Issue No. 2, December 2016
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, M.Ph., Ph.D., the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by the VIMM members.          
Molecular Targeted Immunotherapy for Eradication of Prostate Cancer

  • Prostate cancer (PCa) is the leading cause of cancer deaths in men in the United States despite advances in chemo-, radio- and hormonal-therapies.

  • The absence of curative therapies for advanced or recurrent forms of PCa emphasizes the crucial need to develop innovative treatment strategies that are efficacious, with minimal toxicity, against systemic disease.

  • In pre-clinical experiments, researchers at the VIMM have reported promising results in halting PCa recurrence using a unique combination of molecular therapy, chemotherapy and immunotherapy.

  • This innovative research from the teams led by Dr. Paul B. Fisher and Dr. Xiang-Yang Wang is funded by the U.S. Department of Defense Prostate Cancer Research Program (PCRP) and was recently highlighted on the Congressionally Directed Medical Research Programs (CDMRP) website at http://cdmrp.army.mil/pcrp/research_highlights/16fisher-wang_highlight


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 between the two research teams led by Dr. Paul B. Fisher and Dr. Xiang-Yang Wang at the VIMM. 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.
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 

Paul B. Fisher, M.Ph., Ph.D.
Virginia Commonwealth University
School of Medicine and VIMM 
Xiang-Yang Wang, Ph.D.
Virginia Commonwealth University 
School of Medicine and VIMM 
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 induction of apoptosis or toxic autophagy, promotion of cancer cell killing by activating the immune system, and inhibition of blood vessel formation that supports 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 CTV and a Mcl-1 inhibitor (BI-97D6) in eradicating CaP:
CTV was mixed with targeted microbubbles (MB) and injected intravenously followed by delivery to the prostate region by the UTMD approach. Following release and subsequent infection of the CaP cells, CTV selectively replicates in CaP cells resulting in production of mda-7/IL-24. MDA-7/IL-24 can promote mitochondrial intrinsic apoptosis as well as extrinsic apoptosis, together with ER stress or toxic autophagy in prostate tumors (primary site of infection). BI-97D6, which displays some antitumor activity in CaP as a single agent, synergistically co-operates with CTV in inducing cancer-specific apoptosis. BI-97D6 also stabilized mda-7/IL-24 mRNA further enhancing the production of MDA-7/IL-24 protein, which acts as a cytokine on adjacent uninfected CaP cells or tumors located distantly (lung, bone metastasis) via receptor dimerization and signal transduction culminating in cancer-specific apoptosis. It can also activate anti-angiogenesis effects and antitumor-immune responses further amplifying the antitumor effects of MDA-7/IL-24, thereby culminating in eradicating the primary CaP as well as any metastasis to distant sites in the body.

Figure: Ad.tCCN1-CTV-m7 and BI-97D6 eradicates prostate cancer (CaP): Ad.tCCN1- CTV-m7 (a type 5 adenovirus with a truncated CCN1 promoter driving replication and producing mda-7/IL-24, a Cancer Terminator Virus) was mixed with targeted microbubbles (MB) specific for binding with prostate tumor vasculature which overexpresses VCAM-1, and injected i.v. followed by targeted delivery in the prostate region by the ultrasound targeted microbubble destruction (UTMD) approach. Following infection, Ad.tCCN1-CTV-m7 selectively replicates in CaP cells producing mda-7/IL-24, which on translation produced secretory cytokine MDA-7/IL-24. MDA-7 induced apoptosis via Bcl-2-dependent (mitochondria), ER stress or toxic autophagy in prostate tumor (primary site of infection). BI-97D6 synergistically co-operated with Ad.tCCN1- CTV-m7 in inducing cancer-specific apoptosis. BI-97D6 also stabilized mda-7/IL-24 mRNA further enhancing the activity of mda-7/IL-24. The secreted MDA-7/IL-24 acts on adjacent uninfected CaP cells or tumor cells located distantly (lung, bone metastasis) via receptor dimerization and signal transduction culminating in cancer-specific apoptosis. It can also activate anti-tumor-immune responses in further enhancing the antitumor effect of MDA-7/IL-24, and thus eradicate both primary CaP and CaP metastases. [Sarkar S et al., Oncoimmunology, 5(3), e1078059. PMCID:PMC4839355]
Publications:
Sarkar S, Pradhan A, Das SK, Emdad L, Sarkar D, Pellecchia M, Fisher PB. 2016. Novel therapy of prostate cancer employing a combination of viral-based immunotherapy and a small molecule BH3 mimetic. Oncoimmunology, 5(3), e1078059. PMCID:PMC4839355.

Yu X, Wang H, Li X, Guo C, Yuan F, Fisher PB, Wang XY. 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. PMCID:PMC4873369.

Sarkar S, Quinn BA, Shen XN, Dash R, Das SK, Emdad L, Klibanov AL, Wang XY, Pellecchia M, Sarkar D, Fisher PB. 2015. Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic. Oncotarget. 6(13):10712-27. PMCID:PMC4484414.

Menezes ME, Bhatia S, Bhoopathi P, Das SK, Emdad L, Dasgupta S, Dent P, Wang XY, Sarkar D, Fisher PB. 2014. MDA-7/IL-24: multifunctional cancer killing cytokine. Adv Exp Med Biol. 818:127-53. PMCID:PMC4633013.

Dash R, Azab B, Quinn BA, Shen X, Wang XY, Das SK, Rahmani M, Wei J, Hedvat M, Dent P, Dmitriev IP, Curiel DT, Grant S, Wu B, Stebbins JL, Pellecchia M, Reed JC, Sarkar D, Fisher PB. 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. PMCID:PMC3102401.

About the Investigators: Paul B. Fisher, MPh, PhD, is Professor and Chair of Human and Molecular Genetics (HMG), Director of the VCU Institute of Molecular Medicine (VIMM) and Thelma Newmeyer Corman Chair in Cancer Research in the VCU Massey Cancer Center (MCC), Virginia Commonwealth University, School of Medicine, Richmond, VA. Xiang-Yang Wang, PhD is a Professor in HMG, Mary Anderson Harrison Distinguished Professor of Cancer Research in the VCU MCC and Associate Scientific Director of Immunology and Infectious Diseases of the VIMM. Siddik Sarkar, PhD and Anjan K. Pradhan, PhD are both postdoctoral research scientists in HMG. Swadesh K. Das, PhD and Luni Emdad, MBBS, PhD are both Assistant Professors in HMG and Members of the VIMM. Devanand Sarkar is an Associate Professor in HMG, Associate Scientific Director of Therapeutics in the VIMM, and a Harrison Foundation Distinguished Professor in Cancer Research in the VCU MCC. Maurizio Pellecchia, PhD, is Adjunct Professor at the Sanford-Burnham-Prebys Discovery Institute (SBPDI) and Professor of Biomedical Sciences and Director of the Center for Molecular and Translational Medicine, Daniel Hays Endowed Chair in Cancer Research, University of California Riverside, School of Medicine, Riverside, CA.