Gene Therapy for Cancer
Broad research activities
Systemic and targeted gene therapy for cancer, targeting anti-apoptotic Bcl-2 family members for effective therapy of oral squamous carcinomas.
Developing an effective systemic and targeted gene therapy for cancer
A major challenge for effective gene therapy is the ability to specifically deliver the therapeutic directly into diseased tissue without exposure to the immune system, particularly with a systemic approach in an immune competent animal model. Progress in gene therapy has been hampered by concerns over the safety and practicality of viral vectors, particularly for intravenous delivery, and the inefficiency of currently available non-viral transfection techniques. We will explore novel targeted-delivery approaches to develop a site-specific delivery and henceforth therapy in immune competent transgenic mouse cancer model. These approaches of systemic gene delivery will facilitate development of efficient, selective and non-toxic modes for gene therapy using therapeutically beneficial genes that offer significant potential to translate into a Phase I/II clinical trial. For therapeutic arms we will explore the tumor suppressor activity of 1) human melanoma differentiation gene-7/Interleukin-24 (mda-7/IL-24) and 2) Suppressor of AP-1 regulated by IFN (SARI) in oral squamous cacinomas. mda-7/IL-24 shows ubiquitous anti tumor effect, its mode of action involves preferential induction of apoptosis in cancer cells while exerting no discernible toxic effects toward normal cells by eliciting unique potent “antitumor bystander activity” as a consequence of autocrine secretion. Similarly, forced expression of SARI resulted in tumor-selective growth inhibition and induction of apoptosis in prostate cancer, malignant glioma and metastatic melanoma cells. Although the precise molecular mechanism by which SARI induces tumor-suppressing activity requires further clarification, preliminary studies revealed that forced expression of SARI resulted in inhibition of DNA binding of activator protein (AP-1) complexes and, consequently, it selectively inhibited AP-1-dependent gene expression. Targeting anti-apoptotic Bcl-2 gene family for effective therapy of Oral squamous carcinomas: Despite intensive investigation, oral cancer remains formidable clinical challenges resulting in high frequencies of morbidity and mortality. Reprogramming tumor cells to undergo programmed cell death (apoptosis) represents a promising and powerful strategy for treating both local and metastatic disease. Ways of achieving this objective involve the selective down regulation of dysregulated oncogenes and/or expression/activation of apoptosis-inducing genes or their products in tumor cells. For example the role of Bcl-2 family members is critical for onset and progression of cancer. Dysregulation of Bcl-2 family members including myeloid cell leukemia-1 (Mcl-1) is often implicated in the acquisition of resistance to apoptosis in malignant cell lines. Mcl-1 plays a pivotal role in cancer cell survival, including that of oral cancer cells, suggesting involvement of this gene in oral squamous carcinogenesis. Over expression of Mcl-1 protects cells from apoptosis induced by a variety of stress-promoting agents. Considering the fact that Mcl-1 is over expressed in the majority of oral cancers, we hypothesize that selectively targeting Mcl-1 alone or in combination with other conventional anti cancer drugs or potential tumor suppressors might provide an effective therapeutic for this metastatic disease.
Dr. Neera Singh, DBT-Biocare Scientist
Project: Proteomic profiling of saliva and oral premalignant lesions by reverse-phase protein array to identify potential diagnostic biomarkers
Dr. Swati Chauhan, DST-WOSA
Mr. Sabindra Kumar Samal, CSIR-SRF
Project: Role of DEAD-box polypeptide 3 (DDX3) in Oral Squamous Cell Carcinoma (OSCC)
Mr. Santanu Maji, DST-INSPIRE-SRF
Project: Role of antiapoptotic proteins in Oral Squamous Cell Carcinoma (OSCC)
Mr. Omprakash Shriwas, UGC-JRF
Project: Role of glucose metabolism in Oral Squamous Cell Carcinoma (OSCC)
Miss Laxmipriya Pattanaik (Lab Technician)
Miss. Manashi Priyadarshini (Project Assistant)
