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Moein, Anita

University of British Columbia

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, and a master regulator for many cancer types. Massive efforts dedicated to the development of drugs targeting PI3K signaling, however, the number of approved inhibitors remains limited. Thesis objectives were to acquire a better understanding of the PI3K/AKT/mTOR pathway dynamic response by developing mechanistic preclinical and clinical pharmacokinetic (PK)-pharmacodynamic (PD) models. Conducted a retrospective assessment of the translational PK-PD modeling performance with apitolisib, a dual PI3K/mTOR inhibitor. Integrated PK-PD-Efficacy models developed for xenografts bearing human renal cell adenocarcinoma (RCC) and patients with solid tumors show a steep sigmoid curve linking pAkt inhibition to tumor growth inhibition and quantified that a minimum of 35% to 45% pAkt modulation is needed for tumor shrinkage in patients based on platelet-rich plasma surrogate matrix and in xenografts based on tumor tissue matrix. Based on this relationship, constant pAkt inhibition of 61% and 65% would be necessary to achieve tumor stasis in xenografts and patients, respectably. Developed a longitudinal exposure-tumor growth inhibition (TGI) model to characterize and compare everolimus (mTORC1 inhibitor) vs apitolisib’s (dual PI3K/mTORC1/2 inhibitor) ability to inhibit tumor growth, and quantitated each drug’s efficacy decay caused by emergence of tumor resistance over time in patients with metastatic-RCC. The estimated on-treatment tumor growth rate constant was 1.7-fold higher for apitolisib compared to everolimus. Half-life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib suggesting a faster rate of tumor re-growth for apitolisib patients likely due to the emergence of resistance. Developed longitudinal TGI models to characterize tumor response in women with ER+/HER2- advanced/metastatic breast cancer undergoing treatment with fulvestrant alone or in combination with the PI3K inhibitor, taselisib. Assessed impact of clinically relevant covariates on TGI metrics and identified patient subsets most likely to benefit from these treatments. Based on results, additive/potentially synergistic anti-tumor effects were observed in patients treated with the taselisib-fulvestrant combination. In conclusion, these methods and results underscore the significance of model informed drug development for targeted cancer therapy throughout the drug development lifecycle.

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2024-07-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88734

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/