Management and Oversight will be provided by three components of ICMIC: 1) Office of the PI;2) the Governing Board (for Program Management and Project Oversight);3) an External Oversight and Review Committee. This is the same organizational structure originally proposed in 2000, and has worked well during the current period of funding. Thus, little change in our current organizational structure is proposed. The Office of the Principal Investigator will be the central administrative unit and will coordinate the individual components and activities of ICMIC. The Office will serve two main functions: A) it will provide overall leadership and direction for ICMIC, B) it will provide the infrastructure and resources to coordinate the activities and interactions of the PI between five advisory committees: 1) a Governing Board for Program Management and Project Oversight;2) Project Development: 3) Specialized Resources: 4) Career Development: and 5) External Oversight.. The Office of the PI will be responsible for the overall planning, execution, monitoring and evaluation of all ICMIC functions. Office resources will be used to organize meetings of the 'Think Tank"""""""", the Governing Board, the External Oversight and Review Committee, and other committees as outlined in this application. Additionally, it will disseminate written communications such protocols, progress reports of the research and developmental projects, and take care of the myriad administrative details associated with hiring and managing personnel. Also it will exercise financial overview of the entire ICMIC program and its components, and prepare the annual non-competitive renewal applications. The office will be staffed by a half-time office manager-secretary who will be responsible for administrative activities related to ICMIC such as scheduling meetings, taking and transcribing minutes from these meetings and initiating follow-up as necessary, distributing information to ICMIC personnel, typing correspondence, filing and coordinating travel arrangements as necessary. As noted above, the PI will provide overall guidance and direction for ICMIC. This will be accomplished through the Office of the PI and through the Pi's responsibilities as chairman of the Governing Board, oversight of the operations of Specialized Resources, and by participation as a member of the """"""""Think Tank"""""""" for Project Development. The Governing Board will be the internal advisory committee;the PI will chair this committee and it will include the Project Leaders, selected key program/departmental chairman, and the individual specialized resource directors. The Governing Board and the PI will review the recommendations of three Advisory Committees and define ICMIC policy. The advisory recommendations will be submitted by the External Oversight Committee (annual), the Resource Utilization Summary (annual) and the Career Development Committee (annual). The Board and the PI will be responsible for: 1) establishing new research directions or a new focus of investigation;2) the acquisition of equipment for a new imaging modality or upgrades to existing imaging equipment;3) establishing budget and resources allocation priorities;4) evaluation of new research proposals and periodic (annual) review of established projects using ICMIC and SAIRP resources;and 5) review the annual report of the External Oversight and Review Committee. The Board and the PI will work closely together. The Board will submit yearly recommendations to the PI for implementation. Since the PI will be chairman of the Governing Board, differences between the Board and the R will be resolved prior to submission of the final recommendations. In the unlikely event that a substantial difference of opinion between a majority of the Board and the PI exists, the PI can """"""""veto"""""""" itemized components of the Board's recommendation. However, this """"""""veto"""""""" can be nullified by a greater than two-third majority vote of the Board, following review of the Pi's """"""""veto"""""""". If a """"""""veto"""""""" or a """"""""veto nullification"""""""" occurs between the R and the Board, this event will be described in the annual report of ICMIC to NIH. During the past 5 years of ICMIC operations, no significant differences between the PI and the Board developed. The External Oversight and Review Committee will be the external advisory body;it will meet annually, review and evaluate the progress and plans for each of the project areas, and construct a report with recommendations which will be sent to the Office of the PI (and will be reviewed by the Governing Board). The members of this external advisory body were chosen for their expertise in areas of molecular and cellular biology, vector targeting, gene therapy as well as expertise in PET and NMR imaging. The current external advisory committee consists of Dr. William Eckelman, Ph.D., chairperson (Chief Scientific Officer, Molecular Tracer LLC, Bethesda, MD);Dr. David Spector, (Gene Expression Program Leader and Professor, Cold Spring Harbor Laboratory), Dr. Joseph Ackerman (Chair, Chemistry Department and William Greenleaf Eliot Professor of Physical Chemistry in Arts and Sciences, Washington University in St. Louis), Dr. Joseph Bertino (Chair and Professor, Neuroscience and Cell Biology, Cancer Institute of New Jersey, UMDNJ, Robert Wood Johnson Medical School);Dr. Alan Fischman (Chief, Nuclear Medicine, Massachusetts General Hospital). Developmental Fund: (decision-making and oversight responsibilities) A major organizational strength of this proposal and our current ICMIC operations is the continuation of the Project Development """"""""Think Tank"""""""". This organizational entity operates within the Developmental Fund and is designed to stimulate focused and fluid interactions between investigators at MSKCC. """"""""New"""""""" developmental projects are discussed and refined by multidisciplinary interactions within this group. The four Developmental Projects (DP) that were initially proposed and implemented in our currently funded ICMIC included: a) Imaging Dihydrofolate Reductase Gene Amplification;b) In Vivo Imaging of Genetically Modified T Lymphocytes;c) Imaging Spheroid Growth and Vascularization, In Vivo;d) Imaging &Dosimetry of 86Y/90Y-labeled anti-GDI 9 & CD20 Antibodies. Of these, three (a-c) were highly successful leading to peer-reviewed publications [8] and they provided pilot data for several grant applications, of which 3 have been funded. The fourth developmental project (d) was canceled mid-term because 86Y-yittrium was unavailable due to the transition and installation of a new cyclotron at MSKCC (of note, 86Y-yittrium has recently been made available to MSKCC investigators and is now included as Developmental Project A in this renewal application). An additional four developmental projects were or are being funded through the Developmental Fund: e) Surrogate Imaging of HIF1-a Expression; f) Real-time Visualization of Stem/Progenitor Cell Engraftment;g) Non-invasive Quantitative PET Imaging of Tumor Response with EGFR, HER2, VEGFR, PSMA, a6b4 binding ligands;h) Development of a Non-suicidal 5FU Reporter System for Molecular Imaging. There are three """"""""success stories"""""""" with respect to individuals who participated in Developmental Projects during the initial ICMIC funding period. Two junior or mid-level ICMIC-funded investigators have left MSKCC for tenured positions at other institutions (Debabrata Banerjee (DP-a) - University of New Jersey Medical Center (UNJMC), and George Sguoros (DP-b) - Johns Hopkins University Medical Center). Another, Michel Sadelain (DP-c), was recently appointed as a tenure track Member (Professor) in the Dept. of Human Genetics at MSKCC, and is a participant in this renewal application. Letters describing their assessment and experiences under the MSKCC IGMIC program, and the impact of ICMIC on their scientific and career choices are included at the end of Section B. The developmental projects proposed in this renewal application include the following: Project A: Imaging and dosimetry of Yttrium 86/Yttrium 90 labeled anti-CD19 and CD 20 antibodies using PET (Joseph Jurcic) Project B: Imaging Oxygen-independent Regulation of HIF-1 alpha (Inna Serganova) Two individual developmental projects (Projects A and B) are described in detail in Section E. In addition to these two developmental projects, we expect that three or four more two-year developmental projects will evolve through the """"""""Think Tank"""""""" structure we propose for the Developmental Fund (see below). The'Think Tank"""""""" will continue to be a loosely structured organization in which interested investigators will attend depending on the topics being discussed;it. will meet bi-monthly. The participants at """"""""Think Tank"""""""" meetings will consist of a creative mix of senior and more junior scientists within ICMIC, with an emphasis on the early-to-mid career (mid-level) ICMIC investigators. The co-Leaders of the """"""""Think Tank"""""""" will reflect the focus on younger participants and will include a range of disciplines. The co-Leaders will include Drs. Vladimir Ponomarev, Inna Serganova (reporter gene imaging), David Solit (clinical oncology), and Peter Smith-Jones (radiochemistry). Under the guidance of senior participants, this group of competent younger investigators will increasingly play a leading role in the management of the Development Fund. An example of topics and questions that could be addressed by the Think Tank include: 1) Is it possible to image activation or repression of a particular signal transduction pathway that is an important step in the transformation of tumor cells to a more malignant phenotype, or for the action of a particular anti-cancer drug? 2) What is the relationship of uptake and retention at the tumor site of radiolabeled tyrosine kinase inhibitors, or HSP-90 inhibitors on the pharmacodynamics of tumor response as measured by non-invasive imaging approaches? 3) What is the time course of adoptive immunotherapy response as measured by non-invasive imaging methods, and how does this relate to uptake and migration of immune cells into the tumor region. 4) What is the impact of targeted radiotherapy as measured with Y-86 radiolabeled antibodies, and functional imaging of tumor treatment effect, as measured by FDG uptake or FLT uptake in the clinic? The Think Tank is considered to be the """"""""heart and soul"""""""" of our ICMIC, in which young and mid-level investigators will have the opportunity to exercise greater interaction and assume greater responsibility within ICMIC. It is the place for vigorous interaction and discussion between """"""""worker bees"""""""". It is the place where investigators with different expertise will interact in a multidisciplinary environment. The Think Tank is where the """"""""action is"""""""";it is the """"""""place to be"""""""", especially for younger investigators. One responsibility of the Think Tank will be to review and discuss aJi developmental projects prior to their presentation to the PI and the Governing Board. It is expected that this review and interaction with the multidisciplinary expertise on the Think Tank will substantially improve and refine the developmental projects. The Think Tank concept has already been successful in developing and refining several of the Research Projects and Developmental Projects during the current funding period, and this is expected to continue into the future. The major change in the Think Tank concept proposed in this application is to shift operations and participation to a younger generation of investigators. It is expected that the Developmental Fund will be used to support 3 to 4 additional (new) Developmental Projects during years 3 through 5 of this proposal. We expect that most new developmental projects will be generated through an individual investigator's interactions with the Think Tank. Although this route of new Development Project generation is not required, it will be the preferred route. Developmental Projects will be supported for two years with the possibility of a one year extension. This was optimal based on our experience during the current funding period. It is expected that most of these projects will generate sufficient preliminary data to support a subsequent submission of an RO1 application by the individual investigators. All new developmental projects will be submitted as a written 5- to 6-page document using PHS-398 format (mini-RO1). It will initially be submitted to the Think Tank for consideration and review (see above). After this review and refinement based on Think Tank recommendations, the written application will be forwarded to the PI, along with a brief assessment by one of the co-Leaders of the Think Tank. The PI along with the Governing Board will perform a final review prior to acceptance of a new.Developmental Project. The PI and Governing Board will vote to """"""""accept as is"""""""", """"""""request specific changes prior to acceptance"""""""", or """"""""reject with explanation"""""""". The decision of the PI and the Governing Board will be communicated to the Development Project applicant through the Office of the PI in an official letter. Another responsibility of the Think Tank will be to provide the PI and Governing Board with a brief assessment of the activities and topics that generated particular interest and may be worthy of consideration for further development. This brief written assessment will be provided quarterly to the PI by the co-Leaders of the Think Tank, and will be presented at the quarterly meeting of the Governing Board. The PI will be a participant of the Think Tank and, therefore, will be directly appraised of new and exciting developments emanating from Think Tank activities. Any costs incurred by the Think Tank will be funded through the Office of the PI. Specialized and Core Resources: (decision-making and oversight responsibilities) Most of the Specialized Resources that will be used by ICMIC investigators already exist at MSKCC, within the structure of the institutional Core Facilities (SKI), or as components of hospital based departments (e.g., PET facilities within the Nuclear Medicine Service of the Department of Radiology, Memorial Hospital). A list of all Core/Resource services at MSKCC is provided in Section D, and those that are likely to be used by ICMIC investigators are also described briefly in Section D. Those that will be used extensively by ICIMIC investigators and will be considered """"""""non-funded"""""""" ICMIC resources in this proposal include: 1) Animal Imaging (MRI/MRS, microPET, microSPECT, microCT, bioluminescence, fluorescence, quantitative autoradiography), 2) Radiation Facilities, 3) Molecular Cytology, 4) Monoclonal Antibody Core, 5) Flow Cytometry, 6) Organic Synthesis, 7) Preclinical Pharmacology, 8) Office of Clinical Research. The institutional Core Facility directors (SKI) have confirmed the availability of these resources for ICMIC investigators. It should also be noted that the co-directors of the animal imaging resources (MRI/MRS. PET/SPECT/CT. optical and autoradiography) are Project leaders of the ICMIC proposal (Drs. Larson and Koutcher). These established and well-functioning MSKCC Core Facilities and the Departmental Imaging Services are available to all MSKCC investigators on a """"""""fee for service"""""""" basis. Thus, the MSKCC Core Facilities and Departmental Services used by ICIMIC investigators will be funded from the .individual Projects on a """"""""fee for service"""""""" basis. This provides the simplest accounting and is the most costeffective use of existing facilities at MSKCC. We have also identified three additional resources that will be provided funds through the Specialized Resources component of ICMIC, because they are focused on ICMIC projects and are considered essential to the successful implementation of our proposal. These Specialized Resources include: 1) Cyclotron and Radiochemistry. 2) Gene Transfer and GMP Resource, and 3) Image Analysis and Biostatistics Resource. A brief description of the three Specialized Resources for which we are requesting funding is provided below and a more detailed description is given in Section D. The decision to develop an existing facility (e.g., Cyclotron and Radiochemistry) into a Specialized Resource was in-part based upon the degree to which personnel from the Core/Resource would participate in the planning and development of ICMIC Research Projects. The concept of a Specialized Resource (both ICMICfunded and non-funded) is that it could be a subset of, as well as a conduit into, a greater Core or Departmental Facility at MSKCC. Each Specialized Resource represents the allocation of a portion of the Core that will be focused on tasks related to the projects of ICMIC. Members of Specialized Resources will be recruited onto one or more Research Projects of ICMIC, where they will be """"""""team members"""""""" (in many cases they will be coinvestigators) involved in all phases of experiment design, implementation and analysis. In addition, a portion of their time will be allocated to the maintenance and development of Resource infrastructure and capabilities germane to the ICMIC projects. This allocation will primarily come in the form of a percentage of salary support for individuals identified as members of the Specialized Resource, and in some cases ICMIC will provide funds for specific equipment items required by individual projects or to develop new directions of research. One member of each Specialized Resource will be identified as the Resource """"""""Leader"""""""". This person will be responsible for Resource infrastructure development and administrative interactions within ICMIC, including the P.I., Research Project Leaders, the Think Tank and the Governing Board. Our expectation and objective is to create an environment within ICMIC where Specialized Resource personnel will be active participants in the research and developmental projects, and not simply function as a """"""""service"""""""". Specialized Resource, support through ICMIC is being requested for Cyclotron/radiochemistry, Gene Transfer-GMP and Image Analysis and Biostatistics Resource. The Cyclotron/radiochemistry resource will receive ICMIC support for for primarily the addition of a post-doctoral physics fellow whose research focus is novel techniques to enhance the production of radionuclides using an accelerator. The fellow will also receive the appropriate hands-on training in the operation of the MSKCC TR 19/9 cyclotron such that his training should provide additional extended support for the cyclotron operation as is one of the aims of the research effort being proposed for the cyclotron core in this grant application. The radionuclides and radiopharmaceuticals produced by the Cyclotron/radiochemistry resource will be used by all five projects and both Developmental Projects. The Gene Transfer-GMP resource will receive ICMIC support for the development, testing and implementation of two human reporter genes that will be applied in patient studies in Projects 1 and 2. The Gene Transfer-GMP resource will construct retroviral bicistronic vectors for Project 1 and Project 2. For Project 1, single and double reporter vectors with selection markers will be constructed;the former in clinical trials and the latter in animal models. For Project 2, these vectors will express the chimeric antigen receptor (CAR) targeted to PSMA linked to a reporter gene. Upon identification of the adequate reporter constructs for clinical applications in Projects 1 and 2, the Gene Transfer-GMP resource will 1) produce clinical grade retroviral vector stocks 2) optimize and validate the ex-vivo transduction of the patients cells 3) perform the clinical transduction of the patient cells, and will assist in the construction of a novel reporter gene for Projects 1 and 2. During the current ICMIC funding period, the Image Analysis and Biostatistics Resource established a database server system for ICMIC investigators, provided consultation services and developed image correction and registration procedures. Although general biostatistics support is provided to all investigators at MSKCC through the Department of Biostatistics/Epidemiology, we decided to combine biostatistics with our image storage and analysis support into a single specialized resource for ICMIC in order to facilitate the interaction and flow of image and numeric data from acquisition through comparative and statistical analysis. The contributions of the Cyclotron Radiochemistry, Gene Transfer and GMP, and Image Analysis and Biostatistics Resource are essential to the projects of ICMIC and will be in part funded through ICMIC. In addition, several well-established institutional cores, including the Animal Imaging Core, Molecular Cytology, Monoclonal Antibody Core, Flow Cytometry, Organic Synthesis, Preclinical Pharmacology, and the Office of Clinical Research will be used extensively by ICMIC investigators. Access to these institutional cores will be on a fee for service basis (or will be available without cost, supported by the MSKCC infrastructure (e.g., Biosafety and Radiation Facilities). The costs for utilization of MSKCC core facilities will be funded through the budgets of the individual projects. The operations of the Specialized Resources and institutional cores will, not only support the individual projects, but ajso will establish and provide a rich dialog between the investigators and resource personnel. The operations of the Specialized Resources will be structured less like a service and rather more like a """"""""consulting firm"""""""". Resource personnel will be available to be """"""""recruited"""""""" onto (i.e. become team members of) multiple research projects within the IGMIC. In essence, their allegiance will not be resource alone, but rather to the individual projects and to ICMIC as a whole. Decision-making and oversight responsibilities will be provided by the PI and Governing Board. The eight Resource Leaders will be members of the Governing Board. Given the diverse character and established institutional structure (MSKCC Core Program) under which most of the Specialized Resources operate, oversight and decision-making will be accomplished at several levels. For the established MSKCC Cores or Services that facilitate and ensure institutional, city, state and federal guidelines, there will be little oversight and decision making on the part of ICMIC. In fact, the reverse relationship will exist (e.g., Biosafety and Radiation Safety Services). It is important to note that the Leaders of the key imaging (MRI/MRS, PET/SPECT/CT, optical and autoradiography) and cyclotron/radiochemistry resource components of ICMIC are also the Heads of these resources/cores within the administrative structure of MSKCC and will be members of the Governing Board. This should minimize any potential disagreement between ICMIC utilization of these Specialized Resources that will operate within the existing facilities of the MSKCC Core Program. One of the Specialized Resource Leaders (Bradley Seattle) will organize an annual summary statement of Specialized Resource activities, contributions and budget requests and specific recommendations for the PI. This annual summary will be presented to the Governing Board, where it will be reviewed. Recommendations for changes in resource operations and utilization, acquisition of new equipment or upgrades to existing equipment, and personnel and budget will be made by the PI and Governing Board. The relationship between the Specialized Resources of ICMIC and the established MSKCC Core Program described above will be slightly modified to accommodate the recently funded Small Animal Imaging Resource Program (SAIRP). The SAIRP (J. Koutcher, P.I.;R24 CA83084-01) will up-grade and establish state-of-the-art resources and the administrative infrastructure for performing small animal MRI/MRS, PET and quantitative autoradiography by MSKCC investigators (see abstract in Appendix 1). The SAIRP is considered to be an important resource for several of the research and developmental projects proposed for ICMIC in this application, and small animal studies within ICMIC projects will be performed within the context of the SAIRP. This relationship and proposed interactions are described in greater detail below (Additional Research Activities and Interactions).
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