Issue No. 19, August 2018
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.     
Recombinant MDA-7/IL-24 suppresses prostate cancer bone metastasis through down regulation of the Akt/Mcl-1 pathway
 
  • Bone metastasis is the ultimate stage of prostate cancer progression and the primary cause of prostate cancer mortality. There is no effective therapy for prostate cancer bone metastasis.
 
  • MDA-7/IL-24 is a secreted cytokine that is growth suppressive against a broad spectrum of human cancers. A recent study by Pradhan and colleagues has shown that recombinant MDA-7/IL-24, delivered as a pure His-tagged protein, induced significantly less metastatic lesions in mouse femurs compared to untreated control animals and did not induce any toxicity in animal models.

  • Mechanistically, recombinant MDA-7/IL-24 deregulates RANKL-induced osteoclastic differentiation and regulates this osteoclastic differentiation through the Akt-Mcl-1-pathway.

  • Mcl-1 inhibitors synergistically act with MDA-7/IL-24 to reduce bone metastasis in experimental bone metastasis animal models.

  • This is the first demonstration that purified recombinant MDA-7/IL-24 protein can provide therapy in a human prostate cancer-induced bone metastasis animal model and this effect can be enhanced with a small molecule inhibitor targeting Mcl-1.
 
Prostate cancer (PC) is a principal cause of cancer-associated morbidity in men. Although 5-year survival of patients with localized PC approaches 100 percent, survival decreases precipitously after metastasis. Bone is the preferred site for disseminated PC cell colonization, altering the equilibrium of bone homeostasis and resulting in weak and fragile bones. Currently, no curative options are available for PC bone metastasis. MDA-7/IL-24 is a well-studied cytokine established as a therapeutic in a wide array of cancers when delivered as a gene therapy. In this study, Fisher ’ s group explored the potential anti-cancer properties of MDA-7/IL-24 delivered as a recombinant protein. Using bone metastasis experimental models, animals treated with recombinant MDA-7/IL-24 had significantly less metastatic lesions in their femurs compared to control groups. The inhibitory effects of MDA-7/IL-24 on bone metastasis resulted from cancer-specific killing and inhibition of osteoclast differentiation, which is necessary for bone resorption. Gain- and loss-of-function genetic approaches document that pro-survival Akt and Mcl-1 pathways are critically important in the anti-bone metastatic activity of MDA-7/IL-24. Previous findings from the Fisher lab indicated that MDA-7/IL-24 gene therapy and Mcl-1 inhibitors cooperate synergistically. Similarly, a Mcl-1 small molecule inhibitor synergized with MDA-7/IL-24 pure protein and induced robust anti-bone metastatic activity. This study expands the potential applications of MDA-7/IL-24 as an anti-cancer molecule and demonstrates that the purified recombinant protein is non-toxic in pre-clinical animal models and has profound inhibitory effects on bone metastasis, which can be enhanced further when used in combination with a Mcl-1 inhibitory small molecule.
Figure legend:
Schematic representation of MDA-7/IL-24-mediated inhibition in progression of prostate cancer induced bone metastasis through modulation of the bone microenvironment.
Anjan K Pradhan, a postdoctoral research scientist in Dr. Paul Fisher ’ s laboratory at VCU, is the lead author of this paper, and performed much of the biological and animal work. The study was published in Molecular Cancer Therapeutics* and also highlighted in the Beyond the abstract section in UroToday**.
The present studies were supported by the National Foundation for Cancer Research (PBF), NIH grant P50 CA058236 (to P.B. Fisher and M.G. Pomper) and NCI Cancer Center Support Grant to VCU Massey Cancer Center P30 CA016059 (to P.B. Fisher and D. Sarkar).
Publications:
 
 
**MDA-7/IL-24: A Potential Therapeutic for Prostate Cancer Bone Metastasis – Beyond the Abstract: Written by:   Anjan K. Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xue-Ning Shen, Luni Emdad, Swadesh K. Das, Devanand Sarkar and Paul B. Fisher. https://www.urotoday.com/recent-abstracts/urologic-oncology/investigative-urology/105753-mda-7-il-24-a-potential-therapeutic-for-prostate-cancer-bone-metastasis-beyond-the-abstract.html
 

About the Investigators: Paul B. Fisher, MPh, PhD, FNAI 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. Anjan K. Pradhan, PhD, the first author of this research study, and Sarmistha Talukdar, PhD are postdoctoral research scientists in HMG. Praveen Bhoopathi, PhD, is an Instructor in HMG. Xue-Ning Shen, MD, is a senior technician in the Fisher laboratory performing animal studies. Luni Emdad, MBBS, PhD and Swadesh K. Das, 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.