Prem Seth, Ph.D.

Director, Gene Therapy Program                                                                                                    
ENH-Research Institute
Evanston Hospital
Haematolgy-Oncology
pseth@northwestern.edu
847-570-2317
Faculty Website

Current Research

Novel Gene Therapeutic Strategies for Targeting Bone Metastasis

Nearly 200, 000 women are diagnosed with breast cancer each year in the United States. The majority of patients with advanced breast cancer will develop bone metastasis resulting in bone destruction. This causes considerable morbidity including bone pain, pathological fractures, spinal cord compression and hypercalcemia. Therefore, there is a need to develop novel approaches to prevent and treat bone metastasis.

Our laboratory is developing a therapeutic approach that will destroy the primary tumor, and simultaneously inhibit the bone metastasis associated with breast cancer. We plan to learn whether a strategy which combines the oncolytic effects of an adenoviral vector with selective expression of soluble form of TGFß receptor II (sTßRII) offers a therapeutic advantage. We chose to target the TGFß pathway because high levels of TGFß protein enhance tumor invasion, bone metastasis, and contribute to osteoclastogenesis. There are two types of functional TGFß receptors - ßRI, and ßRII. Inactivating TGFßRII function can inhibit TGFß-mediated signal transduction lending support to the model that the inhibition of TGFß function by sTßRII can inhibit bone metastasis.  

In the recent years, replicating oncolytic adenoviral vectors have shown promise as effective anti-tumor agents. However, their potential to control bone metastasis has not yet been explored Using an oncolytic adenoviral vector expressing sTßRII, we are testing the hypothesis that the viral backbone will be oncolytic to the tumor cells, and the vector-mediated production of sTßRII and secretion into the blood will block the effects of TGFß, together inhibiting metastatic potential of cancer cells. We are also testing the feasibility of using adenoviral vectors for RNAis delivery. Adenoviral vectors expressing RNAis to target TGFß pathway are being generated and tested in vitro and in the animal models.

Recent Publications

Iyer S, Wang ZG, Akhtari M, Zhao W, Seth P Targeting TGF Beta Signaling for Cancer Therapy Cancer Biology Therapy 2005 (3): 261-266.

Seth P Vector-Mediated Cancer Gene Therapy: An Overview Cancer Biology Therapy 2005 (4): 512-517.

Turturro F, Heineke HL, Drevyanko TF, Link CJ, Seth P.    Adenovirus-p53-mediated gene therapy of anaplastic large cell lymphoma with t (2; 5) in a nude mouse model.  Gene Ther 2000 Jun;7(11):930-933.
 
Zhao W., Kobayashi M., Ding W, Yuan L., Seth P, Cornain S, Wang J, Okada F, Hosokawa M.  Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II.  Cancer Immunol Immunother 2002 Sep;51(7):381-388.
 
Turturro F, Seth P.  Prolonged adenovirus-mediated expression of p27 kip1 unveils unexpected effects of this protein on the phenotype of SUDHL-1 4 cells derived from t(2;5)-anaplastic large cell lymphoma.  Leukemia Res 2003 Apr;27(4):329-35.