A Randomized Controlled, Open Labeled, Two Arm, Study of Addition of Everolimus to Standard of Care in Carcinoma Gallbladder

Gallbladder cancer is the most common malignant tumour of thebiliary tract [1]. It is also the most aggressive cancer of the biliary tractwith the shortest median survival from the time of diagnosis [2]. While theincidence rate of GBC varies widely, it has a unique distribution pattern insome regions, where Chile, India, some other Asian countries, Eastern European,and Latin American countries have reported more cases than the rest of theworld every year [3-5]. The other factors, which associated with chronicinflammation and disease pathogenesis, such as hepatobiliary stones, liverflukes, and Salmonella frequently observed in these areas, also constitute theother high-risk factors of bile tract cancer (BTC) including GBC.[6]

 Currently, radical resection is the most effective strategy topotentially cure GBC. The non-surgical therapies engaged in patients wereprimarily composed of chemotherapy and radiotherapy. additional therapeuticstrategies including next-generation sequencing (NGS), whole-exome sequencing(WES), RNA-sequencing (RNAseq), and single-cell isolation, as well ascharacterization that have fundamentally opened a novel view enabled toglobally identify genetic and epigenetic features and key molecules aspotential therapeutic target.

 Advanced or unrespectable locally advanced disease has a poorprognosis with limited systemic treatment options [7]. Combinationplatinum-gemcitabine chemotherapy is an active first-line treatment regimen[8].in particular, specific target treatment, immune therapy, vaccine therapy, biotherapyand nanoparticles have been intensively developed in preclinical and clinicaltrials.

 One of target treatment is mTOR inhibitors, as The mTOR signalingpathway has critical roles in mammalian metabolism and physiology. Thede-regulated activity of mTOR is involved in many pathophysiologicalconditions, such as aging, Alzheimer’s disease, diabetes, obesity, and cancer[9].

Everolimusis a derivative of rapamycin that selectively inhibits mTORC1 (mammalian targetof rapamycin complex 1), a key protein kinase complex which regulates cellgrowth, proliferation and survival. Activation of mTORC1 is mediated by thephosphatidylinositol 3-kinase (PI3K) pathway through activation of AKT/ PKB andsubsequent inhibition of the tuberous sclerosis complex [10].