the-art experimental cancer models in vitro and in vivo to identify homogeneous subgroups of cancer patients to dissect the pathogenesis of cancer and design tailored and fully validated personalized therapeutic approaches. The Iavarone Lab will explore three main areas: the identification of homogeneous groups of brain tumors sharing activation of the same biological pathways; the study of cancer heterogeneity at the single cell level to accurately inform tumor classifications; and the therapeutic prediction emerging from the identification of driver modules and synthetic lethal relationships of malignant glioma. Dr. Iavarone and his team plan to develop and apply novel technologies for high-throughput transcriptomic and proteomic analysis of individual cells within malignant glioma tissues. The successful outcome of their work will be an integrated computational-experimental pipeline that will be able to mechanistically identify the determinants of tumor genomes and phenotypes of solid tumors. This information will be of invaluable significance to decipher evolving tumor dependencies and provide the most accurate therapeutic predictions.
Title: Arthur L. and Lee G. Herbst Professor of Obstetrics and Gynecology; Chair, Department of Obstetrics and Gynecology
Institution: University of Chicago
Research: Metastatic ovarian cancer (OvCa) is the leading cause of death from gynecologic cancer. Despite aggressive chemotherapy and surgery, 80% of patients experience intraabdominal progression or recurrence. The Lengyel lab concentrates on elucidating the biology of OvCa metastasis, focusing on how deregulation of the tumor microenvironment, especially adipocytes, promotes OvCa metastasis and chemotherapy resistance. The Lengyel lab defined the contribution of multiple cell types in the tumor microenvironment to metastasis, revealing the critical role of methyltransferases in the reprogramming of normal fibroblasts into cancer-associated fibroblasts. They also elucidated the role of lipids in metabolic remodeling, a crucial component of metastasis. Their experimental approach will span functional cellular assays to study adhesion, migration, and invasion; confocal imaging, biochemical activity assays, and newly devised methods to test the functionality of adipocytes and immune cells in vitro and in vivo. Dr. Lengyel and his team aim to target the metabolic processes identified in the OvCa tumor organ to enhance the anti-tumor therapy response, potentially halting the inexorable progression of this deadly disease.
Title: Professor of Genetics and Medicine, Harvard Medical School
Institution: Dana-Farber Cancer Institute
Research: The introduction of new targeted therapies and immunotherapies has led to significant decreases in lung cancer mortality in the United States in recent years but there remains an urgent need to continue to improve the prevention, diagnosis, and treatment of this deadly disease. The Meyerson Lab, which focuses on adenocarcinoma, seeks to understand somatic genome alterations in human lung cancer, to use this understanding to elucidate lung cancer pathogenesis, and in turn to improve diagnosis and treatment. The lab continues to advance the knowledge of lung cancer genomes and their function, to describe novel oncogenic mutations in lung cancer and the duplication of super-enhancer elements near known oncogenes, and to analyze the cancer-causing activity of lung adenocarcinoma mutated genes. Organizing their research into three broad categories including single gene alterations, immunological target identification, and genome-wide features, Dr. Meyerson and his team plan to use the knowledge gained from their work to deepen their understanding of human lung adenocarcinoma and drive novel and effective treatments for lung cancer patients.
Title: Arthur H. and Isabel Bunker Professor of Hematology and Immunobiology; HHMI Faculty Scholar; Director, Center of Molecular and Cellular Oncology
Institution: Yale University
Research: Every day, humans produce ~25 million new B-cells that express autoreactive, potentially harmful, autoantibodies. To prevent pervasive autoimmune disease, a powerful mechanism, termed “negative selection”, is in place to eliminate autoreactive B-cells. In this renewal of his 2015 Outstanding Investigator Award, Dr. Müschen and his team have discovered that negative selection also removes pre-malignant B-cells that could give rise to B-cell leukemia and lymphoma. Leveraging negative selection as a unique vulnerability of B-cell tumors represents a previously unrecognized opportunity for treatment and prevention. Importantly, B-cell malignancies that are resistant to conventional chemotherapy remain fully sensitive to pharmacological engagement of negative selection. This concept is based on three recent discoveries by the Müschen laboratory that they will pursue further: (1) Regulation of energy-abundance as the central determinant of negative B-cell-selection: Pathological B-cell signaling induces ATP-depletion and energy stress leading to cell death. (2) B-cells are the smallest of all cells and have fewer mitochondria than any other cell type, which are central determinants of negative selection mechanisms. (3) Discovery of a PI3K-signaling code that distinguishes between normal and pathological signaling pre-malignant and autoreactive B-cells. Transient PI3K-activation upon antigen-encounter promotes survival, persistent PI3K-signaling in pathological B-cells induces negative selection.
Title: Professor of Systems Biology and Biological Informatics; Gerald and Janet Carrus Professor; Director, Program for Mathematical Genomics Columbia University; Co-leader, Genomics and Epigenomics Research Program, Herbert Irving Comprehensive Cancer Center
Institution: Columbia University
Research: Cancers are dynamic biological entities whose clonal architecture can change under strong selection pressures, such as exposure to therapy. Recent discoveries by the Rabadan Lab and other groups have provided a glimpse of the complexity of the clonal architecture of many tumors, their dynamics under therapy, and their interactions with the immune system. The lab’s recent work has shown that tumor evolution does not proceed in a random fashion but through a highly structured process, and that future dominant subclones can both be identified and targeted. The quantitative approaches developed by Dr. Rabadan and his team in the last few years are particularly tailored to elucidate the evolutionary patterns of clonal systems under strong selection. The central hypothesis is that tumor and stroma coevolve in an orchestrated fashion. Seeding clones can be identified through genomic and single cell longitudinal sampling. These clones can be targeted, and in order to characterize these clones we need to develop new quantitative approaches. The overarching goal is to uncover the mechanisms by which small tumor and stromal populations coevolve and drive tumor progression and the emergence of drug resistance, using glioblastoma as a model.
Title: Professor, Departments of Pharmacology and Medicine; Director, Division of Cancer Biology
Institution: University of California, San Diego
Research: Cancer progression and relapse remain the reality of current cancer therapy. In this renewal of her 2015 Outstanding Investigator Award, Dr. Reya and her lab will work to understand the root causes of this persistent problem. With this renewal, the Reya Lab plans to focus on four major areas over the next several years: defining how benign lesions progress to aggressive malignancies; understanding cancer heterogeneity and the mechanisms that uniquely protect therapy resistant cells; tracing the origins and evolution of distinct subtypes of disease; and developing strategies for early detection and early interception of cancer. Collectively, their studies will provide a deeper understanding of the key challenges in cancer biology that face us today and identify new approaches to therapies that may improve patient outcomes.
Institution: Memorial Sloan Kettering Cancer Center
Research: Small cell lung cancer (SCLC) is characterized by rapid growth, early dissemination, and exceptionally poor prognosis. The Rudin Lab has driven fundamental advances in the understanding and characterization of SCLC and has excelled in successfully translating many discoveries into clinical testing, including many active trials currently being conducted by their clinical team. Their new research focuses on areas including recent extensive single cell profiling data that has defined the exceptional intra- and inter-tumoral heterogeneity of primary human SCLC. They have a long-standing interest in lineage plasticity, including histologic transformation from lung adenocarcinoma to SCLC, and tumor evolution between SCLC subtypes. The group also has developed a new technology allowing controlled in vivo CRISPR/Cas9 gene editing in PDX mouse models. Using a multipronged approach, the Rudin lab seeks to define novel therapeutic targets for this recalcitrant malignancy.
Title: Professor of Cell Biology, and of Medicine (Oncology); Associate Director for Basic Science, Albert Einstein Cancer Center; Co-Director, Blood Cancer Institute
Institution: Albert Einstein College of Medicine – Montefiore Health System
Research: Clinical outcome in Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) has not significantly improved over the past 50 years and cure rates remain below 15% in the majority of patients. Novel approaches are needed to improve understanding of the disease pathogenesis and enable more effective therapeutic intervention. In MDS and AML, transcriptional dysregulation is key to confer the pathognomonic features of cellular dysplasia and a myeloid differentiation block. The Steidl Lab’s recent work has discovered an unexpected degree of subclonal heterogeneity, including transcription dynamics and plasticity, in normal and (pre)malignant hematopoietic stem and progenitors. Dr. Steidl and his team will utilize novel tools for stem cell subclonal analysis in patients, as well as newly developed longitudinal mouse genetic models of pre-leukemic stem cell progression to study stem cell subclonal dynamics and their regulation in the initiation and progression of MDS and AML. Their research aims at delineating the molecular regulation of pre-cancerous cell states with the goal to enable their therapeutic targeting. Such an approach holds the promise of achieving lasting remissions or even preventative intervention in MDS and AML, and possibly other malignancies arising from pre-malignant conditions.
Institution: University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center
Research: Inhibitory mechanisms within the tumor microenvironment (TME) represent major barriers to effective anti-tumor immunity. Although striking efficacy has been reported with inhibitory receptor (IR) blockade, it’s clear that additional inhibitory mechanisms will need to be targeted to substantially improve therapeutic outcome in most tumor types and for patients. Regulatory T cells (Tregs) are potent inhibitors of anti-tumor immunity and require novel approaches to limit activity selectively in tumors. Dr. Vignali and his team plan to focus on two major questions: Are there other cytokines or suppressive mechanisms used by Tregs in the TME? And are there other mechanisms that impact Treg stability, function and survival in the TME? This will have a significant impact on understanding how Tregs manipulate and control the TME, will provide novel targets and modalities for therapeutic intervention in cancer, and will inspire others to develop novel approaches to target Tregs in cancer and other diseases.
Institution: Dana-Farber Cancer Institute
Research: B-cell Lymphoma 2 (BCL-2) proteins participate in a dynamic interaction network that determines whether a cell will live or die. Deregulation of this essential signaling pathway underlies the pathogenesis of human cancer and resistance to treatment. The Walensky lab will develop unique chemical probes and apply the latest analytical technologies to tackle longstanding enigmas of the apoptotic pathway, including (1) how death proteins become activated and permeabilize the mitochondria, (2) novel modes of BCL-2 family protein regulation, and (3) unanticipated interaction partners that integrate apoptosis with critical cellular signaling pathways. By revealing new apoptotic mechanisms, targets, binding surfaces, and molecular modulators, the lab aims to both inform fundamental cancer biology and provide next-generation treatments for reactivating apoptosis in human cancer.
Institution: Massachusetts General Hospital
Research: DNA replication problems collectively known as replication stress are major sources of genomic instability in cancer cells and also a vulnerability of cancer that can be targeted therapeutically. Unfortunately, the current understanding of replication stress in cancer cells, how DNA replication is altered by different oncogenic events, and whether altered replication can give rise to distinct cellular vulnerabilities is very limited. Building this understanding would greatly enhance the ability to detect and exploit replication stress in cancer therapy. The Zou Lab has extensively studied the functions and regulation of the ATR checkpoint pathway, the master regulator of replication stress response in human cells. Their work has contributed significantly to the current models of stress sensing and signaling during DNA replication. These studies revealed that replication stress not only exerts cell autonomous effects on the genome, but also cell non-autonomous effects in cell populations. This knowledge gives a comprehensive understanding of the molecular underpinnings of replication stress in cancer cells and its impact on the genome of cancer cells, cell populations in tumor microenvironments, and the cancer cell-specific vulnerabilities that it gives rise to. The new concepts and findings could have transformative impacts on the research of cancer and cancer therapy.