Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality.
Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality.
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DOI：
10.15252/emmm.201404271
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发表时间：
2015-04
影响因子：
11.1
通讯作者：
Harris AL
中科院分区：
文献类型：
--
作者：
McIntyre A;Harris AL
抗血管生成治疗增加了许多癌症患者的无进展生存期，但由于耐药性，即使在结肠癌（平均6-8周）中，对总生存期也几乎没有影响。目前许可的靶向治疗均抑制VEGF信号传导（表1）。已经确定了对抗VEGF疗法的抗性的许多机制，其使得癌症能够绕过血管生成阻断。此外，在过去的十年中，有越来越多的证据表明缺氧和代谢反应在肿瘤适应抗血管生成治疗中发挥的作用。低氧肿瘤反应通过转录因子低氧诱导因子（HIF）诱导主要基因表达、代谢和表型变化，包括增加的侵袭和转移。将抗血管生成药物与肿瘤缺氧和代谢适应抑制剂相结合的临床前研究已经显示出很大的前景，并且已经发起了联合临床试验。考虑到血管正常化与抗血管生成药物所见灌注减少的相反作用，了解个体患者的反应和反应时间为个性化治疗干预的范例提供了进一步的障碍。在临床前和临床研究中，正在研究针对缺氧肿瘤微环境的其他方法，这些方法有可能与抗血管生成疗法联合产生合成致死性，作为未来的治疗策略。
Anti-angiogenic therapy has increased the progression-free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6–8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table1). Many mechanisms of resistance to anti-VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti-angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia-inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre-clinical studies combining anti-angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti-angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre-clinical and clinical studies that have potential for producing synthetic lethality in combination with anti-angiogenic therapy as a future therapeutic strategy.
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影响因子：
5.7
作者：
Bola BM;Chadwick AL;Michopoulos F;Blount KG;Telfer BA;Williams KJ;Smith PD;Critchlow SE;Stratford IJ
通讯作者：
Stratford IJ
影响因子：
3.9
作者：
Gökmen-Polar Y;Goswami CP;Toroni RA;Sanders KL;Mehta R;Sirimalle U;Tanasa B;Shen C;Li L;Ivan M;Badve S;Sledge GW Jr
通讯作者：
Sledge GW Jr
影响因子：
3.7
作者：
Balgi AD;Diering GH;Donohue E;Lam KK;Fonseca BD;Zimmerman C;Numata M;Roberge M
通讯作者：
Roberge M
影响因子：
7.7
作者：
Choudhry, Hani;Schoedel, Johannes;Oikonomopoulos, Spyros;Camps, Carme;Grampp, Steffen;Harris, Adrian L.;Ratcliffe, Peter J.;Ragoussis, Jiannis;Mole, David R.
通讯作者：
Mole, David R.
影响因子：
11.2
作者：
Franco, M;Man, S;Kerbel, RS
通讯作者：
Kerbel, RS