Development of new targeted therapies for breast cancer
Development of new targeted therapies for breast cancer
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DOI：
10.1007/s12282-007-0003-2
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发表时间：
2008-01-01
期刊：
影响因子：
4
通讯作者：
Miller, Kathy D.
中科院分区：
文献类型：
--
作者：
Doyle, Danielle M.;Miller, Kathy D.
真正靶向治疗的临床应用依赖于鉴定生物学相关、可重复测量且与临床获益明确相关的特定分子特征（靶标）。理想情况下，靶点应该对肿瘤的恶性表型至关重要。目标必须在容易获得的临床样品中容易测量。靶点的中断、干扰或抑制应在肿瘤表达靶点的显著比例的患者中产生临床应答，但在肿瘤不表达靶点的少数患者中产生临床应答。因此，靶向治疗提供了双重希望，即最大限度地提高疗效，同时最大限度地减少毒性。对恶性肿瘤标志物的严格审查为考虑潜在靶点和新的治疗干预提供了一个框架。恶性肿瘤的标志包括不受控制的增殖、对负生长调节不敏感、逃避凋亡、缺乏衰老、侵袭和转移、血管生成和基因组弹性。现有疗法主要通过细胞毒性剂、电离辐射或抑制雌激素受体和HER2生长因子信号传导途径来靶向增殖。治疗的进一步改进必须攻击恶性肿瘤的其他标志，无疑将伴随着更好的手段，个别患者选择这样的治疗。事实上，这些特征中的每一个都提供了治疗的机会。如果不这样认为，就等于假设一个特征在生物学上至关重要，但在治疗上却不重要，这是一个不太可能的悖论。
Clinical application of truly targeted therapy relies on identification of a specific molecular feature (the target) that is biologically relevant, reproducibly measurable and definably correlated with clinical benefit. Ideally the target should be crucial to the tumor's malignant phenotype. The target must be easily measurable in readily obtained clinical samples. Interruption, interference or inhibition of the target should yield a clinical response in a significant proportion of patients whose tumors express the target but in few patients whose tumors do not express the target. As such, targeted therapy offers the twin hopes of maximizing efficacy while minimizing toxicity. A critical review of the hallmarks of malignancy provides a framework for considering potential targets and novel therapeutic interventions. The hallmarks of malignancy include uncontrolled proliferation, insensitivity to negative growth regulation, evasion of apoptosis, lack of senescence, invasion and metastasis, angiogenesis, and genomic elasticity. Existing therapies predominantly target proliferation either with cytotoxic agents, ionizing radiation or inhibition of estrogen receptor and HER2 growth factor signaling pathways. Further improvements in therapy must attack the other hallmarks of malignancy and will undoubtedly be accompanied by better means of individual patient selection for such therapies. Indeed, each of these hallmarks presents a therapeutic opportunity. To believe otherwise would be to assume that a feature is both biologically crucial yet therapeutically unimportant, an unlikely paradox.