Oncolytic adenovirus-mediated therapy for prostate cancer

Abstract

Prostate cancer is a leading cause of cancer-related death and morbidity in men in the Western world. Tumor progression is dependent on functioning androgen receptor signaling, and initial administration of antiandrogens and hormone therapy (androgen-deprivation therapy) prevent growth and spread. Tumors frequently develop escape mechanisms to androgen-deprivation therapy and progress to castration-resistant late-stage metastatic disease that, in turn, inevitably leads to resistance to all current therapeutics, including chemotherapy. In spite of the recent development of more effective inhibitors of androgen–androgen receptor signaling such as enzalutamide and abiraterone, patient survival benefits are still limited. Oncolytic adenoviruses have proven efficacy in prostate cancer cells and cause regression of tumors in preclinical models of numerous drug-resistant cancers. Data from clinical trials demonstrate that adenoviral mutants have limited toxicity to normal tissues and are safe when administered to patients with various solid cancers, including prostate cancer. While efficacy in response to adenovirus administration alone is marginal, findings from early-phase trials targeting local-ized and metastatic prostate cancer suggest improved efficacy in combination with cytotoxic drugs and radiation therapy. Here, we review recent progress in the development of multimodal oncolytic adenoviruses as biological therapeutics to improve on tumor elimination in prostate cancer patients. These optimized mutants target cancer cells by several mechanisms including viral lysis and by expression of cytotoxic transgenes and immune-stimulatory factors that activate the host immune system to destroy both infected and noninfected prostate cancer cells. Additional modifications of the viral capsid proteins may support future systemic delivery of oncolytic adenoviruses.

Sensitisation to mitoxantrone-induced apoptosis by the oncolytic adenovirus Ad∆∆ through Bcl-2-dependent attenuation of autophagy

“…A promising strategy to overcome treatment-resistance in aggressive cancers is to combine cytotoxic drugs with replication-selective oncolytic adenoviruses. Several clinical and preclinical studies have proved the feasibility of this concept, although the mechanisms for the re-sensitisation are mostly unknown 4 , 8 , 14 , 15 , 30 – 32 . We previously demonstrated potent synergistic cell killing with our selective oncolytic mutant Ad∆∆ in combination with mitoxantrone in both cell and in vivo models.…”

Enhancement of adenovirus infection and adenoviral vector-mediated gene delivery by bromodomain inhibitor JQ1

“…Ad vectors have been studied extensively in tumor therapy trials 1 , 2 . In addition to the use of a conditionally-replicative Ad vector for head and neck cancer in China 3 , recent approval of an oncolytic herpesvirus-based treatment by the US Food and Drug Administration (FDA) raises optimism on the potential of viral vectors in cancer therapy 4 .…”

Oncolytic adenovirus carrying SPAG9-shRNA enhanced the efficacy of docetaxel for advanced prostate cancer

“…Because of the specificity of the prostate anatomy, it is easy to accurately locate the location of prostate cancer under ultrasound conditions. Therefore, oncolytic adenovirus can be applied as a new treatment for prostate cancer [19].…”