Prem Seth , PhD

• Undergraduate: BS, University of Delhi, New Delhi, India
• Graduate: MS, GB Pant University, Nainital, India
• Graduate: PhD, University of Western Ontario, London, Ontario, Canada
• Post-Graduate: Post-Doctoral, Laboratory of Molecular Biology, NCI, Bethesda, MD

Novel Gene Therapeutic Strategies for Targeting Cancer:

The majority of patients with advanced breast and prostate cancers will develop bone metastasis resulting in bone destruction. To target skeletal metastases, our laboratory is interested in developing recombinant oncolytic adenoviruses that will kill the cancer cells, and simultaneously produce therapeutic proteins that will target the tumor-bone environment. Once the tumor cells arrive at the bone site, a "vicious cycle" is initiated between the tumor cells, osteoclast and the osteoblast cells. Transforming growth factor-ß (TGFβ) has been shown to a key player involved in the vicious cycle. There are two types of functional TGFβ receptors - βRI, and βRII. Inactivating TGFβRII function can inhibit TGFβ-mediated signal transduction lending support to the model that the inhibition of TGFβ function by sTβRII can inhibit bone metastasis. Using an oncolytic adenoviral vector expressing sTGFβRII, we are testing if the viral backbone will be oncolytic to the tumor cells, and the vector-mediated production of sTGFβRII and its release in the tumor-bone microenvironment will block the effects of TGFβ, together inhibiting metastatic potential of cancer cells. Our initial studies using breast and prostate cancer bone metastases models have shown that systemic delivery of the oncolytic adenovirus expressing sTGFβRII-Fc produces strong inhibition of bone metastases, and the tumor-induced bone destruction. Based on our results, we believe that oncolytic adenoviruses targeting TGFβ can be potentially developed as an anti-tumor agent for the treatment of breast and prostate cancer bone metastases.

• Adjunct Professor, Department of Medicine, Northwestern University

• Member, American Association for Cancer Research
• Member, American Society of Gene and Cell Therapy
• Member, Metastasis Research Society
• Member, International Bone and Mineral Society
• Member, Editorial Board, Cancer Gene Therapy
• Member, Editorial Board, Cancer Biology and Therapy
• Member, Editorial Board, Human Gene Therapy
• Member, Editorial Board, Molecular Therapy: Oncolytics
• American Cancer Society. Permanent member, Molecular Genetics and Oncogenes study section- 2001- 2005
• National Institutes of Health. Ad hoc member SBIR/STTR special study sections, 07/2000, 10/2000, 02/2001, 07/2001, 10/2001, 02/2002, 06/2002, 10/2002, 07/2003
• National Cancer Institute. Ad hoc member, Flexible System to Advance Innovative Research for Cancer Drug Discovery- 03/2004
• American Cancer Society. Member, Site Visit Team, SALK Institute, La Jolla- 10/2005
• National Cancer Institute. Ad hoc member, Developmental Therapeutics study section- 10/2005, 03/2006, 06/2006, 02/2007, 05/2007, 09/2007, 01/2008, 05/2008, 10/2008
• Alliance for Cancer Gene Therapy. Grant reviews committee member- 04/2006, 06/2006
• National Cancer Institute. Ad hoc member, Special Emphasis Panel/Scientific Review Group- ZRG1 ONC-F (02) (M), 05/2006; ZRG1 ONC-K (03) (M), 02/2008
• Susan G. Koman for the Cure Research Program. Ad hoc member, Targeted Therapies (2) study section- 03/2009
• National Institutes of Health. Ad hoc member, Therapeutic Approaches to Genetic Diseases study section-06/2009
• National Cancer Institute. Ad hoc member, Special Emphasis Panel/Scientific Review Group- ZRG1 OTC-K (03) (M), 10/2009; ZRG1 OTC- W 02, 06/2010; ZRG1 OTC-K (06) M, 10/2010; OTC-X (90) 09/2011; ZRG1 OTC (03), 02/2012; ZCA1 SRLB-9 (M1), 03/2012; ZCA1 SRLB-D (M1) R, 03/2012,  ZRG1-OTC-C(02), 01/2013,  ZCA1 SRB-J (O1) Omnibus SEP-12, 06/2014

Publications in Peer-Review Journals: (out of total 129)

1. Xu, W., Zhang, Z., Yang, Y., Hu, Z., Wang, C.H., Morgan. M., Wu, Y, Hutten, R., Xiao. X., Stock, S., Guise, T., Prabhakar, B.S., Brendler, C. and Seth, P. (2014) Ad5/48 Hexon Oncolytic Virus Expressing sTGFβRIIFc Produces Reduced Hepatic and Systemic Toxicities and Inhibits Prostate Cancer Bone Metastases. Mol Ther May 5. doi: 10.1038/mt.2014.80. [Epub ahead of print]
2. Zhang. Z., Zhang, X., Newman, K., Liu, X. and Seth P. (2014) MicroRNA regulation of oncolytic adenovirus 6 for selective treatment of castration-resistant prostate cancer. Mol Cancer Ther 13(1):271.
3. Hu, Z., Gupta, J., Zhang, Z., Gerseny, H., Berg, A., Chen, Y.J., Zhang, Z., Du, H., Brendler, C.B., Xiao, X., Pienta, K.J., Guise, T., Lee, C., Stern, P.H., Stock, S. and Seth, P. (2011) Systemic delivery of oncolytic adenoviruses targeting transforming growth factor-β inhibits established bone metastasis in a prostate cancer mouse model. Hum Gene Ther 23: 871-882.
4. Zhang, Z., Hu, T., Gupta, J., Krimmel, J., Gerseny, H., Berg, A., Robbins, J., Du, H., Prabhakar, B. and Seth, P. (2012) Intravenous administration of adenoviruses targeting transforming growth factor beta signaling inhibits established bone metastases in 4T1 mouse mammary tumor model in an immunocompetent syngeneic host. Cancer Gene Ther 19: 630-636.
5. Hu, Z., Gerseny, H., Zhang, Z., Chen, Y., Berg, A., Zhang, Z., Stock, S., and Seth, P. (2011) Oncolytic Adenovirus Expressing Soluble TGFß ReceptorII-Fc-mediated Inhibition of Established Bone Metastases: A Safe and Effective Systemic Therapeutic Approach for Breast Cancer. Mol Ther 9: 1609-1618.
6. Zhang, Z., Krimmel, J., Zhang, Z., Hu, Z., and Seth, P. (2011) Systemic Delivery of a Novel Liver-detargeted Oncolytic Adenovirus Causes Reduced Liver Toxicity but Maintains the Anti-tumor Response in a Breast Cancer Bone Metastasis Model. Hum Gene Ther 22: 1137-1142.
7. Gupta, J., Robbins, J., Jilling, T., and Seth, P. (2011) TGFbeta-dependent induction of Interleukin-11 and Interleukin-8 involves SMAD and p38 MAPK pathways in breast tumor models with varied bone metastases potential. Cancer Biol Ther 11: 311-116.
8. Hu, Z., Zhang, Z., Guise, T., and Seth, P. (2010) Systemic Delivery of an Oncolytic Adenovirus Expressing Soluble Transforming Growth Factor-beta Receptor II-Fc Fusion Protein Can Inhibit Breast Cancer Bone Metastasis in a Mouse Model. Hum Gene Ther 21: 1623-1629.
9. Hu, Z., Robbins, J. S., Pister, A., Zafar, M. B., Gupta, J., Zhang, Z.-W., Lee, K. J., Neuman, K., Yun, C.-O., Guise, T., and Seth, P.  (2010) A modified hTERT Promoter-directed Oncolytic Adenovirus Replication with Concurrent Inhibition of TGFß Signaling for Breast Cancer Therapy. Cancer Gene Ther 17: 235-243.
10. Seth, P., Wang, Z-G., Pister, A., Zafar, MB., Sung, K., Guise, T., Wakefield, T. (2006) Development of Oncolytic Adenovirus Armed with a Fusion of Soluble Transforming Growth Factor-beta Receptor II and Human Immunoglobulin Fc for Breast Cancer Therapy. Hum Gene Ther 17: 1152-1160.
11. Wang, Z., Zhao, W., Ramachandra, M., Seth, P. (2006) An Oncolytic Adenovirus Expressing Soluble TGF-b Type II Receptor for Targeting Breast Cancer: In Vitro Evaluation. Mol Cancer Ther 5: 367-373.
12. Zhao, W., Kobayashi, M., Ding, W., Yuan, L., Seth, P., Cornain, S., Wang, J., Okada, F., and Hosokawa, M. (2002) Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II. Cancer Immunol Immunother 51: 381-388.
13. Habib, N., Salama, H., Abd, E. L., Abu, M. A., Isac Anis, I., Abd Al Aziz, R. A., Sarraf, C., Mitry, R., Havlik, R., Seth, P., Hartwigsen, J., Bhushan, R., Nicholls, J., Jensen, S. (2002) Clinical trial of E1B-deleted adenovirus (dl1520) gene therapy for hepatocellular carcinoma. Cancer Gene Ther 9:254-259.
14. Jacob, T., Ascher, E., Higorani, A., Gunduz, Y., Yorkovich, W., Seth, P. (2001).  Von-Hippel-Lindau gene therapy: a novel strategy in limiting endothelial cell proliferative activity. Ann Vasc Surg 15:1-6.
15. Rakkar, A, Li, Z., Katayose, Y., Kim, M., Cowan, K. H., and Seth, P. (1998) Adenoviral expression of the cyclin-dependent kinase inhibitor p27/Kip1: A strategy for breast cancer gene therapy. J. Natl. Cancer Institute  90: 1836-1838.
16. Li, Z., Rakkar, A., Katayose, Y., Kim, M., Shanmugam, N., Moul, J. W., McLeod, D. G., Cowan, K. H., and Seth, P. (1998) Efficacy of multiple administrations of a recombinant adenovirus expressing wild type p53 in an immune-competent mouse tumor model. Gene Ther 5: 605-613.
17. Katayose, Y., Kim, M., Rakkar, A., Li, Z., Cowan, K., and Seth, P. (1997) Promoting apoptosis: a novel activity associated with cyclin-dependent kinase inhibitor p27/Kip1. Cancer Res. 57: 5441-5447.
18. Seth, P., Brinkmann, U., Schwartz, G., Katayose, D., Gress, R., Pastan, I, and Cowan, K. (1996) Adenovirus-mediated gene transfer to human breast tumor cells: an approach for cancer gene therapy and bone marrow purging. Cancer Res 56: 1346-1351.
19. Srivastava, S., Katayose, D., Tong, Y. A., McLeod, D. G., Moul, J. M., Cowan, K. and Seth, P. (1995) A recombinant adenovirus vector expressing wild type p53 is a potent inhibitor of prostate cancer cell proliferation. Urology 46: 843-848.
20. Katayose, D., Gudas, J., Nguyen, H., Srivastava, S., Cowan, K. and Seth, P. (1995) Cytotoxic effects of a recombinant adenovirus expressing human wild type p53 on tumor and normal mammary epithelial cells. Clinical Cancer Res 1: 889-898. PMID: 9816059

Books:

1. Book Editor: Seth, P. (1999). Adenoviruses: Basic Biology to Gene Therapy (editor P. Seth). R. G. Landes company, Austin, TX, pp. 1-314.