Mathematical modelling of breast cancer cells in response to endocrine therapy and Cdk4/6 inhibition

被引:12
作者
He, Wei [1 ]
Demas, Diane M. [2 ]
Conde, Isabel P. [2 ]
Shajahan-Haq, Ayesha N. [2 ]
Baumann, William T. [3 ]
机构
[1] Virginia Tech, VT BIOTRANS, Program Genet Bioinformat & Computat Biol, Blacksburg, VA USA
[2] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20007 USA
[3] Virginia Tech, Dept Elect & Comp Engn, Blacksburg, VA 24061 USA
关键词
mathematical modelling; breast cancer; therapy optimization; endocrine therapy; palbociclib; DEPENDENT KINASE 4/6; ESTROGEN-RECEPTOR; GROWTH-FACTOR; RESISTANCE; MECHANISMS; PALBOCICLIB; PACLITAXEL; LETROZOLE; ESTRADIOL; STRATEGY;
D O I
10.1098/rsif.2020.0339
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Oestrogen receptor (ER)-positive breast cancer is responsive to a number of targeted therapies used clinically. Unfortunately, the continuous application of any targeted therapy often results in resistance to the therapy. Our ultimate goal is to use mathematical modelling to optimize alternating therapies that not only decrease proliferation but also stave off resistance. Toward this end, we measured levels of key proteins and proliferation over a 7-day time course in ER+ MCF-7 breast cancer cells. Treatments included endocrine therapy, either oestrogen deprivation, which mimics the effects of an aromatase inhibitor, or fulvestrant, an ER degrader. These data were used to calibrate a mathematical model based on key interactions between ER signalling and the cell cycle. We show that the calibrated model is capable of predicting the combination treatment of fulvestrant and oestrogen deprivation. Further, we show that we can add a new drug, palbociclib, to the model by measuring only two key proteins, cMyc and hyperphosphorylated RB1, and adjusting only parameters associated with the drug. The model is then able to predict the combination treatment of oestrogen deprivation and palbociclib. We illustrate the model's potential to explore protocols that limit proliferation and hold off resistance by not depending on any one therapy.
引用
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页数:12
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