Abcb1a/1b-mediated transport of daraxonrasib across the BBB was validated by oral co-administration of the ABCB1/ABCG2 inhibitor elacridar, resulting in 20-fold increased brain penetration in wild-type mice (P < 0.01). ABCB1 function could limit brain penetration and possibly efficacy of daraxonrasib against brain metastases. Collectively, these preclinical findings may help in optimizing the application of daraxonrasib in clinical settings.

OB-001, a KinetiSol® amorphous solid dispersion formulation of elacridar, was developed to overcome poor bioavailability of crystalline elacridar and evaluated as a strategy to enhance osimertinib brain delivery. OB-001 selectively boosts osimertinib brain exposure while sparing systemic PK. These preclinical data support further evaluation of OB-001 as a strategy to enhance CNS efficacy of osimertinib in EGFR-mutant NSCLC.

Fangchinoline, a bisbenzylisoquinoline alkaloid derived from Stephaniae tetrandrine, is known for its antioxidant and anticancer potential...Fangchinoline exhibits promising anticancer activity by targeting ERBB2 and modulating critical oncogenic and apoptotic pathways. Its ability to upregulate p53 and ROS while suppressing PI3K/Akt/mTOR signalling suggests its strong potential as a HER-2-targeted therapeutic agent.

Inhibition of autophagic flux using Bafilomycin A1 or Tetrandrine rescued cells from apoptosis, confirming that excessive autophagy is the direct cause of cell death...The combination of APO-Cyt C and SA triggers apoptosis by overwhelming the cell with excessive autophagic flux, driven by synergistic inhibition of the mTOR-TFEB axis. These findings highlight the therapeutic potential of modulating autophagy and suggest that combining mTOR inhibitors with lysosome-targeting agents like SA could be an effective anti-cancer strategy.

Celastrol reduced P-gp expression and increased intracellular drug accumulation, comparable to verapamil. Celastrol synergizes with 5-FU to overcome chemoresistance in osteosarcoma by enhancing p53-mediated and -independent apoptosis and inhibiting P-gp-mediated drug efflux. These findings suggest a promising low-toxicity therapeutic strategy, warranting further in vivo and clinical investigations.

P=N/A, N=100, Not yet recruiting, Assiut University

This study describes, for the first time in literature, a suitable approach to develop co-encapsulated magnetic nanoparticles based on fluorescent biotinylated N-palmitoyl chitosan, hydrophobic magnetite, Docetaxel and Verapamil. No significant toxicity was observed for magnetic nanoparticles in the rats. Overall, these findings suggest that the developed magnetic nanoplatforms represents a promising candidate for breast cancer applications and merits further in vivo investigation needed to elucidate the action mechanism of encapsulated therapeutics and their pharmacologic activity.

Among the tested compounds, Tetrandrine, Dauricine, and Olmutinib exhibited robust binding affinities across both wild-type and mutant EGFR configurations, highlighting their potential as effective inhibitors. The integrated approach of combining molecular docking using CB-dock2, ADMET profiling, and Lipinski's rule of five provides a robust framework for preliminary drug candidate screening, potentially accelerating the development of more precise and effective EGFR-targeted therapies. The findings contribute to the growing body of research exploring alternative and more nuanced strategies for inhibiting EGFR-driven oncogenic mechanisms, highlighting the importance of computational methods in identifying novel molecular targets with improved specificity and reduced side effects.

P1/2, N=24, Recruiting, Amsterdam UMC | Not yet recruiting --> Recruiting

P=N/A, N=40, Not yet recruiting, Western Sydney Local Health District

Oxaliplatin-triggered chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of cancer treatment that limits the efficacy of chemotherapy and negatively impacts patients' quality of life dramatically. Notably, inhibition of TXNIP with verapamil reduced oxidative stress levels. Our results demonstrated the use of DRG explants as an efficient model to study the mechanisms of CIPN and screen for potential treatments.

In some cell lines, the fiber modification F5RGD10(2C) or verapamil treatment further improves actual spread efficiency. Nelfinavir inhibits spread and plaque formation of oncolytic adenoviruses with the 19KSS-iLQ125Ter modifications, irrespective of adenovirus death protein (ADP) expression...We identified an insertion site downstream of the L3-23K region that supports relatively high hPH20 activity while preserving the enhanced oncolytic potency of the virus. Combining 19KSS-iLQ125Ter with hPH20 expression may potentially improve therapeutic benefit in glioma.