Molecularly targeted nanomedicines against aberrant signalling pathways in cancer

Abstract : Cancer is an extremely complex disease involving intricate signalling pathways. I am interested in exploring the signalling pathways that are preferentially activated in cancer and developing nanomedicines against them. My model of study was drug resistant chronic myeloid leukemia (CML), a type of blood cancer. The proliferating myeloid progenitors in CML carry BCR-ABL fusion gene, formed due to a translocation event between chromosomes 9 and 22. The BCR-ABL fusion protein is a constitutively active tyrosine kinase responsible for leukemiogenesis. For the past few decades, drug resistance is a critical issue in CML. Though BCR-ABL kinase inhibitors Imatinib and Dasatinib have shown an initial response in early stage patients, most of the advanced stage patients have shown drug resistance. The primary reason for resistance was found to be point mutations in the kinase domain. Currently researches are going on to discover inhibitors against mutated BCR-ABL. My aim of the study was to identify the role of alternate signalling pathways in drug resistant CML and develop targeted nanomedicines against them. Molecular characterization of drug resistant CML patient samples showed that, apart from mutations or amplifications of the primary oncogene BCR-ABL, STAT5 protein was significantly over-expressed in drug resistant patients compared to drug sensitive patients. Interestingly, the cells also exhibited deregulated pattern of iron metabolism. I developed protein based nanomedicines against these aberrant signalling in drug resistant CML which caused significant toxicity in drug resistant cells. My current area of interest is to identify potential drug targets in hepatocellular carcinoma (HCC) and develop nanomedicines against them.