Abstract A006: Natural interception of drug resistance in breast cancer: Nanoencapsulation of Terfezia extracts enhances doxorubicin sensitivity in early-onset models

Breast cancer in younger patients is rising at an alarming rate, emphasizing the urgent need for early interception strategies to delay relapse and improve survival outcomes. Resistance to anthracyclines such as doxorubicin remains a major challenge, as resistant cells rapidly exploit alternative pathways to evade therapy. In this context, natural compounds with pleiotropic activity offer a promising avenue to address these limitations. Extracts from desert truffles were evaluated both in their free form and after encapsulation in hydroxypropyl-β-cyclodextrin (HPβCD) nano-complexes, designed to enhance solubility and bioavailability. In vitro studies on drug-sensitive and doxorubicin-resistant breast cancer cells confirmed that both free and nanoformulated extracts exerted significant cytotoxicity, with nanoformulation further amplifying potency and stability. Co-treatment with doxorubicin restored chemosensitivity in resistant cells through opportunistic pathway modulation, resulting in synergistic anticancer activity. In vivo, administration of both free and encapsulated extracts reduced tumor progression, rebalanced endogenous antioxidant defenses, and, importantly, improved tolerability relative to doxorubicin alone. Alongside their anticancer potential, the formulations demonstrated a cardioprotective effect, mitigating one of the most limiting toxicities of anthracycline therapy. Collectively, these findings identify desert truffle formulations both free and nanoencapsulated as promising candidates for intercepting drug resistance in breast cancer. By enhancing the sensitivity of resistant tumors to conventional therapy, reducing systemic toxicity, and conferring cardioprotection, they highlight a novel natural strategy that could be integrated into precision oncology frameworks to address the unmet needs of early-diagnosed patients at high risk of relapse. Citation Format: Roua A. Nouh, Anwar A. Abdelnasser, Mohamed S. Sedeek, Moahmed A. Farag. Natural interception of drug resistance in breast cancer: Nanoencapsulation of Terfezia extracts enhances doxorubicin sensitivity in early-onset models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr A006.