Siyuan Wang, Xiao Zhu, Tianyan Zhou, Wei Lu
Peking University/Pharmacometrics Education Center, Beijing, China
Objective: Increasing evidence indicates that the contributions of cancer stem-like cells (CSCs) may act as hallmarks of cancer development (1, 2). To simultaneously de-bulk the tumor size and prevent cancer recurrence, it’s essential to combine conventional antitumor therapies with CSCs-targeting therapies (3). However, despite documented evidence of the antitumor activity of the combination therapy (4), limited information is available on the quantitative relationship between the drug concentrations and responses. Herein, we present an integrated PK/PD model of sunitinib and dopamine, which can quantitatively connect kinetics of both tumor burden and CSC frequency with the PK profiles.
Methods: Female Balb/c nude bearing MCF-7/Adr xenografts were treated with sunitinib, dopamine alone or in combination. PK profiles of sunitinib and its active metabolite SU12662 could be well fitted by a two-compartment model with first-order absorption. The response mediated by dopamine was incorporated via the on/off effect. Tumor volume and the CSC frequency in the tumor tissues were measured at different time points after drug administration. The final PK/PD model was established in according with the pharmacological process. Simulations were further conducted to achieve the optimum regimens.
Results: In the integrated PK/PD model, the tumor was divided into the CSC subpopulation and the differentiated tumor cell (DTC) subpopulation. A logistic growth model was introduced to describe the growth of CSCs, while the DTCs growth was analyzed by a nonlinear model. CSCs may transit to DTCs and vice versa, with different rate constants. Besides, we further found that sunitinib might increase the population of CSCs, as well as convert the proliferating DTCs to non-proliferating cells; while dopamine demonstrated inhibitive effect on the carrying capacity of CSCs, and promoted the differentiation process from CSCs to DTCs. According to the simulation results, low dose of sunitinib (qd) combined with dopamine (q3d) exhibited potent inhibitive effect on the tumor burden as well as the CSC frequency.
Conclusion: Critically, the present model may provide mechanistic insights into the quantitative pharmacology of sunitinib and dopamine, as well as the relationship between tumor burden and CSC frequency. Moreover, our model may offer reference for clinical practice, in which both of the tumor growth and CSC progression should be taken seriously and controlled precisely.
References:
[1] Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730-7.
[2] Donnenberg VS, Donnenberg AD. Multiple drug resistance in cancer revisited: The cancer stem cell hypothesis. J Clin Pharmacol. 2005;45:872-7.
[3] Ablett MP, Singh JK, Clarke RB. Stem cells in breast tumours: Are they ready for the clinic? Eur J Cancer. 2012;48:2104-16.
[4] Wang S, Mou Z, Ma Y, Li J, Li J, Ji X, et al. Dopamine enhances the response of sunitinib in the treatment of drug-resistant breast cancer: Involvement of eradicating cancer stem-like cells. Biochem Pharmacol. 2015;95(2): 98-109.
Reference: PAGE 25 (2016) Abstr 5994 [www.page-meeting.org/?abstract=5994]
Poster: Drug/Disease modeling - Oncology