Riccardo Dallafavera, Uris Professor Of Pathology And Genetics
Comprehensive Cancer Centercolumbia University Health Sciences
Grant 2P30CA013696-35 from National Cancer Institute, IRG: NCI
Abstract: The Herbert Irving Comprehensive Cancer Center (HICCC) was designated an NCI Cancer Center in 1972 and gained comprehensive status in 1979. The HICCC is a component of Columbia University Medical Center and associated with New York-Presbyterian Hospital (NYPH). During the period 2003-07, CUMC and NYPH have committed over $312.7 million for i) new research initiatives in basic, clinical and population science; ii) new and expanded facilities for laboratory research and clinical activities; iii) recruitment and program restructuring; iv) support of the Center´s administrative office; and v) bridge funding to offset reduced NCI CCSG support. A new Director, Riccardo Dalla-Favera, MD, was appointed in 2005 and given i) authority over new facilities, including the Irving Cancer Research Center (ICRC), a new 10-story building dedicated to cancer research, with state-of-the-art laboratories (100,000 square feet) and incremental clinical (30,000 square feet) space in the Herbert Irving Pavilion (HIP); ii) a broad-based recruitment plan, which has already attracted 8 new faculty members to the HICCC; and iii) restructuring and expansion of the shared resources. The Director has fully reshaped the senior leadership of the HICCC with appointments of a Deputy Director for Clinical Research and Associate Directors for Basic Research, Clinical Research, Population Science, Biomedical Informatics, Shared Resources and Administration. The programmatic structure of the HICCC has been reorganized to increase cancer focus and interdisciplinary collaboration, and now includes 216 members from 22 Departments and 6 Schools, assigned to two Basic Research programs (Cancer Signaling Networks and Cancer Genetics & Epigenetics), three Disease-Specific programs (Breast Cancer, Prostate Cancer, and Lymphoid Development & Malignancy), and two Population Science programs (Cancer Epidemiology and Prevention, Control & Disparities). The HICCC administers and supports a total of 12 Shared Resources, of which four have been recently created. During the period 2003-2007, the HICCC research activities have been documented in a total of 1,441 publications of which 16.7% are inter-programmatic and 19.2% are intra-programmatic. The current NCI funding base is $23.2M (total direct costs), a 32.6% increase over the 2002 NCI funding base of $17.5M (total direct costs). The Center is requesting CCSG support of $3,484,825 (total direct costs) for the initial budget period. OVERALL CRITIQUE The Herbert Irving Comprehensive Cancer Center (HICCC) at Columbia University, established in 1972, exhibits strong leadership, enhanced Institutional support, and strong basic and population sciences research. The HICCC was last reviewed in 2003. At that time, the reviewers concluded that the progress in the HICCC´s clinical and translational research and its initiation of clinical trials lagged behind the advances made in its outstanding fundamental Research Programs. Unevenness in the quality of the Research Programs, in meeting the Essential Characteristics, and in a number of key Organization and Administration areas (particularly, Planning and Evaluation activities), as well as the lack of evidence of substantial Institutional Commitment and inadequate authority of the Director with respect to space and other resources, reduced the overall merit for this Center. As a result, 4 years of funding were recommended, reflecting the concerns noted, and the need to assess progress. This review galvanized a major evaluation, restructuring, and revitalizing of the HICCC. As a result of the profound structural changes undertaken for the HICCC, and the exigencies attendant to the preparation of a CCSG competitive renewal application, the new Director of the HICCC, Dr. Riccardo Dalla-Favera, worked with the NCI to develop an operational plan contingent on a 1-year administrative extension. Riccardo Dalla-Favera, M.D., was appointed Director of the HICCC in March 2005 and has guided the Cancer Center through its transition. To formalize the authority and responsibilities of the HICCC Director over interdisciplinary cancer care as well as the cancer Research Programs, the Dean of the Columbia University Medical Center (CUMC) appointed Dr. Dalla-Favera as Associate Dean of Oncology, a change that nucleated the revitalization process. Based on a formal Strategic Plan developed by Dr. Dalla-Favera, the HICCC has largely completed its major reorganization, developed a new, strong, and committed Leadership Team, reviewed and realigned its membership, refocused its Research Programs and appointed a number of new Program Leaders or Program Co-Leaders with complementary expertise, updated and expanded the Shared Resources, and built a strong bioinformatics infrastructure. Other major accomplishments include the recruitment of a new Deputy Director for Clinical Research, Dr. Edward Gelmann, who has recruited and integrated a cadre of accomplished clinical investigators, and reorganized and strengthened the clinical research infrastructure. Another major recruit is Dr. Carlos Cordon-Cardo, a well known expert in diagnostic and experimental pathology, who is the Leader of the Prostate Cancer Program and the Director of the Molecular Pathology Shared Resource. As a result, the Center´s basic, clinical, and population sciences components are now more synergistically integrated. A new research facility, the Irving Cancer Research Center, opened in 2005, and is under the control of the Director, providing new opportunities to coordinate interdisciplinary cancer research. The HICCC is now better positioned than ever before in its 34-year history to reach its potential as a premier, innovative Cancer Center. The 2003 review of the HICCC CCSG application determined that the overall quality of the Research Programs varied within the three areas of basic, clinical, and population sciences research. Basic science was considered to be outstanding; however, there were concerns regarding cancer focus in some areas, and limited programmatic efforts to add value to the Cancer Center. Within the clinical programs, there was modest investigator-initiated therapeutic clinical trials research, and concerns related to cohesiveness. The Population Science Division was noted to have outstanding leadership and cancer focus, and excellent to very good science, although there was a decline in intra-programmatic collaboration and a limited genomic focus. Overall, there was a need for a well defined mechanism for translational research. As a result of the strategic planning and evaluation process conducted over the past 2 years, and in response to the 2003 Summary Statement, the constituent 11 Research Programs have been consolidated, reorganized, and refocused, decreasing the overall number to seven. These Programs continue to be grouped into three Divisions Basic Science, Disease-Specific, and Population Science. In the Basic Science Division, the Cancer Signaling Networks Program is rated outstanding, and the Cancer Genetics and Epigenetics Program is rated excellent to outstanding. In the Disease-Specific Division, the Lymphoid Development and Malignancy Program is rated excellent to outstanding. The Breast Cancer Program is rated excellent, reflecting the fact that the Program´s translational preventive studies are only at the beginning stages of development, and overall patient accrual to therapeutic clinical trials is somewhat low. The Prostate Cancer Program is rated excellent, because of a relative shortage of investigator-initiated clinical trials compared to industry-sponsored research and inadequate accrual of patients to trials. Finally, in the Population Science Division, the Cancer Epidemiology Program is rated excellent to outstanding, and the Prevention, Control, and Disparities Program is rated outstanding. There has been substantial progress toward expanding intra- and inter-programmatic interactions and collaborations. Although many of the new initiatives have yet to reach maturity, there is emerging evidence that the HICCC is on an extremely positive trajectory, and several excellent examples of translational science were provided. The Overall Quality of the Programs is rated excellent to outstanding. CCSG support is requested for 12 Shared Resources. Confocal and Specialized Microscopy, Transgenic Mouse, Radiation Research, and Biomedical Informatics are rated outstanding. Genomics Technologies and Molecular Pathology are rated excellent to outstanding. Flow Cytometry, Biomarkers, Research Recruitment and Minority Outreach, and Clinical Research Management Office are rated excellent. Biostatistics is rated very good to excellent due to an apparently low collaborative research base, a seeming lack of involvement in the Programs in the Basic Science Division, and a short tenure of the new Director. Proteomics is rated very good to good because the range of services it provides appears typical of a relatively small proteomics facility, and there are concerns that it may lack the personnel and/or resources to be an early evaluator/adopter of new proteomics technologies. Most Shared Resources are heavily used by members of the Cancer Center, although some receive more customized usage than others. This is an expected distribution and, overall, the "value added" of the Shared Resources is readily apparent. The Resource users are active researchers, most of whom are supported by peer-reviewed grants. The Senior Leadership is rated as outstanding to excellent, and Administration is rated as excellent to outstanding. Both ably serve the HICCC. The Center Director, Dr. Dalla-Favera, is rated as outstanding. His vision and remarkable leadership skills are readily apparent, and are imprinted on this restructured Cancer Center. As a component of the restructuring of the HICCC, Dr. Dalla-Favera has assembled an essentially new Senior Leadership Team. Dr. Edward Gelmann, an extremely accomplished basic and translational researcher in the field of prostate cancer pathogenesis, was recruited to the newly-created position of Deputy Director for Clinical Research in February 2007, and he also provides substantial expertise as Chief of Medical Oncology in the CUMC. Dr. Richard Baer, a leading scientist in elucidating the pathogenesis of human cancer, including acute leukemia and, more recently, breast cancer, was appointed as the Associate Director for Basic Research. Dr. Alfred Neugut, an internationally renowned scientist in the field of cancer prevention, assumed the position of Associate Director for Population Sciences. In recognition of the critical role of biomedical informatics in contemporary cancer research, Dr. Andrea Califano, an international leader in the field of systems biology applied to cancer research, was appointed to the newly created position of Associate Director for Biomedical Informatics. Dr. Benjamin Tycko, a leading basic scientist with expertise in cancer genetics and epigenetics, was appointed as Associate Director for Shared Resources. Finally, Ms. Sadie Maloof, an experienced administrator with expertise in research financing and auditing, was appointed as the Associate Director for Administration, subsequent to the submission of the CCSG application. Although many of the Senior Leaders are relatively new to these roles, there is evidence that they function effectively as a team in leading the HICCC. In particular, the impact of the initiatives led by Dr. Gelmann to restructure the clinical research enterprise, and by Dr. Califano to develop and integrate biomedical informatics and systems biology approaches, is substantial. Planning and Evaluation is considered to be excellent to very good, with a recognized need to better formalize the processes to evaluate Cancer Center activities, such as pilot project review and outcomes, and evaluate the progress toward achieving the goals set forth by the Strategic Plan. In addition, the Center would benefit from the development of a more transparent strategic planning process that involves Program Leaders as well as the HICCC membership. The HICCC has an extensive network of consulting bodies, both external and internal (Senior Leadership Team, Internal Advisory Committee, Membership Committee, and the ICRC Space Committee), which appears to be functioning well. Over the past funding period, Developmental Funds (~$148,000 per year) were allowed to accumulate due to the recent appointment of a new Center Director and extensive restructuring activities. In July 2007, the accumulated funds (~$560,000) were used to initiate a Program-specific pilot project program, with the goal of promoting intra-programmatic interactions. The development of such a program is laudatory, as these types of programs are typically a highly effective mechanism for promoting interdisciplinary and translational research. However, the program is too new to assess its success at the present time, and there is a need for a more formal process for the rigorous review of the pilot project applications. In the current application, funds are sought for two major purposes, namely, to support the HICCC Inter-programmatic (InterPro) pilot project funding program, and the HICCC Bridging Award (BrAwa) program, to support cancer-related projects of outstanding merit that were rated at the 20th percentile or better by an NIH Study Section. There is limited enthusiasm for the Bridging Award mechanism that is proposed to be supported by Developmental Funds. The overall plan for the Developmental Funds is rated as excellent to very good. The Essential Characteristics are all met. Cancer Focus, Institutional Commitment, and Center Director are considered to be outstanding, and Facilities is outstanding to excellent. Organizational Capabilities is considered to be excellent because of the need for more effective utilization of the External Scientific Advisory Board and for the development of formal mechanisms to review the Strategic Plan and evaluate the progress in meeting milestones as the Center moves forward. Interdisciplinary and Transdisciplinary Collaboration and Coordination is considered to be excellent, since the HICCC has not yet realized its full potential in promoting translational and transdisciplinary research. Protocol-Specific Research Support (PSRS) is rated good to acceptable because of several significant concerns, including a poorly described process for prioritization of proposed projects and allocation of research nurses, the lack of an adequate of the specific trials that have been supported by PSRS funding and how they have added value to the Center, and concerns that accrual to Institutional and external peer-reviewed therapeutic trials appears to have substantially decreased during the past CCSG funding period. Overall, the Protocol Review and Monitoring System appears to be functioning well and is approved. The Data and Safety Monitoring/NIH Policy is acceptable, with a well detailed summary of the Data and Safety Monitoring (DSM) Committee and the DSM Plan presented in the application that appears to meet all requisite federal guidelines. The Inclusions of Women, Minorities, and Children in Clinical Research are all approved. A presumed value added by the Research Recruitment and Minority Outreach Shared Research to the accrual effort is noted. In summary, the HICCC, which has completed its 34th year of CCSG funding, maintains its well established and internationally-recognized distinction in basic science, prevention, and cancer epidemiology research, with emerging strengths in clinical and translational research. The early signs indicate that the extensive reorganization of the HICCC will yield the anticipated goals of integrating basic, clinical, and population sciences investigations to develop increased translational, interdisciplinary, and transdisciplinary research and to reach its potential as a premier Cancer Center. Overall, the application is rated as of excellent merit, and support for 5 years is recommended. COMPREHENSIVENESS The HICCC has scientific Programs in each of the three areas of basic, clinical, and population sciences research. There is appropriate depth and breadth in the basic and population sciences Research Programs. The clinical research activity in the Disease-Specific Programs is not yet up to the level of the research in the other two areas; however, the HICCC has made important progress, and the necessary elements are largely in place. Interactive collaborations in basic science are extensive; collaborations bridging basic, clinical, and population sciences research are evident, yet not as well developed. There are noteworthy examples of translational research, such as the discovery of PTEN and the subsequent development of a Phase I/II study of RAD001 plus paclitaxel and bevacizumab in patients with advanced triple-negative breast cancer, and a Phase I study of relapsed or refractory lymphoid diseases based on the discovery and characterization of BCL6. This Center meets the criteria for the scientific research-related aspects of comprehensiveness. IRG NOTE In response to the draft Site Visit Report, written comments were received from the Principal Investigator in a letter dated April 7, 2008, accompanied by a slide from the site visit presentation of the Developmental Funds component, titled "Pilot Projects Review Process." These 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. Clarifications and corrections of the text have been made, where appropriate. No changes in merit ratings of individual components were recorded. The response from the Principal Investigator did not adequately address the Committee´s assessment of the need for a clear of the procedures for the application, evaluation, and awarding of pilot project funding, particularly in the case of inter-programmatic pilot projects. The Subcommittee evaluated the site visit team´s budget recommendation and no changes were made in individual budget recommendations, however a further reduction was made in the Overall Budget Recommendation component. Based on an evaluation of the quality of science in the Center, the Subcommittee recommends a budget of $3,876,942, total costs, for the Overall Budget Recommendation (approximates a ratio of 0.15); this recommendation is made to provide the Center an amount of support appropriate to its level of total National Cancer Institute funding and to the overall scientific quality of the Center. The motion for approval of the scientific requirements of the comprehensive designation passed. HUMAN SUBJECTS RESUME THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER 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.) G1A. INCLUSION OF MINORITIES PLAN (Resume) ACCEPTABLE (Also, see the heading, Inclusion of Minorities in Clinical Research.) M1A. INCLUSION OF CHILDREN PLAN (Resume) ACCEPTABLE (Also, see the heading, Inclusion of Children in Clinical Research.) C1A. VERTEBRATE ANIMAL (Resume) ACCEPTABLE SCIENTIFIC REVIEW OFFICER´S NOTES NIH Policy on Sharing of Model Organisms for Biomedical Research The application includes an adequate of the Herbert Irving Comprehensive Cancer Center´s policy on Sharing of Model Organisms for Biomedical Research. Using Columbia University´s technology transfer office, Science and Technology Ventures, the plan for the sharing of model organisms by the Principal Investigator, Dr. Riccardo Dalla-Favera, and the other members of the research team is administratively appropriate. The process for sharing is thoughtful and detailed and fully endorses the PHS goals on sharing of model organisms within the scientific community. Model organisms that are generated in pilot projects will be shared with the non-profit scientific community through the use of material transfer agreement letters or through deposition in a repository or with a commercial distributor. The HICCC and the Institute for Comparative Medicine (ICM) at Columbia University maintain live or frozen embryos of all genetically engineered mice that are available for sharing, subject to animal use guidelines and technology transfer provisions. ESTABLISHED RESEARCH PROGRAMS Cancer Signaling Networks The long-term goals of the Cancer Signaling Networks (CSN) Program are to elucidate the signaling networks that are disregulated in cancer, and to identify molecular components of these networks that can be exploited for patient care. To achieve these ends, the Program will explore three major scientific themes 1. Signaling networks. The signaling pathways and complex regulatory networks relevant to tumor formation will be defined. 2. Nuclear oncoproteins. The contribution of nuclear oncoproteins to cancer signaling networks will be examined, along with the mechanisms by which nuclear proto-oncogenes are malignantly activated. 3. Tumor suppressors. The role of tumor suppressor genes in oncogenic signaling will be studied to ascertain how their protein products suppress tumor formation in normal cells, and why loss of their function leads to malignant transformation. The CSN Program is one of the two Basic Science Programs of the HICCC. It replaces the former Molecular Oncology & Virology Program and has been restructured to increase cancer relevance and to focus on the oncogenic signaling pathways as a means to identify novel molecular targets of scientific and clinical value. The Program will unify the efforts of the various CSN laboratories, enhance collaboration among CSN investigators, stimulate interactions with other HICCC members, and encourage joint scientific projects and grant proposals. We also seek to transmit our understanding of oncogenic signaling to the Disease-based Programs, and so move discoveries in basic science more rapidly to clinical applications. In new efforts, we have expanded our capacity for translational research and incorporated advanced bioinformatics technologies for analysis of signaling networks. Plans are also in place to develop high-throughput screening technologies to identify small molecules that modulate oncogenic signaling. The CSN Program consists of 26 independent scientists (all full members of the HICCC) with a shared interest in the signaling pathways relevant to human malignancy. Its members belong to nine basic science departments and 5 clinical departments, including labs at both the medical center and main campuses of Columbia University. For the last budget year of the grant (July 1, 2006 - June 30, 2007), the CSN Program received a total of $9.8M (direct costs) in cancer-relevant grant support, including $6.0M (direct costs) in NCI funding, $3.6M (direct costs) in other cancer-related peer-reviewed funding, and $0.2M (direct costs) in cancer-related non-peer-reviewed funding. The total number of cancer-related publications by the current Program members since the previous submission (i.e., 2003-present) was 154, with 13.6% inter-programmatic and 12.3% intra-programmatic publications
Project start date: 1997-07-04
Project end date: 2013-06-30
Sponsored Links Lab Supply Mall http://www.labsupplymall.com
Grants awarded to Riccardo Dallafavera
Riccardo Dallafavera, Uris Professor Of Pathology And Genetics
Comprehensive Cancer Centercolumbia University Health Sciences
Grant 2P30CA013696-35 from National Cancer Institute, IRG: NCI
Abstract: The Herbert Irving Comprehensive Cancer Center (HICCC) was designated an NCI Cancer Center in 1972 and gained comprehensive status in 1979. The HICCC is a component of Columbia University Medical Center and associated with New York-Presbyterian Hospital (NYPH). During the period 2003-07, CUMC and NYPH have committed over $312.7 million for i) new research initiatives in basic, clinical and population science; ii) new and expanded facilities for laboratory research and clinical activities; iii) recruitment and program restructuring; iv) support of the Center´s administrative office; and v) bridge funding to offset reduced NCI CCSG support. A new Director, Riccardo Dalla-Favera, MD, was appointed in 2005 and given i) authority over new facilities, including the Irving Cancer Research Center (ICRC), a new 10-story building dedicated to cancer research, with state-of-the-art laboratories (100,000 square feet) and incremental clinical (30,000 square feet) space in the Herbert Irving Pavilion (HIP); ii) a broad-based recruitment plan, which has already attracted 8 new faculty members to the HICCC; and iii) restructuring and expansion of the shared resources. The Director has fully reshaped the senior leadership of the HICCC with appointments of a Deputy Director for Clinical Research and Associate Directors for Basic Research, Clinical Research, Population Science, Biomedical Informatics, Shared Resources and Administration. The programmatic structure of the HICCC has been reorganized to increase cancer focus and interdisciplinary collaboration, and now includes 216 members from 22 Departments and 6 Schools, assigned to two Basic Research programs (Cancer Signaling Networks and Cancer Genetics & Epigenetics), three Disease-Specific programs (Breast Cancer, Prostate Cancer, and Lymphoid Development & Malignancy), and two Population Science programs (Cancer Epidemiology and Prevention, Control & Disparities). The HICCC administers and supports a total of 12 Shared Resources, of which four have been recently created. During the period 2003-2007, the HICCC research activities have been documented in a total of 1,441 publications of which 16.7% are inter-programmatic and 19.2% are intra-programmatic. The current NCI funding base is $23.2M (total direct costs), a 32.6% increase over the 2002 NCI funding base of $17.5M (total direct costs). The Center is requesting CCSG support of $3,484,825 (total direct costs) for the initial budget period. OVERALL CRITIQUE The Herbert Irving Comprehensive Cancer Center (HICCC) at Columbia University, established in 1972, exhibits strong leadership, enhanced Institutional support, and strong basic and population sciences research. The HICCC was last reviewed in 2003. At that time, the reviewers concluded that the progress in the HICCC´s clinical and translational research and its initiation of clinical trials lagged behind the advances made in its outstanding fundamental Research Programs. Unevenness in the quality of the Research Programs, in meeting the Essential Characteristics, and in a number of key Organization and Administration areas (particularly, Planning and Evaluation activities), as well as the lack of evidence of substantial Institutional Commitment and inadequate authority of the Director with respect to space and other resources, reduced the overall merit for this Center. As a result, 4 years of funding were recommended, reflecting the concerns noted, and the need to assess progress. This review galvanized a major evaluation, restructuring, and revitalizing of the HICCC. As a result of the profound structural changes undertaken for the HICCC, and the exigencies attendant to the preparation of a CCSG competitive renewal application, the new Director of the HICCC, Dr. Riccardo Dalla-Favera, worked with the NCI to develop an operational plan contingent on a 1-year administrative extension. Riccardo Dalla-Favera, M.D., was appointed Director of the HICCC in March 2005 and has guided the Cancer Center through its transition. To formalize the authority and responsibilities of the HICCC Director over interdisciplinary cancer care as well as the cancer Research Programs, the Dean of the Columbia University Medical Center (CUMC) appointed Dr. Dalla-Favera as Associate Dean of Oncology, a change that nucleated the revitalization process. Based on a formal Strategic Plan developed by Dr. Dalla-Favera, the HICCC has largely completed its major reorganization, developed a new, strong, and committed Leadership Team, reviewed and realigned its membership, refocused its Research Programs and appointed a number of new Program Leaders or Program Co-Leaders with complementary expertise, updated and expanded the Shared Resources, and built a strong bioinformatics infrastructure. Other major accomplishments include the recruitment of a new Deputy Director for Clinical Research, Dr. Edward Gelmann, who has recruited and integrated a cadre of accomplished clinical investigators, and reorganized and strengthened the clinical research infrastructure. Another major recruit is Dr. Carlos Cordon-Cardo, a well known expert in diagnostic and experimental pathology, who is the Leader of the Prostate Cancer Program and the Director of the Molecular Pathology Shared Resource. As a result, the Center´s basic, clinical, and population sciences components are now more synergistically integrated. A new research facility, the Irving Cancer Research Center, opened in 2005, and is under the control of the Director, providing new opportunities to coordinate interdisciplinary cancer research. The HICCC is now better positioned than ever before in its 34-year history to reach its potential as a premier, innovative Cancer Center. The 2003 review of the HICCC CCSG application determined that the overall quality of the Research Programs varied within the three areas of basic, clinical, and population sciences research. Basic science was considered to be outstanding; however, there were concerns regarding cancer focus in some areas, and limited programmatic efforts to add value to the Cancer Center. Within the clinical programs, there was modest investigator-initiated therapeutic clinical trials research, and concerns related to cohesiveness. The Population Science Division was noted to have outstanding leadership and cancer focus, and excellent to very good science, although there was a decline in intra-programmatic collaboration and a limited genomic focus. Overall, there was a need for a well defined mechanism for translational research. As a result of the strategic planning and evaluation process conducted over the past 2 years, and in response to the 2003 Summary Statement, the constituent 11 Research Programs have been consolidated, reorganized, and refocused, decreasing the overall number to seven. These Programs continue to be grouped into three Divisions Basic Science, Disease-Specific, and Population Science. In the Basic Science Division, the Cancer Signaling Networks Program is rated outstanding, and the Cancer Genetics and Epigenetics Program is rated excellent to outstanding. In the Disease-Specific Division, the Lymphoid Development and Malignancy Program is rated excellent to outstanding. The Breast Cancer Program is rated excellent, reflecting the fact that the Program´s translational preventive studies are only at the beginning stages of development, and overall patient accrual to therapeutic clinical trials is somewhat low. The Prostate Cancer Program is rated excellent, because of a relative shortage of investigator-initiated clinical trials compared to industry-sponsored research and inadequate accrual of patients to trials. Finally, in the Population Science Division, the Cancer Epidemiology Program is rated excellent to outstanding, and the Prevention, Control, and Disparities Program is rated outstanding. There has been substantial progress toward expanding intra- and inter-programmatic interactions and collaborations. Although many of the new initiatives have yet to reach maturity, there is emerging evidence that the HICCC is on an extremely positive trajectory, and several excellent examples of translational science were provided. The Overall Quality of the Programs is rated excellent to outstanding. CCSG support is requested for 12 Shared Resources. Confocal and Specialized Microscopy, Transgenic Mouse, Radiation Research, and Biomedical Informatics are rated outstanding. Genomics Technologies and Molecular Pathology are rated excellent to outstanding. Flow Cytometry, Biomarkers, Research Recruitment and Minority Outreach, and Clinical Research Management Office are rated excellent. Biostatistics is rated very good to excellent due to an apparently low collaborative research base, a seeming lack of involvement in the Programs in the Basic Science Division, and a short tenure of the new Director. Proteomics is rated very good to good because the range of services it provides appears typical of a relatively small proteomics facility, and there are concerns that it may lack the personnel and/or resources to be an early evaluator/adopter of new proteomics technologies. Most Shared Resources are heavily used by members of the Cancer Center, although some receive more customized usage than others. This is an expected distribution and, overall, the "value added" of the Shared Resources is readily apparent. The Resource users are active researchers, most of whom are supported by peer-reviewed grants. The Senior Leadership is rated as outstanding to excellent, and Administration is rated as excellent to outstanding. Both ably serve the HICCC. The Center Director, Dr. Dalla-Favera, is rated as outstanding. His vision and remarkable leadership skills are readily apparent, and are imprinted on this restructured Cancer Center. As a component of the restructuring of the HICCC, Dr. Dalla-Favera has assembled an essentially new Senior Leadership Team. Dr. Edward Gelmann, an extremely accomplished basic and translational researcher in the field of prostate cancer pathogenesis, was recruited to the newly-created position of Deputy Director for Clinical Research in February 2007, and he also provides substantial expertise as Chief of Medical Oncology in the CUMC. Dr. Richard Baer, a leading scientist in elucidating the pathogenesis of human cancer, including acute leukemia and, more recently, breast cancer, was appointed as the Associate Director for Basic Research. Dr. Alfred Neugut, an internationally renowned scientist in the field of cancer prevention, assumed the position of Associate Director for Population Sciences. In recognition of the critical role of biomedical informatics in contemporary cancer research, Dr. Andrea Califano, an international leader in the field of systems biology applied to cancer research, was appointed to the newly created position of Associate Director for Biomedical Informatics. Dr. Benjamin Tycko, a leading basic scientist with expertise in cancer genetics and epigenetics, was appointed as Associate Director for Shared Resources. Finally, Ms. Sadie Maloof, an experienced administrator with expertise in research financing and auditing, was appointed as the Associate Director for Administration, subsequent to the submission of the CCSG application. Although many of the Senior Leaders are relatively new to these roles, there is evidence that they function effectively as a team in leading the HICCC. In particular, the impact of the initiatives led by Dr. Gelmann to restructure the clinical research enterprise, and by Dr. Califano to develop and integrate biomedical informatics and systems biology approaches, is substantial. Planning and Evaluation is considered to be excellent to very good, with a recognized need to better formalize the processes to evaluate Cancer Center activities, such as pilot project review and outcomes, and evaluate the progress toward achieving the goals set forth by the Strategic Plan. In addition, the Center would benefit from the development of a more transparent strategic planning process that involves Program Leaders as well as the HICCC membership. The HICCC has an extensive network of consulting bodies, both external and internal (Senior Leadership Team, Internal Advisory Committee, Membership Committee, and the ICRC Space Committee), which appears to be functioning well. Over the past funding period, Developmental Funds (~$148,000 per year) were allowed to accumulate due to the recent appointment of a new Center Director and extensive restructuring activities. In July 2007, the accumulated funds (~$560,000) were used to initiate a Program-specific pilot project program, with the goal of promoting intra-programmatic interactions. The development of such a program is laudatory, as these types of programs are typically a highly effective mechanism for promoting interdisciplinary and translational research. However, the program is too new to assess its success at the present time, and there is a need for a more formal process for the rigorous review of the pilot project applications. In the current application, funds are sought for two major purposes, namely, to support the HICCC Inter-programmatic (InterPro) pilot project funding program, and the HICCC Bridging Award (BrAwa) program, to support cancer-related projects of outstanding merit that were rated at the 20th percentile or better by an NIH Study Section. There is limited enthusiasm for the Bridging Award mechanism that is proposed to be supported by Developmental Funds. The overall plan for the Developmental Funds is rated as excellent to very good. The Essential Characteristics are all met. Cancer Focus, Institutional Commitment, and Center Director are considered to be outstanding, and Facilities is outstanding to excellent. Organizational Capabilities is considered to be excellent because of the need for more effective utilization of the External Scientific Advisory Board and for the development of formal mechanisms to review the Strategic Plan and evaluate the progress in meeting milestones as the Center moves forward. Interdisciplinary and Transdisciplinary Collaboration and Coordination is considered to be excellent, since the HICCC has not yet realized its full potential in promoting translational and transdisciplinary research. Protocol-Specific Research Support (PSRS) is rated good to acceptable because of several significant concerns, including a poorly described process for prioritization of proposed projects and allocation of research nurses, the lack of an adequate of the specific trials that have been supported by PSRS funding and how they have added value to the Center, and concerns that accrual to Institutional and external peer-reviewed therapeutic trials appears to have substantially decreased during the past CCSG funding period. Overall, the Protocol Review and Monitoring System appears to be functioning well and is approved. The Data and Safety Monitoring/NIH Policy is acceptable, with a well detailed summary of the Data and Safety Monitoring (DSM) Committee and the DSM Plan presented in the application that appears to meet all requisite federal guidelines. The Inclusions of Women, Minorities, and Children in Clinical Research are all approved. A presumed value added by the Research Recruitment and Minority Outreach Shared Research to the accrual effort is noted. In summary, the HICCC, which has completed its 34th year of CCSG funding, maintains its well established and internationally-recognized distinction in basic science, prevention, and cancer epidemiology research, with emerging strengths in clinical and translational research. The early signs indicate that the extensive reorganization of the HICCC will yield the anticipated goals of integrating basic, clinical, and population sciences investigations to develop increased translational, interdisciplinary, and transdisciplinary research and to reach its potential as a premier Cancer Center. Overall, the application is rated as of excellent merit, and support for 5 years is recommended. COMPREHENSIVENESS The HICCC has scientific Programs in each of the three areas of basic, clinical, and population sciences research. There is appropriate depth and breadth in the basic and population sciences Research Programs. The clinical research activity in the Disease-Specific Programs is not yet up to the level of the research in the other two areas; however, the HICCC has made important progress, and the necessary elements are largely in place. Interactive collaborations in basic science are extensive; collaborations bridging basic, clinical, and population sciences research are evident, yet not as well developed. There are noteworthy examples of translational research, such as the discovery of PTEN and the subsequent development of a Phase I/II study of RAD001 plus paclitaxel and bevacizumab in patients with advanced triple-negative breast cancer, and a Phase I study of relapsed or refractory lymphoid diseases based on the discovery and characterization of BCL6. This Center meets the criteria for the scientific research-related aspects of comprehensiveness. IRG NOTE In response to the draft Site Visit Report, written comments were received from the Principal Investigator in a letter dated April 7, 2008, accompanied by a slide from the site visit presentation of the Developmental Funds component, titled "Pilot Projects Review Process." These 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. Clarifications and corrections of the text have been made, where appropriate. No changes in merit ratings of individual components were recorded. The response from the Principal Investigator did not adequately address the Committee´s assessment of the need for a clear of the procedures for the application, evaluation, and awarding of pilot project funding, particularly in the case of inter-programmatic pilot projects. The Subcommittee evaluated the site visit team´s budget recommendation and no changes were made in individual budget recommendations, however a further reduction was made in the Overall Budget Recommendation component. Based on an evaluation of the quality of science in the Center, the Subcommittee recommends a budget of $3,876,942, total costs, for the Overall Budget Recommendation (approximates a ratio of 0.15); this recommendation is made to provide the Center an amount of support appropriate to its level of total National Cancer Institute funding and to the overall scientific quality of the Center. The motion for approval of the scientific requirements of the comprehensive designation passed. HUMAN SUBJECTS RESUME THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER 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.) G1A. INCLUSION OF MINORITIES PLAN (Resume) ACCEPTABLE (Also, see the heading, Inclusion of Minorities in Clinical Research.) M1A. INCLUSION OF CHILDREN PLAN (Resume) ACCEPTABLE (Also, see the heading, Inclusion of Children in Clinical Research.) C1A. VERTEBRATE ANIMAL (Resume) ACCEPTABLE SCIENTIFIC REVIEW OFFICER´S NOTES NIH Policy on Sharing of Model Organisms for Biomedical Research The application includes an adequate of the Herbert Irving Comprehensive Cancer Center´s policy on Sharing of Model Organisms for Biomedical Research. Using Columbia University´s technology transfer office, Science and Technology Ventures, the plan for the sharing of model organisms by the Principal Investigator, Dr. Riccardo Dalla-Favera, and the other members of the research team is administratively appropriate. The process for sharing is thoughtful and detailed and fully endorses the PHS goals on sharing of model organisms within the scientific community. Model organisms that are generated in pilot projects will be shared with the non-profit scientific community through the use of material transfer agreement letters or through deposition in a repository or with a commercial distributor. The HICCC and the Institute for Comparative Medicine (ICM) at Columbia University maintain live or frozen embryos of all genetically engineered mice that are available for sharing, subject to animal use guidelines and technology transfer provisions. ESTABLISHED RESEARCH PROGRAMS Cancer Signaling Networks The long-term goals of the Cancer Signaling Networks (CSN) Program are to elucidate the signaling networks that are disregulated in cancer, and to identify molecular components of these networks that can be exploited for patient care. To achieve these ends, the Program will explore three major scientific themes 1. Signaling networks. The signaling pathways and complex regulatory networks relevant to tumor formation will be defined. 2. Nuclear oncoproteins. The contribution of nuclear oncoproteins to cancer signaling networks will be examined, along with the mechanisms by which nuclear proto-oncogenes are malignantly activated. 3. Tumor suppressors. The role of tumor suppressor genes in oncogenic signaling will be studied to ascertain how their protein products suppress tumor formation in normal cells, and why loss of their function leads to malignant transformation. The CSN Program is one of the two Basic Science Programs of the HICCC. It replaces the former Molecular Oncology & Virology Program and has been restructured to increase cancer relevance and to focus on the oncogenic signaling pathways as a means to identify novel molecular targets of scientific and clinical value. The Program will unify the efforts of the various CSN laboratories, enhance collaboration among CSN investigators, stimulate interactions with other HICCC members, and encourage joint scientific projects and grant proposals. We also seek to transmit our understanding of oncogenic signaling to the Disease-based Programs, and so move discoveries in basic science more rapidly to clinical applications. In new efforts, we have expanded our capacity for translational research and incorporated advanced bioinformatics technologies for analysis of signaling networks. Plans are also in place to develop high-throughput screening technologies to identify small molecules that modulate oncogenic signaling. The CSN Program consists of 26 independent scientists (all full members of the HICCC) with a shared interest in the signaling pathways relevant to human malignancy. Its members belong to nine basic science departments and 5 clinical departments, including labs at both the medical center and main campuses of Columbia University. For the last budget year of the grant (July 1, 2006 - June 30, 2007), the CSN Program received a total of $9.8M (direct costs) in cancer-relevant grant support, including $6.0M (direct costs) in NCI funding, $3.6M (direct costs) in other cancer-related peer-reviewed funding, and $0.2M (direct costs) in cancer-related non-peer-reviewed funding. The total number of cancer-related publications by the current Program members since the previous submission (i.e., 2003-present) was 154, with 13.6% inter-programmatic and 12.3% intra-programmatic publications
Project start date: 1997-07-04
Project end date: 2013-06-30
Role Of BCL6 Mutation In Lymphomagenesis
Riccardo Dallafavera, Uris Professor Of Pathology And Genetics
Institute For Cancer Geneticscolumbia University Health Sciences
Grant 5R01CA107489-05 from National Cancer Institute, IRG: CAMP
Abstract: The Bcl6 gene encodes a zinc-finger transcription factor and is altered by chromosomal rearrangements in its 5´ non-coding region in approximately 30% of diffuse large-cell lymphoma (DLCL). In addition, the 5´ non-coding region of Bcl6 is targeted by somatic hypermutation in normal germinal center (GC) B cells and in GC-derived B cell non-Hodgkin lymphoma (B-NHL). The general goal of this project will be to investigate the role of Bcl6 hypermutation in B-NHL pathogenesis. In particular, the following specific lines of investigations will be pursued 1) Functional consequences of Bcl6 hypermutation; we will investigate the role of Bcl6 mutations on the regulation of Bcl6 expression by determining whether mutations i) affect CD40-mediated Bcl6 downregulation; ii) induce an increased sensitivity to STAT6-mediated IL4 signaling; 2) Role of Bcl6 mutation in lymphomagenesis; transgenic mice carrying NHL-derived mutant Bcl6 alleles will be constructed and examined for the effects of mutations on i) B cell lineage development, ii) tumor development; 3) Examine the role of germinal centers and IgV somatic hypermutation in lymphomagenesis; we will attempt to determine whether the presence of germinal center and/or somatic hypermutation are required for lymphomagenesis using a transgenic mouse model generated by crossing lymphoma prone mice (lambda-myc) with mice that are unable to either form GC (Bcl6delta/delta mice) or undergo somatic hypermutation (AID-/- mice)
Keywords: B lymphocyte, gene expression, gene mutation, neoplasm /cancer genetics, neoplastic growth, nonHodgkin`s lymphoma, pathologic process CD40 molecule, allele, biological signal transduction, cell cycle, chromosome aberration, genetic model, interleukin 4, protein structure, transcription factor cell line, genetically modified animal, human tissue, laboratory mouse, polymerase chain reaction, transfection
Project start date: 2004-05-05
Project end date: 2009-04-30
AIDS Associated Lymphoproliferative Disorders
Riccardo Dallafavera, Uris Professor Of Pathology And Genetics
Institute For Cancer Geneticscolumbia University Health Sciences
Grant 5R37CA037295-25 from National Cancer Institute, IRG: NSS
Project start date: 1984-04-01
Project end date: 2012-06-30