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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.

2022 | 20212020 | 2019 | 2018 | 2017 | 2016 | 2015

Laura D. Attardi, Ph.D., Principal Investigator
Title: Professor, Radiation Oncology - Radiation and Cancer Biology, Professor, Genetics, Catharine and Howard Avery Professor of the School of Medicine
Institution: Stanford University
Research: The Tumor Protein (TP) 53 tumor suppressor gene is mutated in over half of all human cancers, but the mechanisms through which p53 suppresses cancer in vivo remain incompletely understood. The Attardi Lab strives to deconstruct the pathways through which p53 suppresses cancer to elucidate pathways dysregulated upon p53 loss that could ultimately be targeted therapeutically. As recent work has revealed a critical role for alternative splicing in cancer, The Attardi Lab hypothesizes that studying p53 pathways at the post-transcriptional level, such as through splicing and proteomics analyses, will yield novel insights into p53-mediated tumor suppression. Dr. Attardi and her team also study p53-driven differentiation programs involved in cancer suppression and how they relate to normal homeostatic programs. Collectively, these studies will provide crucial new insight into how to modulate p53 pathways in therapeutic strategies for cancer.

Shelley L. Berger, Ph.D.
Title: Daniel S. Och University Professor of Cell and Developmental Biology, Genetics, Biology; Director, Epigenetics Institute; Co-Leader, Tumor Biology Program, Abramson Cancer Center, Perelman School of Medicine
Institution: University of Pennsylvania
Research: Despite progress in conventional small molecule therapeutics and recent immunotherapy, cancer continues to be a devastating disease. Frequent cancer mutations target the tumor suppressor and transcription factor p53, and target epigenetic pathways, underlining key roles as drivers of cancer. Further, while metabolism is primarily mitochondrial, critical functions of metabolic enzymes occur within the cell nucleus. The Berger Lab will investigate novel epigenetic regulation and its intersection with nuclear metabolism, utilizing cancer cell lines and translational mouse models of cancer. Their research will highlight pivotal developmental- and disease-relevant DNA regulatory elements, called enhancers, which their published findings reveal are crucial in wildtype and mutant p53 function. The Berger Lab’s focus on interaction of epigenetic pathways with metabolic pathways directly in the nucleus and related to cancer promises to reveal novel gene regulatory mechanisms involved in tumor formation. Crucially, results from these approaches will guide much-needed future treatments to significantly benefit patients.

Andrea Califano, Dr.
Title: Vagelos College of Physicians and Surgeons, Clyde and Helen Wu Professor of Chemical and Systems Biology, Professor of Biomedical Informatics and Biochemistry and Molecular Biophysics, Professor of Medicine
Institution: Columbia University Health Sciences
Research: The study of cancer has been based on the discovery of individual events, mechanisms, and processes that are involved in the malignant transformation of normal cells. The expectation has been that learning how tumors arise would provide pharmacologically actionable targets to defeat them. Unfortunately, while the cause of many cancers has been thoroughly elucidated, curative therapies remain elusive, especially for the more aggressive subtypes. We have thus proposed that, to systematically identify druggable non-oncogene dependencies, we must first generate and then interrogate the cellular networks that determine the cancer cell dynamics, including in response to drug perturbations, mutations, and signals from the tumor microenvironment (TME). To address this challenge, the Califano Lab will create the first generation of genome- and proteome-wide network models that can effectively predict the probabilistic, time-dependent response of mammalian cells to small molecule and genetic perturbations, as well as their ability to plastically reprogram across the relatively small number of molecularly distinct states detected in virtually all human malignancies. The Califano Lab will leverage a range of state-of-the-art experimental and computational advances, developed over the last six years with R35 funding, for the creation of systematic, large-scale Transcriptional Regulator Knock-down (TREK) single cell profiles at multiple time points. These new cellular network models will also allow rapid, systematic elucidation of mechanisms that have been traditionally studied via low-throughput, hypothesis-driven assays.

Junjie Chen, Ph.D.
Title: Professor and Chair, Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Institution: University of Texas, MD Anderson Cancer Center
Research: It is well established that defects in DNA damage response (DDR) pathways accelerate tumorigenesis. Significant efforts have been devoted to target defective DDR pathways to improve outcome for cancer patients. The Chen Lab will determine mechanistically how several essential DDR genes/proteins control cell proliferation and DNA damage repair. They plan to establish separation of function mutations to further explain the key roles of these DDR genes and pathways both in vitro and in vivo and will investigate the DDR defects in cancer therapy in vivo. The Chen Lab anticipates that knowledge gained from these studies will help us design better treatment strategies for cancer patients.
Craig M. Crews, Ph.D.
Title: John C. Malone Professor of Molecular, Cellular, and Developmental Biology, Department of Chemistry, Department of Pharmacology
Institution: Yale University
Research: The post-genomic era has not significantly changed the number of proteins pursued by drug companies and this lack of new cancer drug targets has resulted in too many ‘me too’ drugs and wasted effort. To address this need, The Crews Lab has focused on developing the new field of ‘Targeted Protein Degradation’. Moving forward, the Crews Lab plans to develop this technology further through the identification of key degradable oncogenic driver proteins and through the development of tumor-selective PROTACs. Moreover, the clinical validation of PROTACs supports the development of additional novel therapeutic modalities based on heterobifunctional compounds that co-opt various intracellular machineries. These innovative approaches have the potential to be new drug development paradigms that could have a significant impact by dramatically expanding the protein classes one can target pharmaceutically. Finally, for the past 27 years, the Crews Lab has focused on translating research from their lab into both new oncology-focused ventures and a FDA-approved drug, thus demonstrating truly ‘bench-to- bedside’ research that is not common in academia today.

Ruth Etzioni, Ph.D.
Title: Professor Public Health Sciences Division, Fred Hutch, Rosalie and Harold Rea Brown Endowed Chair Fred Hutch
Institution: Fred Hutchinson Cancer Center
Research: The field of cancer diagnostics is in a rapidly expanding growth phase that goes hand in glove with the precision medicine revolution. However, the rapid pace at which new technologies are entering the marketplace makes rigorous evaluation via controlled studies infeasible for all but a relative few. The Etzioni Lab’s research will harness the modeling and analytics skillset developed by Dr. Etzioni over nearly three decades of cancer early detection research to build a framework and tools for evidence generation around novel cancer diagnostics more generally. This work will focus on novel  technologies that are being adopted with wide-ranging practice implications and serious evidence gaps: Examples will include multi-cancer early detection testing, and PSMA-PET/CT imaging for treatment targeting in prostate cancer. The successful execution of the research program will improve our understanding of how novel cancer diagnostics impact clinical and policy relevant outcomes so that these technologies can be used wisely and equitably to improve care for all cancer patients.

Michael Fiore, MD, MPH, MBA
Title: Professor of Medicine
Director, University of Wisconsin Center for Tobacco Research and Intervention (UW-CTRI)
Institution: University of Wisconsin-Madison
Research: Although smoking is a leading cause of cancer and results in worse cancer prognoses, only half of cancer patients who smoke are offered help in quitting during cancer care, and it is unclear that the help they are offered is effective. The work of the Fiore Lab is designed to transform oncology practice so that smoking cessation is an integral part of treatment for all cancer patients who smoke. The Fiore Lab will identify intervention strategies that increase smoking treatment engagement and effectiveness when implemented in oncologic care. In addition, their work will systematically assess best practices via electronic health record (EHR)data extraction of intervention delivery, healthcare costs, short-term cancer treatment outcomes overall, and by patient demographics. The work being done by the Fiore Lab seeks to extend and adapt transformative EHR-facilitated system changes that enhance smoking treatment in primary care to the high-priority cancer care context. Their work will demonstrate the benefits of such system changes to cancer patients in terms of costs, smoking cessation, and cancer recovery.

Irene Ghobrial, M.D.
Title: Director, Clinical Investigator Research Program, Lavine Family Chair for Preventative Cancer Therapies, Professor of Medicine, Harvard Medical School
Institution: Dana-Farber Cancer Institute
Research: Multiple Myeloma (MM) is the second most common hematologic malignancy and is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Preliminary research shows that a prevalence rate of monoclonal protein in 45% of individuals ages >50y and having an early immune dysregulation that the Ghorbiral Lab termed Monoclonal Gammopathy of Indeterminate Potential (MGIP). To begin to delineate mechanisms by which these early MGIP clones progress to MGUS and further lead to MM, the Ghobrial Lab plans to explore the host intrinsic (age, race, germline risk factors) and acquired (inflammation, antigenic activation) risk factors on the expanding clone and its environment that influences its behavior. They believe the next frontier in MM research is to understand how one develops myeloma and treat it early before end-organ damage. Identifying and preventing the development of the earliest stages of MM will lead to transformative approaches to treatment and serve as a model of cancer prevention. The Ghobrial Lab hypothesizes that defining risk as ancestry scores and genomic signatures, instead of defining risk by self-identified race, can improve risk prediction for MM. This approach will allow the field to transition from a purely demographic definition of risk to a biological one.

Tyler Jacks, Ph.D.
Title: David H. Koch Professor of Biology, Daniel K. Ludwig Scholar, Co-director, Ludwig Center at MIT
Institution: Massachusetts Institute of Technology
Research: Over the past three decades, the Jacks Lab has been a recognized leader in the development and characterization of genetically engineered mouse models of cancer, among other pre-clinical models. While the Jacks Lab has investigated many cancer types over time, their new work is focused on models of lung adenocarcinoma and pancreatic ductal adenocarcinoma. By developing and deploying tools of genetic engineering and genetic profiling, such as CRISPR-based methods and single-cell analysis, the lab has pioneered new models and analytical approaches that have allowed for a deeper understanding of disease progression, including interactions between developing tumors and the immune system. In addition to further exploration of tumor-immune interactions in lung cancer, single-cell profile methods will be augmented by spatial transcriptomics to characterize the changes in gene expression—in cancer cells and other cell types within the tumor microenvironment—in situ, rather than in dissociated cells. The lab is hopeful that these studies will investigate the nature of the antigens and antigen combinations that induce effective T cell priming and activation, including through prophylactic and therapeutic vaccinations. Results of these experiments will inform new therapeutic approaches, including novel cancer vaccine strategies, in human cancer patients.

Raghu Kalluri, M.D., Ph.D.
Title: Professor and Chair, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Institution: The University of Texas MD Anderson Cancer Center
Research: Trillions of exosomes, a subset of extracellular vesicles, are naturally present in the blood and tissue, and all cells secrete them into the extracellular milieu. The Kalluri Lab is currently working to address key unanswered scientific questions related to the basic biology of exosomes, their functional role in pathogenesis and therapeutic intervention of pancreatic cancer, a disease with dismal prognosis, and on the rise in the United States.  The team plans to address the functional role of exosomes in the complex interplay between cancer cells, and the cells of the tumor microenvironment to enable initiation and progression of cancer.  On the applied front, the lab will exploit their established platform for FDA approved, clinical grade GMP exosomes production. Through their work, they will investigate the potential of engineered exosomes to target driver oncogenes and other cancer drivers to modulate the pancreatic cancer immune microenvironment/tumor immunity to facilitate therapeutic response. The work of the Kalluri Lab is rooted in the expertise they have developed within their research program over the last decade. Their track record provides the rationale and guidance for a higher chance of feasibility of the proposed studies, with potential for translational application.

David Kirsch, M.D., Ph.D.
Title: Barbara Levine University Distinguished Professor
Institution: Duke University
Research: Dr. Kirsch is a physician-scientist radiation oncologist, who specializes in the care of patients with bone and soft tissue sarcomas. The Kirsch Lab will develop and apply sophisticated mouse models of sarcoma to dissect molecular mechanisms of sarcomagenesis and develop novel therapeutic approaches. In addition, they will utilize sophisticated mouse models to study mechanisms of normal tissue injury from radiation and elucidate mechanisms of tumor response to radiation therapy alone or in combination with immunotherapy.

Timothy J. Ley, M.D.
Title: Lewis T. and Rosalind B. Apple Professor of Oncology in Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University School of Medicine
Institution: Washington University School of Medicine
Research: The long-term goal of the Ley Lab is to develop effective, precision therapies directed against the initiating mutations of Acute Myeloid Leukemia (AML). In this renewal of his previous R35 award, Dr. Ley and his team will use primary human AML samples, induced pluripotent stem cells (iPSCs), and genetically engineered mouse models to further evaluate the molecular mechanisms involved in preleukemic reprogramming, and progression to AML. In addition, They will also perform comprehensive proteomic studies to complete "proteogenomic" datasets for these initiating events, including the identification of the hematopoietic proteins that interact with initiating proteins, and the development of quantitative deep-scale proteomic and phosphoproteomic datasets broadly representative of all AML subtypes. Additional approaches for developing mechanistically driven therapies designed to prevent initiating mutations will be developed as their work continues.

Title: Professor of Biostatistics, TH Chan School of Public Health; Professor of Statistics, Faculty of Arts and Sciences
Institution: Harvard University
Research: The Lin Lab focuses on developing and applying scalable, interpretable and transferable statistical and machine learning (ML) methods for integrative analysis of massive germline whole genome sequencing (WGS) and somatic whole exome sequencing (WES) data, epidemiological and clinical data, collected in large-scale multi-ethnic biobanks, population and clinical studies of cancer, and experimental multi-omic functional data, such as single cell RNA/ATAC-seq data. Dr. Lin and her team’s goal is to use advanced data science methods and different types of population, clinical, and experimental data to accelerate progress in advancing from cancer gene mapping to mechanisms to cancer prevention and medicine, discover new effective trans-ethnic precision cancer prevention and treatment strategies, and reduce health disparities in cancer genetic research. The Lin Lab will apply the proposed methods in lung cancer and breast cancer genetic epidemiological and clinical studies and biobanks. They will also develop open access cluster and cloud-based software of these methods and data resources, and make them available to the cancer research community through various platforms, including the NIH Data Commons.

Brendan D. Manning, Ph.D.
Title: Professor and Acting Chair, Molecular Metabolism, Harvard T.H. Chan School of Public Health; Professor, Cell Biology, Harvard Medical School
Institution: Harvard T.H. Chan School of Public Health​​​​​​​​​​​​​​
Research: Cancer is a disease of uncontrolled cell growth. Under this renewal, Dr. Manning and his team study the regulation and function of a ubiquitous cell signaling pathway that serves as the gatekeeper of cell growth. They are defining how the most common oncogenes in human cancer impinge on this pathway to drive growth-promoting metabolic processes within tumors and how the nutrient microenvironment of tumors impacts this regulation. Thus, this research is focused at the interface of oncogenic signaling networks and cellular metabolic networks, with the overarching goal of uncovering novel and selective therapeutic strategies that distinguish tumor cells from normal cells.

Title: Professor of Chemical Biology and Molecular Therapeutics​​​​​​​
Institution: University of California Berkeley​​​​​​​
Research: One of the most significant challenges facing cancer drug discovery is that over 90% of the proteome is currently considered “undruggable” because most proteins do not possess known binding pockets or “ligandable hotspots” that can be pharmacologically and functionally targeted for therapeutic benefit. Tackling the undruggable proteome requires the development of innovative technologies for ligand discovery and the discovery of novel therapeutic modalities to functionally manipulate the undruggable proteome for therapeutic benefit. The Nomura Lab is focused on reimagining druggability by advancing and applying chemoproteomic platforms to tackle the undruggable proteome, towards developing next-generation therapies and therapeutic modalities for cancer.

Title: Dean, Gerstner Sloan Kettering Graduate School
Member, Cell Biology Program
Institution: Sloan Kettering Institute for Cancer Research​​​​​​​
Research: Cells respond to stress by upregulating adaptive mechanisms that promote survival or by undergoing cell death when the stress is too severe. Cancer cells take advantage of stress responses in order to survive within harsh cancer microenvironments, and understanding which adaptive mechanisms are utilized to avoid cell death is critical to gaining new knowledge that may be exploited for cancer therapy. It has also become clear that there is not one, but in fact many different forms of cell death that can occur in response to stress. The Overholtzer Lab has shown that some mechanisms have unique effects on the dynamics of cell populations, and that some promote, while others may hinder, therapeutic responses. The work of Dr. Overholtzer and his team will focus on two major areas of discovery: How is cell death regulated in response to stress, and how do particular mechanisms contribute to controlling population dynamics?; and how do cells respond to nutrient starvation through adaptive mechanisms that involve lysosomes? Through their work, they will exploit recent findings and methods they have developed to study these overarching questions through an integrated set of cell biological approaches with a focus on imaging-based studies.

Title: Professor of Medicine, Harvard Medical School​​​​​​​
Institution: Dana-Farber Cancer Institute​​​​​​​
Research: Breast cancer is the most common cancer and the leading cause of cancer deaths in women worldwide. While targeted and immune therapies have improved patient outcomes, a significant fraction of patients fail to respond to treatment and die of their disease. The Polyak Lab focuses on understanding breast tumor evolution using interdisciplinary approaches and improve the clinical management of breast cancer patients based on this knowledge. Through their current research, Dr. Polyak and her team are trying to decipher the breast tumor ecosystem at the single cell level, conduct functional studies to gain mechanistic insights underlying ITH, and design and test novel therapeutic approaches for heterogeneous breast tumors. The Polyak Lab hopes that an improved understanding of how ITH drives disease progression will lead to changes in clinical practice, including the development of novel, more effective individualized combination treatment strategies.

Title: Joan and Sanford I. Weill Department of Medicine; Co-Director, Cornell Center for Research on End-of-Life Care, Irving Sherwood Wright Professor of Geriatrics/Professor of Sociology in Medicine, Weill Cornell Medicine​​​​​​​
Institution: Weill Medical College of Cornell University
Research: Despite great strides that have been made in the understanding and treatment of cancer, the number of cancer deaths remains on the rise and cancer remains the 2nd leading cause of death in the United States. The Prigerson Lab will focus on oncologist communication; cancer disparities; and psychosocial distress by leveraging data, theories, and the clinical and scholarly resources (colleagues and collaborators) already put in place by the initial R35 award. In doing so, Dr. Prigerson and her team will be able to improve oncologist delivery of high quality end-stage cancer care; increase the frequency and effectiveness of their prognostic disclosures; promote cancer patients’ prognostic understanding; ensure the equitable delivery of end-stage cancer care; address unmet psycho-social-spiritual care needs, reduce psychosocial distress of patients and caregivers to enhance their mental health, promote informed decision-making, and patients’ receipt of value-concordant care. Continued research in this area will enable Dr. Prigerson and her team to help ensure that dying cancer patients and their caregivers receive the highest quality of end-stage cancer care possible.

Title: Theresa and Eugene M. Lang Professor​​​​​​​
Institution: Rockefeller University​​​​​​​
Research: Over the past two decades Dr. Ravetch and his team have focused on clarifying the mechanisms by which anti-tumor immunotherapies elicit their therapeutic effects. As a result, the importance of Fc-FcγR mediated effector pathways for the elimination of tumors has been elucidated, resulting in the optimization of these interactions in second-generation anti-tumor immunotherapeutics with improved clinical activity. While these strategies have resulted in more effective anti-tumor antibodies (Abs) with significantly improved survival, the long-term goal of immunotherapy is to develop therapeutic strategies that will elicit memory responses that will effectively eliminate recurrences and thus result in long-term survival. Dr. Ravetch and his team aim to mechanistically investigate general strategies to accomplish this goal by focusing on inducing tumor vaccination using anti-tumor monoclonal Abs (mAbs), defining the mechanisms by which agonistic and antagonistic immunomodulatory mAbs enhance anti-tumor vaccination, and exploring how the tumor microenvironment may be manipulated in order to augment these immunotherapeutic strategies. Their preliminary results have indicated that anti-tumor Abs can elicit long-term cellular memory responses when appropriate Fc-FcγR interactions are integrated into these Abs. Manipulating both the cellular effector responses and the tumor microenvironment through the use of Fc-optimized immunomodulatory Abs can augment these pathways to result in long-term memory responses.

Title: Professor of medicine, surgery, and molecular and medical pharmacology, Director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center (JCCC), Director of the Parker Institute for Cancer Immunotherapy (PICI) Center at UCLA.​​​​​​​
Institution: University of California Los Angeles​​​​​​​
Research: The Ribas lab aims to build on the progress of their previous work to develop new therapies for patients with melanoma and studying the mechanistic basis of response and resistance to melanoma immunotherapies. The Ribas Lab is currently conducting research focused on three primary themes, the first is centered on how cancer cells are recognized or escape T cells, focusing on the antigen presentation machinery, the second is based on the key role of IFN-g in shaping an antitumor immune response, and the third is focused on the T cell function and target recognition, and in particular in avoiding T cell dysfunction upon repeated antigen exposure. In addition, the Ribas Lab will analyze the transcription factors that guide a superior in vivo expansion and antitumor activity of adoptively transferred T cells. The Ribas lab will use state-of- the-art approaches to analyze large numbers of patient biopsies,  CRISPR screens for mechanistic analyses, and model systems to improve responses and treat resistance to cancer immunotherapies.

Title: Professor, Medicine, Harvard Medical School, Professor, Medicine, Beth Israel Deaconess Medical Center​​​​​​​
Institution: Beth Israel Deaconess Medical Center​​​​​​​
Research: Error-free DNA repair initiated at the sites of replication fork stalling is critical for the prevention of genomic instability in cycling cells. Defects in stalled fork repair have been directly implicated in cancer predisposition. A major goal of the Scully Lab is to define the genetic regulation and mechanisms of stalled fork repair in mammalian cells. Dr. Scully and his team will develop new techniques for analyzing DNA structural intermediates at stalled replication forks, chromatin responses to fork stalling and protein composition of the stalled mammalian replication fork. These studies may also identify new molecular targets for therapy of breast and ovarian cancer—as exemplified by the Scully lab’s recent identification of a novel synthetic lethal interaction between mutations of BRCA1 and FANCM. Through their work, they expect to make discoveries in this field that will open the door to new therapies in HBOC and other forms of cancer.

Title: Robert Francis Furchgott Professor and Chairman, Department of Biochemistry and Molecular Genetics, Director of the Simpson Querrey Institute for Epigenetics; Editor, Science Advances​​​​​​​
Institution: Northwestern University Feinberg School of Medicine at Chicago​​​​​​​
Research: Studies from Shilatifard’s laboratory for over 25 years have been addressing why chromosomal translocations involving the MLL gene into different genes on different chromosomes result in the pathogenesis of the same cancer. In 1996, Shilatifard made a pivotal observation by identifying the first function for any of the MLL translocation partners, the ELL protein, as an RNA Polymerase II elongation factor and linking for the first-time transcriptional elongation control to cancer.  His steadfast studies during the ensuing years, demonstrated that other MLL translocation partners are found within the same complex he named the Super Elongation Complex (SEC). He also biochemically isolated MLL and its homologues in a complex he named COMPASS (Complex of Proteins Associated with Set1) as the first histone H3K4 methyltransferase, linking epigenetics to cancer. His studies funded by the NCI/OIA have made significant inroads and leading to the development of extremely promising target-specific, epigenetic drugs for cancer.

Title: Leon Hess Professor, Senior Attending Physician​​​​​​​
Institution: Rockefeller University​​​​​​​
Research: The Tavazoie Lab studies the molecular alterations that contribute to metastasis formation, a poorly understood process and primary cause of solid cancer deaths. It has long been thought that metastasis is caused by somatic metastasis driver mutations—postulated alterations that have yet to be identified. Dr. Tavazoie and his team will use allelic variants of ApoE as powerful genetic entry points to understand the molecular events underlying metastasis formation, where they will define how ApoE signals are received by cells and how ApoE mediates cellular events. They will also extend the concept of hereditary metastasis genetics to additional cancers and genes and apply their reverse genetic and modeling approaches to breast cancer metastasis. To achieve this understanding, they will employ innovative optical, physiological, genetic modeling and screening methods to interrogate mouse and human metastatic transitions. Through their continued work, the Tavazoie Lab will be able to establish the first human genetics guided framework for understanding the molecular mechanisms governing metastasis formation—enabling new avenues for its therapeutic treatment and prevention.

Title: Professor, Pharmacology​​​​​​​
Institution: University of California San Diego​​​​​​​
Research: Essential regulation of the cellular machinery is achieved by a network of highly dynamic signaling molecules, that, when dysregulated, allow cancer cells to misinterpret or ignore signals that normally tell cells to stop dividing or begin apoptosis, leading to uncontrolled tumor growth. Dr. Zhang and her team seek to establish a new conceptual framework to specifically understand the cellular organization of molecular activities. They hypothesize that cellular biochemical activities are spatially organized into an “activity architecture” and dysregulated driver molecules can re-organize and re-structure this activity architecture, leading to loss of control over cell growth, division, and death. They will focus on developing innovative technologies, including super-resolution activity imaging, to illuminate the biochemical activity architecture across different scales. Another focus is to elucidate how the disorganized cAMP-PKA activity architecture leads to tumorigenesis in FLC and further discover novel, cancer-relevant biomolecular condensates. Additionally, they will focus on investigating the spatiotemporal regulation of ERK that is critical for its physiological functions and identifying the vulnerable connections in the re-organized cancer-driving architecture in pancreatic cancer, which is a deadly cancer that is addicted to the Ras-ERK pathway. This work should also facilitate the development of new therapeutics through developing novel assays for evaluating Ras inhibitors and measuring target engagement.

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