DESCRIPTION (provided by applicant): This application is to renew the NCI Cancer Center P30 Support Grant for the Cancer Therapy & Research Center (CTRC) at the University of Texas Health Science Center at San Antonio (UTHSCSA) for years 17-21. The CTRC at UTHSCSA merged with the formerly-independent CTRC to form this new entity (hereinafter called "CTRC"). This merger, in the form of a $150 million gift, the largest gift in UTHSCSA history, and among the largest in University of Texas history, brings full alignment to our Cancer Center activities. With this merger and realignment, the CTRC has re-entered a period of significant growth and improvement in the quality of its clinical, basic, translational and population-based research programs. Our NCI funding base has increased from $8,453,756 in 2006 to $11,050,146 in 2007. We serve a vast geographic region in and around San Antonio and South Texas, larger than the state of Pennsylvania and comprising 4.4 million inhabitants. Our population is predominantly Hispanic and dominated by individuals in lower socioeconomic strata with the lowest rates of health insurance coverage in the nation. We have worked to serve the disadvantaged for years, and are now also re-focusing more research and clinical efforts to understand better the specific cancer-related risks and disease patterns in Hispanics, and to serve the needs of our citizens better. We have significant community outreach, wellness and cancer screening programs reaching these disadvantaged populations. These efforts are greatly helped in that leaders in our Cancer Center and at UTHSCSA are Hispanic. We request support for three research programs, ten shared resources, seven senior leaders, one staff investigator, modest developmental funds, and commensurate administrative support. Our three research programs are Cancer Prevention and Population Sciences, Experimental and Developmental Therapeutics, and Cancer Development and Progression. Our shared resources are Antibody, Biostatistics and Informatics, Flow Cytometry, Genomics, Macromolecular Interactions, Macromolecular Structure, Mass Spectrometry, Optical Imaging, Pathology, and Research Administration. The CTRC will continue its record of promoting inter-programmatic and intra-programmatic collaborations, and strategic use of developmental funds, in combination with significant institutional commitment and a successful record of philanthropic support that in sum ensures a synergistic return on investment not possible without the P30 infrastructure and guidance.
OVERALL CRITIQUE: The Cancer Therapy and Research Center (CTRC) is a matrix center within the University of Texas Health Science Center at San Antonio (UTHSCSA). It is now based on the merger of the formerly independent CTRC with the UTHSCSA. The themes of the CTRC include: finding better ways to prevent, diagnose and treat cancers, serving the cancer related needs of San Antonio and South Texas and focus on the unique health needs of the catchment area of the CTRC. Common to these themes is an expressed interest in translational research, in taking new discoveries from the bench to patient care. The application emphasizes that much of the CTRC catchment area is Hispanic, and that it is dominated by individuals of lower socio-economic status (SES) with very poor health insurance coverage. The application stresses that the CTRC is focusing additional research and clinical effort to better address the cancer and other disease risks of Hispanics. The application calls attention to a number of distinct characteristics of the CTRC. The size of the catchment area is larger than the state of Pennsylvania, with a population exceeding 4 million people. Approximately 60% of the civilian population of San Antonio and 65% (with some counties having 90%) of the residents of South Texas are self-identified as Hispanic. Many of these residents are poor and subject to severe health disparities.
The Institute for Drug Development (IDD) at UTHSCSA is widely recognized for its ability to move drugs from creation to FDA approval. The CTRC has for years been a leader in development of early phase cancer clinical trials. The CTRC should be able to leverage UTHSCSA assets to advance the CTRC mission and programs, including the Barshop Institute, the Clinical and Translational Science Award (CTSA), the Greehey Children's Cancer Research Institute, the Institute of Biotechnology, the UTHSCSA Research Imaging Center. There is extremely strong community support, including philanthropy. The state of Texas supports the cancer research infrastructure at about $300 million for all of Texas.
The most important change in the CTRC since the last review is that the formerly independent CTRC was merged into the UTHSCSA in November, 2007. As part of this merger, the CTRC donated its 47,000 sq. ft. IDD and 330,000 sq. ft. CTRC research buildings, with all land and equipment, and its $72 million endowment. The value of this donation amounted to some $150 million. As the merger took place, Dr. Coltman, the director of the formerly independent CTRC, stepped down, and UTHSCSA became the parent institution for the P30 grant. Since then, there have been 3 interim directors, Dr. Boldt, Dr. Mundy, and Dr. Slaga. Dr. Curiel became the permanent director of the San Antonio Cancer Institute (SACI), in late 2006; in December 2007, SACI became the CTRC. Dr. Frank Giles became the Deputy Director, while Dr. Slaga became Associate Director for Basic Science. A number of critical recruitments have been made to medical oncology, radiation oncology, and cancer population and prevention science. In addition, increased emphasis was placed on translational research. In late 2006, the leadership decided that two of the five cancer center programs, Genitourinary Cancer and Aging, did not have adequate NCI grant support, translational activity and cancer focus to contribute to the CCSG program. These programs were disbanded, and their members transitioned into the remaining programs.
The CTRC is built around three programs. The Cancer Development and Progression Program, with 46 members and $2,372,913 in peer reviewed NCI funding, is rated very good to excellent. Several themes within the program are viewed as very strong. However, the lack of strong evidence of interaction or synergy among the themes of the program detracted from the rating. The Experimental and Developmental Therapeutics Program, with 31 members and $2,749,982 in peer-reviewed NCI funding, was rated very good. The addition of a basic science component to the program was viewed positively, but the linkage of this basic science to the clinical trials efforts remains to be actualized. In addition, some concern was expressed over the continuing emphasis in the program on industry-sponsored trials and the limited role of investigator initiated studies from Program members. The research in this program was uneven with some efforts clearly interesting and novel and others not at all novel and not productive. The Cancer Prevention and Population Science Program, with 13 full members and $4,870,685 in peer-reviewed funding, is rated very good to good. The depth and breadth of the research emanating from this program were seen as limiting. The research in this program could be more hypothesis-driven. In addition, reviewers were concerned by the lack of concrete plans to take advantage of the opportunities afforded by the ethnic heterogeneity in the catchment area of the CTRC.
Overall quality of the three Programs is rated very good. The programs were not seen as adding significantly to one another and intra-programmatic interaction was not strong. Synergy among the themes within the programs was generally weak, and synergy among the programs was not apparent. The 96 members of the CTRC are aligned with one of the programs: 48 with Cancer Development and Progression, 31 with Experimental and Developmental Therapeutics and 13 with Cancer Prevention and Population Science. During the past grant period, the CTRC, in response to the previous review, has deleted some members who are not funded or active in one of the programs. Overall, direct-cost of peer-reviewed funding stood, on September 15, 2008, at $21,772,711 in direct costs, with $11,924,767 in direct costs from NCI. Some $5,936,352 is from other NIH sources.
These programs are supported by a total of 10 shared services. Antibody Production is rated excellent to very good because of the low usage by Center members. Flow Cytometry is rated outstanding. Genomics is rated very good to excellent as it has the correct services but there are concerns regarding overlap of service and cost-effectiveness. Macromolecular Interactions is rated very good as it provides routine, useful services to the research efforts of the Center; it is anticipated that better, more sensitive instrumentation will enhance this service. Macromolecular Structure, Mass Spectrometry, and Pathology are rated excellent. Optical Imaging is rated outstanding to excellent. Biostatistics and Informatics is rated very good to excellent as the usage appears not to be tracked and it was difficult to evaluate the services available. Office of Research Administration, shared resource for the support of clinical trials, is rated very good to excellent as it seems to be for the benefit of industry trials as opposed to investigator initiated trials within the Center. Moreover, there are concerns regarding data entry and capture.
Protocol Review and Monitoring System is given conditional approval. There were serious concerns that the Protocol Review Committee lacked sufficient medical expertise, that attendance was not adequate, and that a quorum could be obtained that lacks medical expertise. The Data and Safety Monitoring Plan is rated acceptable (approval).
The six Essential Characteristics are all met. Facilities is rated outstanding. Organizational Capabilities is rated very good to excellent. Interdisciplinary and transdisciplinary collaboration and cooperation is rated very good to good. Cancer Focus is rated excellent to outstanding. Institutional Commitment is rated excellent to very good. The Center Director is rated excellent to outstanding.
Staff Investigator support was requested for one CTRC investigator: LuZhe Sun, Ph.D. Dr. Sun is eligible for support, in that he is funded by peer reviewed grants. However, Dr. Sun does not meet the guideline criteria for a Staff Investigator since a definable role for this investigator in helping the Center achieve its objectives above and beyond his own research was not described, and therefore the request for funds for this position is not recommended.
Under Organization and Administration, Senior Leadership is rated very good to excellent as, despite the many strengths of this leadership team, there are several concerns remaining from the last previous review such as the lack of a senior administrator, and the lack of attention to the critical scientific questions and hypothesis driven grant submissions in population-research. In response to this latter concern, the previous five Programs have been reduced to three Programs. However, given the deficiencies with the current scientific Programs, the lack of interaction among the programs, and the short time this structure has been in place, the effectiveness of the senior leaders in overseeing the reorganization of the programs has yet to be determined. One of the major concerns of the previous review was whether the senior leadership had the ability to foster strong interactions and therefore develop an outstanding base of scientific and clinical activities.
Planning and Evaluation is rated very good as there has been an uneven implementation of External Advisory Board recommendations, which would benefit the Center. Dr. Curiel has named and filled a number of committees to provide candid input to guide decision-making. The senior leadership includes the PI, Dr. Tyler Curiel; the Deputy Director and Associate Director for Clinical Research, Dr. Giles; the Associate Director for Basic and Translational Research, Dr. Slaga; the Associate Director for Prevention and Population Research, Dr. Pollock; the Associate Director for Shared Resources and Internal Education, Dr. Susan Naylor; The Interim Associate Director for Administration, Ms. McCarroll, and the Director of the Institute for Health Promotion Research, Dr. Ramirez. There is a P30 Executive Committee that is described as meeting monthly. This committee is apparently charged with day-to-day management of the CTRC. There is also an Internal Advisory Committee. The major charge of this committee appears to be clinical affairs. The External Advisory Board (EAB), chaired by Dr. Ruckdeschel, is comprised of experts in medical oncology, cancer prevention, tumor immunology, epidemiology and biostatistics, hematology/oncology, and administration, and pediatric oncology. This EAB convened early in 2008, compiling a report that was circulated to the executive committee, internal advisory committee, and key representatives of UTHSCSA leadership. There is a Scientific Leadership Committee, charged with advising the Director on basic and translational research. These leaders, all full professors, are from a wide variety of scientific disciplines. There is a Pilot Project Review Committee, charged with distributing pilot funds on the basis of request vetting. There is a Protocol Review Committee, charged with ensuring patient safety and research quality by providing internal oversight. There is an Office of Research Administration, responsible for the submission and implementation of research studies associated with clinical, translational and basic science research programs. There is a Data Safety and Monitoring Committee, the chair of which reports to Dr. Giles. It appears as if many of the key facets of effective leadership are in place at the CTRC. Although it may be some time before the effectiveness of this leadership is clear, the indications are that this structure should be effective. It was of some concern that, at the site visit, the investigators were unable to provide updated information on the status of members of at least one of the research programs.
Developmental Funds is rated very good to excellent as there should be support for generating multi-investigator grant applications and some of the stated request are not allowed by the Cancer Center Guidelines. Administration is rated good as it is treated as a core resource rather than for leadership in management of the Center and still lacks a permanent administrator.
Outreach to increase diversity has been extensive, and has been facilitated by the recruitment in 2006 of Dr. Amelie Ramirez. Dr. Ramirez pointed out during the review that one of her first goals has been to establish trust and rapport with the Hispanic community in San Antonio and South Texas. Dr. Ramirez has submitted a large, collaborative grant to guide breast cancer research among Hispanic women in South Texas.
The components, Inclusion of Women, Minorities, and Children are approved. The application reports efforts to take advantage of the clinical experience afforded by patients treated by CTRC. These include higher-incidence cancers of the colon, lung, female breast and prostate. During the 2007 calendar year, 46 colon cancer patients, 24 lung cancer patients, 28 female breast cancer patients and 14 prostate cancer patients were accrued to clinical protocols.
In summary, Dr. Curiel has been Director of the merged Cancer Center for a little over a year and has started to organize the Center into what could be a successful Cancer Center. However, it is clearly early in the process. The application details attention to critical comments in the previous, 2002 review. There has been an excellent effort to respond to these. In addition, the investigators have attempted to take advantage of some of the suggestions of the External Advisory Board and seemingly ignored others that would have benefitted the center. The CTRC has yet to realize synergies between research themes within its research programs and has not yet fully initiated the necessary efforts to translate its research into the clinic. It is hoped that this very good Cancer Center will be able to demonstrate significant progress in the three years of funding that is recommended.
IRG NOTE
In response to the draft Site Visit Report, Dr. Tyler Curiel sent written comments, in an email dated March 18, 2009, pointing out factual errors in the Report. The comments and the draft Site Visit Report were considered by the NCI IRG Subcommittee A members during the discussion, final assessment, and scoring of the application. A change in the merit rating of the Cancer Center Director was made and is now rated excellent to outstanding. Appropriate changes in the text have been made. No changes in individual budgets was recommended, but based on its assessment of the overall quality of science in the Center, the Subcommittee recommended a further reduction to $1,587,593, total costs, an amount of support appropriate to its level of total National Cancer Institute funding. (This recommendation does not reflect an evaluation of the institution's indirect cost rate.) The priority score for the application reflects concerns that remain after the merger of the CTRC with UTHSCSA, the major reorganization of the programs, and the appointment of a new director.
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
There were no concerns expressed regarding the protection of human subjects in the proposed studies.
INCLUSION OF WOMEN PLAN (Resume): ACCEPTABLE
The plan to include women in the proposed studies is acceptable. G1A
INCLUSION OF MINORITIES PLAN (Resume): ACCEPTABLE
The plan to include minorities in the proposed studies is acceptable. M1A
INCLUSION OF CHILDREN PLAN (Resume): ACCEPTABLE
The plan to include children in the proposed studies is acceptable. C1A
VERTEBRATE ANIMAL (Resume): ACCEPTABLE
There were no concerns expressed regarding the care and use of vertebrate animals in the proposed studies.
SCIENTIFIC REVIEW OFFICER'S NOTES: It should be noted that the total direct costs requested on the cover page of the application and the total obtained by summing each of the component requests differs. The sum of the individual components is $490 greater that the total on the cover page.
NIH Policy on Sharing of Model Organisms for Biomedical Research: The application does not address the NIH Policy on Sharing of Model Organisms for Biomedical Research.
Policy for Genome-Wide Association Studies (GWAS): 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
Cancer Development and Progression
DESCRIPTION (provided by applicant): The Cancer Development and Progression (CDP) research program, one of the three current and interactive programs of the Cancer Therapy & Research Center (CTRC) at the University of Texas Health Science Center at San Antonio (UTHSCSA), has evolved from the merging of essential elements of several cancer center programs since the last competitive renewal. The major thematic areas under CDP are: (1) Genomic Integrity, (2) Aging and Cancer, (3) Chronic Inflammation and Cancer, and (4) Women's Cancer. The reorganization reflects some significant changes in the previous program areas, including the departure of several key members and new cancer focus areas brought to the Center by newly recruited cancer research scientists. The new programmatic structure provides a consolidated platform that is more conducive to collaborative and integrative cancer research. All of the above themes have the potential to develop or re-develop into strong, stand-alone programs in the future, and are expected to do so.
The overarching scientific goals of the CDP Program are: 1) to integrate basic research in genomic integrity, age-related cancer susceptibility, tumor microenvironment, and hormone actions and therapeutic resistance in women's cancer to gain a deeper understanding of cancer development and progression; (2) to foster cross-disciplinary collaboration between CDP and the research programs in population studies and experimental and developmental therapeutics; and (3) to translate findings of genetic instability, tumor immunity, obesity/ nutrition, and hormone resistance into better cancer prevention and treatment.
Currently, the CDP research program has 23 key cancer-focused and funded members and another 25 funded members who conduct cancer-related research that contributes to the understanding of cancer development and progression. Cancer research in the CDP Program receives a total of $7.5 million in peer-reviewed funding (direct), of which $2.4 million is from the NCI (direct). In the current funding period, researchers in the CDP program have made a number of major accomplishments in many areas of cancer biology. These include discoveries of novel factors in double strand DNA break repair, new molecular links between genetic instability and aging, important insight into host-tumor interactions, and molecular interplay of hormone synthesis and actions in breast cancer development. With new cancer research focus, reconfigured interactive programmatic structure, and strong leadership, the CDP Program is well positioned to synergize and integrate further the multi-disciplinary cancer research ongoing in our Cancer Center.
RELEVANCE: The broad yet thematically linked research themes in the CDP Program represent a strong foundation for basic cancer-focused research in the Cancer Center. By integrating trans-disciplinary efforts to address the fundamental problems in cancer development and progression, this Program has the tremendous potential of leading to new cancer prevention and treatment strategies. |