This is a new Cancer Center Support Grant application from the University of Texas Southwestern (UTSW) Simmons Cancer Center (Simmons Cancer Center). The Simmons Cancer Center is organized as a matrix center that integrates cancer research, clinical cancer care, and cancer control outreach across the University of Texas Southwestern Medical Center and its affiliated hospitals, UTSW University Hospital, Parkland Health and Hospital System, and the Children's Medical Center of Dallas. The Center includes 177 members from 30 departments and centers who work together to promote innovations in cancer diagnosis, treatment and control and build on the outstanding science and the tradition of excellence in clinical training at UTSW. Total extramural annual cancer research support exceeds $75 million of which $22.7 million is from the NCI, Department of Defense and ACS. The Center includes a Lung Cancer SPORE, a NCI Early Detection Research Network award, a NCI Small Animal Imaging Resource, and a NCI sponsored P01 to identify novel small molecular leads for cancer therapeutics. Strong partnerships with the region's safety net hospitals provide opportunities to serve the special needs of a large and growing Hispanic population and to engage underrepresented groups in research. This CCSG application requests support for senior leadership, four scientific research programs, six shared resources, protocol specific research, protocol review and monitoring, planning and evaluation activities, developmental funds, and administration. OVERALL CRITIQUE: The Simmons Cancer Center (SCC) of the University of Texas Southwestern Medical Center (UTSWMC) has submitted a new application for a Cancer Center Support Grant under the leadership of Dr. James K.V. Willson. A prior planning grant application in 2002 under different leadership was not funded, and the current new application reflects a strong re-organization and focus. Support is requested for four programs: Chemistry and Cancer, Development and Cancer, Cancer Cell Networks, and Molecular Therapeutics of Cancer;seven shared resources: Genomics, High-Throughput Screening, Small Animal Imaging, Tissue Management, Cancer Center Biostatistics, and Clinical Protocol and Data Management, as well as PRMS, Protocol-Specific Research Support, and Data and Safety Monitoring. Also, support for the infrastructure aspects of Senior Leadership, Planning and Evaluation, Developmental Funds, and Cancer Center Administration. Dr. Willson was recruited and assumed the leadership of the SCC in October 2004. He organized a strategic planning process, recruited a well-qualified External Advisory Board, organized the current scientific program structure, and recruited full-time clinical leadership. The SCC also developed seven shared resources and capitalized on the existing institutional shared resources as well. The Chemistry and Cancer Program (CCP) is rated excellent. This is a very strong scientific program derived from a long-standing Program Project Grant (PPG) whose aim is to discover small molecule chemicals relevant to human cancer. The CCP has benefited from the SCC and several scientific discoveries have already been made and carried beyond identification of the chemical compound of interest. However, the """"""""bottom-up"""""""" approach to initiating collaborations cited at the site visit does not adequately convey a well-organized approach to guarantee enhanced integration and growth. The CCP Leaders may need a more pro-active approach to engage other program investigators to collaborate in developing new compounds. Better-defined criteria for how to select projects for development, and how to move them forward beyond identification might be helpful. Nevertheless, interactive projects have started, and important new leads have been identified ahead of pharmaceutical companies. The Development and Cancer Program (DCP) is rated outstanding to excellent. The highly qualified leaders exemplify the spectrum of the potential directions of this program. The DCP is built on the historical strength of developmental biology including use of model organisms at UTSW. Research in the Program is very strong and is described in two broad themes of: 1) host-tumor interactions and 2) stem cells and cancer stem cells. Focused directions were described that represent potential new collaborations, which will strengthen the program. Translational research is a strongly articulated goal and the DCP has already started to move in a translational direction, with examples cited for current activities including a NCI PPG that has already been awarded. Integration is being promoted although the current percent of publications that are collaborative is modest. New goals are built on several key findings that are emerging as potential collaborative focal points. Translational potential has commenced particularly in NF1 and anti-angiogenesis arenas. Leadership will play an important role in promoting a culture of collaborative, transdisciplinary research. The Cancer Cell Networks Program (CCNP) is rated excellent to very good. The CCNP is a basic to translational program that is built on the historical strength of cell signaling at UTSW. This newly constructed program contains very strong investigators and leadership that could provide important value added benefit to the SCC. The investigators conduct world-class science with 32 R01s, and $22 million of funding of which 18% is from the NCI, with publications in very high impact journals. These metrics speak to the enormous potential and value added benefit of this program. The collaboration between Drs. Manglesdorf and Minna clearly demonstrate how this program can contribute to the Center. Dr. White is very dynamic and his leadership will help to organize and lead this program forward. Dr. Cobb is a highly qualified institutional leader and great scientist, and a greater engagement in this program would be helpful. While the leaders meet frequently, there is incomplete recorded evidence of faculty program meetings. Enthusiasm for the program was tempered by the concern that the scientific composition/theme had sufficient integration to enhance future collaborations. A clearer definition of the interactions and cancer focus of this highly productive group of investigators needs to be more explicitly articulated. The Molecular Therapeutics in Cancer Program (MTCP) is rated excellent to very good. This is a very strong scientific program led by a highly accomplished physician scientist, with a very strong cancer focus, and supported by several multi-investigator grants. As a pre-clinical lung cancer program this could be an exceptional program. In review of the External Advisory Board (EAB) minutes, it was decided that the MTCP was organized to include a diverse set of funded projects and activities, originally considered for another program, making this combined program's focus less clear. While the science is very strong, the various themes now lack integration and cohesion. The realization of the goal of identifying new targets from this and other programs is still nascent. The MTCP goal of becoming the main hub for the other programs'translational research activities is not, as yet, realized, although several examples show the potential within lung cancer as exemplified by Dr. Schiller's trial of an anti-telomerase agent with other chemotherapy. The realization of this goal will likely need more clinical research faculty and phase I capabilities, as already recognized by the SCC leadership. The Overall Quality of the Programs is rated excellent. The SCC has assembled four programs each with very strong basic science and a strong cancer focus, and outstanding individual science by members. The range of scores, outstanding to very good, reflects unevenness in how well the programs are functioning at a programmatic level. There are challenges in the integration of scientific themes in the MTCP and CCNP. There is potential for all programs to increase intra-programmatic interactions and build interactions across the Center with increased engagement of all leaders in this endeavor. Seven shared resources are requested in the CCSG application, and 11 shared resources are provided by the institution. Overall, the shared resources serve the SCC membership well. The Genomics Shared Resource is rated excellent. This shared resource leverages the institutional microarray facility and provides a value added service by providing consultation on the design, advice on platforms, and sample preparation for the array as well as assistance in analysis of data. The institutional microarray facility, however, functions autonomously and is not well integrated with complicated billing and chargebacks and small and primitive data storage capabilities, reflecting a lack of SCC planning input. The High Throughput Screening Shared Resource is rated outstanding to excellent. Live Cell Imaging Shared Resource is rated as outstanding to excellent;this shared resource has a very knowledgeable leader and great equipment and the highly dispersed microscopes should become more integrated when a new facility for this resource is prepared. An intra-vial microscope might also be helpful. The Small Animal Imaging Shared Resource is rated excellent to outstanding. Two bioluminescent microscopes are located both in and outside of the animal barriers, and pathology validation is enthusiastically embraced. The small animal MRIs are contained in the Advanced Imaging Center and are not part of the SCC shared resource. The relatively low usage in the Small Animal Imaging Shared Resource was viewed as a concern and more proactive recruitment might be helpful. The Tissue Management Shared Resource is rated excellent;this shared resource is situated in Pathology, offers expert pathology consultation, and assists in the conventional acquisition of tissue and tissue preparation. An added value is the acquisition of consent for tissue by the shared resource. Use of this shared resource remains modest, including the high quality Lung P50 grant, which uses a tissue core at M.D. Anderson. The Cancer Center Biostatistics Shared Resource is rated excellent to very good. This new resource assists in the development of clinical protocols, participates in appropriate committees and is gaining usage with the basic scientists. Concern was raised about the cancer relevant expertise, and specific recruitment may yet be needed. This resource assists investigators with their bioinformatics needs, but the details of data storage, analytical tools, as well as usage metrics need more explicit definition. The Clinical Protocol and Data Management Shared Resource is rated excellent;all of the appropriate components are in place, and the protocol and clinical trial data are managed by the ONCORE database. An institution-wide activation of the VELOS database is to be implemented soon, but the potential disruption is likely to be relatively minimal in view of the low usage of this shared resource. The Protocol Review and Monitoring System (PRMS) is approved. The processes are felt to be complete with the appropriate activities and authorities. The PRMS has made an excellent start on closing the poorly accruing studies;the study prioritization has just started. Protocol-Specific Research is rated very good. This resource is designed to support feasibility or early phase I trials of exceptional scientific merit for duration of one year. While the examples for support by this mechanism are of high quality, not all are eligible for support under this CCSG mechanism, such as the correlative studies, phase II trials or trials of longer duration. Data and Safety Monitoring/NIH Policy is rated acceptable. Under Organization and Administration, Senior Leadership is rated excellent to outstanding. Overall, these leaders show a strong working relationship that has been instrumental in persuading the Institutional Leadership and partner organizations, such as Parkland Hospital, to come together with outstanding resources and commitment to build a new Cancer Center. Drs. Willson and Schiller complement each other very well. Drs. White and Skinner also show great promise in fulfilling their roles to lead basic and population sciences, respectively. Dr. Euhus appears to manage clinical resources to facilitate patient trials, but there is no clear indication of who oversees the intellectual drive for translational and experimental therapeutics, besides the Deputy Director. There is no clear line of authority over the Molecular Therapeutics of Cancer Program. The success of the translational research enterprise is critical for the Center to move forward towards becoming a leader in the field and it is important for the Institute to pay special attention to its leadership, its focus and its ability to expand beyond lung cancer. In addition, there appears to be an oversight in not including the Associate Director of Administration in the Senior Leadership. Planning and Evaluation is rated as outstanding. Planning and evaluation began with a strategic plan led by Dr. Willson. A well qualified External Advisory Board (EAB) was assembled, and the EAB advice was helpful and has been mostly implemented. Planning and evaluation led to the development of SCC specific shared resources, the leveraging of institutional resources, and four SCC scientific programs. The need for a phase I program has been recognized, but a plan has not yet been well articulated. The clinical translational activities are still early, and further clinical faculty will be needed to capitalize on the potential for translational trials. Development Funds is rated exceptional. Development Funds will be leveraged with additional institutional resources to provide $570,000 to fund new faculty projects and pilot projects to encourage new areas of cancer research. Overall, the proposed use of Development Funds is well presented and review mechanisms are in place to assure that projects of the highest quality and potential receive funding. Strong examples of how funds have already been used for awards to new investigators and for multi-investigator projects yielding significant research results and interactions were provided. Administration is rated outstanding. The administration leader is very well qualified and experienced. His team is a highly integrated team that is cross-trained for optimal effectiveness, and the team plays a very large role in the SCC. There are well developed SOPs in place for nearly all issues. The administration team has an appropriate grasp on the operating aspects of the SCC, and facilitates the SCC functions and shared resources. The data are handled on line, and the institution has mandated a new database system for financial management. A separate team handles the financial issues of the clinical services. The Essential Characteristics of the SCC are all met. Facilities is rated as outstanding. The 94,420 sq. ft. of space under the Director's control is dispersed on 2 closely linked campuses, and an additional 75,000 sq. ft. of Departmental space are to be used by SCC members. Some of the SCC laboratory space remains unassigned, and available for growth and realization of the SCC and Dr. Willson's strategic vision. Organizational Capabilities is rated as excellent. The SCC Director is well positioned to influence the Cancer research, resources and clinical care at the UTSWMC. The operating committees of the SCC appear well organized and functional. The number of Associate Directors, and other senior leaders was purposefully made large to effectively engage all the strong institutional leaders, and a Senior Leadership Council serves as the executive working group. The role of the Disease Oriented Teams and Leaders in the scientific agenda of the SCC is not entirely obvious, and may impact on the accrual onto the needed translational trials. The SCC EAB is well developed and helpful. Transdisciplinary Collaboration is rated excellent to very good. Strengths include the rising inter- and intra-programmatic collaboration with 11% and 25% shared publications respectively, multiple new multi-investigator grants including NCI P01, U01, and U24 as well as a T32 Cancer Biology Training. The translational opportunities are just beginning, and the number of studies derived from the SCC programmatic science and accrual to theses studies has yet to reach its potential. Programmatic interactions are not yet optimal in every program, and this concern was raised by the EAB in, """"""""The challenge of this Center is to harness this powerhouse of basic science talent into cohesive scientific research programs that emphasize both intra- and inter programmatic interaction."""""""" Cancer Focus is rated as outstanding. There is a growing number of cancer focused grants and publications, and excellent initial recruitments into the clinical sciences. The impact of the SCC is already seen in the movement of well-established basic scientists towards cancer relevant projects as well as the recruitment of cancer-focused investigators. Institutional Commitment is rated as outstanding to exceptional. The appropriate structure and authorities have been developed. UTSWMC has committed to support the unfunded portions of the SCC leadership, administration, and development funds for the term of the initial grant award, but make no commitment for this specific support beyond the initial grant award. There is also no comment on how further growth might be supported beyond development activities. However, there are $50 million over 5 years in philanthropic monies for recruitment, $20 million in philanthropic monies over 10 years for cancer control and over $5 million in support of SCC faculty from endowments. The SCC also has a dedicated Development Officer who reports to the UTSWMS Development Office. Center Director is rated exceptional. Dr. Willson is a highly qualified physician scientist with a long and distinguished history of scientific achievement and leadership;he has developed a clear vision for the center, which he initiated with a strategic planning process. He has already recruited very strong and effective leadership from within and from outside the Institution, and has established the momentum to lead the SCC into a premier NCI-designated Cancer Center. The Inclusion of Women in Clinical Research is approved. The Inclusion of Minorities in Clinical Research is approved with a notation of an exceptional approach for the community activity, planning, and self-evaluation. The Inclusion of Children in Clinical Research is approved. In summary, the SCC under Dr. Willson's very able leadership has made considerable progress in knitting together the very strong individual basic scientists into four well defined and cancer focused programs. The individual science within these programs remains strong, but the range of scores in the outstanding to very good range reflects an unevenness in how well the programs function at a programmatic level. There are challenges in the integration of scientific themes in the Molecular Therapeutics of Cancer Program as well as the Cancer Cell Network Program. There is great potential for all programs to increase intra-programmatic interactions across the Center with increased engagement of all leaders. The development of a robust translational trials program could propel the SCC into the top tier of NCI-designated Cancer Centers. This application is rated Outstanding;range of scores: Outstanding to Excellent. Support for 5 years is recommended. IRG NOTE In response to the draft Site Visit Report, Dr. James Willson sent written comments, in a letter dated July 10, 2009, to indicate 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. The merit of the Cancer Cell Networks Program was revoted resulting in a merit rating of excellent to very good and the merit rating of Overall Quality of the Programs was revoted resulting in a merit rating of excellent. Appropriate changes in the text have been made. The priority score for the application reflects the progress that Dr. Willson has made in the overall organization of the Center and committee's confidence in further success. Based on its assessment of the overall quality of science in the Center, the Subcommittee recommended no budget reduction. 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 raised regarding the protection of human subjects in the proposed studies. INCLUSION OF WOMEN PLAN (Resume): ACCEPTABLE The plan for the inclusion of women in clinical studies was acceptable. G1A INCLUSION OF MINORITIES PLAN (Resume): ACCEPTABLE The plan for the inclusion of minorities in clinical studies was acceptable. M1A INCLUSION OF CHILDREN PLAN (Resume): ACCEPTABLE The plan for the inclusion of children in clinical studies is acceptable. C1A VERTEBRATE ANIMAL (Resume): ACCEPTABLE There were no concerns raised regarding the care and use of vertebrate animals in the proposed studies. REVISION NOTE: Revised 8/27/09 and 9/10/09 to correct minor errors. ESTABLISHED RESEARCH PROGRAMS Chemistry and Cancer DESCRIPTION (provided by applicant): The Chemistry and Cancer Program (CCP) seeks to discover small molecule chemicals capable of either antagonizing or agonizing regulatory pathways relevant to human cancer. Research efforts in the CCP proceed from one of two directions, chemistry-to-biology or biology-to-chemistry. In the former case, the discovery process starts with a novel natural product that is cytotoxic to cancer cells. This molecule, and specific derivatives synthesized by organic chemists, is then subjected to biochemical, genetic or molecular biological studies aimed at resolving its precise mode of action. Alternatively, knowledge of a specific biological pathway relevant to human cancer prompts attempts to identify small chemical antagonists or agonists of the pathway. The latter path is prosecuted by high throughput drug screening, rational peptidomimetics, or preparation of synthetic analogs of biological metabolites. In this context, the current scientific program themes are: 1) Identifying the Molecular Targets of Novel Cytotoxic Agents. 2) Biochemical Dissection of Novel, Cancer Cell-Specific Pathways. 3) Smac mimetics and other means of perturbing apoptosis with synthetic chemicals. 4) Regulation and targeting of the hypoxia response pathway with small molecules. The long-term objective of the CCP is to discover """"""""first-in-class"""""""" chemical compounds, some of which may qualify for rigorous pre-clinical development. In doing so, we will provide the scientific expertise and resources from which program- and cancer center-wide translational research can sprout. Therefore, an additional major goal of the CCP is to develop and provide scientific and technical expertise in chemistry, pharmacology and High Throughput screening.
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