Modeling and Predicting Therapeutic Resistance of Cancer

描述（由申请人提供）：即使对常规化疗或靶向治疗具有初始治疗敏感性，肿瘤也可能产生耐药性并复发。对癌症的治疗抗性进行建模和预测的方法在开发更有效的癌症治疗方法中非常有用。我们的长期目标是开发策略来建模，预测和靶向癌症的治疗耐药性。我们提出的方法是利用条件转基因小鼠模型结合计算建模。我们假设，癌基因失活的治疗耐药性可以建模，从而预测作为细胞自主和免疫介导的选择性压力驱动的肿瘤细胞的克隆进化的结果。我们在目标1中的方法是建立一个数学模型，该模型结合了免疫系统和进化动力学的作用，以预测癌基因失活后出现的治疗耐药性。然后，在目标2中，我们将通过实验探讨免疫系统和进化动力学在治疗耐药性出现中的作用。我们将直接研究免疫效应/细胞因子和克隆进化在我们的条件转基因小鼠模型与活体显微镜和生物发光成像。最后，在目标3中，我们将在体内验证我们的数学模型对新情况下出现治疗耐药性的预测。

DESCRIPTION (provided by applicant): Even when there is initial therapeutic sensitivity to a conventional chemotherapy or targeted therapy, tumors can become resistant and recur. Methods that model and predict therapeutic resistance of cancer can be extremely useful in the development of more effective treatments for cancer. Our long-term goal is to develop strategies to model, predict, and target therapeutic resistance of cancer. Our proposed approach is to utilize conditional transgenic mouse models combined with computational modeling. We hypothesize that therapeutic resistance to oncogene inactivation can be modeled and thus predicted as a consequence of clonal evolution of tumor cells driven by both cell autonomous and immune-mediated selective pressures. Our approach in Aim 1 is to build a mathematical model that incorporates the roles of the immune system and of evolutionary dynamics to predict the emergence of therapeutic resistance upon oncogene inactivation. Then, in Aim 2 we will experimentally interrogate the roles of the immune system and of evolutionary dynamics in the emergence of therapeutic resistance. We will directly examine immune effectors/cytokines and clonal evolution in our conditional transgenic mouse model with intravital microscopy and bioluminescence imaging. Finally, in Aim 3 we will validate in vivo our mathematical model's predictions of the emergence of therapeutic resistance under novel circumstances.