Onalespib

Hyperthermic perfusion therapy (HPT) is an emerging and effective treatment for intracavitary tumors, involving circulating a heated solution directly into body cavities such as the peritoneal or pleural spaces, targeting tumors more effectively while minimizing systemic toxicity. However, the clinical application of HPT is currently restricted to intracavitary tumors, and its efficacy is hampered by the up-regulation of thermal stress resistance genes, which enhance the thermal tolerance of cancer cells. Herein, we developed a temperature-sensitive methyl cellulose hydrogel with injectability and removability to enable targeted HPT for the triple-negative breast cancer (TNBC). Using bioinformatics screening, we identified 17-allylamino-17-demethoxygeldanamycin as a potent inhibitor and incorporated it alongside biocompatible cuttlefish ink-derived nanoparticles (CINPs), a natural photothermal agent, into the temperature-sensitive hydrogel. Under near-infrared (NIR) irradiation, CINPs mediate photothermal tumor ablation, while 17-allylamino-17-demethoxygeldanamycin reduces tumor cell resistance to hyperthermia. Moreover, the temperature-responsive phase transition of the hydrogel allows for its complete removal post-treatment, extending the scope of HPT beyond intracavitary tumors and minimizing inflammation at the injection site. This material-engineered HPT approach, achieved remarkable outcomes in both orthotopic and metastatic tumor models, inhibiting breast cancer progression and lung metastasis. These findings highlight the potential of materials-based HPT as an effective treatment for TNBC.

Heat shock protein 90 (HSP 90) and its isoforms are a group of homodimeric proteins that regulate several cellular processes, such as the elimination of misfolded proteins, cell development and post-translational modifications of kinase proteins and receptors. Due to its involvement in extracellular matrix (ECM) remodelling, myofibroblast differentiation and apoptosis, HSP 90 has been investigated as a key player in the pathogenesis of lung fibrosis. Idiopathic pulmonary fibrosis (IPF) is the most common and deadly interstitial lung disease, due to the progressive distortion of lung parenchyma related to the overproduction and deposition of altered ECM, driven by transforming growth factor-β (TGF-β) dependent and independent pathways. The inhibition or induction of HSP 90 is associated with a reduced or increased expression of TGF-β receptors, respectively, suggesting a role for HSP 90 as a biomarker and therapeutic target in IPF. Experimental drugs such as geldanamycin and its derivatives 17-AAG (17-N-allylamino-17-demethoxygeldanamicin) and 17-DMAG (17-dimethylaminoethylamino-17-demethoxigeldanamycin), along with AUY-922, 1G6-D7, AT-13387, TAS-116 and myricetin, have been found to reduce lung fibrosis in bothin vivoandin vitromodels, supporting the role of this emerging target. This review aims to illustrate the structure and biological function of HSP 90 in the context of IPF pathobiology, as well as perspective application of this molecule as a biomarker and therapeutic target for IPF.