The recently reorganized Duke Comprehensive Cancer Institute (DCCI) is charged to serve as the center of all Duke activities in cancer, with an imperative to oversee all of the Duke cancer operations in the future. As a matrix center in one of the largest biomedical research institutes, the DCCI has been continuously supported by the National Cancer Institute (NCI) for over 36 years, by leveraging Duke's basic research strengths with significant clinical oncology research excellence which is enabled by treating 5,581 new cancer patients annually, enrolling over 1,000 patients annually onto therapeutic clinical trials, and enhanced by the presence of national oncology research resources, such as the data and statistical centers of two NCI-funded cooperative groups. Total membership in the DCCI is 285 members, with members having an increasingly prominent focus in cancer research and increased amount of NCI funding since 2004. Total funding for program members is $331,617,013, of which $269,525,804 is from peer-reviewed sources. A cancer focus is illustrated by $77,785,582 or 23.5% of funding from the NCI, the American Cancer Society or the Department of Defense. From 2004-2008, program members published 6,941 papers in peer-reviewed journals cited in PubMed. Of these publications, 10% are the result of intra-programmatic collaborations and 19% due to inter-programmatic collaborations. In this competitive renewal application, we request support for our membership in 11 Research Programs supported by 17 Shared Resources. DCCI members made significant scientific advances including: the development of innovative genomic tests to predict which cancer patients would respond to specific chemotherapy, and basic insight into critical signaling pathways in cancer and developmental biology. The DCCI oversees all cancer related philanthropy at Duke, and these funds have been used to support recruitment of new members, innovative pilot projects, support of multidisciplinary research, and new laboratory and administrative space. This application for ongoing support of the DCC articulates the principles, goals and strategies for propelling the DCCI to fully leverage the enormous advances in biomedical research at Duke and beyond, to improve and extend the lives of cancer patients with cancer and at risk for cancer, and delivering these to society. OVERALL CRITIQUE: The mission statement of the Duke Comprehensive Cancer Institute (DCCI) is that it seeks to: 1) extend and improve the quality of life for the patient with cancer, to extend and improve the lives of populations with cancer or at risk of cancer, and to contribute to society via cancer research;2) perform research of the cause, prevention, treatment and cure of cancer and associated conditions;and 3) serve as a focal point for discovery, development and delivery of novel concepts in cancer detection, prevention and treatment to patients and to society. The DCCI was recently reorganized. Formerly the Duke Comprehensive Cancer Center (DCCC), which was founded in 1972 and which had been funded since 1972, the DCCI was formed in 2008. The primary goal of this realignment, completed with the support of the Dean Nancy Andrews, M.D., of the School of Medicine, was to better align cancer research and care. The DCCI is distinct from the DCCC in that it possesses additional institutional resources and infrastructure;much of this is in the form of clinical trials support. The designation as an institute at Duke also enables enhanced oversight over components of the departments, as well as over the Health System and improved cancer-related communication and coordination among basic science departments. Because of the recency and significance of the administrative changes of the past year, the DCCI has not yet implemented a strategic plan;however, the strategic plan, under development at the time of application submission, was available at the site visit. There is now a new structure of leadership for the DCCI. The Cancer Medicine Leadership Council is comprised of representatives of the relevant Duke clinical and research units (i.e., Health System, hospital, departments, centers and institutes). This council has input into major strategic and operational decision-making. The Senior Leadership Committee, described as the major decision-making body of the DCCI, meets bi-weekly, with attendance mandatory. There is also an Executive Committee which meets monthly is charged with reviewing membership, resource allocation, and policy. Although basic science is well represented among the research programs, the application emphasizes translation from cancer control to basic science to phase l and ll clinical trials and to participation in the NCI cooperative groups, in large scale epidemiologic studies and health services research. Overall accrual to clinical trials, a key element of impact, is impressive. Most of the diseases studied at DCCI accrue well to clinical trials. Overall, accrual to investigator initiated clinical trials is high. The DCCI is comprised of 11 research programs: Cell Regulation Transmembrane Signaling;Nucleic Acid Biology;Structural and Chemical Biology;Cancer Genetics and Genomics;Cancer Biology;Radiation Oncology;Neuro-Oncology;Experimental Therapeutics;Hematopoietic Cell Transplantation and Hematological Malignancies;Breast and Ovarian Cancer;and Cancer Prevention, Detection and Control. The DCCI defines in cancer-related funding sources include the NCI, American Cancer Society (ACS), Department of Defense (DOD) and Komen Foundation. The Cell Regulation and Transmembrane Signaling Program, with 36 members and 732 cancer-related publications and $26 million in peer-reviewed funding, including $3 million from NCI, the DOD and ACS, was rated very good to excellent. Although the overall quality of science in this program is outstanding, cancer focus and collaboration among the members could be improved. The Nucleic Acid Biology Program, with 20 members and 290 peer-reviewed publications and $7.2 million in peer-reviewed funding, including $790,000 from NCI, DOD and ACS, was rated very good to good. This program was seen as comprised of two groups that did not really share a common focus;collaboration was limited, and its leaders did not demonstrate sufficient evidence of intent in improving the program. Previous reviews, including external advisory board (EAB) reviews, had questioned the cancer focus of the program, but this did not appear to have changed significantly. The Structural and Chemical Biology Program, with 21 members and 432 peer-reviewed publications and $8.7 million in peer-reviewed funding, including $1.3 million from NCI, DOD and ACS, was rated very good;while there is some very strong research in the program, there is a lack of apparent cancer focus and a clearly articulated vision of the program. The Cancer Genetics and Genomics Program, with 21 members and 449 peer-reviewed publications and $25 million peer-reviewed funding, including $8.7 million from NCI, the DOD and ACS, was rated outstanding to excellent. The Cancer Biology Program, with 37 members and 625 publications and $22 million in peer-reviewed funding, including $6.2 million from NCI, DOD and ACS, was rated good to very good;the degree to which the three themes of emphases of this program actually come together as a program was not clear. The Radiation Oncology Program, with 24 members and 424 peer-reviewed publications and $12.8 million in peer reviewed funding, including $4.8 million from NCI, DOD and ACS, was rated outstanding to exceptional. The Neuro-oncology Program, with 26 members and 612 peer-reviewed publications and $10 million in peer-reviewed funding, including $5.1 million from the NCI, DOD and ACS, was rated exceptional to outstanding;it was described by one reviewer as the paradigmatic translational program. The Experimental Therapeutics Program, with 27 members and 628 peer-reviewed publications and $13.7 million in peer-reviewed funding, including $9.4 million from NCI, DOD and ACS, was rated excellent to very good to outstanding. Strengths noted in this program included the phase I research, grants support, and the publications in high impact journals. The Hematopoietic Cell Transplantation and Hematological Malignancies Program, with 35 members and 706 publications and $64 million in peer reviewed funding, including $2.7 million from the NCI, DOD and ACS, was rated very good to excellent to good;a major concern regarding this program was its heavy dependence on industry funding. The Breast and Ovarian Oncology Program, with 29 members and 737 peer-reviewed publications and $10.5 million in peer-reviewed funding, including $8.1 million from NCI, DOD and ACS, was rated exceptional to outstanding;the program is highly translational, yet it has basic science strengths and has contributed significantly to high-impact journals. The Cancer Prevention, Detection and Control Program, with 45 members and over 1,100 peer-reviewed publications and $21 million in peer reviewed funding, including about $3 million from the NCI, DOD and ACS was rated excellent. Dr. Abernethy's presentation was excellent;she is doing an excellent job of melding the elements of the program into a more coherent unit. The Overall Quality of the Program was rated excellent to very good. Several very impressive programs are part of the DCCI, however there were concerns regarding several programs having diffuse cancer focus and weakness in their intra-programmatic and inter-programmatic synergy. The research programs are supported by 17 shared resources. These shared resources were rated as follows: High Resolution NMR Spectroscopy/X-ray Crystallography, very good;DNA Analysis/ Automated Sequencing and Phosphorimaging, very good;Light Microscopy, outstanding;Flow Cytometry, excellent;Transgenic and Knockout Mouse, outstanding;Immunoincompetent Rodent and Biohazard, very good to excellent;DNA Microarray, outstanding to exceptional;Radiochemistry, very good to excellent;Optical Molecular Imaging and Analysis, outstanding to excellent;Proteomics, outstanding;Tissue and Blood Procurement, very good to good;Pharmaceutical Research, excellent to outstanding;Clinical Cell Processing and Cell Culture, good to very good to satisfactory;Information Systems, outstanding to excellent to exceptional;Bioinformatics, excellent;Biostatistics, excellent to very good;and Clinical Trials was rated excellent to very good. The Protocol Review and Monitoring System (PRMS) was conditionally approved. There is a need for closer scrutiny of accrual and closure of poorly accruing trials;the accrual monitoring should be part of the PRMS activities. There are also concerns that need to be addressed regarding committee appointments, and that protocol reviews should be provided in more detail and the protocol document should include pertinent drug and toxicity data. Protocol-specific research support received an excellent to very good rating. Data and Safety Monitoring/NIH Policy was rated acceptable (approval). The component, Inclusion of Women in Clinical Research, was approved as was the Inclusion of Minorities in Clinical Research;a minority report recommending disapproval was made for the latter component. The Inclusion of Children in Clinical Research was approved. Senior leadership was evaluated as very good to excellent. Planning and evaluation was rated very good to excellent. Developmental funds was rated excellent to very good. Administration was rated good to satisfactory. Under the current leadership, there are notable discoveries which impact directly on cancer detection and treatment as well as strengths in basic science research. The leadership team consists of prominent scientists with the majority having significant administrative experience. A number of them are also departmental heads and leaders of the medical school, and as such, play important roles in providing strong cancer advocacy to the University. Many members of the leadership team have a history of working together in the development of this Center. All of the essential characteristics were met. Among the essential characteristics, facilities were rated excellent;organizational capabilities was rated good to very good;transdisciplinary collaboration was rated very good to excellent;cancer focus was rated very good to excellent;institutional commitment was rated outstanding to excellent;and the center director was rated excellent to outstanding. As strengths, the Center has recruited well and excelled in research, which contributes to the areas of outstanding science seen in many of the programs. To the leadership's credit, the Center has been able to attract high caliber scientists to serve as program leaders. Based on the overall increase in cancer related funding, the overall cancer focus has improved;however the membership definition of cancer focus appears to be somewhat overly inclusive and there are missed opportunities for some of the basic science programs to move outstanding researchers to be directly involved in research. The uneven quality of the programs and issues related to the program reorganization raised in the critiques require the leadership's attention;variability in the quality of the information provided by the programs detracted from enthusiasm for the application. Although the overall translational activities at the Center are impressive, the limited emphasis on translational aspects, by some of the basic science programs, requires the attention of the leadership. In addition, guidance is needed for the improvement of the intra- and inter-programmatic collaborations, especially for those programs with limited joint publications and participations in P01 and SPORE grants. The overall evaluation of the DCCI notes that there are pockets of very strong research within the Center and the reviewers were convinced that there is great potential for the Center to continue, under Dr. Lyerly's leadership, to advance under its new status as an institute within Duke University. This application is rated Very Good;range of scores: Excellent to Very Good. Support for five years is recommended as requested. COMPREHENSIVENESS (Stage I) Research exists in the areas of basic, clinical, and cancer control, prevention, and population studies that is productive. The Cancer Center has programmatic areas with breath and depth, including research in the areas of cancer control, prevention, and population studies. There is at the DCCI significant depth and strength in cancer research, with much of that research appearing as publications in extremely strong, influential journals. Evidence was presented in the application and at the site visit that interactions occur between these three essential areas of research, some notable. Although overall the translational activities at the Cancer Center are impressive, enhancement of translational activities of some basic science programs would be beneficial, as would improvements of intra- and inter-programmatic collaborations among some programs. The potential for further growth is noted. This Cancer Center fulfills the scientific requirements of comprehensive designation. Thus, the research-related aspects of comprehensiveness were approved. Assessment: Approval IRG NOTE In response to the draft Site Visit Report, written comments were received from the principal investigator in a letter dated August 3, 2009. The comments and the draft Site Visit Report were carefully considered by the NCI IRG, Subcommittee A, members during the discussion, final assessment, and scoring of the application. A motion to re-vote the merit of the Structural and Chemical Biology Program did not pass. The component, Inclusion of Minorities in Clinical Research, was recommended for approval;a minority report recommending disapproval was made for this component. Clarifications and corrections of the text have been made, where appropriate. This application is rated Very Good;range of scores: Excellent to Very Good. The motion for five years of support, as requested, passed. In the Overall Budget Recommendation, based on its assessment of the overall quality of science in the Center, the Subcommittee recommended $6,343,041 (total costs);this recommendation is made to provide the Center an amount of support appropriate to its level of total National Cancer Institute funding. The motion for approval of the scientific requirements of comprehensive designation (Stage I) was approved;see heading, Comprehensiveness (Stage I). HUMAN SUBJECTS RESUME THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW ADMINISTRATOR TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES: PROTECTION OF HUMAN SUBJECTS (Resume): ACCEPTABLE (Also, see the heading, Data and Safety Monitoring/ NIH Policy) INCLUSION OF WOMEN PLAN (Resume): ACCEPTABLE (Also, see the heading, Inclusion of Women in Clinical Research.) INCLUSION OF MINORITIES PLAN (Resume): ACCEPTABLE (Also, see the headings, Inclusion of Minorities in Clinical Research and Scientific Review Officer's Note.) INCLUSION OF CHILDREN PLAN (Resume): ACCEPTABLE (Also, see the heading, Inclusion of Children in Clinical Research.) VERTEBRATE ANIMAL (Resume): ACCEPTABLE SCIENTIFIC REVIEW OFFICER'S NOTE: Clinical Cell Processing and Cell Culture Shared Resource: This budget is contingent upon evidence of funded cell therapy trials. The early development of the human cancer stem cell purification is not yet established and would be more appropriately covered under Developmental Funds. Also, aspects of this shared resource appear to overlap with the functions of a core in P01 CA78673 (PI: Dr. Clay). Minority Report: Inclusion of Minorities in Clinical Research: A minority of the review team voted against the motion for approval;it is the minority opinion that this component be recommended for disapproval. Little progress has occurred in the accrual of minorities to clinical trials at DCCI. Even more striking is the recognition by DCCI that their referral base is in excess of 30% minority population. In 2002, minorities represented approximately 14.5% of the patients accrued to clinical trials;in 2008 minorities accounted for 12.4% of the accrual. Of the minority accrual, 10.9% were African American (similar to 10.7% in 2002). In contrast, the DCCI tumor registry lists 18.9% of the patients treated at DCCI as minorities of which 16.7% are African American. Thus, based on the data provided at the time of the site visit, when compared to the demographics in the DCCI Tumor Registry and when compared to the DCCI catchment area, the under-representation of minorities accrued to therapeutic clinical trials continues as a concern. Information regarding accrual to non-therapeutic trials as distributed at the site visit indicated 25.6% of the accruals were minorities and 23.2 % were African Americans;details of the regional demographics were not presented. Minority accrual, however, needs to be referenced against the catchment area, not just those registered at the Center. The deficiency in the accrual of minorities to clinical trials is again acknowledged by the applicants and some plans previously articulated are outlined. These plans include the use of the Duke Oncology Network and the plans to draw upon the expertise of the cancer prevention research group, who in the prior application were shown to have slightly more success in accruing minorities to their non-therapeutic trials. An area of some success has been the increase in minority accrual onto CALGB and breast cancer trials, and the establishment of a patient navigator is seen as a positive step. Of concern, however, is despite a formal health disparities theme in the Breast and Ovarian Cancer Program, the overall minority accrual remains unchanged and metrics to evaluate the plan for interventions are still lacking. Overall, the efforts in the intervening years have not been enough to bring about sufficient change;thus, concerns remain that the strategies proposed now may not be sufficiently different. Part of the problem may rest in not having an individual specifically identified with responsibility for oversight of the recruitment of minorities. The hiring of a treatment navigator is recognized as an appropriate first step, but not sufficient to bridge this deficiency. Given that this deficiency was noted in the two prior CCSG reviews, this matter deserves greater attention at the level of the DCCI Director's Office and perhaps other Medical Center leadership. Recruitment of a Health Disparities Program Coordinator to manage disparities may also be helpful, but should not dissuade the leadership from relocating this responsibility to the Director's office. It is noted that the prior CCSG review expressed concern that without greater intervention, this component might be disapproved. NIH Policy on Sharing of Model Organisms for Biomedical Research: The application does not specifically address the NIH Policy on Sharing of Model Organisms for Biomedical Research. Policy for Genome-Wide Association Studies (GWAS): The applicant does not specifically address this policy. A plan is not provided for GWAS studies supported through CCSG elements. [NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088.] For additional information, see http://grants.nih.gov/grants/gwas/. Program staff is responsible for assessing the appropriateness and adequacy of proposed data sharing plans. Program concerns regarding data sharing plans must be resolved prior to making awards. ESTABLISHED RESEARCH PROGRAMS Cell Regulation and Transmembrane Signaling DESCRIPTION (provided by applicant): The goal of the Program in Cell Regulation and Transmembrane Signaling is to foster scientific interactions between members of the Duke Comprehensive Cancer Institute (DCCI) who have interest in understanding the biology involved in regulating cell proliferation and death. The Program continues to attract individuals interested in aspects of cell signaling. Currently, the Program includes 36 members from 9 different basic and clinical departments. To foster an outstanding forum for scientific discourse and collaboration, the Program remains organized into one of four interest groups that include: 1) transmembrane signaling;2) intracellular signaling;3) cell proliferation and death;and 4) signaling and disease. The program sponsors three distinct educational activities, the University-wide weekly seminar series """"""""The Signal Transduction Colloquium"""""""" (STQ), the most attended series on campus;a graduate course in Cellular Signaling, taken by the majority of biomedical graduate students;and an Annual Offsite Retreat. The last two years'retreats each featured more than 20 platform and 100 poster presentations by members, students and fellows. Speakers for the STQ selected by a panel of Program members come primarily from outside the Duke University Medical Center to represent the broad interests of the membership (See list of invited speakers since 2004, Appendix P1). Each colloquium speaker meets with interested members of the Program and lunches with students in the Molecular Cancer Biology Graduate Program immediately after completion of the seminar. The diversity of experimental approaches used by the members of this Program represents an effective asset for promoting cross-fertilization of ideas aimed at understanding cell growth and regulation. During the last grant period, members of the Program have published 800 papers in primary peer-reviewed journals of which 732 or 90% bear directly on cancer-related problems. Finally nearly 15% of the cancer-related publications (98) are the result of intra-programmatic or inter-programmatic collaboration among DCCI members. At the present time, there are 36 program investigators. Total funding for program members is $29,744,441, of which $26,385,208 is from peer-reviewed sources. A cancer focus is illustrated by $2,991,535 or 11.3% of funding from the NCI, the American Cancer Society or the Department of Defense.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Center Core Grants (P30)
Project #
2P30CA014236-36
Application #
7766881
Study Section
Subcommittee G - Education (NCI)
Program Officer
Shafik, Hasnaa
Project Start
1997-01-01
Project End
2014-12-31
Budget Start
2010-09-03
Budget End
2010-12-31
Support Year
36
Fiscal Year
2010
Total Cost
$6,070,886
Indirect Cost
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Galaz-Montoya, Monica; Wright, Sara J; Rodriguez, Gustavo J et al. (2017) ?2-Adrenergic receptor activation mobilizes intracellular calcium via a non-canonical cAMP-independent signaling pathway. J Biol Chem 292:9967-9974
Lanier, Megan L; Park, Hyeri; Mukherjee, Paramita et al. (2017) Formal Synthesis of (+)-Laurencin by Gold(I)-Catalyzed Intramolecular Dehydrative Alkoxylation. Chemistry 23:7180-7184
Shi, Qiong; Liu, Hongliang; Han, Peng et al. (2017) Genetic Variants in WNT2B and BTRC Predict Melanoma Survival. J Invest Dermatol 137:1749-1756
Woyach, Jennifer A; Ruppert, Amy S; Guinn, Daphne et al. (2017) BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin Oncol 35:1437-1443
Wang, Yanru; Freedman, Jennifer A; Liu, Hongliang et al. (2017) Associations between RNA splicing regulatory variants of stemness-related genes and racial disparities in susceptibility to prostate cancer. Int J Cancer 141:731-743
Fayanju, Oluwadamilola M; Hall, Carolyn S; Bauldry, Jessica Bowman et al. (2017) Body mass index mediates the prognostic significance of circulating tumor cells in inflammatory breast cancer. Am J Surg 214:666-671
Leu, David; Spasojevic, Ivan; Nguyen, Huy et al. (2017) CNS bioavailability and radiation protection of normal hippocampal neurogenesis by a lipophilic Mn porphyrin-based superoxide dismutase mimic, MnTnBuOE-2-PyP5. Redox Biol 12:864-871
Sauer, Scott J; Tarpley, Michael; Shah, Imran et al. (2017) Bisphenol A activates EGFR and ERK promoting proliferation, tumor spheroid formation and resistance to EGFR pathway inhibition in estrogen receptor-negative inflammatory breast cancer cells. Carcinogenesis 38:252-260
Pan, Yongchu; Liu, Hongliang; Wang, Yanru et al. (2017) Associations between genetic variants in mRNA splicing-related genes and risk of lung cancer: a pathway-based analysis from published GWASs. Sci Rep 7:44634
Yin, Jieyun; Liu, Hongliang; Liu, Zhensheng et al. (2017) Pathway-analysis of published genome-wide association studies of lung cancer: A potential role for the CYP4F3 locus. Mol Carcinog 56:1663-1672

Showing the most recent 10 out of 480 publications