Ongoing studies:
Quinone as drug targets against homologous recombination deficient tumors
Rakesh S Nair & Priya Srinivas

(Project in collaboration with Dr Chuxia Deng, NIDDK, NIH, USA and Dr Mahesh Kumar J, Centre for Cellular and Molecular Biology, Hyderabad, India)
The in vivo model seems to deliver us the efficient tumor markers which could help to design better drug systems. We have to provide substantial ex vivo/in vivo evidence for translating the functional signature of apoptosis attributed by the plant derived lead molecules. We are studying the efficacy of brca1 mutated breast tumors and its dynamics over growth retardation in the presence of standard chemotherapeutic agents and other chemo sensitivity augmenting factors in xenograft models and BRCA1 knocked out transgenic models.

Isolation, Characterization and Therapeutic interventions of Breast cancer Stem Cells from BRCA1 Knockout Mouse Models.
Veena Somasundaram, Priya Srinivas

BRCA1 germ line mutations have been identified in nearly 50% of hereditary breast cancers and approximately 80% of cases with both hereditary breast and ovarian cancers. Decreased BRCA1 expression due to hypermethylation of the BRCA1 promoter or loss of BRCA1 allele has been reported in 30-40% of sporadic breast cancers as well. Therefore, BRCA1 may play a cardinal role in breast cancer development. The role of BRCA1 in human mammary stem cell fate has been examined using both in vitro systems and humanized NOD/SCID mouse model and it has been found that BRCA1 defect increases stem-like behaviour in the normal human mammary cells. Thus, BRCA1 is a regulator of mammary stem cell fate. It has been reported that mouse mammary tumors induced by conditional deletion of BRCA1 respond to therapy with doxorubicin or docetaxel but eventually become resistant to the drug. Thus, there exists a cellular sub-compartment within the tumor which remains resistant to therapy and causes the relapse. This sub set of cells shows “stem-like” behaviour. These cells if isolated and characterized may provide a useful model for drug development for improving the existing treatment regimens.

Designing of Metal based anticancer molecules functionally mimicking standard chemotherapeutic agents.
Rakesh S Nair, Priya Srinivas
Project in collaboration with Cochin University of Science and Technology, Cochin, India

To succeed in the therapy, the increased susceptibility of malignant cells to pro-apoptotic action of chemotherapeutic agents exceeding that of normal counterparts would be necessary. However, in tumor cells the apoptotic pathways are frequently misregulated due to inactivation or down-regulation of pro-apoptotic genes, or as a consequence of over expression of anti-apoptotic factors. Therefore, the application of new agents possessing higher selectivity towards malignant cells is necessary. The cancer cells show a primary or acquired resistance to cisplatin. Therefore, extensive effort to develop novel cisplatin analogs with equivalent or greater antitumor activity and a lower toxicity has been made. This made us to develop anticancer molecules which are coordination complexes of transition metal series. Application of combinatorial drug chemistry and cancer biology for screening the lead molecules are used in this study.

Effect of Cancer Associated Fibroblasts on BRCA1 defective breast cancer cells: Relation to aggressiveness
Sreelatha KH & Priya Srinivas

Worldwide, breast cancer is considered to be the most common cancer in women, after skin cancer, representing 16% of all female cancers. But still an effective drug to prevent or to cure the deadly disease has not been found out other than chemotherapy and surgical removal of the cancerous tissues. Recent studies indicates that the tumor progression is characterized by local accumulation of extracellular matrix components and connective tissue cells surrounding the tumor cluster, a phenomenon called tumor stroma interaction. The presence of Cancer Associated Fibroblasts (CAFs), one of the major tumor stroma components seems to be a necessary requirement for the growth and dissemination of several tumor cells as they secrete proteins that may stimulate adhesion, motility and escaping from the local growth control as well as angiogenesis. By studying the effect of Cancer Associated Fibroblasts (CAFs) on cancer cells, the main aim is to understand the possible role of the stromal component in the development and invasive nature of breast cancer.

Studies on Regulation of Cell Growth by BRCA1/2 in Prostate Cancer Cells: Influence of Certain Selected Quinones
Reshma R S & Priya Srinivas

The prostate is the most consistently reported site for cancer susceptibility in male carriers of BRCA1 mutation. Even though prostatic cancer is increasing the etiology of BRCA1/2 related prostatic cancer and their risk remains poorly understood, their optimal clinical management is not yet defined. Therefore, in this study we plan to analyze the effect of plumbagin and related quinones in comparison to standard drugs in prostate cancer cells with regard to BRCA1/2 absence/ presence. We have analysed the binding capacity of the drugs with androgen receptor by molecular docking studies.

Research Funding