Our laboratory is studying the processes that, when defective, allow human cells to develop malignant characteristics. Ultimate idea is to develop cancer biomarkers that will aid in better diagnosis, prognsis and treatment.
Tumor suppressor genes & Oncogene network: Cancer chemoresistance, Gene therapy and Targeted therapy
Chemoresistance is a major obstacle to successful cancer therapy. Since defects in apoptotic pathways often lead to chemoresistance, our interest is to study how tumor suppressor genes are regulated and function during cancer development. We have demonstrated the importance of p53 in histone deacetylase (HDAC) inhibitor based chemotherapy and in chemoresistant breast cancer and leukemia having notch1 overexpression and activated PI3-kinase-Akt/PKB-mTOR-eIF4E pathway. This study also suggests the utility of inhibitors of either PI3 kinase or mTOR in reversing the Notch1-mediated chemoresistance.
We have shown that p73, a p53 homologue, is regulated by the viral oncoprotein E1A, thereby suggesting an important role for p73 during cellular transformation. We have developed a replication-deficient adenovirus expressing p73 (Ad-p73) and demonstrated its utility as a potential cancer gene therapy reagent. Ad-p73 is particularly useful against cervical cancer, where p53-based therapeutic approach is not effective.
In another study, we have established the mechanism of growth inhibition by Activator Protein 2 α (AP-2α), a developmentally regulated transcription factor, and further showed that the apoptosis induction by AP-2α involves transcriptional repression and activation of mitochondrial apoptotic pathway. More importantly, AP-2α was established as an important chemosensitivity determinant.
We have also demonstrated direct involvement of BRCA1/2 in hereditary breast and ovarian cancer among Indian women and developed a better mutation screening technique for large genes like BRCA1.
Understanding glioma development
Gliomas are the most common brain cancers with an incidence of 12 per 100,000 people. Diffuse infiltrating astrocytomas include the following entities: 1. Diffuse astrocytoma (DA; WHO Gr. II), 2. Anaplastic astrocytoma (AA; WHO Gr. III) and 3. Glioblastoma multiforme (GBM; WHO Gr. IV). The prognosis of patients with these tumors is dismal and GBM, which is the most malignant phenotypic variant, has a mean survival of 10-12 months. Currently, available treatment options are multimodal, which include surgery, radiotherapy and chemotherapy. But these only marginally increase survival in GBM patients. To find new diagnostic and therapeutic strategies, a better understanding of the biological pathway(s) leading to glial tumorigenesis is warranted.
Novel Glioblastoma markers
Using microarray based expression profiling, we identified several differentially regulated grade-specific genes. Independent validation by real time RT-qPCR analysis found GADD45a and FSTL1 to be up regulated in most GBMs (both primary and secondary) while SOD2 and AEBP1 were up regulated in majority of primary GBMs. Further, identification of the grade-specific expression of GADD45a and FSTL1 by immunohistochemical staining reinforced our findings. Analysis of retrospective GBM cases with known survival data revealed that cytoplasmic overexpression of GADD45a conferred better survival while the coexpression of FSTL1 with p53 was associated with poor survival.
A potential malignant astrocytoma/glioblastoma serum marker with prognostic value. Pre-B-cell colony enhancing factor 1 gene (PBEF1) encodes Nicotinamide phosphoribosyltransferase (NAmPRTase), which catalyses the rate limiting step in the salvage pathway of NAD metabolism in mammalian cells. Using cDNA microarray based expression profiling of different grades of astrocytomas, we identified several fold increased levels of PBEF1 transcripts in GBM samples. PBEF1 serum levels were substantially elevated in many of the AA and GBM patients. In patients with astrocytoma, serum PBEF1 level correlated with tumor-grade and is highest in GBM. PBEF1 expression in the tumor tissue along with its co-expression with p53 was found associated with poor survival.
Glioma Serum proteomics
Human blood plasma and serum, serve as the most important sources for discovering candidate disease biomarkers. Serum proteins have diagnostic, prognostic and therapeutic use. Using combinantion of 2D gel electrophoresis and MALDI-TOF, we found Haptoglobin as high grade specific glioma serum marker. Its utility as a prognostic markers and its role in glioma development is under investigation
PS.Reddy, R.Britto, K.Vinnakota, Aparna H, HK.Sreepathi, B.Thota, A.Kumari, Shilpa BM, Vrinda MS. Umesh S, C.Samuel, M.Shetty, A.Tandon, P.Pandey; S.Hegde, AS.Hegde, Anand B, BA Charamouli, V Santosh, P Kondaiah, K. Somasundaram M. R. S Rao (2008) Novel Glioblastoma Markers with Diagnostic and Prognostic Value Identified Through Transcriptome Analysis. Clinical Cancer Research 2008 14: 2978-87
PS Reddy, S Umesh, B Thota, A Tandon, P Pandey, AS Hegde, Anandh B, BA Chandramouli, V Santosh, MRS Rao, P Kondaiah and K. Somasundaram (2008) PBEF1/NAmPRTase/ Visfatin: A potential malignant astrocytoma/glioblastoma serum marker with prognostic value Cancer Biol Ther 2008 (Accepted)
Britto R, S Umesh, A Hegde, S Hegde, V Santosh, B Chandramouli and K Somasundaram (2007) Shift in AP-2α Localization Characterizes Astrocytoma Progression Cancer Biol Ther 6:413-418
Wajapeyee N, R Britto., HM Ravishankar and K Somasundaram (2006) Apoptosis induction by AP-2α involves transcriptional repression of Bcl-2. (2006) J. Biol. Chem. 281:16207-16219
Mungamuri SK., XH Yang, ADThor and K Somasundaram. (2006) Survival signaling by Notch1: mammalian Target of Rapamycin (mTOR)- dependent inhibition of p53. Cancer Research 66: 471.