Small molecules and targeted therapies in distant metastatic disease.
Small molecules and targeted therapies in distant metastatic disease.
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DOI：
10.1093/annonc/mdp254
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发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
Schadendorf D
中科院分区：
文献类型：
--
作者：
Hersey P;Bastholt L;Chiarion-Sileni V;Cinat G;Dummer R;Eggermont AM;Espinosa E;Hauschild A;Quirt I;Robert C;Schadendorf D
化疗，生物制剂或两者的组合对转移性黑色素瘤患者的生存几乎没有影响。在理解与黑色素瘤发展相关的遗传变化方面的进展导致了有希望的新药物的可用性，这些药物抑制信号细胞途径中上调的特定蛋白或抑制抗凋亡蛋白。索拉非尼（RAF/RAS/MEK通路的多激酶抑制剂）、elesclomol（STA-4783）和oblimersen（G3139）（靶向抗凋亡BC 1 -2的反义寡核苷酸）正在与化疗联合进行III期临床研究。靶向突变体B-Raf（RAF 265和PLX 4032）、MEK（PD 0325901、AZD 6244）、热休克蛋白90（tanespimycin）、mTOR（依维莫司、deforolimus、temsirolimus）和VEGFR（阿西替尼）的药物在临床开发的早期阶段显示出一些前景。受体酪氨酸激酶抑制剂（伊马替尼、达沙替尼、舒尼替尼）可能在治疗携带c-Kit突变的黑色素瘤患者中发挥作用。虽然通常作为单一药物进行研究，结果令人失望，但新的靶向药物应在联合治疗中进行更彻底的评估。合理使用新靶向药物的未来还取决于分析技术的成功应用，这些技术能够对患者进行分子分析，并选择可能的治疗应答者。
Chemotherapy, biological agents or combinations of both have had little impact on survival of patients with metastatic melanoma. Advances in understanding the genetic changes associated with the development of melanoma resulted in availability of promising new agents that inhibit specific proteins up-regulated in signal cell pathways or inhibit anti-apoptotic proteins. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, elesclomol (STA-4783) and oblimersen (G3139), an antisense oligonucleotide targeting anti-apoptotic BCl-2, are in phase III clinical studies in combination with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) may have a role in treatment of patients with melanoma harbouring c-Kit mutations. Although often studied as single agents with disappointing results, new targeted drugs should be more thoroughly evaluated in combination therapies. The future of rational use of new targeted agents also depends on successful application of analytical techniques enabling molecular profiling of patients and leading to selection of likely therapy responders.
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6.2
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