Prostate Stem Cell Antigen (PSCA) is a cell surface protein expressed by a majority of prostate cancers.Over the past 4 years, we have (1) validated PSCA as a target for prostate cancer therapy (2) shown thatPSCA may be a marker of PTEN null prostate cancers (3) demonstrated that a monoclonal antibodytargeting PSCA inhibits prostate cancer progression and metastasis in vivo (4) shown that antibody againstPSCA induces cell death by an Fc-independent mechanism and (5) developed humanized PSCA antibodiesthat retain activity and may be used in the clinic. In parallel, a fully human anti-PSCA antibody wasdeveloped in collaboration with industry and successfully translated into Phase I trials in men with metastaticprostate cancer. In the current application, we propose to develop and test a radiolabeled PSCA antibodyfragment to molecularly image prostate cancer with SPECT and PET scans. A PSCA-targeted molecularimaging probe has the potential to improve the ability to detect advanced and metastatic prostate cancer. Itmay be used to classify tumors at the molecular level based on the level and extent of PSCA expression,which may identify tumors with PTEN mutation or that respond to PSCA antibody therapy. Finally, a PSCA-targeted molecular imaging probe might be used to monitor response to therapy (eg. PSCA antibody therapyor drugs that target the PIS kinase-PTEN-Akt pathway). A humanized PSCA minibody has already beenconstructed and yields striking images of PSCA-positive xenografts with excellent pharmacokinetics (i.e hightumor uptake and rapid clearance from normal tissues).
The Aims of this study are (1) to develop and testengineered antibody fragments in contolled biological systems (2) to assess PSCA antibody fragments toimage transgenic models of prostate cancer, and (3) to perform a pilot imaging trial in men with metastaticprostate cancer. These studies have the potential to advance prostate cancer imaging in the age of targetedtherapies and to link more closely the diagnosis and treatment of this disease. Layman statement: Thisapplication proposes to develop a new test to identify metastatic prostate cancer and to classify tumors atthe molecular level by a noninvasive means. We will develop an antibody that is radiolabeled and binds tothe protein PSCA on the surface of prostate cancer cells. Mice and then men administered this antibody willbe imaged with SPECT scans in order to detect localized or metastatic prostate cancer.
Showing the most recent 10 out of 339 publications
