A SPATIOTEMPORAL MODEL TO SIMULATE CHEMOTHERAPY REGIMENS FOR HETEROGENEOUS BLADDER CANCER METASTASES TO THE LUNG.
A SPATIOTEMPORAL MODEL TO SIMULATE CHEMOTHERAPY REGIMENS FOR HETEROGENEOUS BLADDER CANCER METASTASES TO THE LUNG.
复制标题
模拟异质性膀胱癌肺部转移化疗方案的时空模型。
DOI：
10.1142/9789813207813_0056
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发表时间：
2017
影响因子：
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通讯作者：
Costello,JamesC
中科院分区：
文献类型：
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作者：
KanigelWinner,KimberlyR;Costello,JamesC
肿瘤由异质细胞群组成。体细胞遗传畸变是异质性的一种形式，它允许克隆细胞适应化疗应激，从而为耐药性的产生提供了途径。肿瘤的计算机模拟为快速、定量实验提供了一个平台，可以廉价地研究组成异质性如何导致耐药性。因此，我们已经建立了一个时空模型的肺转移起源于原发性膀胱肿瘤，纳入一线化疗的体内药物浓度，从膀胱癌细胞系的耐药数据，肺转移的血管密度，并在耐药性的细胞化疗生存的收益。在转移性膀胱癌中，一线药物方案包括6个周期的吉西他滨加顺铂（GC），在每个21天周期的第1天同时给药，吉西他滨在第8天给药。吉西他滨和顺铂之间的相互作用已被证明在体外具有协同作用，并在患者中产生更好的结局。我们的模型显示，在用该方案进行模拟治疗期间，GC协同作用确实开始杀死对顺铂更耐药的细胞，但发生耐药细胞的再增殖。方案后群体是原始的、接种的耐药克隆和/或已经获得对顺铂、吉西他滨或两种药物的耐药性的新克隆的混合物。肿瘤耐药增加的出现与GC方案治疗的转移性膀胱移行细胞癌患者的5年生存率6.8%定性一致。该模型可进一步用于探索临床相关变量的参数空间，包括优化细胞死亡的药物递送时间，以及患者特定数据，如血管密度，阻力增加率，疾病进展和分子特征，并且可以扩展用于毒性数据。该模型是特定于膀胱癌的，以前在这种情况下没有建模，但可以适用于代表其他癌症。
Tumors are composed of heterogeneous populations of cells. Somatic genetic aberrations are one form of heterogeneity that allows clonal cells to adapt to chemotherapeutic stress, thus providing a path for resistance to arise. In silico modeling of tumors provides a platform for rapid, quantitative experiments to inexpensively study how compositional heterogeneity contributes to drug resistance. Accordingly, we have built a spatiotemporal model of a lung metastasis originating from a primary bladder tumor, incorporating in vivo drug concentrations of first-line chemotherapy, resistance data from bladder cancer cell lines, vascular density of lung metastases, and gains in resistance in cells that survive chemotherapy. In metastatic bladder cancer, a first-line drug regimen includes six cycles of gemcitabine plus cisplatin (GC) delivered simultaneously on day 1, and gemcitabine on day 8 in each 21-day cycle. The interaction between gemcitabine and cisplatin has been shown to be synergistic in vitro, and results in better outcomes in patients. Our model shows that during simulated treatment with this regimen, GC synergy does begin to kill cells that are more resistant to cisplatin, but repopulation by resistant cells occurs. Post-regimen populations are mixtures of the original, seeded resistant clones, and/or new clones that have gained resistance to cisplatin, gemcitabine, or both drugs. The emergence of a tumor with increased resistance is qualitatively consistent with the five-year survival of 6.8% for patients with metastatic transitional cell carcinoma of the urinary bladder treated with a GC regimen. The model can be further used to explore the parameter space for clinically relevant variables, including the timing of drug delivery to optimize cell death, and patient-specific data such as vascular density, rates of resistance gain, disease progression, and molecular profiles, and can be expanded for data on toxicity. The model is specific to bladder cancer, which has not previously been modeled in this context, but can be adapted to represent other cancers.