Transcription-Based Molecular Imaging and Gene Therapy for Castration-resistant and Metastatic Prostate Cancer in Translational Models
The advanced stage of prostate cancer is the second leading cause of cancer-related death for American men. Novel, effective treatment options and more cancer-specific diagnostic tools are urgently needed to facilitate patient management. Here, we explored the construction and application of an array of gene-based molecular imaging and therapeutic vectors in a variety of clinically relevant settings. These vectors exploit prostate cancer-specific promoters to control the transcription of imaging reporter genes or therapeutic genes, and thus can achieve stringent cancer selectivity. We showed that gene-based imaging vectors can detect prostate cancer metastasis earlier than conventional imaging modalities; we also developed a dual-reporter imaging system that can specifically interrogate the activation/inhibition status of androgen receptor, and thus monitor the efficacy of androgen deprivation and androgen receptor blockade therapies. Further, we explored the applicability of gene-based vectors in detecting circulating tumor cells and have obtained promising results. Moreover, we employed two strategies to improve the clinical usability of viral vectors in immunocompetent hosts (such as humans). In the first strategy, we used a broad-acting immunosuppressant, rapamycin, to reduce the scale of adenovirus-induced inflammatory responses and also to decrease the eliminating effects of host adaptive immune system on viral vectors and viral-infected, transgene-expressing cells. Rapamycin significantly augmented the magnitude and prolonged the duration of virus-delivered transgene expression, and thus enhanced the diagnostic capability of these imaging vectors. The second approach took advantage of the versatile surface modifying ability of non-viral reagents. We designed a polypeptide coating that can non-covalently bind to adenoviral particles and confer protections against blood components such as neutralizing antibodies and coagulation factors. The coating significantly decreased the inhibitory effects of neutralizing antibodies on adenoviral transduction and markedly abrogated coagulation factors-mediated hepatocyte infection. Furthermore, this polypeptide coating reduced the antigenicity of adenoviral vectors in vivo, greatly diminished anti-adenovirus antibody production, and therefore could facilitate repeated administration of viral vectors in immunocompetent hosts. Overall, we herein present a substantial amount of evidence supporting the pre-clinical and translational use of gene-based imaging and therapeutic vectors to assist the management of patients with advanced, treatment-refractory prostate cancer.