Assistant Professor, Biochemistry and Molecular Biology
- The role of PP2A subunits in pancreatic and prostate cancer pathogenesis
- Pre-clinical validation of EGFR family member inhibitors and metabolic pathway specific inhibitors.
- Identify and explore the mechanism (s) associated with the cancer cells developing resistance towards currently available treatment regimens.
- Generation of mouse models (pancreatic and prostate cancer) to understand cancer pathogenesis and to test the efficacy of chemo-radiotherapies.
Cancer arises as a consequence of activation of kinases (enzymes), in contrary, there are enzymes that play opposite roles to that of kinases, known as phosphatases. Protein phosphatase 2A (PP2A) is one of the major serine-threonine phosphatases composed of three subunits: catalytic (C), scaffold (A), and regulatory (B) subunit, with functional and expressional variability in various tissues. In prostate cancer, we observed an association between deregulation of PP2A subunits PP2AAα and B56γ contribute to the development of androgen-independent (AI) prostate cancer progression. Our functional analysis also revealed that knockdown of PP2A-Aα/β subunit results in increased migratory property of PCa cells by modulating AKT, FAK and β-catenin signaling. Based on our previous experience we made an attempt to explore the role and mechanisms associated with PP2A regulatory subunit in the initiation, promotion, growth and advancement of pancreatic cancer. Among various B subunits, we specifically detected a high level of PR55α form (one of the regulatory subunit) of PP2A expression in cancerous cell lines whereas the basal level of expression in the normal ductal epithelial cell line. Subsequently, we also demonstrated a link between PP2A-PR55α overexpression and poor survival of pancreatic cancer patients. Through in vitro and in vivo assays, we show that AKT, ERK and β-catenin signaling are disrupted upon suppression of PP2A-PR55α. Currently, we are developing mice model with PP2A-PR55α knockout in the background of KrasG12D; Pdx-1 Cre model.
Another important aspect of our focus is to evaluate the therapeutic effects of irreversible pan-EGFR family inhibitors, canertinib, and afatinib on multiple cellular properties such as proliferation, migration and survival of pancreatic cancer cells. Later, we identified this novel effect of panEGFR inhibitors could exert anti-tumor and reducing metastasis burden via inhibiting EGFR-STAT1 mediated mechanism for MUC4 down-regulation, in vitro and in vivo. Additional work has focused on identifying new genes and their related products that can specifically differentiate between radiotherapy resistant and non-resistant cancer cells. Additional work focused on utilizing FDA approved drugs to test as novel radiosensitizer to abrogate therapy resistance using 3D tumoroids and mouse models, which would be the way to enhance conventional treatment modalities.
We are involved in the generation of genetically engineered mouse models mimicking pancreatic and prostate cancer pathogenesis. Previously, we have developed and published the well-established Pten conditional knockout and Hi-MYC mouse models of prostate cancer. Currently, we are developing an aggressive models for investigation and evaluation of therapeutics in prostate cancer.