Research Projects

Rational of the research: The incidence of TC in India is growing rapidly and India is on the 4th position for new cases of thyroid cancer in the world (Figure 1, OTD). TC is within top ten leading cancer among Indian female population. Anaplastic thyroid cancer (ATC) is one of the most aggressive, lethal cancers with median survival less than 6 months (Ref 1-4). Hence, it is utmost important to find a better therapeutic options and newer compounds for the treatment of ATC and other undifferentiated TC. In the last decade, Estrogen Related Receptor-γ (ERRγ) has been emerging as a potential biomarker and therapeutic target in various cancers including thyroid, breast, prostrate, liver, endometrial and gastric cancer (ref. 9-18). Ji-Hyun Kim et. al, (Ref. 13) demonstrated that treatment of ERRγ inverse agonist inhibit the growth of hepatocellular carcinoma cells. Recently, Myeong HK et. al. (Ref. 14,) reported ERRγ as tumor suppressor gene and they shown the benefit of using ERRγ agonist (DY131) in gastric cancer. Audet-Walsh et. al. (Ref. 15) reported ERRγ expression as a biomarker in prostate cancer progression. Recently, Emmalie et al. (Ref. 16,) have shown that the treatment of selective ERRα/γ Inverse Agonist, SLU-PP-1072, induces apoptosis in prostate cancer cells. For the last 10 years, I have reported that treatment of ERRγ inverse agonist (GSK5182) to ATC/ PTC cells upregulate NIS function making the cells susceptible to radio iodine therapy (Ref. 17, 19) J Nuc Med. 2015 and Cells. 2023). We further discovered a potent ERRγ inverse agonist DN200434 which increase NIS expression in in vivo mouse model and inhibition tumor during radiation therapy (Ref. 18, Clin Can Res. 2019). Tyrosine kinase inhibitors like Sorafenib and Lenvatinib have been tried for the treatment of ATC but the outcomes are not promising (Ref. 5,6,8,20). MK2206 is a highly selective inhibitor of pan-Akt, and has been employed in various preclinical and clinical trials for thyroid cancer (Ref. 21-24) Hypothesis and Preliminary studies From our previous data, DN200434 strongly induced cell cycle arrest as well as apoptosis in ATC/PTC cells. MK2206 is also known to strongly induced apoptosis to all solid tumours including thyroid cancer cells. Both these drugs, DN200434 and MK2206 seems to kill the cancer cells by different mechanism. The treatment of DN200434 could inhibit tumor growth in dose dependent manner in in vivo (figure 10, OTD) but single therapy is not enough to completely control the tumor growth. When, we recently performed combination treatment of DN200434 and MK2206 at much lower dose, we observed synergetic killing of ATC and PTC cells (Figure 11, OTD). However, we need to investigate the mechanism of cell death. Herein, we proposed to investigate the combination therapy of DN200434 and MK2206 in ATC and PTC in vitro and in vivo. This combination will definitely provide a promising therapeutic option for the treatment of ATC and PTC.