Prostate and pancreatic cancers are among the most common and difficult to treat cancers. Major dilemmas in the management of prostate cancer include the difficulty of discriminating between aggressive and indolent forms of the disease and the need for improved treatment of high-risk and castrate resistant metastatic disease. In the case of pancreatic cancer, the major problems are late diagnosis and high lethality. One major barrier to progress and an unmet need in both diseases is the relative absence of effective molecular imaging tracers/tools that can guide patient management. Antibodies can provide highly specific probes for molecular targets, and can be combined with positron emission tomography (PET) to provide sensitive and quantitative detection. Novel immunoPET imaging agents will be developed based on engineered antibody fragments directed towards Prostate Stem Cell Antigen (PSCA), a cell surface biomarker expressed by a majority of prostate and pancreatic cancers which is also a promising therapeutic target. Two fragment formats, cys- diabody and cys-minibody, will be evaluated to explore their different kinetics and clearance routes in vivo and identify the optimal format(s) for imaging prostate and pancreatic cancer. Protein engineering will be employed to generate multifunctional fragments that can be radiolabeled with positron-emitting radionuclides 124I, 89Zr, or 18F using a variety of conjugation strategies. Promising PSCA-targeted antibody agents will be evaluated by immunoPET in mouse models of prostate cancer disease progression and in genetically engineered mouse models of prostate cancer. Candidate engineered fragments will also be used to image pancreatic ductal adenocarcinoma in xenograft and genetically engineered mouse models of pancreatic cancer. These fully humanized immunoPET probes can be readily translated to the clinic to address pressing questions in clinical management, including staging of newly diagnosed, recurrent and metastatic prostate and pancreatic cancers;quantification of PSCA expression in vivo to improve selection and classification of patients for PSCA-targeted therapy;and monitoring disease response to therapy, particularly in sites such as bone where cancer-specific imaging is difficult (e.g. prostate cancer).

Public Health Relevance

Prostate and pancreatic cancers are among the most common and difficult to treat cancers, with major challenges in accurately diagnosing and staging disease, as well as monitoring response to therapy. One major barrier to progress is the absence of effective molecular imaging tracers/tools that can guide patient management. Here we propose to develop novel cancer-specific molecular imaging agents based on engineered antibodies that recognize PSCA, a cell surface biomarker expressed in pancreatic and prostate cancer, to provide a disease-specific approach for imaging in newly diagnosed and recurrent disease, and to stratify patients at the molecular level in order to guide the use of both traditioal and targeted therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA174294-02
Application #
8641677
Study Section
Special Emphasis Panel (ZRG1-SBIB-Q (03))
Program Officer
Menkens, Anne E
Project Start
2013-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$402,633
Indirect Cost
$141,183
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Knowles, Scott M; Zettlitz, Kirstin A; Tavaré, Richard et al. (2014) Quantitative immunoPET of prostate cancer xenografts with 89Zr- and 124I-labeled anti-PSCA A11 minibody. J Nucl Med 55:452-9
Knowles, Scott M; Tavaré, Richard; Zettlitz, Kirstin A et al. (2014) Applications of immunoPET: using 124I-anti-PSCA A11 minibody for imaging disease progression and response to therapy in mouse xenograft models of prostate cancer. Clin Cancer Res 20:6367-78
Wu, Anna M (2014) Engineered antibodies for molecular imaging of cancer. Methods 65:139-47