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Principal Investigator

Dr. Pritha Ray

Principal Investigator

Research Interests

  • Investigating the role of mutant p53 in regulation of PIK3CA-Akt signaling pathway and autophagy in platinum resistant EOC cells
  • Investigating the potential of PI3KCA inhibitors for platinum resistant and relapsed EOC patients
  • Understanding the association of Cancer Stem cell and autophagy from EOC cell lines and EOC patient derived primary cells and tissues in recurrent settings
  • Investigating the association of mutant p53 with Her2, CCND1 and CCNE1 in gastric cancer cell lines and patient tissues
  • Investigating influence of autophagy and IGF1R signaling upon metastasis in orthotopic EOC and gastric cancer mouse model through non-invasive molecular imaging
  • Understanding the role of differential Notch-Jagged 1 interaction in EOC tumor-stroma to assess the functional consequence of disease progression
  • Investigating role of RUNX1 and ID protein in CSC differentiation and platinum resistance

Additionally, we actively collaborate with clinicians and scientists across India and other part of the globe to develop nano-therapeutic strategies, characterize biophysical properties of chemoresistant cells and other domains. All together we take a holistic approach to develop new/alternate therapeutic strategies for combating the deadly ovarian and gastric cancers.

RESEARCH

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 to validate alternative therapeutic strategies or to assess the genetic and molecular perturbation from drug resistant relapsed tumors for developing new treatment modalities. 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 alternate/new therapeutic strategies for epithelial ovarian cancer (EOC) and gastric cancer (GC). Both these cancers though differ in their prevalence rate, are primarily treated with cytotoxic drugs and exhibit high mortality due to drug resistance and relapse. Very few targeted therapy approaches are routinely practiced for EOC and GC treatments thus creating a lot of scope for understanding the resistant disease biology to find alternative therapeutic strategies. Using indigenously developed chemoresistant cellular models, various cellular and molecular assays, subcutaneous and orthotopic mouse models, non-invasive molecular imaging and clinical samples, we aim to investigate the molecular and functional signature of primary and resistant EOC and GC cell lines and samples.

Over the years we deciphered the molecular mechanism and the consequences of loss of p53 mediated regulation of PIK3CA-AKT signaling as a key driver of chemoresistance development Gaikwad et al, Plos One, 2013, Thakur & Ray, Mol. Oncol., 2016, Gaikwad et al, Int. J. Biochem. Cell Biol., 2015, Thakur & Ray, J. Exp. Clin. Cancer Res., 2017). In absence of p53 control, an active NF-κB-TNFα-PIK3CA bimodal loop nurtures the CSC homeostasis through persistent NF-κB production under cisplatin treatment in the platinum resistant EOC cells (Thakur & Ray, J. Exp. Clin. Cancer Res., 2017). 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 Lett., 2014). An intricate co-operation between RUNX1 and FOXO3A transcriptionally regulate this pulsatile nature of IGF1R expression at different stages of resistance and this interaction relies on the AKT activation status (Dhadve et al, Mol Basis Dis, 2020). Intriguingly, this pulsatile IGF1R expression imparts distinct MAPK/ERK or PI3K/AKT pathway activation at different stages of resistance resulting in unique biochemical and cellular processes such as differential autophagic flux and functional heterogeneity in cancer stem population (Singh et al, Sci. Rep., 2016; Bishnu et al, Cell Death Dis., 2021). IGF1R level has been found to be positively correlated with better prognosis and hCTR1 level in a small population of high grade serous ovarian cancer patients (Deo et al, Biomarkers in Medicine, 2019). We also show Metformin, an anti-diabetic drug when continuously treated with platinum-taxol is able to slow the process of resistance development (Bishnu et al, Int. J. Biochem. Cell Biol., 2018). All these studies suggest intricate and complex pathways are exclusively or coordinately play role at different stages during development of platinum resistance and it is possible to design therapeutic interventions upon identifying these nodes.

We are also actively engaged in developing reporter gene based new molecular sensors to monitor transcriptional regulation, translational regulation and protein-protein interaction in vitro and in preclinical mouse model using non-invasive molecular imaging techniques. We have recently developed a novel in vivo-autophagy sensor that allows us to measure the kinetics of autophagy flux and effects of specific inhibitors from live cells to live animals in real time (Bishnu et al, Cell Death Dis., 2021). Similarly we also measured protein-protein interaction leading to AKT and ERK activation through BRET (Bioluminescence Resonance Energy Transfer) sensors in platinum resistant cell lines and for the first time from recurrent EOC patient derived primary cells (Bishnu et al, Transl. Oncol., 2021).

Ongoing Research Projects

  • Role of IGF-1R in ovarian cancer metastasis

    Role of IGF-1R in ovarian cancer metastasis

    For epithelial ovarian cancer (EOC), the incidence of relapse is overwhelming and is attributed to acquired chem… more

  • Understanding the modulation in MAPK/ERK and PI3K/AKT signalling during acquirement of drug resistance

    Understanding the modulation in MAPK/ERK and PI3K/AKT signalling during acquiremen…

    Dynamic modulation of key kinases govern development of chemo resistance through multiple mechanisms. Currently… more

  • Consequence of differential activation of Notch signalling in ovarian cancer progression and chemo resistance

    Consequence of differential activation of Notch signalling in ovarian cancer progr…

    Cellular communication and interactions are critical and essential for the sustenance and progression of complex… more

  • Investigating the role MAPK-ERK & PI3K-AKT signalling on autophagic flux in Ovarian Cancer Stem Cells

    Investigating the role MAPK-ERK & PI3K-AKT signalling on autophagic flux in Ov…

    Cancer stem cells (CSCs), a minor population in bulk of tumour are implicated in relapse and resistance after th… more

  • Investigating therapeutic potential of PIK3CA inhibitors for ovarian cancer carrying oncogenic mutant p53

    Investigating therapeutic potential of PIK3CA inhibitors for ovarian cancer carryi…

    Wild-type p53, a tumour suppressor, has been reported to downregulate PIK3CA expression in ovarian cancer. Molec… more

  • Investigating key molecular signatures to design new therapeutic approaches for Gastric Cancer

    Investigating key molecular signatures to design new therapeutic approaches for Ga…

    In the last few decades, the treatment regimen for Gastric Cancer (GC) remains unchanged with minimal scope of t… more

  • Investigating the influence of mutant p53 on autophagy in epithelial ovarian cancer cells

    Investigating the influence of mutant p53 on autophagy in epithelial ovarian cance…

    Therapy resistance and metastasis are both considered to be severe impediments in cancer therapy. Several report… more

Lab Members

Alumni

PUBLICATIONS

Contact

Office Contact

Dr. Pritha Ray

KS-338A, Advance Centre for Treatment Research & Education in Cancer, Tata Memorial Centre, (ACTREC), Plot No. 1 & 2, Sector 22, Kharghar, Navi Mumbai-410210. Maharashtra India.+91 (022) 2740 5000/ 6873 5000 pray@actrec.gov.in Lab Website

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