Small molecule inhibitors of JAK signalling in preventing cancer progression

Apart from their role in cellular proliferation, differentiation and function, JAK-STAT signalling is a prime factor in tumorigenesis. Gain-of-function mutations in JAKs and STAT molecules have been reported in both haematological and non-haematological tumours. JAK-STAT involvement in GBM pathogenesis has also been reported. Increased JAK-STAT signalling has been reported to maintain the stemness of the GBM cells and thereby, it facilitates tumour relapse following surgery and chemotherapy. Therefore, inhibition of JAK-STAT signalling in GBM remains a possible therapeutic option. As the epigenetic machinery in the tumour cells are unstable and they are prone to frequent modifications, genetic intervention to downregulate JAK-STAT activity in GBM cells is not a very attractive option. Small molecule inhibitors of JAKs or STATs are a better option to inhibit their activity in GBM and holds promise as reported in multiple studies. Using two specific JAK3 inhibitors WHI-P131 (4-(4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline) and PF-956980 (((3R,4R)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)(pyrrolidin1-yl)methanone) we have recently shown that both these inhibitors are very effective in blocking GBM cell proliferation, neurosphere formation, and in inducing differentiation to neurons and other neuronal lineage cells. Interestingly, these effects were executed by downregulating the stem cell characteristics of the GBM cells. The proposed project will extend this study and will look in detail the underlying mechanisms by which JAK inhibitors could control GBM pathogenesis.

(i) Gene expression changes induced by JAK inhibition in GBM cells by RNA sequencing.
(ii) Protein expression changes following JAK inhibition by proteomic analysis.
(iii) Changes in metabolism following JAK inhibition, resulting in growth inhibition but enhanced differentiation of GBM cells, by Seahorse analysis.