Research Projects

Breast cancer remains a major cause of mortality, largely due to cancer stem cells (CSCs) that drive tumor initiation, metastasis, and therapy resistance. Traditional treatments often fail to eliminate CSCs, resulting in recurrence. Recent research from the host lab has uncovered a critical role for AMP-activated protein kinase (AMPK) in supporting the survival and drug resistance of breast cancer stem cells (BCSCs). Although AMPK is typically a master regulator of energy homeostasis and a tumor suppressor in normal cells, in the tumor context—especially under stress conditions such as matrix detachment—AMPK supports cancer cell survival. AMPK activation enhances expression of stemness genes and induces epithelial-to-mesenchymal transition (EMT), while its inhibition reduces CSC sphere formation, impairs tumor initiation, and improves chemotherapy response. Notably, Rangarajan et al. (2022) demonstrated that dual targeting of AMPK and chemotherapy significantly reduces the CSC pool and enhances treatment efficacy in breast cancer models. Earlier work also showed that pharmacological AMPK activation can induce EMT and metastasis, whereas its inhibition limits cancer spread. These findings highlight AMPK as a double-edged sword and a promising therapeutic target, particularly in aggressive subtypes like triple-negative breast cancer (TNBC), which exhibit high AMPK activity correlated with poor prognosis. Despite its potential, there is a lack of specific AMPK inhibitors. Existing compounds like Compound C (Dorsomorphin) and Sunitinib selectivity, affecting multiple kinases and leading to off-target effects. However, recent studies have identified new candidate molecules with AMPK-inhibitory properties. For example, BAY-3827 and PF-3758309 have shown efficacy in prostate and pancreatic cancer models, respectively, underscoring the potential of chemical libraries to yield more selective inhibitors. This proposal aims to identify and develop new, selective AMPK inhibitors through a unique collaboration with Dr. Durga Prasad Hari (IISc), whose expertise in synthetic organic chemistry has generated a novel chemical library using bioisosterism strategies, creating compounds that are both potent and selective. His chemical library includes unique structures not found in commercial libraries. Through our ongoing collaboration, we can screen these novel molecules for AMPK inhibition and iteratively optimize promising hits for improved selectivity and efficacy. In summary, this interdisciplinary project addresses a critical need in breast cancer therapy: selectively targeting AMPK to impair CSC survival and prevent relapse. By bridging cancer biology with innovative organic synthesis, we aim to discover next-generation AMPK inhibitors with potential for early intervention in aggressive breast cancer subtypes.

AMPK inhibitors, Cancer stem cell therapy, EMT, AMPK signaling, TNBC, Synthetic organic chemistry