Coletti Roberta, Pugliese Andrea, Lunardi Andrea, Caffo Orazio, Marchetti Luca
Fondazione The Microsoft Research, University of Trento Centre for Computational and Systems Biology (COSBI), 38068 Rovereto, Italy.
Department of Mathematics, University of Trento, 38123 Trento, Italy.
Cancers (Basel). 2021 Dec 28;14(1):135. doi: 10.3390/cancers14010135.
Prostate cancer (PCa) is one of the most frequent cancer in male population. Androgen deprivation therapy is the first-line strategy for the metastatic stage of the disease, but, inevitably, PCa develops resistance to castration (CRPC), becoming incurable. In recent years, clinical trials are testing the efficacy of anti-CTLA4 on CRPC. However, this tumor seems to be resistant to immunotherapies that are very effective in other types of cancers, and, so far, only the dendritic cell vaccine has been approved. In this work, we employ a mathematical model of CRPC to determine the optimal administration protocol of , a particular anti-CTLA4, as single treatment or in combination with the , by considering both the effect on tumor population and the drug toxicity. To this end, we first introduce a dose-depending function of toxicity, estimated from experimental data, then we define two different optimization problems. We show the results obtained by imposing different constraints, and how these change by varying drug efficacy. Our results suggest administration of high-doses for a brief period, which is predicted to be more efficient than solutions with prolonged low-doses. The model also highlights a synergy between and , which leads to a better tumor control with lower doses of . Finally, tumor eradication is also conceivable, but it depends on patient-specific parameters.
前列腺癌（PCa）是男性群体中最常见的癌症之一。雄激素剥夺疗法是该疾病转移阶段的一线治疗策略，但不可避免的是，PCa会对去势产生耐药性（CRPC），从而变得无法治愈。近年来，临床试验正在测试抗CTLA4对CRPC的疗效。然而，这种肿瘤似乎对在其他类型癌症中非常有效的免疫疗法具有抗性，并且到目前为止，只有树突状细胞疫苗已被批准。在这项工作中，我们采用CRPC的数学模型来确定一种特定的抗CTLA4作为单一治疗或与另一种药物联合使用时的最佳给药方案，同时考虑对肿瘤群体的影响和药物毒性。为此，我们首先引入从实验数据估计的毒性剂量依赖函数，然后定义两个不同的优化问题。我们展示了通过施加不同约束获得的结果，以及这些结果如何随药物疗效变化。我们的结果表明，短期内给予高剂量药物预计比长期低剂量给药方案更有效。该模型还突出了两种药物之间的协同作用，这使得在较低剂量的情况下能更好地控制肿瘤。最后，根除肿瘤也是有可能的，但这取决于患者的特定参数。
