Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities.

Autor: Zhou YT; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China., Chu JH; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China., Zhao SH; Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China., Li GL; Gusu School, Nanjing Medical University, Suzhou, 215000, China.; School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China., Fu ZY; Department of Breast Disease Research Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China., Zhang SJ; School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China., Gao XH; School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.; Jiangsu Hengrui Medicine Co. Ltd, Shanghai, 200245, China., Ma W; School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China., Shen K; Jiangsu Hengrui Medicine Co. Ltd, Shanghai, 200245, China., Gao Y; QSPMed Technologies, Nanjing, 210000, China., Li W; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China., Yin YM; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. ymyin@njmu.edu.cn., Zhao C; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. chenzhao22@njmu.edu.cn.; School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China. chenzhao22@njmu.edu.cn.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Jun; Vol. 45 (6), pp. 1287-1304. Date of Electronic Publication: 2024 Feb 15.
DOI: 10.1038/s41401-024-01232-9
Abstrakt: HER2-positive (HER2 + ) metastatic breast cancer (mBC) is highly aggressive and a major threat to human health. Despite the significant improvement in patients' prognosis given the drug development efforts during the past several decades, many clinical questions still remain to be addressed such as efficacy when combining different therapeutic modalities, best treatment sequences, interindividual variability as well as resistance and potential coping strategies. To better answer these questions, we developed a mechanistic quantitative systems pharmacology model of the pathophysiology of HER2 + mBC that was extensively calibrated and validated against multiscale data to quantitatively predict and characterize the signal transduction and preclinical tumor growth kinetics under different therapeutic interventions. Focusing on the second-line treatment for HER2 + mBC, e.g., antibody-drug conjugates (ADC), small molecule inhibitors/TKI and chemotherapy, the model accurately predicted the efficacy of various drug combinations and dosing regimens at the in vitro and in vivo levels. Sensitivity analyses and subsequent heterogeneous phenotype simulations revealed important insights into the design of new drug combinations to effectively overcome various resistance scenarios in HER2 + mBC treatments. In addition, the model predicted a better efficacy of the new TKI plus ADC combination which can potentially reduce drug dosage and toxicity, while it also shed light on the optimal treatment ordering of ADC versus TKI plus capecitabine regimens, and these findings were validated by new in vivo experiments. Our model is the first that mechanistically integrates multiple key drug modalities in HER2 + mBC research and it can serve as a high-throughput computational platform to guide future model-informed drug development and clinical translation.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: