David A. Fruman - US grants

DESCRIPTION (provided by applicant): The long-range goal of this project is to define the mechanism of phosphoinositide 3-kinase (PI3K) signaling in lymphocytes. As PI3K is required for lymphocyte proliferation, advances in this area may lead to novel strategies for the treatment of immunodeficiency, autoimmunity, transplant rejection and cancer. The central hypothesis guiding this application is that the PI3K regulatory isoforms p85alpha and p85beta have distinct functional roles in lymphocyte signaling. To test this hypothesis, this investigator?s laboratory has generated mice lacking either p85alpha or p85beta. p85alpha-deficient mice exhibit B cell defects similar to those seen in mice lacking Btk, BLNK or PLCgamma2. These findings support a model that PI3K activation is important for membrane assembly of a signaling complex that facilitates PLCgamma2 activation and sustained calcium flux. T cells and B cells rely on distinct proteins to carry out many of the signaling steps that link the antigen receptor to calcium flux and proliferation. For example, calcium flux in T cells is regulated by Itk, a functional homolog of Btk. Preliminary results suggest that p85beta may be an important PI3K regulatory isoform in T cell signaling. This application has three specific aims: Aim 1 is to test the model that p85alpha is required for activation of Btk and PLCgamma2 leading to sustained Ca2+ flux. Biochemical assays will be used to analyze signaling in primary B cells and immortalized B cell lines lacking p85alpha. Aim 2 is determine if p85beta is required for T cell proliferation and cytokine production. Aim 3 is to determine whether p85beta is required for activation of Itk, PLCgamma1, and sustained Ca2+ flux in T cells. Biochemical assays will be used to analyze signaling in purified T cells. These studies will increase our understanding of PI3K signaling, a central control point in lymphocyte proliferation.

DESCRIPTION (provided by applicant): Our laboratory studies mechanisms of phosphoinositide 3-kinase (PI3K) signaling in lymphocytes. We are currently funded by grant # 1 RO1-AI50831-01 to determine the specific roles of individual PI3K isoforms in lymphocyte activation. This work relies on standard functional and biochemical assays to characterize lymphocytes from mice lacking specific PI3K isoforms. However, traditional biochemical approaches to measuring signaling enzyme activity have significant limitations, especially when applied to primary lymphocytes. Advances in single cell analysis of signaling events offer powerful tools to advance our understanding of PI3K, as well as other critical signaling systems. In keeping with the developmental emphasis of this R21 mechanism, this application seeks to develop an emerging technology, the laser micropipet system (LMS), to study PI3K-dependent signals at the single cell level. Our first objective is to develop optimal conditions for studying lymphocytes using LMS. Our second aim is to apply this technology to address the role of the PI3K regulatory isoform p85alpha in activation of different downstream signaling molecules.

5-(6)-carboxyfluorescein diacetate succinimidyl ester; CCL21; CCL21 gene; CFDA-SE; CFSE; CKb9; CRISP; Cell Locomotion; Cell Migration; Cell Movement; Cells; Cellular Migration; Class; Computer Retrieval of Information on Scientific Projects Database; Funding; G-Proteins; GTP-Binding Proteins; GTP-Regulatory Proteins; Generations; Glass; Grant; Guanine Nucleotide Coupling Protein; Guanine Nucleotide Regulatory Proteins; Hour; Image; Institution; Investigators; Isoforms; Life; Lipids; MGC34555; Mammals, Mice; Mice; Motility; Motility, Cellular; Murine; Mus; NIH; National Institutes of Health; National Institutes of Health (U.S.); Protein Isoforms; Receptor Signaling; Research; Research Personnel; Research Resources; Researchers; Resources; SCYA21; SLC; Source; Staining method; Stainings; Stains; System; System, LOINC Axis 4; T-Cells; T-Lymphocyte; TCA4; Thymus-Dependent Lymphocytes; Toxin; UV laboratory microscope; Ultraviolet Microscopes; United States National Institutes of Health; cell imaging; cell motility; cellular imaging; fluorescence microscope; fluorescence/UV microscope; fluorescent microscope; imaging; in vivo; laboratory fluorescence light microscope; thymus derived lymphocyte

DESCRIPTION (provided by applicant): The goal of this project is to study how a novel class of cancer therapeutics impact lymphocyte function. These compounds are active-site inhibitors of the bserine/threonine kinase mTOR (mammalian target of rapamycin). The mTOR kinase is present in two complexes, termed mTORC1 and mTORC2, with distinct substrates and function. The natural compound rapamycin is a selective mTOR inhibitor that potently suppresses lymphocyte proliferation, and is used clinically for immunosuppression. However, rapamycin is an allosteric mTORC1 inhibitor that does not acutely inhibit mTORC2. Novel, active-site (ATP-competitive) mTOR inhibitors block all functions of both mTOR complexes and have more potent cytostatic and cytotoxic effects than rapamycin in cancer cell lines. Consequently, there are worldwide efforts to develop active-site mTOR inhibitors for cancer therapy. The immunoregulatory properties of active-site mTOR inhibitors, however, have not been reported. Defining the effects of these agents on lymphocyte activation will reveal their potential as novel immunosuppressants, while also addressing concerns about host defense and anti- tumor immunity in the cancer therapy setting. Our preliminary data suggest that active-site mTOR inhibitors are selectively toxic to leukemia cells compared to nontransformed lymphocytes. In this project we will use a carefully selected set of experimental approaches to address one specific aim: to compare the effects of rapamycin and active-site mTOR inhibitors on lymphocyte activation and differentiation. We will use both in vitro and in vivo systems, and study both T cells and B cells. Inhibitors will be studied over a concentration range to facilitate comparisons of potency. For T cells, we will use T cell receptor-transgenic systems to measure proliferation in response to cognate antigen. We will employ adoptive transfer approaches to assess T cell expansion in vivo. We will also measure cytokine-mediated survival and T helper differentiation. For B cells, we will measure proliferation and survival in response to different mitogens and cytokines. We will compare the differentiation of B cells into antibody-secreting cells and their ability to produce antibodies in immunized mice. We will correlate the functional responses of lymphocytes with signal transduction events, to determine the molecular basis for inhibitor effects. PUBLIC HEALTH RELEVANCE: This project will study a newly discovered class of anti-cancer drugs and determine how they affect the immune response. This work will help us understand and predict potential side effects of these drugs on the immune system of cancer patients. In addition, we might find evidence that the drugs will be useful to treat immune-related diseases.

DESCRIPTION (provided by applicant): mTOR is a serine/threonine kinase that is expressed ubiquitously. The mTOR enzyme is present in two cellular complexes, TORC1 and TORC2. mTOR was discovered and named based on its interaction with the drug rapamycin. This compound is an allosteric inhibitor that partially blocks TORC1 activity and generally does not inhibit TORC2 function. Rapamycin treatment of T and B lymphocytes profoundly blocks proliferation triggered by antigen and other mitogens, and rapamycin (sirolimus; Rapamune(R)) is an FDA-approved immunosuppressant. However, rapamycin and analogs have lesser effects on proliferation in other cellular systems including cancer cells. Although the effects of rapamycin on lymphocytes have been studied for 20 years, it remains unclear why the compound induces a profound block of proliferation selectively in lymphocytes. Paradoxically, a novel class of ATP-competitive mTOR kinase inhibitors (TOR-KIs) causes less immunosuppression than rapamycin despite causing more complete inhibition of both TORC1 and TORC2. The goal of this project is to define mechanisms by which rapamycin selectively blocks proliferation of normal lymphocytes. Based on preliminary data, we propose two hypotheses that form the basis of separate specific aims. Aim 1 will test the hypothesis that rapamycin causes more complete and sustained inhibition of S6 kinases, key substrates of TORC1. There are two S6 kinases, S6K1 and S6K2, but their roles in lymphocyte activation and proliferation have not been reported. We will use a novel mouse model that will allow a chemical genetic approach to specifically inhibit S6K activity in normal T and B cells. We will use this model to compare the effects of S6K inhibition with the effects of rapamycin and TOR-KIs. Aim 2 will test the hypothesis that rapamycin inhibits kinase-independent functions of mTOR. We will generate a novel mouse strain in which kinase-dead mTOR can be expressed in a cell-specific manner. This will allow us to test the prediction that lymphocytes expressing kinase-dead mTOR will retain residual proliferation that remains sensitive to rapamycin. We will also begin a candidate approach to test possible kinase-independent mTOR functions. PUBLIC HEALTH RELEVANCE: A drug called rapamycin is used to suppress the immune system and prevent rejection of organ transplants. However, it is not known why rapamycin selectively blocks the activation of immune cells, compared to other cell types. This proposal seeks to solve this long-standing question.

DESCRIPTION (provided by applicant): Most cancer cells display activation of phosphoinositide 3-kinase (PI3K) and the downstream enzymes AKT and TOR. Targeting the PI3K/AKT/TOR network is a promising strategy for cancer therapeutics, yet it is not clear which target profile will provide the best balance of efficacy and tolerability. Compounds that partially inhibit TOR (such as rapamycin) or compounds that inhibit both PI3K and TOR (such as PI-103) have significant limitations in efficacy and/or tolerability. A major breakthrough in this field has been the identification of novel compounds that are highly potent, selective, small molecule competitive inhibitors of TOR. Termed active-site TOR inhibitors, these compounds fully inhibit the TOR enzyme when it is present in TORC1 or TORC2, two distinct multiprotein complexes. Compared to rapamycin, an allosteric inhibitor, active-site TOR inhibitors have a broader effect on key signaling pathways and are more effective at suppressing survival of murine and human leukemia cells. Remarkably, these compounds are less immunosuppressive than rapamycin despite their greater anti-leukemic efficacy. Active-site TOR inhibitors appear equally effective in leukemia models as the less selective PI3K/TOR inhibitors, yet are considerably better tolerated in mice. Several active-site TOR inhibitors are in early stage clinical trials. The overall objective of this proposal is to refine and extend our understanding of active-site TOR inhibitors, with the ultimate goal of improving the health of cancer patients. We will focus on B cell malignancies, since active-site TOR inhibitors have dramatic effects in B cell leukemia models yet the mechanism of action remains poorly understood. The proposal has two specific aims. First, we will establish the mechanisms by which active-site TOR inhibitors trigger leukemia cell death. In this aim we will use genetic approaches to test the hypothesis that both TORC1 and TORC2 mediate survival signaling in leukemia cells. This will be accomplished using inducible Cre-mediated knockout systems and shRNA-mediated knockdown. We will then test the roles of TORC1 and TORC2 substrates in maintaining survival in leukemia cells. Second, we will define mechanisms of cellular resistance to active-site TOR inhibitors. As with any targeted molecular approach, subtypes of cancer cells display differing sensitivity to active-site TOR inhibitors. An emerging theme in drug development is the need to identify effective combinations of targeted agents. Using cell lines that do not undergo apoptosis in response to TOR inhibition, we will use candidate and global approaches to identify druggable mechanisms of resistance. We will then test combination strategies in vitro and in vivo. Identifying mechanisms of resistance and applying appropriate drug combinations will broaden the potential application of active-site TOR inhibitors.

DESCRIPTION (provided by applicant): This project will be a campus-wide effort at UC Irvine to broaden the training of biomedical PhD students and postdoctoral fellows. The NIH Biomedical Research Workforce report concluded that graduate training should no longer focus exclusively on preparing scientists for academic research. Faculty, students and administrators at UC Irvine agree that we must recognize and nurture non-academic career paths for PhD trainees. To accomplish this objective, we propose a program called UCI-GPS (UC Irvine Graduate Professional Success) that will encourage students and postdoctoral fellows to prepare for a variety of career options. The program leadership will include faculty, students, staff, and non-academic partners. The proposal has four Specific Aims: (1) EXPLORE: Increase awareness and interest in science-related careers outside academic research; (2) TRAIN: Improve communication and other skills needed to pursue alternative career paths; (3) EXPERIENCE: Provide hands-on experience through internal and external internships; (4) TRANSITION: Build networks that allow trainees to prepare for and transition to science-related careers. The program will transcend department, program, and school boundaries. Students in ten different PhD programs, and postdoctoral fellows in participating departments, will gain access to a diverse menu of professional development activities. A system of professional development credits will encourage participation in activities, including: Seminars and Workshops: PhD degree holders in various science-related professions will visit campus to give lectures and meet participants; Courses: fee waivers will allow participants to gain access to valuable online courses to develop key skills sought by employers; participation in existing classes that specifically develop oral and written scientific communication skills will be expanded; Networking: quarterly mixers will be established to facilitate professional connections in workforce sectors of interest; a mentoring program will also be established; Internships: qualified trainees will have the opportunity to serve as interns for one month or more in diverse work environments outside the academic research laboratory, with support from graduate fellowship funds. Program activities will focus on developing skills that are not generally acquired during academic research training. We will track outcomes of UCI-GPS trainees and an external evaluator will monitor the program impact. The Principal Investigator and Co-Investigators of the UCI-GPS program have a strong track record of graduate training and mentorship, with complementary expertise in different disciplines and experience in the private sector. Together with other key stakeholders on the UCI campus, the UCI-GPS leadership is committed to increasing the percentage of PhD trainees who make successful transitions to science-related careers. This goal aligns with our industry partners who seek a better-trained biomedical workforce.

? DESCRIPTION (provided by applicant): Support is requested for continuation of the Training Program in Cancer Biology and Therapeutics (CBT) at the University of California, Irvine. Despite decades of research, cancer is the #1 killer of adults under 85. Thus, there remains a substantial need for new therapies, diagnostics and preventions that will not be met by business as usual approaches. The goal of this program is to meet this need by providing UCI graduate students and postdocs with comprehensive, highly interdisciplinary training that includes cancer biology, the most current research methods, and a focus on translational science such as the development of novel cancer therapeutics and diagnostics. The foundation we provide together with professional development activities offered will produce a cohort of well-trained experts armed to successfully attack the cancer problem from vantage points in both academia and industry. The Program benefits from outstanding institutional support from the UCI Chao Family Comprehensive Cancer Center (a NCI-designated comprehensive cancer center), the UCI Cancer Research Institute, Graduate Division, and other campus offices. The Program provides research opportunities across the cancer continuum from etiology to therapeutics, encompassing faculty from the School of Biological Sciences, basic and clinical departments in the School of Medicine, and the department of Chemistry. There are twenty-eight training faculty, each with a cancer-focused research program and established record of training. We request support for four postdoctoral and four predoctoral trainees; one additional predoctoral position will be supported by our Graduate Division. Over the last two years, we have carried out a rigorous self-evaluation with input from trainees, faculty, and external advisors. This process has led us to implement a revised program that meets the specific needs of current UCI trainees. The Program is led by a new Director and co-Director, both mid-career faculty with outstanding records of research productivity and training. A continuing element of the Program will be a rigorous and well-defined set of courses (Cancer Biology parts A and B, Clinical Cancer for Basic Scientists, Cancer Biology Journal Club), that build knowledge about basic and clinical/translational cancer research. Other strong components that will continue are the biennial CBT program retreat and the annual symposium in basic cancer biology. A fundamental change will be greater flexibility for trainees to choose courses and activities based on their Individual Development Plan (IDP) that they will update annually. Other new elements will be a Research-in- Progress series, a quarterly seminar series featuring eminent cancer researchers from academia and industry, and enhanced opportunities for exposure to clinical cancer care and research. The Program will implement substantial improvements to recruiting approaches for both predoctoral and postdoctoral trainees, including innovative methods to recruit underrepresented minorities. Lastly, CBT trainees will benefit from an exciting new emphasis on professional development, supported in part by a new NIH-BEST award to UC Irvine.

? DESCRIPTION (provided by applicant): This proposal focuses on B-cell acute lymphoblastic leukemia (B-ALL). Despite a dramatic increase in cure rates over the past decades, a subset of children with B-ALL continues to have unacceptably high rates of relapse. Leukemias in this high-risk group include Philadelphia chromosome positive (Ph+) cases driven by the BCR-ABL tyrosine kinase, but the majority are Ph- negative. Many high-risk Ph-negative B-ALL cases can now be designated as Ph-like B-ALL due to similar gene expression and activation of tyrosine kinases. Emerging data indicate that Ph-like B-ALL is also prevalent in adolescent and young adult patients. Importantly, Ph-like leukemias show decreased kinase signaling upon treatment with tyrosine kinase inhibitors (TKIs) in vitro and TKI treatment suppresses disease in xenograft models. These findings establish strong rationale for clinical testing of TKIs matched to patient-specific genomic lesions in Ph-like B-ALL. However, TKI resistance develops in many cancers, emphasizing the need to target additional survival mechanisms. Using xenograft models of adult Ph+ B-ALL we have reported that second generation, ATP- competitive inhibitors of mTOR work in synergy with TKIs targeting the BCR-ABL oncogene. Combining mTOR kinase inhibitors (TOR-KIs) with TKIs causes regression of leukemia to a greater extent than TKI alone or TKI plus rapamycin, even in tumors with intrinsic resistance to BCR-ABL kinase inhibitors. mTOR kinase inhibitors are well tolerated at therapeutic doses. Because the TKI/TOR-KI combination works well in Ph+ B-ALL xenografts, we believe similar combinations will be effective in Ph-like B-ALL. This project will test this hypothesis, with the goal of obtaining proof-of- concept data supporting clinical trials of TKI plus TOR-KIs in children, adolescents and young adults with Ph-like B-ALL. We will accomplish this objective using cells from established Ph-like B-ALL xenografts, provided by collaborators. The first specific aim is to evaluate the efficacy of dual pathway inhibition on xenografted Ph-like leukemia samples. Endpoints will be percent leukemia cells in the bone marrow, and fraction of cycling cells in the leukemia versus normal bone marrow cell populations. The second specific aim is to test whether the combination treatments suppress survival signaling in B-ALL cells more profoundly than single treatments. We will address this in part through phosphoflow analysis of cells obtained from bone marrow of xenografted mice. We will also validate an emerging technology, CYTOF, for multiparameter analysis of the phosphoproteome in B-ALL cells from bone marrow of treated mice. These studies may lead to new approaches to prevent relapse in high-risk B-ALL and biomarkers to monitor response to therapy.

? DESCRIPTION (provided by applicant): The mammalian target of rapamycin (mTOR) drives lymphocyte growth, division, and differentiation following antigen stimulation. mTOR is a protein kinase that functions in two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric mTORC1 inhibitor that profoundly suppresses B cell proliferation and differentiation. Conversely, elevated mTORC1 activity is seen in lymphocytes from patients with autoantibody-driven disorders including arthritis and lupus. However, the mechanisms by which mTORC1 signaling promotes B cell differentiation remain poorly defined. We have reported that genetic or pharmacological inhibition of mTORC1 suppresses antibody class switching in activated B cells. Subsequently we identified novel roles for eukaryotic initiation factor 4E (eIF4E), a downstream mTORC1 effector, in promoting B cell proliferation and antibody class switching. eIF4E regulates the translation of subsets of mRNAs in a cell type-specific manner, and is opposed by eIF4E-binding proteins (4E-BPs) that are direct substrates of mTORC1. Using novel chemical tools and genetic mouse models we have determined that the roles of mTORC1, 4E-BPs and eIF4E in class switching can be separated from their roles in proliferation. The general goal of this proposal is to define the mechanisms by which mTORC1 and eIF4E promote antibody class switching. The first Aim is to test the hypothesis that efficient class switching requires eIF4E an is opposed by 4E-BPs. We will measure isotype switching in activated B cells from mice with increased or decreased expression of eIF4E or 4E-BPs, in the presence or absence of RAP. Novel compounds that inhibit mTORC1 through an ATP-competitive manner will also be used. The role of the 4E-BP/eIF4E signaling axis will also be tested in vivo by measuring antibody responses and germinal center formation in immunized mice. The second Aim will define the mechanisms by which eIF4E regulates translation of mRNAs involved in B cell differentiation. Increasing evidence indicates that translation efficiency varies widely among individual mRNAs, and that regulated translation modulates the proteome to a similar degree as transcriptional and epigenetic regulation. In accord, genome-wide translatome studies have uncovered novel regulatory mechanisms in tumorigenesis and other processes. We will use ribosome profiling for global, unbiased identification of eIF4E targets that are differentially translated in activated B cells undergoing antibody class switching. This project is significant because a greater understanding of the translatome controlled by eIF4E and suppressed by mTORC1 inhibition might reveal novel strategies for suppressing pathogenic autoantibody responses, with a better therapeutic window than rapamycin. This work will also shed light on potential immunosuppressive effects of eIF4E inhibitors under development for cancer.

Project Summary The goal of this proposal is to evaluate the feasibility of using HMGCR inhibitors (statins) to enhance efficacy of ABT-199 in preclinical models of B cell cancers. ABT-199 (venetoclax) is a small molecule inhibitor of BCL-2, a key pro-survival protein that is highly expressed in many leukemias and lymphomas. Statins are commonly used to control plasma cholesterol levels and are among the most widely prescribed medications worldwide. However, statins are also known to have anti-cancer potential. We have observed potent synergy of statins combined with ABT-199 in human cell lines derived from diffuse large B cell lymphoma (DLBCL). This synergy is also seen in murine B lymphoma cells derived from a genetically engineered mouse model. Using a BH3 profiling assay, we observed that simvastatin increases mitochondrial priming, correlating with its ability to synergize with ABT-199. Mechanistic studies support the hypothesis that statins prime lymphoma cells for apoptosis by blocking prenylation pathways downstream of mevalonate production by HMG-CoA-reductase. In this proposal we will build on these findings to address the feasibility of the statin/ABT-199 combination. The first Aim is to determine whether statins can achieve pharmacological exposure in tumor cells at a clinically relevant dose. We will compare three different statins in a mouse lymphoma model to identify the optimal statin and minimal dose with pharmacodynamic activity. The second Aim will be to evaluate the efficacy and toleratibility of the statin/ABT-199 combination in lymphoma models. Using a mouse syngeneic B cell lymphoma driven by BCL-2 and MYC, we will assess differences in lymphoma outgrowth and mouse survival, and correlate with a pharmacodynamic marker of statin action. We will also examine drug effects on survival of primary human lymphoma cells in vitro. In parallel we will measure the impact of drug treatments on normal lymphocytes using both the in vivo mouse model, and using peripheral blood mononuclear cells from healthy human volunteers. The third Aim is to test whether mitochondrial priming provides a predictive biomarker of statin efficacy. Using dynamic BH3 profiling, we will determine whether increased mitochondrial priming by statins correlates with response to the statin/ABT-199 combination. Together these experiments will establish efficacy, tumor selectivity, and a predictive biomarker for the combination of statins plus ABT-199, providing proof-of-concept to support future clinical trials in aggressive lymphomas.

Project 003 - Project Summary/Abstract - Systems, Pathways & Targets (SPT) The Systems, Pathways & Targets (SPT) Program is a newly formed program (created in 2011) that integrates cancer-focused members from two prior programs with new members who have expertise in the systems biology of cancer. SPT members focus on cellular signaling, tissue morphogenesis and computational modeling/bioinformatics. The overarching goal of this program is to identify key proteins or points of crosstalk for therapeutic intervention. To achieve this goal, three aims are proposed: 1) Identify key targets in signaling pathways, developmental pathways, and metabolic programs that are relevant to cancer initiation, progression, and therapeutic resistance, 2) Develop multi-disciplinary teams to study tumor heterogeneity and microenvironment/cellular interactions, 3) Diversify multi-disciplinary approaches to develop new therapeutic strategies. SPT members include cell biologists, immunologists, geneticists, developmental biologists, computational scientists, and clinicians. Dr. David Fruman and Dr. John Lowengrub direct the program as co- leaders. Their expertise in cellular signaling and drug development (Fruman) and systems biology of the tumor microenvironment (Lowengrub) embody the scientific breadth of basic research in the program, their partnering with basic and physician scientist members demonstrates the collaborative nature of SPT. Since the last renewal, exciting progress has been made in the identification of new targets in cancer cells and the development of small lead compounds against those targets. The first subset of these molecules are making their way to the bedside in the form of pre-clinical tests and clinical trials. Strategic partnering with members of the Chemical and Structural Biology (CSB) program has led to the synthesis of a second subset of molecules for evaluation in pre-clinical assays. In addition, SPT members have collaborated with bioengineers in the Onco-Imaging and Biotechnology (OIB) program for the development of new tools for cancer research. New collaborations with members of the Cancer Prevention, Outcomes and Survivorship (CPOS) program show promise in identifying and addressing issues in the catchment area of the cancer center. In the future, the SPT program leadership will continue to leverage the unique breadth and synergy among its members to build collaborative teams that tackle long-standing problems using bold and innovative approaches. Membership: 55 Members from 17 Departments Funding: $2,731,793 NCI (Totals); $9,767,626 Other Peer-Reviewed (Totals) Publications: 588 Publications, 15% Inter-programmatic; 12% Intra-programmatic

Support is requested to continue a successful cancer research training program at the University of California, Irvine (UCI). This newly renamed Training Program for Interdisciplinary Cancer Research (IDCR) builds on a foundation of more than 40 years of experience developing PhD students and postdoctoral fellows to become scientific leaders. As the nature of cancer research and treatment have evolved, so has the focus of our training program. We emphasize interdisciplinary approaches to advance knowledge in cancer biology and treatment, offering trainees a highly collaborative environment that includes faculty mentors from five different Schools at UCI. Coursework emphasizes critical analysis of research literature in cancer and related disciplines, the most current research methods, and a focus on translational science such as the development of therapeutics and diagnostics. The scientific foundation we provide together with professional development activities offered will produce a cohort of well-trained experts armed to successfully attack the cancer problem from vantage points in both academia and industry. The Program benefits from outstanding institutional support from the UCI Chao Family Comprehensive Cancer Center (a NCI-designated comprehensive cancer center), the UCI Cancer Research Institute, Graduate Division, and other campus offices. The Program provides research opportunities across the cancer continuum from etiology to therapeutics, encompassing faculty from the Schools of Biological Sciences, Medicine, Pharmacy and Pharmaceutical Sciences, Physical Sciences, and Engineering. There are thirty training faculty, each with a cancer-focused research program and extramural funding. We request support for four postdoctoral and four predoctoral trainees; one additional predoctoral position will be supported by our Graduate Division. The Program is led two co-Directors, both senior faculty with outstanding records of research productivity and training, and a history of collaboration. In preparation for this renewal application, we have carried out a rigorous self-evaluation with input from trainees, faculty, and externaladvisors. This process has led us to implement a revised program that meets the specific needs of current UCI trainees. A continuing element of the Program will be a rigorous and well-defined set of courses (?Cancer Biology parts A and B?, Clinical Cancer for Basic Scientists) that build knowledge about basic and clinical/translational cancer research. Other strong components that will continue are the biannual program retreat, the annual symposium in basic cancer research, and access to exceptional professional development opportunities (established under a NIH-BEST award and continuing with campus support). A fundamental change will be to redesign our journal clubs and research-in-progress talks to maximize interaction with diverse training faculty and expand active learning of interdisciplinary cancer research approaches. We will also implement several changes in program administration to increase faculty participation and to optimize mentoring, evaluation, and recruitment.