Among the leading causes of cancer-related morbidity and mortality worldwide, breast
cancer presents fundamental challenges, such as tumor heterogeneity and therapeutic resistance. The
tumor microenvironment (TME), comprising stromal components, signaling molecules, immune
cells, and the extracellular matrix, has demonstrated a pivotal role in tumor progression, invasion, and
therapeutic response. In this review, we comprehensively summarize the state-of-the-art and novel
therapeutic strategies developed to reprogram the TME in breast cancer. From clinically established
treatments, such as endocrine therapy, antibody-drug conjugates, and HER2-targeted therapy, to
emerging agents, such as siRNA-mediated gene silencing, nanomedicine, and immunotherapy, each
class of therapeutic strategy, along with the corresponding clinical and preclinical outcomes, is detailed
by category. The evidence for and impact of TME heterogeneity and differences in molecular
subtypes on therapeutic efficiency are highlighted, and biomarker-guided patient stratification is further
emphasized to support precision therapy. Mechanistic challenges, such as immunosuppression,
ECM remodeling, and hypoxia-associated resistance, were analyzed, and mechanistic conflicts or
synergistic interactions between strategies were identified. Tumor microbiome modification and AIdriven
discovery of novel biomarkers are presented as emerging perspectives in TME-targeting therapy.
Despite significant advances, translation barriers, such as the lack of predictive biomarkers and
the divergence in therapeutic outcomes between patients and animal models, are critically reviewed
and discussed. The integration of TME-targeted and individualized therapeutic strategies may offer
promising prospects toward achieving durable clinical outcomes in breast cancer treatment.
P. Shankar, Gowthamarajan Kuppusamy, Apsara Unni et al.· Current Cancer Therapy Revie...· 0 citations
INTRODUCTION
The objective was to design, synthesize, and evaluate novel naphthoxy and phenoxy amide derivatives as potential poly(ADP-ribose) polymerase-1 (PARP1) inhibitors, aiming to identify compounds with improved binding affinity, favorable pharmacokinetic properties, and enhanced anticancer activity compared with existing PARP1 inhibitors.
METHODS
A series of naphthoxy and phenoxy amide derivatives (A1-A9 and B1-B9) were evaluated using combined computational and experimental approaches. Molecular docking against PARP1 (PDB ID: 4ZZZ) was performed using Glide to assess binding affinity. ADMET and drug-likeness properties were predicted via SWISS-ADME, and binding free energies were refined using Prime MM-GB/SA. The lead compound B2 underwent a 50-ns molecular dynamics simulation using Desmond. In vitro cytotoxicity was assessed against MCF-7 human breast cancer cell lines.
RESULTS
Compounds B2 and B3 exhibited strong docking scores comparable to the reference PARP1 inhibitor and demonstrated favourable ADMET profiles. MM-GB/SA analysis supported their high binding affinity toward PARP1. Molecular dynamics simulations revealed that compound B2 formed a stable complex within the PARP1 active site. In vitro assays showed enhanced cytotoxic activity of B2 against MCF-7 cells.
DISCUSSION
The findings highlight the effectiveness of combining computational and biological approaches to identify promising PARP1 inhibitors, with B2 showing strong binding, stability, and cytotoxicity, despite lacking in vivo validation.
CONCLUSION
Overall, compound B2 emerged as a promising PARP1 inhibitor with strong binding affinity, structural stability, and significant in vitro anticancer activity, warranting further optimization and preclinical investigation.
Hardha Balachandran, Subhajit Majumder, Gowramma Byran et al.· Current Medicinal Chemistry· 0 citations