Toward a Drug Development Path That Targets Metastatic Progression in Osteosarcoma
Toward a Drug Development Path That Targets Metastatic Progression in Osteosarcoma
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DOI：
10.1158/1078-0432.ccr-13-2574
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发表时间：
2014-08-15
影响因子：
11.5
通讯作者：
Bernstein, Mark
中科院分区：
文献类型：
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作者：
Khanna, Chand;Fan, Timothy M.;Bernstein, Mark
尽管原发肿瘤治疗成功，肺转移的发展仍然是骨肉瘤患者死亡的最常见原因。30多年来，传统的药物开发途径需要药物来诱导已建立的病变消退，但并没有给骨肉瘤患者带来改善。基于我们对转移生物学的不断了解，现在我们专注于开发靶向转移进展的治疗方法是合理和必要的。为了推进这一议程，在马里兰州的贝塞斯达召开了一次转移和骨肉瘤社区关键意见领袖和专家会议。这次会议的目的是提供一个“视角”，建立一个临床前转化路径，可以支持对独特靶向转移表型的潜在治疗药物的早期评估。虽然关注骨肉瘤，但许多癌症类型都需要这种观点。会议达成的共识包括：转移进展的生物学与转移特异性靶点/过程相关，可能不会影响肉眼可检测的病变;转移特异性过程的靶向是可行的;需要严格的临床前数据来支持转移特异性药物转化为人体试验，其中可测量疾病的消退不是预期结果;临床前数据应包括对作用机制的理解，有效暴露和反应的药效学标志物的验证，有效性的几种小鼠模型的使用，以及在可行的情况下，包括患有自然发生的骨肉瘤的狗，以确定新药在微转移疾病环境中的活性。(C)2014年AACR。
Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a "Perspective" that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting. (C) 2014 AACR.