NATIONAL CANCER INSTITUTE Academic Radiology, Vol 7, No 5, May 2000

Institution: University Of Virginia Charlottesville

Charlottesville, VA 22903 Fiscal Year: 1998 Department: Radiology Project Start: 01-Jun-98 Project End: 31-Dec-99 ICD: National Cancer Institute IRG: ZRG7

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ASTATINE AND IODINE RADIOLABELED MONOCLONAL ANTIBODIES

Grant Number: 2R37CA42324-14 PI Name: Zalutsky, Michael R.

Abstract: The goal of this research proposal is to increase the clinical utility of labeled monoclonal antibodies (mAbs) for di- agnostic and therapeutic nuclear medicine through the develop- ment of more effective approaches for labeling mAbs and mAb fragments with radioiodine nuclides and 211At. Iodine-131 is the most frequently used nuclide clinical radioimmunotherapy, but its usefulness has been compromised by in vivo dehalo- genation of mAbs labeled via conventional procedures. Better mAb radioiodination methods also would facilitate the use of (123)I and SPECT, and 124I and PET, for lesion detection and dosimetry estimation. Astatine-211 emits alpha-particles that have a higher radiobiological effectiveness and shorter range than beta-particles and, for certain therapeutic applications, may be better matched to the characteristics of the tumor. In this continuation application, we propose to focus on radio- halogenation strategies for mAbs that are internalized rapidly into tumor cells after binding to antigen. This emphasis is in response to the emergence of the epidermal growth factor re- ceptor variant III (EGFRvIII) as a tumor-specific target on glio- mas, breast carcinomas and other tumors. EGFRvlII, a mutant receptor with a deletion in the BGFR extracellular domain is not found on normal tissues. Our hypothesis is that optimizing labeling methods for internalizing mAbs such as anti-EGFRv]II will enhance tumor retention and tumor-to-normal tissue ratios, thereby improving their clinical potential as diagnostic and therapeutic agents for tumors expressing EGFRvIII. Our spe- cific aims are: 1) To label anti-EGFRvIII mAbs and fragments with radioiodine nuclides and 211At using N-succinimidyl 5- iodo-3-pyridinecarboxylate and N- succinimidyl 5-[211At] astato-3-pyridinecarboxylate and evaluate their potential as di- agnostic and therapeutic radiopharmaceuticals; 2) To investi- gate other strategies for labeling mAbs and fragments with ra2 dioiodine and 211At including use of alternate positively charged templates, D-amino acid linkers, and new ap- proaches involving oligosaccharide conjugation; and 3) To investigate the nature of the high- and low-molecular weight

labeled catabolites generated in tumor cells in vitro and tu- mor and normal tissues in vivo and use these data as a guide for developing improved methods for labeling mAbs.

Thesaurus Terms: monoclonal antibody, neoplasm/cancer ra- dionuclide diagnosis, neoplasm/cancer radionuclide therapy, radionuclide scanning/imaging, radiopharmacology cytotoxic- ity, diagnosis design/evaluation, drag metabolism, epidermal growth factor, glioma, growth factor receptor, method develop- ment, molecular weight, neoplasm/cancer ilnmunotherapy, neoplastic cell, nonhuman therapy evaluation, pyridine car- boxylate, radiation dosage athymic mouse, bioimaging/bio- medical imaging, iodine, laboratory rat, radionuclide, ra- diotracer

Institution: Duke University Durham, NC 27706

Fiscal Year: 1999 Department: Radiology Project Start: 01-Sep-85 Project End: 31-Jan-04 ICD: National Cancer Institute IRG: RNM

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RESEARCH TRAINING IN ONCOLOGY IMAGING

Grant Number: 5T32CA09630-11 PI Name: Zerhouni, Elias A.

Abstract: DESCRIPTION (Applicant's Description): The program proposes to provide research training in oncological imaging for postdoctoral fellows interested in a career in aca- demic radiology and related fields. The program structure in- cludes didactic and laboratory exposure and provides basic scientists and physicians with opportunity to gain research training in state-of- the-art medical imaging facilities. The unique aspect of this training program is that it combines train- ing within an imaging core with training in either a basic sci- ence, such as molecular oncology or cancer biology, or in an imaging modality, such as CT or MR. The exposure of both clinical and basic science research is strong feature of this program. The M.D. and Ph.D. trainees who complete this program will be uniquely qualified for a variety of posi- tions in academic radiology oriented towards research in clinical oncology and oncological imaging. This program addresses the pressing need to encourage physicians and re- searchers in radiology to develop and maintain a research focus and to keep pace with the rapid influx of imaging and diagnostic methods which require an increasing amount of technical expertise. Areas of research expertise include: functional (MRI, MRS and PET) imaging of human and animal tumors, intraarterial delivery of drugs active in the treatment of brain tumors, development of inhibitors of tu- mor angiogene-sis, applications of bioerodible, sustained-

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release polymers, monitoring of the proliferative state and therapeutic response of brain tumors, biochemical and clinical pharmacology studies of anti-tumor agents, com- puter modeling of interactions of alkylating agents with deoxynucleotides and polynucleotides, in vivo NMR spec- troscopy as a noninvasive monitor of the biochemistry and physiology of malignant tumors, image guided navigation of surgical instruments for tumor surgery and image pro- cessing of CT and MRI data for tumor 3-D reconstruction, interactive 2-D and 3-D imaging, automated volumetrics, and radiation therapy planning. The multi-disciplinary train- ing program described in this proposal draws its strength from the participation of faculty members from numerous departments, including radiology, oncology, medicine, neu- rosurgery, biomedical engineering, urology and pathology. Extensive research facilities available to trainees not only re- flect the wide variety of disciplines contributing to the pro- gram but also the commitment of the Johns Hopkins Medical Institutions to training future leaders of biomedical research.

Thesaurus Terms: There are no thesaurus terms on file for this project.

Institution:

Fiscal Year: Department: Project Start: Project End: ICD: IRG:

Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 1999 Radiology 01-Aug-89 29-Sep-02 National Cancer Institute NCI

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FAST DYNAMIC 3D MRI USING ADAPTIVE SPATIAL ENCODING

Grant Number: 5R01CA78299-02 PI Name: Zientara, Gary P.

Abstract: DESCRIPTION (Adapted from Applicant's Ab- stract): The main goal of this project is the development of a fast dynamic 3D MRI method using adaptive spatial encoding that can acquire a high resolution MRI dates (256x256x256) operating in near real-time as possible (1 dataset per 1-2 seconds) with minimal hardware modifications to a standard

MRI scanner. This goal lies well outside the possibilities of current MRI methods like echo planar techniques that employ Fourier encoding and specialized gradient hardware. A num- ber of applications of interventional MRI, a focus in our hos- pital, have the specific requirement for dynamic 3D MRI that can operate on an "open" MR scanner with no specialized gradient coils. The most important of these applications is the MRI monitoring of the timecourse of thermal therapies dur- ing which non-uniform heating of tissue occurs due to tissue heterogeneity and nearby vessels. Another important applica- tion is the near real-time 3D tracking of probes and catheters used for minimally invasive therapies. Specifically, we pro- pose to develop, implement, test and optimize a dynamic 3D MRI method that encodes adaptively in two directions using high flip angle 2D spatially selective RF excitations to imple- ment a minimal set of near-optimal encodes computed from the multidimensional Singular Value Decomposition (MSVD) of a 3D image estimate (formed from recently acquired data) computed per acquisition, combined with frequency encoding in the third direction. The accomplishment of the main objec- tive of this project is only possible due to three significant technological advances. First, and most important regarding spatial encoding, the applicants reported recently having de- veloped the MSVD, a powerful numerical mathematical tool that can determine near-optimal 3D spatial encoding. Second, a simple fast numerical procedure has been developed in their laboratory for the computation of RF pulse waveforms for implementing non-Fourier encodings using high flip angles (90=A1) for high SNR scans. Third, at their facility, they have the operating capability for near real-time adaptive 2D MRI using a commercial MR system with the minor modifi- cation of an additional attached workstation.

Thesaurus Terms: biomedical equipment development, clini- cal biomedical equipment, magnetic resonance imaging com- puter assisted patient care, neoplasm/cancer thermotherapy, patient monitoring device, phantom model bioimaging/bio- medical imaging, human data

Institution:

Fiscal Year: Department: Project Start: Project End: ICD: IRG:

Brigham And Women's Hospital 75 Francis St Boston, MA 02115 1999

01-Jul-98 30-Jun-01 National Cancer Institute DMG

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