The Central theme of Research Project 4 (RP4) is to refine the current use of Positron Emission Tomography (PET) in prostate cancer as pharmacodynamic and predictive biomarkers during antiandrogen therapy. During ICMIC-2, we performed molecular imaging (Ml) in more than 100 castrate resistant prostate cancer (CRPC) patients using F-FDHT as a marker of androgen receptor (AR) signaling, and F-FDG as a marker of glycolysis. We observed heterogeneity between lesions, with some lesions exhibiting only F-FDG uptake, some only F-FDHT uptake, and some uptake for both tracers. We also found that the F-FDG uptake, as measured by SUVmax, correlated inversely with prognosis in CRPC. Furthermore, we have also participated in the preclinical and early clinical development of two exciting new, next generation antiandrogens (abiraterone and MDV3100), for which Ml studies appear extremely promising in helping to optimize their use in the clinic. During ICMIC-3, we shall exploit Ml imaging study results, as well as human tissue samples obtained from image-directed biopsy analysis and animal models to better understand the molecular basis for these Ml phenotypes. Our research plan includes the following Specific Aims (SA): SA 1: To link the F-FDG and F-FDHT imaging phenotypes in human prostate cancer with underlying genetic alterations;The hypothesis is that the radiotracers F-FDG and V-FDHT mark genetically and metabolically distinct subgroups of human prostate cancer. A novel genome wide analysis strategy will be used which we have previously applied successfully in breast cancer. SA 2: To develop AR-PET Radioligands as a pharmacodynamic biomarker for optimal dosing of novel AR antagonists;the hypothesis is that AR-directed radiopharmaceuticals can determine saturating doses of AR-antagonists in a preclinical PCamodel, SA 3: To explore V-FDG-PET as an early response biomarker during AR-targeted therapies;the hypothesis is that successful inhibition of androgen receptor activity, alone or - in PTEN deficient cells - In combination with PI3K/mT0R inhibition, results in a decrease in F-FDG-uptake as an early marker of treatment response to next generation antiandrogens. SA 3 will also determine whether V-FDG-PET imaging, performed at multiple time-points during drug therapy, can serve as an early marker of response and resistance to novel AR-antagonists in in-vivo models of human prostate cancer. A unique team of co-leaders enriches the study plan with highly complementary skills, in AR pharmacology, genetic analysis and Ml.

Public Health Relevance

|n 2010, 27,000 US patients will die of advanced Prostate Cancer. Recently, promising new drugs which block hormone action (antiandrogens) have been developed, but these agents are only effective in 50% of the patients, and those who do not respond may experience unpleasant side effects, such as seizures. Positron Emission Tomography based molecular imaging will help select individual patients who will respond to these drugs and increase the chance for cure by guiding how much drug to give and when to give it.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA086438-13
Application #
8567120
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2013
Total Cost
$234,969
Indirect Cost
$106,341
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Rodina, Anna; Wang, Tai; Yan, Pengrong et al. (2016) The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 538:397-401
Lee, Sang-Gyu; Gangangari, Kishore; Kalidindi, Teja Muralidhar et al. (2016) Copper-64 labeled liposomes for imaging bone marrow. Nucl Med Biol 43:781-787
Demoin, Dustin Wayne; Shindo, Masahiro; Zhang, Hanwen et al. (2016) Synthesis and evaluation of an (18)F-labeled pyrimidine-pyridine amine for targeting CXCR4 receptors in gliomas. Nucl Med Biol 43:606-11
Arevalo-Perez, Julio; Paris, Manuel; Graham, Michael M et al. (2016) A Perspective of the Future of Nuclear Medicine Training and Certification. Semin Nucl Med 46:88-96
Cheal, Sarah M; Xu, Hong; Guo, Hong-Fen et al. (2016) Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity ⁸⁶Y- or ¹⁷⁷Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates. Eur J Nucl Med Mol Imaging 43:925-37
Wang, Xiuyan; Rivière, Isabelle (2016) Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol Ther Oncolytics 3:16015
Cherkassky, Leonid; Morello, Aurore; Villena-Vargas, Jonathan et al. (2016) Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest 126:3130-44
Kadota, Kyuichi; Sima, Camelia S; Arcila, Maria E et al. (2016) KRAS Mutation Is a Significant Prognostic Factor in Early-stage Lung Adenocarcinoma. Am J Surg Pathol 40:1579-1590
Mayor, Marissa; Yang, Neng; Sterman, Daniel et al. (2016) Immunotherapy for non-small cell lung cancer: current concepts and clinical trials. Eur J Cardiothorac Surg 49:1324-33
Adusumilli, Prasad S (2016) Spread through alveolar spaces: An aerogenous invasion in pulmonary adenocarcinomas. J Thorac Cardiovasc Surg 152:73-4

Showing the most recent 10 out of 177 publications