Dr Pritha Ray

Drug resistance still impedes successful cancer chemotherapy. In current clinical practice, drug resistance is often detected late during the course of treatment which leaves less scope for further management of the molecularly heterogeneous resistant cells. It is therefore, would be worth detecting acquirement of resistance early for effective alternative treatment and avoid toxicity of the first line chemotherapy. Development of resistance towards chemotherapeutics and targeted therapeutics involve multiple signaling pathways which are differentially altered in different cell types. The multifactorial nature of resistance development poses a strong barrier to overcome the challenge of therapeutic resistance. There is a pressing need to understand the course of resistance development, signaling pathways and underlying molecular interactions using cellular and preclinical models and clinical samples.

The prime focus of my lab is to investigate and detect the key molecular switches associated with chemoresistance and develop strategies for early detection of acquired chemoresistance in epithelial ovarian cancer. Our tools involve indigenously developed chemoresistant cellular models, various cellular and molecular assays, mouse models and most importantly clinical samples. Real time monitoring of molecular and cellular evolution of chemoresistance from living subjects through noninvasive molecular imaging techniques is a major approach for our research. Acquirement of resistance against cisplatin and paclitaxel is a major challenge for women suffering from epithelial ovarian cancer particularly from high grade serous subtype which is most prevalent (~85-90%) in India and around the world. Failure to identify actionable target mutations in primary and recurrent ovarian cancer by recent whole genome analysis suggests that we must look beyond genomic alteration and investigate the biology of ovarian cancer progression and resistance development to find alternative therapeutic strategies.

Over the years we showed that cisplatin and paclitaxel exert their toxicity through binding of activated p53 on PIK3CA promoter and thereby inhibiting cell proliferation and survival (Gaikwad et al, Plos One, 2013). Dual imaging of NF-κb activation and PIK3CA promoter modulation in maintenance of cisplatin resistance was performed in real time (Gaikwad et al, Int. J. Biochem & CellBiol, 2015). Intriguingly, we find that upregulated IGF-1R expression is an essential event for initiation of chemoresistance while maintenance of resistance is taken care by activated Akt (Singh et al, Cancer Letters, 2014).

Many of these findings could potentially lead to effective therapeutic strategies and our current research focuses on

  • Identifying transcriptional regulators of PIK3CA gene in chemoresistant cells
  • Dissecting role of IGF-1R in resistance development, cancer progression and metastasis
  • Understanding influence of p53 upon cell survival and apoptotic genes in resistant cells
  • Investigating the association of IGF-1R-Akt axis with Cancer Stem cells during resistance
  • Developing novel reporter vectors to monitor protein-protein interaction

Additionally, we actively collaborate with faculties across India and other part of the globe to develop nanotherapeutic strategies, characterize biophysical properties of chemoresistant cells and explore role of Notch signaling in ovarian cancer progression. All together we take a holistic approach to develop therapeutic strategies for combating the deadly ovarian cancer.