Posted November 15, 2016
Paul B. Fisher, M.Ph., Ph.D.; Virginia Commonwealth University, School of Medicine
Xiang-Yang Wang, Ph.D.; Virginia Commonwealth University, School of Medicine

The absence of curative treatments for advanced, metastatic prostate cancer (PCa) highlights the crucial need for development of new, innovative treatment strategies. To address this need, the PCRP funded two separate Synergistic Idea Development awards, in FY10 and FY13, to support collaborative efforts at Virginia Commonwealth University between two research teams led by Dr. Paul Fisher and Dr. Xiang-Yang Wang. The synergy between these laboratories brings together experts in molecular, cellular, and immune biology to develop methods to attack PCa on multiple fronts by combining immunotherapy with other treatment modalities such as radiation therapy, chemotherapy, and targeted molecular therapy.

Melanoma differentiation associated gene-7/Interleukin-24 (MDA-7/IL-24), a unique therapeutic cytokine discovered in Dr. Fisher's laboratory, holds promise for cancer therapy due to its multiple antitumor properties demonstrated in nearly all cancers, including PCa. This agent directly kills cancer cells through viral replication, promotes cancer cell killing by activating the immune system with MDA-7/IL-24, and inhibits blood vessel formation stimulating cancer growth. Under their PCRP-funded work, the Fisher and Wang laboratories created cancer terminator viruses (CTV) that selectively replicate and produce MDA-7/IL-24 in tumor cells resulting in direct killing of cancer cells and stimulation of the immune system without harming normal cells. To further augment therapeutic efficacy, the CTV was combined with a small molecule inhibitor of Mcl-1, a critical protein mediating cancer cell growth and survival, resulting in enhanced cancer-specific killing by the CTV.

In vivo applications of this combinatorial scheme in animal models of PCa were facilitated by using an ingenious delivery approach being pioneered by Drs. Fisher and Wang that employs ultrasound-targeted microbubble destruction (UTMD). The UTMD method permits the delivery of the CTV, as well as therapeutic proteins or chemotherapeutic agents, directly to the prostate gland and its surrounding vasculature in a surreptitious manner by incorporating viruses in microbubbles that are subsequently disrupted using targeted ultrasound. These new reagents and innovative combinatorial cancer killing and immune modulating strategies are now primed for clinical applications for the therapy of advanced prostate cancer. The team is currently working on moving this therapy into the clinic with the hopes of improving treatment options for patients with metastatic PCa.

Combinatorial effect of a MDA-7/IL-24-producting cancer terminator virus, Ad.tCCN1-CTV-m7, and small molecule inhibitor of Mcl-1, BI-97D6, in eradicating local and metastatic prostate cancer.
Courtesy of the institution, Virginia Commonwealth University

Publications:

Sarkar S, Pradhan A, Das SK, et al. 2015. Novel therapy of prostate cancer employing a combination of viral-based immunotherapy and a small molecule BH3 mimetic. Oncoimmunology. 4;5(3):e1078059

Yu X, Wang H, Li X, et al. 2016. Activation of the MDA-5-IPS-1 Viral Sensing Pathway Induces Cancer Cell Death and Type I IFN-Dependent Antitumor Immunity. Cancer Res. 76(8):2166-76

Sarkar S, Quinn BA, Shen XN, et al. 2015. Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic. Oncotarget. 6(13):10712-27.

Menezes ME, Bhatia S, Bhoopathi P, et al. 2014. MDA-7/IL-24: multifunctional cancer killing cytokine. Adv Exp Med Biol. 818:127-53.

Dash R, Azab B, Quinn BA, et al. 2011. Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity. Proc Natl Acad Sci U S A. 108(21):8785-90

Public and Technical Abstracts:

Targeting Danger-Sensing Pattern Recognition Receptors for Prostate Cancer Therapy

Molecular-Targeted Adoptive Immune Therapy for Eradication of Metastatic Prostate Cancer

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