The objective of the proposed study is to obtain clinical correlates on an ongoing investigator-initiated investigational new drug (IND) at the University of Virginia. There are two major components to this proposed study. First, we request funding to test the hypothesis that an adenoviral toxic gene, Ad-OC-TK, plus an orally bioavailable Valacyclovir (Val) could induce maximal cell-kill in recurrent primary and metastatic prostate cancers. Laboratory evidence suggests that both cancer epithelium and its supporting stroma express a common protein, osteocalcin (OC). Delivering and expressing a toxic gene, herpes simplex thymidine kinase (TK), in an adenoviral construct could result in the most efficacious control of recurrent prostate cancer and its metastases. We propose to take advantage of the availability of cancer tissue specimens and biologic fluids such as blood and urine from patients to conduct the evaluation of the immunological status of the prostate cancer tissues obtained prior to, during, and after toxic gene therapy. Clinical correlates on apoptosis, activated partial thrombosplatin time (aPTT) and radiographic imaging in patients treated with toxic gene therapy will be obtained. Second, we request funding to expand our on-going clinical trial to treat additional prostate cancer patients with skeletal metastasis. The hypothesis to be tested is that Ad-OC-TK/Val will cause most effective tumor regression at the skeletal site. We propose to evaluate parallely the clinical correlates in biopsy tissue, blood, and urine samples obtained from patients treated with maximum doses of Ad-OC-TK.
The specific aims of this proposal are: 1) to determine the level and distribution of Ad-OC-TK expression In prostate cancer cells at recurrent primary and metastatic lymph node and bone sites. A number of markers will be evaluated to assess viral distribution and delivery. Detection of other bone matrix protein expression of proteins such as OC, osteonectin (OSN), and bone sialoprotein (BSP) will be studied; 2) to assess and compare Ad-OC-TK induced anti-tumor immunity in tumor specimens obtained from recurrent primary and metastatic lymph node and bone sites. Immunohistochemistry, RT-PCR, bioassay, and enzyme linked immunoassay will be used to assess both local anti-tumor immunity and circulating anti-adenoviral antibodies; 3) to obtain clinical correlates in tumor and blood specimens obtained from patients before, during, and after Ad-OC-TK/Val therapy. Apoptotic indices, blood coagulation profiles, and radiographic imaging analyses will be evaluated; 4) to recruit at least 12 patients with minimum bone metastasis, and to treat these patients with intratumoral Ad-OC-TK/Val injection. We hope this will allow us to evaluate whether this form of gene therapy will be safe and efficacious in patients with bone metastasis. The ultimate goal of this study is to provide strong background information, which will assist us in development of future trials to incorporate """"""""re-targeted"""""""" virus injected systemically to eradicate disseminated prostate cancer at both bone and soft tissue sites.
