Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation.
Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation.
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DOI：
10.1158/0008-5472.can-17-0084
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发表时间：
2017-06-01
期刊：
影响因子：
11.2
通讯作者：
Klinghoffer RA
中科院分区：
文献类型：
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作者：
Frazier JP;Bertout JA;Kerwin WS;Moreno-Gonzalez A;Casalini JR;Grenley MO;Beirne E;Watts KL;Keener A;Thirstrup DJ;Tretyak I;Ditzler SH;Tripp CD;Choy K;Gillings S;Breit MN;Meleo KA;Rizzo V;Herrera CL;Perry JA;Amaravadi RK;Olson JM;Klinghoffer RA
肿瘤内高度异质性和患者间多样性挑战了精确医学指导的新型癌症药物开发方法的愿景。这种复杂性在临床前药物开发过程中很少准确建模，阻碍了临床药物疗效的预测。为了解决这个问题，我们开发了比较体内肿瘤学（CIVO）阵列显微注射技术，以测试肿瘤对直接在患者肿瘤中同时微剂量多种药物的反应性。在这里，在一项对18名软组织肉瘤（STS）犬患者的研究中，CIVO捕获了复杂的患者特异性肿瘤反应，包括局部暴露于不同化疗药物后的癌细胞和多种免疫浸润。CIVO还将患者特异性肿瘤对最有效的药物多柔比星的耐药性进行了分类，并进一步评估了临床前自噬抑制剂PS-1001逆转多柔比星耐药性。在CIVO鉴定的阿霉素耐药肿瘤亚组中，PS-1001导致抗肿瘤活性增强，巨噬细胞浸润增加，并使这种浸润偏向M1极化。在活体肿瘤和不同免疫活性患者人群中同时评价和交叉比较多种药物和药物组合的能力可能为做出明智的药物开发决策提供基础。这种方法也代表了一种可行的功能方法，以补充目前的精确肿瘤学策略。
The vision of a precision medicine–guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient’s tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies.