Kaposi's sarcoma (KS), an AIDS-defining malignancy, is always associated with Kaposi's sarcoma herpesvirus infection (KSHV or HHV-8). Chemotherapy gives approximately a 50% response rate. Radiation plays only a palliative role in the management of KS because it is disseminated. We propose a novel approach to delivering targeted radiation to disseminated KS. The approach involves trapping a nucleoside analog (FIAU) in KSHV-infected cells (FIAU retention). The virus encodes a thymidine kinase (TK) that will selectively phosphorylate FIAU. The viral TK is only likely to be expressed in a minority of cells in KS. However, in preclinical models bortezomib is a potent inducer of KSHV TK, and phosphorylation results in trapping radiolabeled FIAU in cells allowing tumor imaging and therapy. Cutaneous involvement with AIDS-related KS presents the unique opportunity to assess directly the radiation concentration and the expression of viral RNA and viral antigens in tumor tissue. We propose to evaluate bortezomib-induced enzyme targeted radiation (BETR) therapy in patients with AIDS-related KS. The possibility of having readily available biopsy specimens with which to work, which is somewhat unique to this malignancy, provides a rare opportunity to correlate imaging findings directly with changes in viral expression in tumor tissue in human subjects. We propose a trial to evaluate targeting of FIAU to KS in a dose-response study with bortezomib, to evaluate the safety and toxicity of fixed-dose [1311JF1AU in combination with bortezomib, to describe biopsy correlates of [1241JF1AU retention, and to characterize the objective response to the therapy with  FIAU. Because we believe that the doses of bortezomib approved for use as single agent therapy in the treatment of multiple myeloma are likely to be higher than are needed for imaging, our trial begins with lower doses and escalates to the standard clinical dose.
This research component will incorporate molecular imaging to treat KS and monitor treatment efficacy. Since KS presents with cutaneous involvement it provides a unique opportunity to study biopsies with immunohistochemistry and quantitative analysis of viral RNA expression to detect viral antigens, and autoradiography to determine the  radioactivity concentration in specimens in conjunction with imaging.
|Winnard Jr, Paul T; Bharti, Santosh K; Penet, Marie-France et al. (2016) Detection of Pancreatic Cancer-Induced Cachexia Using a Fluorescent Myoblast Reporter System and Analysis of Metabolite Abundance. Cancer Res 76:1441-50|
|Chan, Kannie W Y; Jiang, Lu; Cheng, Menglin et al. (2016) CEST-MRI detects metabolite levels altered by breast cancer cell aggressiveness and chemotherapy response. NMR Biomed 29:806-16|
|Azad, Babak Behnam; Chatterjee, Samit; Lesniak, Wojciech G et al. (2016) A fully human CXCR4 antibody demonstrates diagnostic utility and therapeutic efficacy in solid tumor xenografts. Oncotarget 7:12344-58|
|Penet, Marie-France; Chen, Zhihang; Mori, Noriko et al. (2016) Magnetic Resonance Spectroscopy of siRNA-Based Cancer Therapy. Methods Mol Biol 1372:37-47|
|Xu, Xiang; Yadav, Nirbhay N; Zeng, Haifeng et al. (2016) Magnetization transfer contrast-suppressed imaging of amide proton transfer and relayed nuclear overhauser enhancement chemical exchange saturation transfer effects in the human brain at 7T. Magn Reson Med 75:88-96|
|Mascini, Nadine E; Cheng, Menglin; Jiang, Lu et al. (2016) Mass Spectrometry Imaging of the Hypoxia Marker Pimonidazole in a Breast Tumor Model. Anal Chem 88:3107-14|
|Chatterjee, Samit; Lesniak, Wojciech G; Gabrielson, Matthew et al. (2016) A humanized antibody for imaging immune checkpoint ligand PD-L1 expression in tumors. Oncotarget 7:10215-27|
|Penet, Marie-France; Kakkad, Samata; Pathak, Arvind P et al. (2016) Structure and Function of a Prostate Cancer Dissemination Permissive Extracellular Matrix. Clin Cancer Res :|
|Lesniak, Wojciech G; Oskolkov, Nikita; Song, Xiaolei et al. (2016) Salicylic Acid Conjugated Dendrimers Are a Tunable, High Performance CEST MRI NanoPlatform. Nano Lett 16:2248-53|
|Behnam Azad, Babak; Lisok, Ala; Chatterjee, Samit et al. (2016) Targeted Imaging of the Atypical Chemokine Receptor 3 (ACKR3/CXCR7) in Human Cancer Xenografts. J Nucl Med 57:981-8|
Showing the most recent 10 out of 198 publications