E. 1. Mode of Selection of Developmental ProjectsFor this competitive renewal of the ICMIC grant, details of decision making and oversight responsibility areincluded in 'Organization and administration' section B. of this application. Two developmental projects willbe selected and funded each year at the level of $50,000 each. The two developmental projects whichhave been selected are described in section E.3. below.E. 2. Progress during prior funding period 2000-2005During the prior ICMIC grant period, we were particularly concerned about integrating molecular imagingwithin key programs and components of MSKCC scientific activities. A secondary goal was to selectprojects which had an opportunity to spin off into NIH funded research, or to integrate investigators andnovel technologies into ICMIC infrastructure. In a brief summary of ongoing and completed projects, weemphasize how these goals were met for the individual projects, and to what extent these contributed to thedevelopment of additional peer-reviewed research in. molecular imaging.Developmental Project A. Imaging Dihydrofolate reductase gene amplificationProject Leader: J.R.BertinoWe have carried out a series of experiments to determine whether treatment of tumor bearing nude ratsimplanted with tumors generated from human colon cancer HCT-8 cells transduced with a retrovirusconstruct containing DHFR-HSVTK with antifolates will lead to an increase in gene expression. Our resultssuggest that in vivo treatment of these animals with TMTX results in increased gene expression of thefusion 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 thetumors 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 ofDHFR. Lymphoma Research Foundation, was recently obtained and will provide a bridge to NIH funding.Developmental Project B. In Vivo Imaging of Genetically Modified T LymphocytesProject Leader: M. SadelaineThe developmental project focused on the study of a receptor specific for PSMA, a cell surface antigenover-expressed in human prostate cancer. When introduced in primary T cells by retroviral-mediated genetransfer, the Pz1 receptor redirects cytolytic activity against PSMA-positive tumor cells. The therapeuticactivity 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 VivoProject Leader: G. Sgouros ,The general objectives of this proposal were to develop a model by which the seeding and vascularizationof 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 tumorvasculature and/or tumor cells (e.g. alpha-emitter-labeled J591) or that inhibit neovascularization (e.g. MMPinhibitors, thalidomide).Developmental Project D. Imaging & Dosimetry of 86Y/90Y-labeled anti-GDI9 & CD20 Antibodies.Project Leader: J. JurcicShortly after this project was developed, problems emerged within our cyclotron and this project wasdeferred until Y-86 production could be guaranteed. This is one of the new projects in the ICMICcompetitive renewal.Developmental Project E. Surrogate Imaging of HIF-1 a ExpressionProject Leader: R. BlasbergThis developmental project focuses on the assessment 'surrogate' marker imaging paradigms formonitoring activated hypoxia-inducible factor 1 (HIF-1) expression in tumor tissue using establishedradiolabeled probes that are being (or soon will be) used in clinical/patient studies. It will also includemagnetic resonance imaging (MRI) and spectroscopy (MRS) which will provide additional uniqueinformation. The overall hypothesis of this proposal is that reliable assessments of HIF-1 expression can beobtained from a combination of specific PET and MRI/MRS imaging paradigms, and that it is possible todistinguish 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) betweenthe surrogate marker images and the images of HIF-1aand VEGF expression. The overall hypothesis thatwill be tested is that reliable assessments of HIF-1 a expression can be obtained from a combination ofspecific PET and MRI/MRS imaging paradigms.Developmental Project F. Imaging In vivo Trafficking and Engraftment of TransplantedStem/Progenitor CellsProject Leader: D. BanerjeeThe ability to follow the trafficking of gene marked long term repopulating progenitor/stem cells by sensitivehigh resolution non invasive in vivo imaging techniques will have significant impact in the field oftransplantation as well as cancer gene therapy. The present proposal aims to develop a sensitivenoninvasive imaging method, by building on existing technologies to monitor in vivo trafficking, dynamics ofengraftment as well as transgene expression of transduced long term repopulating stem/ progenitor cellsfollowing bone marrow transplantation. To determine in real time the in vivo trafficking of gene marked longterm repopulating stem/progenitor cells in living mice using non invasive imaging.
The aim of these studiesis to determine whether the proposed approach is sensitive enough to permit in vivo imaging of stemcell/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-JonesThis project is a multidisciplinary approach involving the nuclear medicine research lab, (Larson) and thesignal 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 torapidly assess the concentrations of these proteins on the cell surface can show the existence of metastaticdisease or an indication as to the effectiveness of a particular therapy. Several targets have been identifiedand include Erb1 (EGFR), Erb2/neu (HER2), VEGFR, PSMA, CA IX and alpha6beta4 integrin. In currentclinical trials of new anti cancer agents, there is no easy way to determine these protein levels. Currentmethodologies are invasive (i.e. tumor biopsies) and subjective. The purpose of this work was to developnew methods for the non invasive determination of EGFR, HER2, VEGFR, PSMA and alpha6beta4 proteinlevels using specific radioligands and positron emission tomography (PET).So far, this project has resulted in the development and introduction of a novel methodology for themeasurement of HER2 receptor in response to the action of the drug 17- AAG. As such, this is an exampleof a new class of tumor response agents, Which interrogate specific molecules that are either client proteinsor targeted molecules for molecular targeted therapies. In addition, we have shown that the her 2 declineis measurable and living subjects, and occurs much more rapidly than corresponding FDG changes in thesame tumors. At present this information has been used to develop a patient protocol, and we anticipatethat it will be possible to introduce this into clinical research within the next 12 months. In addition, for therenewal, Project 5 and four will utilize these methodologies in both in the laboratory and in patients forassessing 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 aslaboratory tools have been valuable in the assessment of EGFR levels, and are incorporated into project tothree 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 ofintroducing new investigators or innovative technologies into the molecular imaging capabilities of ICMIC, inimportant areas of biology and clinical science. In addition, we believe that these developmental projectscould 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 theclinic, as a way to provide improved dosimetry for anti-lymphoma therapy using targeted radionuclides inthe form of 90Y-targeted anti-lymphoma antibodies. Project B provides novel laboratory tools forinterrogating HIF-1a, a biology pathway that is highly relevant to cancer, and which relates strongly to otherprojects, within the current ICMIC.
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