Research Projects

Breast cancer is a highly heterogenous disease with a wide range of morphological traits, and variable response to various treatment options. Triple-negative breast cancer (TNBC) is one of aggressive breast tumor subtypes. TNBC patients does not respond to any hormonal or anti-HER2 therapy and currently lacks specific therapeutic options. TNBC patients have a higher risk of early metastasis than other breast cancer subtypes, and patients with residual disease after chemotherapy have a worse overall survival rate than non-TNBC patient. Cancer stem cells (CSCs) have been hypothesised as having a key role in tumor biology. CSCs undergo self-renewal, are pluripotent, and are involved in recurrence, metastasis, heterogeneity, and drug and radiation resistance of tumors. CSCs are regulated by intracellular signalling pathways, including Wnt, NF-κB, Notch, Hedgehog, JAK-STAT, PI3K/AKT/mTOR, TGF/SMAD, PPAR, and extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, and exosomes. Among these pathways, JAK-STAT pathway has a complex role in maintaining and promoting CSC characteristics. Directly, STAT3 interacts with transmembrane glycoproteins expressed by normal stem cells and is a biomarker for CSC identification and isolation. Moreover, feedback activation of STAT3 is involved in anticancer drug resistance. Thus, to potentially destroy CSCs, drugs, vaccines, antibodies and CAR-T cells that target the STAT3 pathway are effective. Given that STAT3 is a noteworthy prospective therapeutic target and has a significant oncogenic function in TNBC, numerous STAT3 antagonists have been discovered. These inhibitors hold great potential in treating the aggressive disease of TNBC, which otherwise has minimal therapeutic options. One category among these inhibitors include retinoids. Retinoids exert control over a range of processes central to cancer formation and maintenance, such as proliferation, differentiation and apoptosis among others. For several solid and haematological cancers, retinoids have been contemplated and implemented as prophylactics and as therapeutics. A fourth-generation retinoid, trifarotene, was designed to limit off-target effects by targeting a specific retinoic acid signalling pathway with higher selectivity. In light of this strategy, our lab has revealed the significance of this drug by repurposing this for breast cancer treatment using combinational approach which further signifies its therapeutic potential and promising role in eradicating the resistance in breast cancer. Herein, we hypothesize that using combination therapy with drugs (such as trifarotene) targeting bulk tumor cells and CSCs will effectively reduce tumor burden, therapeutic resistance and disease relapse. Moreover, use of combination therapy may act in a synergistic manner thus reducing drug dose, and enhancing tumor inhibition while reducing toxic effects.