Trever G. Bivona, Ph.D. - US grants

DESCRIPTION (provided by applicant): This five-year mentored career development award is structured to facilitate my development into an independent, laboratory-based physician scientist in the field of translational thoracic oncology. As an MD-PhD physician scientist, my clinical experiences as a medical oncologist caring for patients with lung cancer inspire the bench science in which I engage. These clinical experiences also provide opportunities to translate scientific discoveries to improve the treatment of patients with lung cancer. My primary mentor is Dr. Charles Sawyers, an international leader in translational oncology. Memorial Sloan-Kettering Cancer Center provides an ideal setting in which to perform patient-oriented, lab-based research. In the laboratory we investigate the mechanism(s) by which some cancer cells acquire dependence upon signaling by an oncoprotein for their survival (oncogene addiction). We have focused on human lung cancers that harbor activating mutations in the epidermal growth factor receptor (EGFR). Human lung adenocarcinomas with activating mutations in EGFR often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs) but the magnitude of tumor regression is variable and transient. We hypothesized that the heterogeneity of treatment response may result from genetic modifiers that regulate the degree to which tumor cells are dependent on the mutant EGFR and, hence, the magnitude and duration of response in patients treated with EGFR TKIs. We used an RNA- interference (RNAi) screening strategy to rationally identify companion therapeutic targets that, when inhibited, might enhance the response of EGFR-mutant lung cancers to the EGFR TKI erlotinib. In initial experiments, we showed that knockdown of CD95/Fas and several components of the NF?B pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF?B through overexpression of the intermediates c-FLIP or IKK, or silencing of I?B, rescued EGFR-mutant lung cancer cells from EGFR TKI. Genetic or pharmacologic inhibition of NF?B enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF?B inhibitor I?B predicted for improved response and survival EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF?B as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers. We propose to further test the hypothesis that the CD95/Fas-NF?B pathway and EGFR are rational companion therapeutic targets in EGFR-mutant lung cancers using state-of- the-art murine models, additional human clinical data, and pathway-selective NF?B pharmacologic inhibitors in the following Specific Aims: 1) Determine if CD95/Fas-NF?B signaling is sufficient to induce EGFR TKI resistance using in vivo models of EGFR- mutant lung cancer, 2) Determine if increased CD95/Fas-NF?B signaling occurs in EGFR-mutant transgenic lung cancer models and patients that are resistant to EGFR TKI, 3) Determine if pathway-selective NF?B inhibitors enhance EGFR TKI responses in EGFR-mutant lung cancer models as a prelude to a clinical trial in appropriately selected patients. More broadly, these studies provide insight into the mechanisms by which tumor cells acquire oncogene dependence and escape from oncogene inhibition.

DESCRIPTION (Provided by the applicant) Abstract: A critical challenge facing medicine is the development of more effective and less toxic systemic therapies for cancer patients. A new paradigm for the development of systemic cancer therapeutics has emerged over the last decade with the move away from broadly cytotoxic agents to targeted therapies. This has been enabled by the identification of specific alterations that drive oncogenesis in a wide variety of tumor types and the development of small molecules or antibodies that specifically target these oncogenic drivers. In some genetically defined subsets of cancer patients whose tumors harbor an oncogenic driver (e.g. mutant EGFR, ALK gene fusions, mutant B-RAF), pharmacologic oncogene inhibition has become standard of care. Despite dramatic clinical successes achieved with inhibitors of driver kinases that promote tumor growth, responses in patients are rarely complete and also vary in duration. Strategies to enhance initial responses and to prevent or overcome resistance to inhibition of oncogenic drivers are needed. A significant obstacle to the optimal use of targeted cancer therapies is the lack of a coherent strategy to develop appropriate combinations that will enhance response rates and prevent or overcome resistance. Defining systematically rational companion targets whose combined inhibition can achieve maximal therapeutic efficacy and improve the survival of cancer patients is a major and seemingly insurmountable challenge facing oncology. Fortunately, emerging functional genomics technologies provide an unprecedented opportunity to accelerate the design of effective targeted cancer polytherapies. The goal of this proposal is to create an intellectual foundation and experimental platform that will optimize the personalized treatment of cancer patients and improve their survival using as a model system lung cancer, the leading cause of cancer mortality in the US. We propose a conceptually and technically innovative, systematic, and interdisciplinary approach to efficiently design effective cocktails of targeted cancer therapies that synergistically destroy human lung cancers by acting against essential oncogenic networks in tumor cells. Our unified approach integrates complementary tools including cancer genomics, unbiased double RNA interference loss of function genetic screens, systems network analyses, clinical therapeutics, and prospectively acquired human clinical data. Our approach will allow us to discover unexpected mechanisms that regulate the dependence of a tumor on a driver oncogene that promotes its growth and to identify rare synergistic gene interactions and signaling networks in oncogene- driven tumors that allow them to evade treatment with an oncogene inhibitor. The payoff of these studies will be both an improved understanding, at the basic level, of the functions of human oncogenes and, at the translational level, a new model to accelerate the development of effective rational combinations of targeted therapies at unprecedented scale. If successful, we envision that this approach will lead to effective cancer polytherapies for molecularly defined subsets of lung cancer patients and can be applied to cancers broadly. Public Health Relevance: Cancer is a major public health problem because it is the second most common cause of death in the US. Personalized treatments that specifically target proteins that drive cancer growth in an individual patient are leading to improved responses in some cancer patients but an overwhelming obstacle to the success of such targeted therapy is treatment resistance. To overcome this challenge, we propose a conceptually and technically innovative, systematic, and interdisciplinary approach that is transformative because it will allow us to efficiently design effective cocktails of targeted cancer therapies that synergistically destroy human lung (and other) cancers and, thus, will have a major impact on the ability of personalized treatments to increase the survival of, and potentially even cure, patients with lung and other lethal cancers.

DESCRIPTION (provided by applicant): Lung cancer, the most common subtype of which is non-small cell lung cancer (NSCLC), is the most common cause of cancer mortality in the US. Improved, rational treatments are needed. NSCLC's with activating mutations in the epidermal growth factor receptor (EGFR) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs) but the magnitude of tumor regression is variable and transient. We hypothesized that the heterogeneity of treatment response may result from genetic modifiers that regulate the degree to which tumor cells are dependent on mutant EGFR and, hence, the magnitude and duration of response to EGFR TKI treatment in patients. Through a pooled RNA-interference (RNAi) screening strategy we found that knockdown of CD95 and several components of the NF-kB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-kB promoted resistance to EGFR TKI in EGFR-mutant lung cancer models. Genetic or pharmacologic inhibition of NF-kB enhanced erlotinib-induced apoptosis in EGFR-mutant lung cancer models. Increased expression of the NF-kB inhibitor IkB predicted for improved response and survival EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-kB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers. We propose to further test the hypothesis that the CD95-NF-?B pathway and EGFR are rational companion therapeutic targets in EGFR-mutant lung cancers using pathway-selective NF-?B pharmacologic inhibitors, state-of-the-art murine lung cancer models, and prospectively acquired human lung cancer clinical data in 3 innovative and integrated Specific Aims: 1) Determine the effects of pathway selective pharmacologic inhibitors of NF-kB in EGFR-mutant lung cancer using cellular and in vivo models. Here we will test the hypothesis that pharmacologic inhibition of NF-kB, together with EGFR, will enhance responses in EGFR-mutant lung cancer cellular and murine models. We will also define the mechanisms whereby NF-kB inhibition potentiates cell death induced by EGFR TKI treatment. 2) Determine if CD95-NF-?B signaling is sufficient to induce de novo EGFR TKI resistance in the native tumor environment. Here we will test the hypothesis that selective activation of the CD95-NF-kB signaling axis is sufficient to induce de novo resistance to EGFR TKI treatment in the native tumor environment. We will use transgenic murine models of EGFR-mutant lung cancer in conjunction with transgenic murine models of CD95 ligand that allow for selective activation of CD95 pro-survival output via NF-kB. 3) Determine if increased CD95-NF-?B signaling promotes EGFR TKI acquired resistance in EGFR- mutant lung cancers. Here we will test the hypothesis that increased CD95-NF-kB signaling promotes acquired resistance to EGFR TKI treatment in vivo using both EGFR-mutant lung cancer murine models and prospectively acquired human clinical specimens and data. Our overall goal is to define the strategies for CD95-NF-kB inhibition most likely to be maximally effective in appropriately selected lung cancer patients.

PROJECT ABSTRACT The Administrative Core will provide leadership, coordination and oversight for BATAR-UP with the overarching goal of synergizing the research conducted in the two research projects and the rest of the DRSC network. Led by Co-PI Dr. Bivona and supported by a dedicated Program Manager, the Administrative Core will have three primary goals: 1) oversee the project management of BATAR-UP to ensure that the project milestones are met and scientific interactions are optimized; 2) organize intra- and trans-institutional activities, including internal advisory board activities, monthly research team meetings, and the annual retreat; and 3) organize interactions with the other national DRSC Centers and the broader scientific community, including facilitating scientific exchanges and collaborations and assembling datasets, presentations, and manuscripts for data dissemination.

PROJECT ABSTRACT The proposed Bay Area Team Against Resistance U54 Project (BATAR-UP) is an interdisciplinary effort of investigators to apply their knowledge and expertise to dissect the molecular and cellular basis of incomplete response and resistance to current treatments and to identify new treatment strategies to better neutralize or eliminate residual disease and prevent resistance. This translational approach will be part of the NCI's Drug Resistance and Sensitivity Centers Network to develop innovative strategies to understand and combat mechanisms of tumor resistance and exploit tumor sensitivity to anti-cancer therapies. To accomplish this, BATAR-UP will support two projects and one core driven by a multidisciplinary team of investigators at UCSF and Stanford University. Project 1 will define and interrogate the molecular and cellular basis of residual disease in lung cancers treated with targeted inhibitors in clinical use. We will prioritize for initial study both EGFR-mutant and ALK gene rearrangement positive lung cancers, given their importance as key molecular disease subtypes and our prior published work and expertise. We will harness genetic and transcriptomic analysis of clinical samples (liquid and tumor biopsies) to provide a molecular view of the evolution of response, residual disease, and acquired resistance. We will generate organoid and PDX models and apply cutting-edge functional screens (genetic, pharmacologic, and targeted proteomic assays) to identify key vulnerabilities that could be therapeutically exploited, including with CTEP agents. This systematic approach will allow us to reveal the basis of the incomplete response and residual disease that drives EGFR and ALK inhibitor resistance and pinpoint therapeutic strategies to intercept the evolution of residual disease and eventual acquired resistance. Project 2 will define and interrogate the molecular and cellular basis of resistance and residual disease in lung cancers treated with current immunotherapies, including PD-1 and PD- L1 antibodies. Leveraging shared platforms in synergy with Project 1, we will perform systematic analyses of liquid and tumor biopsy specimens (and ex vivo models) obtained from patients longitudinally before and during treatment and upon acquired resistance. We will focus our studies on EGFR and ALK wild type patients, including squamous cell lung cancer and adenocarcinoma patients where immunotherapy has shown efficacy but is typically non-curative. We will leverage (1) a novel lung cancer organoid model wherein tumor biopsies are cultured as both tumor epithelium and their endogenous tumor infiltrating lymphocytes (TILs) en bloc as a cohesive unit, and (2) deep droplet-based single-cell RNA-seq analysis. Our systematic approach will help define the basis of the incomplete response and residual disease that contributes to immunotherapy resistance and identify potential new therapeutic strategies to help convert these incomplete responses into curative outcomes. Our Administrative Core will provide leadership, coordination and oversight for BATAR-UP with the overarching goal of synergizing the research conducted in the 2 Projects and the entire DRSC network.

Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) the predominant histologic subtype of lung cancer and lung adenocarcinoma the major subset of NSCLC. Despite recent clinical progress with the use of specific targeted therapies, drug resistance remains a problem that limits patient survival. We propose a conceptually and technically innovative, multidisciplinary and collaborative project to improve the survival of lung cancer patients. We aim to capitalize on our recent discovery of the Hippo-YAP signaling pathway as a critical molecular circuit and therapeutic target in the many cancers driven by hyperactivation of RAS-RAF-MEK-ERK (RAS-MAPK) signaling, in which we have a long-standing interest. Resistance to RAF-MEK targeted therapy is a major clinical challenge in these cancers. RAF-MEK inhibitor treatment elicits a profound initial response in most BRAF mutant patients, but these responses are short-lived and some BRAF mutant and almost all RAS mutant patients fail to respond initially due to resistance. Through an unbiased genetic screen in BRAF mutant non-small cell lung cancer (NSCLC) cells, we discovered the Hippo pathway effector YAP acts as a parallel survival input to promote resistance to RAF-MEK inhibitor therapy. Combined YAP and RAF-MEK inhibition was synthetically lethal in several BRAF mutant tumor types and also in RAS mutant tumors. YAP promoted RAF-MEK inhibitor resistance in these tumors by increasing levels of the anti-apoptotic factor BCL-xL and suppressing levels of the pro-apoptotic factor BIM, intriguingly, in cooperation with MAPK signaling. Co-suppression of both YAP and MAPK signaling was required to suppress BCL-xL and increase BIM levels sufficiently to trigger apoptosis. Increased YAP was a biomarker of worse response to RAF-MEK inhibition in clinical samples with BRAFV600E, establishing the clinical relevance of our findings. These data reveal YAP as a novel mechanism of resistance to RAF-MEK targeted therapy and support co-suppression of YAP and MAPK signaling as a promising new therapeutic strategy. We propose to further test the hypothesis that YAP signaling is a critical molecular switch that regulates the biological and clinical response to targeted anti-cancer drugs, specifically in MAPK pathway driven NSCLCs, in 3 Specific Aims. In Aim 1, we will define the role of YAP in modulating targeted therapy response in key MAPK pathway driven NSCLC subsets, such as those with NF1 inactivation and EML4-ALK gene rearrangements (ALK+). We will further dissect the molecular function of YAP in resistance and basis of YAP-MAPK signaling crosstalk. In Aim 2, we will define a pharmacologic strategy to suppress YAP and enhance targeted therapy response, facilitating clinical translation. In Aim 3, we will define the role of YAP as a biomarker and target in NF1-altered and ALK+ NSCLC specimens, in addition to its role in BRAF/RAS mutant tumors established in our prior work. Overall, our project will offer new insight into the basis of therapy resistance and could improve patient survival.

Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) the predominant histologic subtype of lung cancer and lung adenocarcinoma the major subset of NSCLC. Despite recent clinical progress with the use of specific targeted therapies, drug resistance remains a problem that limits patient survival. A promising strategy to combat cancer drug resistance is to deploy rational upfront polytherapies that suppress the survival and emergence of resistant tumor cells. However, in most tumors with oncogenic receptor kinases, the optimal initial polytherapy strategy is unclear because receptor kinases typically engage multiple effector pathways, and which of these individual pathways, if any, is most critical to tumor cell survival is poorly defined. We recently demonstrated in models of NSCLC harboring the recurrent oncogenic ALK receptor kinase fusion (EML4-ALK or ALK+) that the RAS-MAPK pathway, but not other known ALK effectors, is required for tumor cell survival. We revealed that EML4-ALK drives RAS-MAPK signaling by engaging all three major RAS isoforms (H, N-, K-RAS) via the HELP domain of EML4. MAPK pathway reactivation via either genomic amplification of KRASWT (wild-type) or downregulation of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibition. Accordingly, upfront ALK and MEK co-inhibition enhanced both the magnitude and duration of initial response in EML4-ALK NSCLC in vitro and in vivo models. Furthermore, genomic amplification (or gene duplication) of KRASWT or downregulation of DUSP6 was observed in ALK+ lung adenocarcinoma patients with acquired ALK inhibitor resistance. Together, our findings provided new insight into the function of RAS-MAPK signaling in EML4-ALK NSCLC and the rationale for upfront ALK + MEK inhibitor co-treatment to improve patient outcomes, a novel clinical trial we are leading. Moreover, the findings indicated an unanticipated role of the EML4 partner in EML4-ALK oncogene function and RAS signaling. Here, we will further extend our initial discovery to test the overall hypothesis that RAS activation and signaling is a hallmark of oncogenic ALK function in NSCLC. In Aim 1, we will define the biological basis of RAS-MAPK signaling and dependence in EML4-ALK NSCLC, dissecting the molecular and cell biological control mechanisms governing RAS activation and signaling in ALK+ tumors. In Aim 2, we will define the mechanism(s) that may limit curative response to ALK + MEK inhibitor polytherapy in ALK+ NSCLC patients, levering cutting-edge CRISPR-based genetic screening studies and patient tumor samples from our ALK + MEK inhibitor clinical trial. Overall, these multi-disciplinary, collaborative, patient-focused studies spanning biochemical, genetic, pharmacologic, cell biological, and patient cohort and tumor molecular analysis will provide fundamental insight into the function and control of RAS and oncogenic ALK signaling in cancer and further enhance our novel rational polytherapy strategy. Our ultimate goal is to ensure we transform ALK+ NSCLC from a lethal disease into a chronic or curable condition through biologically-based precision medicine.

PROJECT SUMMARY Our general strategy is to take advantage of novel tools and methodologies that we have developed during our first CTD^2 funding period- more specifically pioneering and applying CRISPR based technologies to aid the discovery and characterization of novel cancer targets and their modulators? using innovative high throughput screening methods. Our end goal is to uncover optimal combinations of perturbagens with the potential to eliminate all cancer cells, despite their clonal heterogeneity and environmental context. One goal is to elucidate new molecular targets with the goal to overcome acquired drug resistance. We build upon an exciting system allowing us to quantitate genotypic and phenotypic cell heterogeneity for hundreds of thousands of single cancer cells. We propose a battery of therapeutic small molecule screens to identify candidate driver genes associated with drug resistance and with recurrent mutations from TCGA, TARGET, CGCI, ICGC and related initiatives. The overall goal is to identify synthetic gene combinations necessary for clinical resistance and related to inter- and intra-tumor heterogeneity. We will develop and apply methodologies for the identification of genes influencing heterotypic cell-cell interactions in tumors. Tumor evolution is a challenging area of research, largely due to the complexity of cell types and behaviors. In this aim, high-throughput screens will be performed to identify non-cell autonomous synthetic lethal and synthetic viable interactions relevant to tumor microenvironment interactions. These studies will include primary T-effector/cancer cell interactions to identify new therapeutic targets and cancer associated macrophage and fibroblast/cancer cell screens to identify genes mediating therapeutic resistance. These systems are made possible by using a currently unpublished screening platform that may help to identify genes important for cancer initiation, maintenance, and possibly metastasis. Since we will use primary and cancer tissue, our unique platform will recapitulate as much as possible the characteristics of tumors in patients and address an important challenge in cancer research. We have developed a novel means to establish genetic epistatic interactions in mammalian cells and will expand upon our efforts to generate specific libraries to map the subset of targets identified in the above screens. In this aim, we will address targets and mechanisms by delineating where targets act in the pathway by probing cancer-defining molecular interdependencies, using the novel targets and screening systems described above. The end goal is to uncover the optimal combination of perturbagens with the potential to eliminate all cancer cells, despite their clonal heterogeneity.

PROJECT SUMMARY The discovery of specific molecular drivers of oncogenesis has led to a shift in the treatment of cancer patients, with a move away from the use of conventional cytotoxic chemotherapy and towards molecularly targeted agents that are often more effective and less toxic (e.g. EGFR and ALK inhibitors and immune- checkpoint inhibitor immunotherapies). However, this success of targeted inhibitors and immunotherapy has highlighted the challenge and importance of drug resistance. While patients often benefit from an initial and profound response to these current treatments, the vast majority of responses are incomplete and result in a residual disease state that serves as a prelude to subsequent tumor progression (acquired resistance). While several studies have delineated mechanisms of acquired resistance to treatment with various targeted inhibitors and immunotherapy, very little is known about the mechanisms underlying incomplete response and residual disease during initial treatment. This is a critical knowledge gap to fill to understand the longitudinal trajectories cancer cells take during treatment to form a drug-resistant tumor that leads to the clinical demise of patients. In Project 1, we will dissect the basis of incomplete response and resistance to targeted therapy and identify new treatment strategies to neutralize or eliminate residual disease and forestall resistance. We propose to do so through the prism of lung cancer, the foremost cause of cancer mortality worldwide and a paradigm-defining malignancy that illustrates both the successes and challenges of targeted therapy (and immunotherapy). A unique and transformative feature of our project is the ability to capture clinical specimens that include both liquid and tumor biopsies longitudinally from patients treated with targeted therapy (and immunotherapy), both early following treatment initiation and at maximal radiographic tumor response (residual disease). Coupled with our expertise in innovative methodologies such as tumor molecular profiling, genetic and pharmacologic screens, and organoid and patient-derived xenograft modeling, this capability to capture clinical samples from patients with residual disease affords an unprecedented window into the evolution of response and resistance in patients that can be leveraged to therapeutically target the residual disease state to enhance the magnitude and duration of response in patients. We will complement discovery efforts with the focused analysis of candidate modulators of residual disease that we have already uncovered. We propose 2 Specific Aims to characterize and therapeutically suppress residual disease during targeted therapy in NSCLC: Aim 1 will define the molecular portrait and identify therapeutic targets in targeted therapy residual disease in oncogene-driven non-small cell lung cancer (NSCLC). Aim 2 will functionally test the impact of target engagement to eliminate residual disease in oncogene-driven NSCLC patient-derived organoid and patient- derived xenograft (PDX) models.

Project Summary As knowledge of the molecular drivers of oncogenesis and tumor progression has grown, so too has our ability to deploy more effective and less toxic molecular therapies. For example, targeted cancer therapies such as ALK and EGFR inhibitors in lung cancer are leading to improved clinical outcomes. However, not all patients benefit from this emerging precision medicine approach, such as patients with KRAS-mutant cancers, and those patients who do benefit initially from targeted therapy ultimately succumb to tumor progression due to drug resistance. Gaining a better understanding of the aberrant cell signaling regulation driving cancer initiation, progression, and drug resistance is essential to expand, and improve, molecular treatment options for patients to extend their survival. A major gap in the field is that very little is known about the potential presence and function of subcellular structures that can organize cell signaling in a cancer-specific manner to promote cancer pathogenesis. By studying the molecular determinants of response and resistance to ALK targeted therapy in ALK gene rearrangement lung adenocarcinoma, we discovered that oncogenic ALK gene rearrangements are uniquely and exquisitely dependent on RAS-RAF-MEK-ERK (RAS/MAPK) signaling for growth and survival. Our studies revealed that the basis of the dependence is that this oncogenic ALK activates RAS from an intracellular, cytoplasmic compartment instead of a lipid-membrane compartment in cells. This was surprising because receptor kinases such as native ALK and RAS both canonically signal exclusively from a lipid-membrane compartment such as the plasma membrane. Our findings prompt the intriguing hypothesis that RAS signaling can occur from a protein granule in the cytoplasm, rather than a lipid- membrane compartment in certain cancers. We propose four Specific Aims that leverage genetic, proteomic, biophysical, and cell biological studies to test this hypothesis, with the goal of demonstrating for the first time in mammalian cells that RAS signaling can emanate from the cytoplasm, in an organized protein-based structure that lacks lipid-membranes. We will test this hypothesis initially in lung cancers with oncogenic ALK and expand to those with oncogenic signaling caused by other aberrant kinase gene fusions that may signal from a similar intracellular protein-based platform. If our hypothesis is true, the findings will transform our understanding of the molecular basis of cancer and overturn 25 years of dogma that holds that RAS signaling can only occur from a lipid-membrane compartment. The findings will generate a new understanding of the role of protein granules in cancer pathogenesis, thereby ascribing an unanticipated biological function for this emerging class of subcellular structures. Our efforts hold important implications for designing entirely novel diagnostic and therapeutic strategies to exploit the pathognomonic subcellular organization of oncogenic signaling to improve treatment options for patients in the future. This project could have broad impacts on the understanding of cancer pathogenesis and pave the way for new molecular strategies to better control cancer.

Project Summary/Abstract The goal of the UCSF Paul Calabresi Career Development Award for Clinical Oncology is to foster the development of the next generation of clinical scientists to be effective partners with discovery scientists and conduct high impact and innovative patient-centered cancer research. The Program will be housed in the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC), bringing to bear the exceptional research, clinical, and training environment of one of the world?s leading health sciences institutes. This multidisciplinary training program will leverage strengths in basic cancer research, experimental therapeutics, and clinical research methodology. Two experienced physician-scientists (one clinical researcher and one laboratory-based scientist) will direct the Program. An accomplished group of faculty will bring expertise in cancer-related clinical and translational research, imaging, patient-reported outcomes, biomarkers, healthcare disparities, community engagement, and biostatistics. Building on recent research and technology advancements and key areas for training identified in our HDFCCC strategic review, the two-year Program (which incorporates mentored research, career development guidance, and a core curriculum) is designed to facilitate completion of the year-long Advanced Training in Clinic Research certificate program in Year 1 (epidemiologic and biostatistical methods). Year 2 will focus on mentored research, professional skills, and achieving independence. An Advisory Committee (15 UCSF faculty, 6 external advisors) will work with the program directors to select up to four K12 Scholars, monitor Scholar progress, and identify opportunities for program improvement. Eligible candidates (within five years of training) will be selected from a diverse pool of UCSF faculty and well-established postdoctoral training programs in medical oncology, pediatric malignancies, neuro-oncology, radiation oncology, and surgical oncology. Each Scholar will work with at least one clinically focused and one laboratory-based mentor on their career development committee to design an individual career development plan outlining goals and tailored didactic and hands-on training experiences (including short clinical and laboratory rotations, grant-writing workshops, etc.) that will ensure competency across four core areas: (1) Clinical research methods; (2) Principles of translational cancer research and drug development; (3) Academic success skills and (4) Responsible conduct of research. New K12 program activities, including a 5-day bootcamp (Clinically Driven Discovery Science in Cancer: From the Bench to the Bedside), a seminar series (From Concept to Completion: Strategies for Successful Cancer Clinical Trials), and embedded patient-oriented cancer research experiences (e.g. scientific protocol review, presenting to the Community Advisory Board) will benefit Scholars who are directly supported by K12 funding and other UCSF faculty and trainees with an interest in clinical-translational cancer research. Upon graduation, scholars will have the tools to lead independent, rigorous, and impactful patient-centered clinical research programs.