Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer.
Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer.
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DOI：
10.1126/scitranslmed.aad7842
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发表时间：
2016-02-24
影响因子：
17.1
通讯作者：
Gatenby RA
中科院分区：
文献类型：
--
作者：
Enriquez-Navas PM;Kam Y;Das T;Hassan S;Silva A;Foroutan P;Ruiz E;Martinez G;Minton S;Gillies RJ;Gatenby RA
传统的癌症治疗策略假设通过最大限度地杀死肿瘤细胞来实现最大的患者益处。然而，通过消除对治疗敏感的群体，这种策略加速了耐药克隆的出现，这些克隆在没有竞争对手的情况下增殖，这种进化现象被称为“竞争性释放”。我们提出了一种进化导向的治疗策略，旨在维持一个稳定的群体的化学敏感细胞，限制耐药克隆的增殖，利用健身成本的耐药表型。我们用紫杉醇治疗了MDA-MB-231/luc三阴性和MCF 7雌激素受体阳性（ER+）乳腺癌，这些乳腺癌在小鼠乳腺脂肪垫中原位生长，使用与磁共振成像监测的肿瘤反应相关的算法。我们发现，初始控制需要更强化的治疗，定期应用药物，使肿瘤生长曲线的指数曲线转向平台。该阶段的剂量跳跃算法不如可变剂量算法成功。然而，一旦实现了初始肿瘤控制，就用逐渐减小的药物剂量来维持。在60%至80%的动物中，肿瘤大小的持续下降允许长达几周的时间间隔，其中不需要治疗。通过适应性治疗控制的肿瘤的磁共振图像和组织学分析显示血管密度增加和坏死减少，表明由肿瘤体积的强制稳定导致的血管正常化可能有助于用较低的药物剂量进行肿瘤控制。我们的研究表明，使用现有化疗药物和常规临床成像的基于进化的治疗策略可以延长不同临床前乳腺癌模型的无进展生存期。
Conventional cancer treatment strategies assume that maximum patient benefit is achieved through maximum killing of tumor cells. However, by eliminating the therapy-sensitive population, this strategy accelerates emergence of resistant clones that proliferate unopposed by competitors—an evolutionary phenomenon termed “competitive release.” We present an evolution-guided treatment strategy designed to maintain a stable population of chemosensitive cells that limit proliferation of resistant clones by exploiting the fitness cost of the resistant phenotype. We treated MDA-MB-231/luc triple-negative and MCF7 estrogen receptor–positive (ER+) breast cancers growing orthotopically in a mouse mammary fat pad with paclitaxel, using algorithms linked to tumor response monitored by magnetic resonance imaging. We found that initial control required more intensive therapy with regular application of drug to deflect the exponential tumor growth curve onto a plateau. Dose-skipping algorithms during this phase were less successful than variable dosing algorithms. However, once initial tumor control was achieved, it was maintained with progressively smaller drug doses. In 60 to 80% of animals, continued decline in tumor size permitted intervals as long as several weeks in which no treatment was necessary. Magnetic resonance images and histological analysis of tumors controlled by adaptive therapy demonstrated increased vascular density and less necrosis, suggesting that vascular normalization resulting from enforced stabilization of tumor volume may contribute to ongoing tumor control with lower drug doses. Our study demonstrates that an evolution-based therapeutic strategy using an available chemotherapeutic drug and conventional clinical imaging can prolong the progression-free survival in different preclinical models of breast cancer.