E. 1. Mode of Selection of Developmental Projects For this competitive renewal of the ICMIC grant, details of decision making and oversight responsibility are included in """"""""Organization and administration"""""""" section B. of this application. Two developmental projects will be selected and funded each year at the level of $50,000 each. The two developmental projects which have been selected are described in section E.3. below. E. 2. Progress during prior funding period 2000-2005 During the prior ICMIC grant period, we were particularly concerned about integrating molecular imaging within key programs and components of MSKCC scientific activities. A secondary goal was to select projects which had an opportunity to spin off into NIH funded research, or to integrate investigators and novel technologies into ICMIC infrastructure. In a brief summary of ongoing and completed projects, we emphasize how these goals were met for the individual projects, and to what extent these contributed to the development of additional peer-reviewed research in. molecular imaging. Developmental Project A. Imaging Dihydrofolate reductase gene amplification Project Leader: J.R.Bertino We have carried out a series of experiments to determine whether treatment of tumor bearing nude rats implanted with tumors generated from human colon cancer HCT-8 cells transduced with a retrovirus construct containing DHFR-HSVTK with antifolates will lead to an increase in gene expression. Our results suggest that in vivo treatment of these animals with TMTX results in increased gene expression of the fusion gene and this increase can be imaged using fluorescence, Gamma camera and PET scanning. Moreover, the increase in gene expression of the DHFR-HSVTK also leads to enhanced sensitivity of the tumors to ganciclovir. The results of the experiments have encouraged us to submit a grant proposal (RO1, in preparation) for therapeutic strategy for lymphoma therapy, utilizing the translational up-regulation of DHFR. Lymphoma Research Foundation, was recently obtained and will provide a bridge to NIH funding. Developmental Project B. In Vivo Imaging of Genetically Modified T Lymphocytes Project Leader: M. Sadelaine The developmental project focused on the study of a receptor specific for PSMA, a cell surface antigen over-expressed in human prostate cancer. When introduced in primary T cells by retroviral-mediated gene transfer, the Pz1 receptor redirects cytolytic activity against PSMA-positive tumor cells. The therapeutic activity of human T cells targeted to PSMA was investigated in vivo in mice bearing established tumors (1). The encouraging results form the basis for Project 2 and the clinical trial proposed therein under aim 3. Developmental Project C. Imaging Spheroid Growth and vascularization, In Vivo Project Leader: G. Sgouros , The general objectives of this proposal were to develop a model by which the seeding and vascularization of IP injected tumor into mice could be monitored by animal PET and MR imaging and, over the longer term (via an R01 mechanism), to use this model to investigate the efficacy of therapeutic agents that target tumor vasculature and/or tumor cells (e.g. alpha-emitter-labeled J591) or that inhibit neovascularization (e.g. MMP inhibitors, thalidomide). Developmental Project D. Imaging &Dosimetry of 86Y/90Y-labeled anti-GDI9 &CD20 Antibodies. Project Leader: J. Jurcic Shortly after this project was developed, problems emerged within our cyclotron and this project was deferred until Y-86 production could be guaranteed. This is one of the new projects in the ICMIC competitive renewal. Developmental Project E. Surrogate Imaging of HIF-1 a Expression Project Leader: R. Blasberg This developmental project focuses on the assessment """"""""surrogate"""""""" marker imaging paradigms for monitoring activated hypoxia-inducible factor 1 (HIF-1) expression in tumor tissue using established radiolabeled probes that are being (or soon will be) used in clinical/patient studies. It will also include magnetic resonance imaging (MRI) and spectroscopy (MRS) which will provide additional unique information. The overall hypothesis of this proposal is that reliable assessments of HIF-1 expression can be obtained from a combination of specific PET and MRI/MRS imaging paradigms, and that it is possible to distinguish between epigenetic constitutive HIF-1 expression from physiological (hypoxia-induced) expression of HIF-1. The objective is to demonstrate a spatial and quantitative relationship (link) between the surrogate marker images and the images of HIF-1aand VEGF expression. The overall hypothesis that will be tested is that reliable assessments of HIF-1 a expression can be obtained from a combination of specific PET and MRI/MRS imaging paradigms. Developmental Project F. Imaging In vivo Trafficking and Engraftment of Transplanted Stem/Progenitor Cells Project Leader: D. Banerjee The ability to follow the trafficking of gene marked long term repopulating progenitor/stem cells by sensitive high resolution non invasive in vivo imaging techniques will have significant impact in the field of transplantation as well as cancer gene therapy. The present proposal aims to develop a sensitive noninvasive imaging method, by building on existing technologies to monitor in vivo trafficking, dynamics of engraftment as well as transgene expression of transduced long term repopulating stem/ progenitor cells following bone marrow transplantation. To determine in real time the in vivo trafficking of gene marked long term repopulating stem/progenitor cells in living mice using non invasive imaging.
The aim of these studies is to determine whether the proposed approach is sensitive enough to permit in vivo imaging of stem cell/progenitor cell transplantation and engraftment. Developmental Project G. Noninvasive Quantative PET Imaging of Tumor Response with EGFR, HER2, VEGFR, PSMA and alpha6beta4 binding Radioligands (2004-2006) Project Leader: P.M. Smith-Jones This project is a multidisciplinary approach involving the nuclear medicine research lab, (Larson) and the signal transduction group (Rosen) in the program of Molecular pharmacology and chemistry within Sloan- Kettering Institute. The project involves two young investigators, Peter Smith-Jones, and David Solit, experts in radiochemistry/ medicinal chemistry and molecular targeting/medical oncology, respectively. Newly emerging cancer therapies are targeting unique cell surface proteins and receptors. The ability to rapidly assess the concentrations of these proteins on the cell surface can show the existence of metastatic disease or an indication as to the effectiveness of a particular therapy. Several targets have been identified and include Erb1 (EGFR), Erb2/neu (HER2), VEGFR, PSMA, CA IX and alpha6beta4 integrin. In current clinical trials of new anti cancer agents, there is no easy way to determine these protein levels. Current methodologies are invasive (i.e. tumor biopsies) and subjective. The purpose of this work was to develop new methods for the non invasive determination of EGFR, HER2, VEGFR, PSMA and alpha6beta4 protein levels using specific radioligands and positron emission tomography (PET). So far, this project has resulted in the development and introduction of a novel methodology for the measurement of HER2 receptor in response to the action of the drug 17- AAG. As such, this is an example of a new class of tumor response agents, Which interrogate specific molecules that are either client proteins or targeted molecules for molecular targeted therapies. In addition, we have shown that the her 2 decline is measurable and living subjects, and occurs much more rapidly than corresponding FDG changes in the same tumors. At present this information has been used to develop a patient protocol, and we anticipate that it will be possible to introduce this into clinical research within the next 12 months. In addition, for the renewal, Project 5 and four will utilize these methodologies in both in the laboratory and in patients for assessing the impact of HSP 90 inhibitor drugs, on HER2 expression. In addition laboratory based methodologies have been developed for measuring EGFR, alpha six beta for, and carbonic anhydrase nine levels in tumor xenografts in the laboratory. These methodologies as laboratory tools have been valuable in the assessment of EGFR levels, and are incorporated into project to three of the MSKCC lung spore, which is currently under review. We intend to continue this work during this work during the 2006 funded grant year. E. 3. Developmental projects planned for the first year of the competitive renewal. These development projects were chosen in part because they are multidisciplinary, and fulfill the goal of introducing new investigators or innovative technologies into the molecular imaging capabilities of ICMIC, in important areas of biology and clinical science. In addition, we believe that these developmental projects could readily provide preliminary data which could be a basis for funding under R 01 grant mechanisms. Project A provides the development of molecular imaging technology which can be correctly utilized in the clinic, as a way to provide improved dosimetry for anti-lymphoma therapy using targeted radionuclides in the form of 90Y-targeted anti-lymphoma antibodies. Project B provides novel laboratory tools for interrogating HIF-1a, a biology pathway that is highly relevant to cancer, and which relates strongly to other projects, within the current ICMIC.
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