Research Projects

Due to the rare phenotype, triple negative breast cancer (TNBC) have limited treatment options like neoadjuvant drugs i.e. epirubicin, paclitaxel etc. With recent rise of recurrent TNBC cases which ultimately develop from drug resistance, there is an urgent need to find a therapeutic solution. It is well known that over-expression of genes such as Pgp/ABCB1, MRP1/ABCC1 (that eject anticancer drugs) are some of the common pathways by which cancer cells acquire drug resistance. In my recent work, we identified a novel gene ‘LXRα’ (upstream of ABCB1 pathway) responsible for developing drug resistance in two independent cohorts of TNBC patients (n=47). Silencing of LXRα shows to downregulated ABCB1 and also re-sensitize cells to low dose of chemotherapeutic drug. On the contrary, upregulation of LXRα (by transfection) increases the drug resistance in TNBC. The finding of LXRα opens up new possibilities to investigate and design novel therapeutics for tackling drug resistance in TNBC. Recently AstraZeneca along with the British research council has started funding on gene therapy showing the importance of this approach in medicine. Currently siRNA based therapeutics are undergoing clinical trials but the major challenge is its effective delivery into the target cells. Although lentiviral or Crispr system mediated delivery of siRNA have been trailed but they failed to address the toxicity issues and safety concerns. In this regard, discovery of advanced lipidic ‘cubosome’ nanoparticles has led to an advancement in many biomedical applications. Cubosomes are fusogenic, with superior encapsulation efficacy, high stability, non-toxic, non-immunogenic, ease of surface conjugation and have outperformed the liposomes in case of siRNA or drug delivery. In order to specifically deliver the therapeutic loaded cubosomes, recombinant ‘Affimer’ proteins are an excellent alternative to monoclonal antibodies as targeting ligand. These affimers exhibit comparable affinity to antibodies for specific cells receptors such as EGFR, are cost-effective for bulk production and non-immunogenic. TNBC has been found to over-express EGFR receptors which plays a major role in tumor progression as well as metastasis. EGFR are also a biomarker for cancer stem cells. Thus the project aims is to develop therapeutic against TNBC using co-delivery system comprised of a siRNA (against LXRα gene) in combination with chemotherapeutic drugs (epirubicin, paclitaxel etc) loaded in cubosome tagged with EGFR targeted Affimer proteins to eliminate drug resistance metastatic TNBC. The siRNA release would silence the drug resistant gene making the TNBC drug sensitive and following drug release would result in death of the tumor cells. EGFR targeting will also be effective for eliminating the circulating metastatic TNBCs. This innovative approach holds promise in overcoming chemoresistance in TNBC for a broader patient population.