Beckman Research Institute/City Of Hope

NIH Research Projects · FY 2026 · 2016-07

Increases in cancer incidence and rising cancer costs highlight the need to advance cancer biology through the growth of a well-trained workforce. Almost all human cancers have alterations in signaling pathways associated with DNA damage response and oncogenic signaling, and such pathways are also the focus of targeted therapies already in the clinic and under development. To train the next generation of cancer researchers, we have developed an institution-wide cancer biology training program for postdoctoral fellows focused on this area of cancer research, called the DNADRS program. This program is housed at the City of Hope, an NCI-designated Comprehensive Cancer Center, which is known internationally for clinical cancer research and has an outstanding record of basic cancer research. This T32 program began in 2016, and this is the first renewal application. The 3 T32-supported postdoctoral trainees supported for up to 3 years are selected for the DNADRS program through a rigorous process, including a personal interview. Each trainee establishes a mentoring committee that includes a physician to foster cross-pollination of ideas between the basic and translational aspects of cancer research. Annual reappointment is based on annual written reports from the trainee and mentoring committee. As part of a recruitment incentive in the DNADRS program, City of Hope will continue to provide an additional postdoctoral trainee position for every T32 trainee recruited, up to a total of 6 positions. Furthermore, to attract the best postdoctoral candidates at a national level, City of Hope continues to commit to salary supplementation for all DNADRS trainees, a stipend for research supplies, and full administrative and faculty salary support. Trainees will be mentored by 18 faculty members, all of whom are performing cancer-focused high-impact research and have a history of mentoring postdoctoral fellows. To enhance their chances of developing into independent cancer researchers, all DNADRS trainees take a unique common curriculum that provides a continuum of learning including scientific coursework that includes ethical conduct of research and proper research design, as well as professional development courses. In addition, trainees participate in cutting-edge research programs, journal clubs, seminars, symposiums, regular luncheons with mentors, mentoring committee meetings, national and international scientific conferences, and finally a yearly DNADRS Symposium. The stellar and comprehensive Shared Resource Facilities associated with the Cancer Center provide training in state of the art technologies. The request for funding to renew this research training grant is justified by our track-record from the last funding cycle of seven successful trainees, the relevance of the research training to cancer, the experience of the mentors, the outstanding commitment of City of Hope, and the varied population of the large geographical area served by our institution.

NIH Research Projects · FY 2024 · 2015-09

PROJECT SUMMARY / ABSTRACT The California Teachers Study (CTS) has collected high-quality and detailed exposure, biospecimens, cancer, and clinical endpoint data on 133,477 female volunteers followed since 1995. The cancers, hospitalizations, and deaths to date are less than half of the total endpoints projected to occur in the CTS over the next 30 years. In the next 5 years, CTS follow-up will include over 37,000 cancers; 455,000 hospitalizations; and 41,000 deaths. This provides a solid foundation for collaborative research using these unique resources. Since 2013, the CTS collected new blood samples from 14,674 participants. Cloud computing and integrated mobile devices generated rich phenotype data and exceptionally low pre-analytical variability for 488,000 aliquots that are being stored as CTS follow-up continues. Since 2015, the CTS modernized its data collection, storage, and analysis infrastructure by implementing a secure data warehouse and flexible analytics environment designed for high-quality and integrated epidemiologic analysis. The CTS includes secure user authentication & authorization; a collaborative workspace with documents, data visualizations, tools, and workflows; metadata; application programming interface (API) capabilities; and a scalable data model. The CTS is now positioned to streamline its resources for long-term sustainability. The goals of this competing renewal are to preserve existing resources that enable research and strategically expand areas that create high-value opportunities. First, we will maintain existing CTS data and extend passive follow-up through efficient cancer, hospitalization, and mortality linkages. These ongoing linkages will generate additional endpoints used for future etiologic, consortial, aging, and other research. Second, we will store the 488,000 high-quality biospecimens collected since 2013. These specimens are all currently available to everyone; ongoing storage will ensure that they remain available to everyone. Third, we will expand capacity by integrating additional targeted geospatial data on climate, extreme weather, built environment, community characteristics, health access, environmental exposures, social vulnerability, and community resilience. The new CTS infrastructure efficiently enables everyone, regardless of their GIS expertise, to rigorously incorporate individual-level geospatial exposures into their analyses. Fourth, because most participants are now over age 65, we will link the CTS with Medicare outpatient data to complement existing data and expand infrastructure for aging, survivorship, comorbidity, and health services research. The recent CTS infrastructure updates added research-ready efficiencies to manage and process complex geospatial, administrative claims, and other CTS data in ways that help all researchers, especially those outside the CTS, conduct integrative, rigorous, and reproducible research. The CTS is an innovation leader with primed assets and decades of promising future research potential. This competing renewal will maintain high-value CTS resources that can address understudied research areas, facilitate broader use by the entire scientific community, and streamline the CTS for long-term sustainability.

NIH Research Projects · FY 2025 · 2014-09

ABSTRACT The scale and scope of scientific collaborations in the Human Islet Research Network (HIRN) bring together extraordinary resources to solve complex problems in type 1 diabetes (T1D). To capitalize on this initiative, extensive efforts are required to coordinate, communicate, and catalyze research effectively. The City of Hope is applying to renew the Human Islet Research Enhancement Center (HIREC), providing the administrative and scientific infrastructure needed for day-to-day operations of the HIRN and capitalizing on existing and emerging resources to propel it forward as an innovative team science engine in T1D research. The specific aims of this project were formed to address critical challenges and requirements, or put simply to engineer, enrich, and empower the future of HIRN. The established team is not only experienced in establishing data centers, systems, and resource distribution networks critical to the HIRN, but also are researchers with expertise in T1D disease pathogenesis, biostatistics, bioinformatics, computational biology, data science, semantic technologies, software development, and the use of Findable, Accessible, Interoperable, and Reusable (FAIR) principles. Discoveries arising from HIRN will profoundly improve our understanding of T1D pathogenesis and expedite the advancement of disease prevention and treatment strategies.

NIH Research Projects · FY 2025 · 2014-05

Retinoid-related orphan receptor gamma t (RORyt) is a transcription factor that regulates the differentiation of Th17 cells in the peripheral immune system and the development of thymocytes in the central immune system. As pathogenic Th17 cells are responsible for tissue damages associated with many types of autoimmune diseases including multiple sclerosis, psoriasis and inflammatory bowel disease, there is a medical need for the development of RORyt-based therapies to treat these autoimmune diseases. However, inhibition of RORyt, that ameliorates Th17-mediated autoimmune diseases, also disrupts thymocyte development and thus prevents the replenishment of the peripheral immune system with T cells critical for clearance of infection by pathogens such as bacteria and virus. Further, inhibition of RORyt activity could lead to the development of cancer. We thus propose to separate RORyt function in Th17 cells and thymocytes by characterizing its shared and unique co-factors in these two types of cells, which will facilitate to achieve the long-term goal of development of RORyt-based therapies for treatment of autoimmune disease with minimum toxic side effects.

NIH Research Projects · FY 2025 · 2014-03

PROJECT SUMMARY As the California Cancer Consortium (CCC), four National Cancer Institute (NCI)-Designated Cancer Centers propose to participate in the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) to conduct early phase clinical trials of experimental therapeutics. The CCC comprises City of Hope (COH, Lead Academic Organization [LAO]), the University of Southern California (USC, Affiliated Organization [AO]), the University of California, Davis (UCD, AO), and Stanford Cancer Institute (SCI, AO), and has a 25-year history as a multidisciplinary group conducting early phase clinical trials of NCI-sponsored investigational new drugs under previous U01 and UM1 Cooperative Agreements and N01 Contracts. Our multidisciplinary group of investigators will contribute to ETCTN Project Teams by leveraging the combined expertise of COH, UCD, USC, and SCI in molecular pharmacology, pharmacokinetics, pharmacodynamics, pharmacogenomics, signal transduction, cell cycle regulation, non-invasive imaging, and bioinformatics to conduct innovative, laboratory-directed early phase developmental and pharmacokinetic studies. We propose to use the combined patient and scientific resources and expertise of UCD, COH, USC, and SCI to accomplish the following Specific Aims: (Aim 1) to use the existing relevant capabilities and scientific leadership of the CCC to enhance the ETCTN program; (Aim 2) to leverage the combined breadth of the clinical programs at COH, USC, UCD, and SCI NCI-Designated Comprehensive Cancer Centers to support the rapid completion of ETCTN trials; (Aim 3) to use the central Data Coordinating Center (DCC) and Biostatistics Core (BC) at COH to facilitate frequent communication within the CCC and with the NCI and ETCTN, provide rapid development and effective oversight of trials, and ensure adherence to policies and procedures; and (Aim 4) to optimize information gained from ETCTN clinical trials by including molecular characterization of patients’ malignancies and incorporating molecular pharmacodynamic endpoints and investigational imaging. These early phase studies will lead to recommended, biologically effective doses, greater understanding of the spectrum of normal tissue toxicity of agents, and initial estimates of efficacy. They will also provide mechanistic validation of the effects of the agents on critical tumor cell targets, correlate drug-related changes in tumor and host biologic markers with clinical outcome, and develop new insights into the therapeutic mechanisms of action of the compounds both in the laboratory and the clinic. As such, they will advance the ETCTN’s overall goal of accelerating the development of novel anticancer agents that capitalize on unique molecular features of individual tumors and identifying appropriate biomarkers to select patients who are most likely to respond to specific agents.

NIH Research Projects · FY 2025 · 2013-09

The rapid and ongoing infusion of genomic information into clinical practice continues to fuel the need for a skilled workforce to navigate genomically-informed patient care. National surveys document the continued gap between the need for, and availability of, clinicians equipped with the knowledge, skills and resources to integrate complex germline and tumor genetic information into practice. This R25 proposal outlines a plan to further the mission of the Clinical Cancer Genomics and Community of Practice (CCGCoP) to help address the continuing demand for clinicians competent in evidence-based cancer genomics care. The CCGCoP is built on the theoretical framework of situated learning, the resources and expertise of the academic cancer center, and a distinguished faculty of recognized thought leaders to deliver a multimodal inter-professional course in genetic cancer risk assessment (GCRA) to clinicians practicing in communities with limited access to GCRA services. Over the current project period, 719 clinicians from varied practice settings have completed the course or are now in session, exceeding our projected accrual by 43%. The aims are to: 1) Continue the established annual CCGCoP Intensive Course, 2) Update the current curriculum and learning assessments, 3) Develop and pilot a Self-directed Review Course to provide a means for course alumni to refresh their knowledge and skills with evidence-based cancer genomics content and case-based activities, and 4) Evaluate the Intensive Course and Self-directed Review on participant engagement, knowledge, case-based skills, learning experience and value to practice, and incorporate into iterative improvements in the self-directed model. Fulfillment of these aims will further our efforts to grow the number of clinicians with practitioner-level proficiency in genetic cancer genetics across the U.S. and internationally. Additionally, our plan to develop and pilot a self-directed cancer genetics review course will support ongoing quality improvement in GCRA for course alumni and will serve as a framework for future development of a fully self-directed version of the intensive course to reach a broader national and international audience of healthcare professionals.

NIH Research Projects · FY 2025 · 2012-09

PROJECT SUMMARY / ABSTRACT Human pancreatic islets are an essential research resource for research on the prevention, treatment, and pathophysiology of diabetes mellitus. Recent data have highlighted important differences between murine and human islets, substantiating the continued need for access to human islets, as the gold standard in diabetes research. City of Hope (COH) is applying for this U24 renewal to remain as the Integrated Islet Distribution Program Coordinating Center (IIDP CC) for the next 5 years, to continue to provide distribution of human cadaveric islets and ancillary tissue for biomedical research to researchers worldwide. Our proposal leverages the significant investment made by NIH over the last 19 years that has established and successfully maintained the IIDP at COH. From qualification and auditing of high-quality Islet Isolation Centers (IICs), to forecasting, tracking, and meeting the needs of investigators, since 2002 our experienced team has worked with 20 different islet isolation laboratories to coordinate the distribution of over 330 million islet equivalents to more than 400 investigators across 16 countries since 2002, supporting 767 peer reviewed publications. Through this renewal we will continue to subcontract with our 5 highly qualified IICs to isolate and distribute human islets and ancillary tissue via our advanced electronic Islet Allocation System (IAS). We will continue to manage the review process for islet receipt, pilot studies, and Opportunity Pool funding. We will further enhance our IAS to broadcast offers online and notify approved waiting researchers of islet availability, in a fair, equitable and time sensitive manner. IIDP will continue to maintain the existing cost recovery system through subscription fees collected from islet researchers, which has garnered a total of $9,303,950 since the implementation of subscription fees to offset the expenses of pancreatic processing for the IICs. We will continue to closely monitor and help to improve the quality of islets distributed, through the continuation of the Human Islet Phenotyping Program (HIPP) that conducts assays on a sample from each islet isolation. IIDP has just added a Human Islet Genotyping Initiative (HIGI) to genotype each isolation as well. Phenotyping and genotyping data, as well as UNOS data, extensive donor and islet isolation data, will be made available to approved investigators through online access to the IIDP Research Data Repository, with IIDP and NIDDK approval of applying scientists. Investigators can easily search the required data, select filter criteria, save their searches, and download the integrated IIDP data for exploratory analyses. Through our proven state-of-the-art administrative, business, technical, statistical, quality assurance, and informatics processes and tools, the accessibility of human islets for investigators conducting essential diabetes mellitus research will be secured. We will continue to provide an indispensable research resource for the diabetes research community by ensuring that the IIDP remains stable, technologically advanced, continually enhanced, and fully responsive to the islet needs of the research community, promoting the next generation of scientific experimentation toward the prevention and treatment of diabetes.

NIH Research Projects · FY 2025 · 2004-07

PROJECT SUMMARY Type 2 diabetes (T2D) impacts ~38 million people in the US, and a shocking >98 million have prediabetes. The transformational anti-obesity drugs address a substantial facet of the obese population with insulin resistance (IR) and type 2 diabetes (T2D). However, their use is limited with certain comorbidities, especially in the T2D- susceptible aging population. Insulin secretion by islet β-cells and peripheral insulin action in skeletal muscle (skm) depend upon exocytosis proteins, and failure of exocytosis is a key cause of susceptibility to (pre)T2D. Thus, there is an unmet need for additional safe/effective (pre)T2D therapies that coordinately improve insulin secretion and insulin action. To diminish these complications and halt progression to T2D, our long-term goal is to understand the signaling and exocytosis mechanisms that can be modulated to prevent or reverse prediabetes. Over the past funding cycle, we identified that the plasma membrane (PM)-localized Syntaxin 4 (STX4) is also a pivotal mitochondrial regulator, culminating as a master regulator of insulin secretion and peripheral insulin action. Provocative preliminary data show that: (i) STX4 is localized to β-cell and skm mitochondria; (ii) skm-specific STX4 enrichment in high-fat-diet (HFD)-obese mice fully restores peripheral insulin sensitivity by preventing mitochondrial dysregulation; (iii) STX4 activation promotes functional capacity in human T2D and prediabetic islet β-cells, as well as in skeletal myotubes; and (iv) STX4 depletion in skm or β- cells impedes mitochondrial turnover by mitophagy. Thus, our central hypothesis is that STX4 is essential for mitochondrial function in skm and β-cells, and that STX4 activation can prevent and/or reverse the damaging effects of diabetogenic stress. The rationale for the proposed research is that once new mechanisms of STX4 are elucidated, and the role of STX4 in glucose homeostasis is understood, STX4-regulated signaling can be modulated to prevent or reverse disease in the face of diabetogenic stimuli. Two Specific Aims (SA) will test our central hypothesis: SA1, we will determine the role of STX4 in skm mitochondrial function, mitochondrial turnover by mitophagy, and reversal of insulin resistance; in SA2, we will determine the role for STX4 in islet β-cell mitochondrial structure and function. We will use innovative inducible skm- and β-cell-specific STX4 transgenic mice, and our novel hit small molecule to evaluate the therapeutic potential of activating STX4 in human islets in vivo/ex vivo, as well as human pancreatic slices, in a translation-focused institutional environment at City of Hope. This work will demonstrate how STX4 subverts diabetogenic stress in skm and islets, providing new insights into how STX4 targeting might be used for prediabetes treatment/prevention of T2D. These results will also positively impact efforts to ameliorate prediabetes because the identified mechanisms are highly likely to provide new therapeutic targeting strategies.

NIH Research Projects · FY 2025 · 2001-09

PROJECT SUMMARY This grant application seeks to renew our status as a Core Clinical Center (CCC) and member of the Steering Committee of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The City of Hope (COH) Hematopoietic Cell Transplantation (HCT) Program has focused its efforts over the last 50 years on the development of Phase I, II and III clinical trials leading to improvements in HCT for the treatment of hematologic malignancy and non-malignant disorders. In addition to developing laboratory-based translational research trials, our program has conducted prospective clinical trials in areas such as reduction of relapse, graft-versus-host disease (GVHD), and CMV infection. During our 20 years as a member of the BMT CTN, we have participated in the development of clinical trials focused on important questions confronting HCT patients, several of which were derived from early phase studies conducted in our program. This proposal summarizes COH CCC capabilities for BMT CTN, our operational and scientific approaches, and our work in clinical trials both in our own institution and in collaborations with the BMT CTN. As part of this application, we also propose a concept for “a Phase 2, platform clinical trial of post-HCT maintenance therapeutics in patients undergoing allogeneic HCT for treatment of TP53-mutated AML or MDS”. The outcomes of AML/MDS with TP53 mutation is dismal, and development of effective therapeutic approach is a true unmet need. HCT is the only potentially curative therapy for high-risk AML/MDS, including those with TP53-mutated diseases, but only a small fraction of patients receives HCT, primarily due to advanced age, poor performance status, and uncontrolled disease. Even after HCT, TP53-mutated MDS/AML are associated with low survival rates primarily due to a very high incidence of relapse. The primary objective of our platform trial is to evaluate the efficacy of different maintenance therapies for TP53-mutated AML/MDS as measured by 1-year progression-free survival (PFS). The first arm to be tested will be magrolimab (MAGRO) and azacitidine (AZA). To further improve HCT outcomes in these high-risk patients, we propose to capture a subset of patients before HCT and incorporate a multidisciplinary team intervention aimed at detoxifying HCT by recording valid measures of functional recovery and creating a paradigm for safer application of allogeneic HCT and proceeding to post-HCT maintenance. This trial is based on the unmet need in the field as recognized at the BMT CTN SOSS 2021 and based on the experience and expertise at COH investigating MAGRO/AZA as post-HCT maintenance therapy (NCT05823480, PI. Al Malki) and assessment of frailty/resiliency in HCT candidates with a multidisciplinary approach to optimize care of these patients at older age or inform clinical condition (NCT04914338, PI. Artz). Moreover, broad collaborations on correlative science will significantly advance our understanding of this highly challenging disorder and interplay between multiple immunologic factors involved with the HCT outcomes.

NIH Research Projects · FY 2026 · 1997-08

The City of Hope Comprehensive Cancer Center (COHCCC) received NCI-designation in 1981 and Comprehensive status in 1998. Led by John D. Carpten, PhD, the COHCCC is composed of 175 full Members, five productive Research Programs, eleven established Shared Resources and one developing Shared Resource, a robust cancer-focused research funding base (76% growth in NCI funding in the current funding cycle), and an active clinical trials portfolio that builds on institutional research discoveries. The COHCCC facilitates advances across the translational research continuum by providing infrastructure, strategic planning, administrative support, and mechanisms for transdisciplinary interactions that catalyze cancer-focused activities traversing basic discovery, clinical, and population-based investigations. These activities are aligned to reduce cancer burden of a highly populated, extensive Catchment Area of nearly 18 million people that encompasses 33,109 square miles and ranges from urban population centers concentrated in Los Angeles and Orange Counties to rural and frontier regions in eastern San Bernardino and Riverside Counties. To foster high-impact, transdisciplinary cancer-focused research, the COHCCC leverages a spectrum of state-of-the-art Shared Resources including in-house GMP manufacturing facilities; informatics and precision medicine resources; notable breadth and depth of in-house experience in conducting clinical trials; and a centralized administrative infrastructure. The COHCCC is also committed to developing the next generation of leaders in basic, clinical, and population-based cancer-related research through robust training initiatives that begin at K-12 outreach and continue through junior faculty development. To enhance cancer prevention, improve early detection, and accelerate translation of novel therapeutic approaches that impact all patients with cancer and their families, the COHCCC will pursue the following Specific Aims: 1) Identify, develop, produce, and advance first-in-field and first-in-human new treatments; 2) Implement four strategic initiatives: advancing precision medicine; expanding cellular therapeutics; promoting access to cancer care; and enhancing clinical research in the clinical network; 3) Assess and address the cancer burden in the COHCCC Catchment Area, promoting early detection, prevention, novel treatments, care during aging, and survivorship; and 4) Advance training and educational initiatives to support the next generation of cancer-focused scientists and clinicians. During the next cycle, the COHCCC will expand on historic strengths and advance critical initiatives that will benefit populations throughout the COHCCC Catchment Area as well as individuals throughout the nation at risk for or affected by cancer.

NIH Research Projects · FY 2026 · 1997-05

Project Summary The long-term goal of this project is to define mechanisms that regulate Okazaki fragment maturation (OFM) and determine how functional alterations in OFM enzymes and/or regulatory mechanisms cause genome instability and cancer. It is known that OFM processes are implemented via the scaffold protein PCNA, which mediates the sequential actions of Pol , flap endonuclease 1 (FEN1), and DNA ligase 1 (LIG1), in the DNA replication machinery. However, there are important knowledge gaps regarding the specific regulatory mechanisms that ensure the various OFM enzymes act sequentially to minimize mutagenesis and to control cell death. Unanswered questions include: How is Pol -mediated displacement DNA synthesis (SDDS) regulated by PARP1 to produce proper RNA-DNA 5' flap substrates for the nuclease FEN1? How are the sequential posttranslational modifications of FEN1 including arginine demethylation implemented to ensure its exit from the “work site” in late S phase? How are FEN1 and LIG1 properly exchanged onto the PCNA platform to ensure orderly OF access and suppression of an alternative, error-prone ligation process? In our preliminary studies, we have revealed mechanistic insights underlying OFM: i) PARP1 localizes to replication forks at early/middle but not late S phase, controlling SDDS by Pol. Its inhibition causes accumulation of 5' flaps in cells. ii) FEN1 arginine demethylation allows its dissociation from PCNA. JMJD1B is the arginine demethylase that mediates FEN1 arginine demethylation. JMJD1B localization to replication sites depends on histone chaperone FACT. iii) FEN1 and LIG1 sequentially co-localize with PCNA, allowing their orderly access to DNA substrates. iv) FEN1 S187A mutation or JMJD1B deletion similarly leads to PARP1 accumulation, histone PARylation, and LIG3 recruitment, similar to LIG1 knockdown cells. PARP1 inhibition is synthetically lethal with LIG1 knockdown. Based on these findings, we hypothesize that PARP1-regulated SDDS by Pol, FACT-mediated JMJD1B recruitment to demethylate FEN1 for its proper drop-off, and PCNA-coordinated FEN1 and LIG1 sequential access to OFs are crucial regulatory mechanisms for efficient and accurate OFM processes. Therefore, human cells with gene mutations and/or under stress conditions that disrupt these regulatory mechanisms will induce alternative, potentially faulty OFM processes for survival, leading to genome instabilities, cancer predisposition, and development of resistance to cancer therapy. To elucidate these regulatory mechanisms, we aim to i) determine the roles of PARP1 in controlling Pol -mediated SDDS to ensure proper formation of short 5' flaps for FEN1 cleavage; ii) determine how FACT-mediated arginine demethylase JMJD1B recruitment regulates FEN1 dynamics at replication forks; and iii) define the mechanism by which PCNA coordinates orderly access of FEN1 and LIG1 to OFs and suppresses an alternative, LIG3-mediated OF ligation process. gained will improve our understanding of cancer etiology and may inform treatment. The knowledge

NIH Research Projects · FY 2024 · 1992-09

Abstract The Paul Calabresi Career Development Award for Clinical Oncology (K12 Program) at the City of Hope Comprehensive Cancer Center has been funded for more than 25 years. The overarching goal of the K12 Program is to develop a new generation of clinical oncology investigators capable of translating basic advances in cancer biology into novel strategies for the diagnosis, therapy, and prevention of malignant disease. To this end, the K12 Program provides a structured, multidisciplinary approach to training and mentoring junior faculty to ensure their success as clinician researchers and leaders in cancer research. Eligible candidates are within five years of completing their training and are selected from a variety of specialties. The Principal Investigator/Program Director, Associate Director, Program Administrator/Curriculum Director, and seven faculty members constitute the Advisory Committee. This Committee selects the Scholars, regularly assesses their academic progress, and provides input on the curriculum. Annually, two external advisors evaluate the overall program and the progress of the current Scholars. The four-year K12 Program begins with the year-long Clinical Investigator Training Program, which provides structured coursework in topics including study design, statistics, team building, protocol writing, good clinical practice, responsible conduct of research, and grant writing. Practical skills training in leadership and data presentation are incorporated throughout the four years. Each Scholar identifies a clinical and laboratory mentor who provide support throughout the Scholar’s completion of a translational research project, for which they are guaranteed protected time. The Scholars meet quarterly with the Advisory Committee and formally present their research progress biannually for critique and input on their progress. The Program Director and Associate Director meet individually with the Scholars on a quarterly basis to review the critiques of the Advisory Committee and to provide Scholars with the opportunity to troubleshoot any problems or barriers to their career development. Scholars are also encouraged to provide suggestions for program improvement. The K12 Program continues to evolve with the addition of new mentors and enhancements to the curriculum. Participation in the program is considered prestigious by both the Scholars and their mentors. The value of the K12 Program is evident in the success and productivity of our Scholars. The nineteen K12 Scholars enrolled in the past 10 years have produced 853 publications, 227 of which are first-author publications, and 199 of which are senior-author publications. They have been awarded 109 grants including three NIH R01s, an NIH R03, an NIH R21, four other NIH grants, 25 foundation grants, and 75 others. Eighteen of the nineteen Scholars continue as academic faculty and all have been promoted or are in the process of being promoted to the level of Professor or Associate Professor, emphasizing the ability of our program to train independent clinical investigators.