Testicular cancer: Determinants of cisplatin sensitivity and novel therapeutic opportunities.
Testicular cancer: Determinants of cisplatin sensitivity and novel therapeutic opportunities.
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DOI：
10.1016/j.ctrv.2020.102054
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发表时间：
2020-08-01
影响因子：
11.8
通讯作者：
de Jong, Steven
中科院分区：
文献类型：
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作者：
de Vries, Gerda;Rosas-Plaza, Ximena;de Jong, Steven
睾丸癌（TC）是15 - 40岁男性中最常见的实体瘤。TC是高度非整倍体，12 p等染色体是最常见的染色体异常。TC的突变率低，KIT和KRAS的复发突变仅在腺瘤中以低频率观察到。总体治愈率很高，即使在转移性环境中，这是由于TC的顺铂敏感性优异。影响顺铂敏感性的因素包括DNA损伤修复缺陷和对DNA损伤的超敏凋亡反应。尽管如此，约10-20%的转移性TC患者不能通过基于顺铂的化疗治愈。耐药机制包括OCT 4的下调和未能诱导MKA和NOXA、MDM 2水平升高以及PI 3 K/AKT/mTOR通路的过度活跃。几种临床前方法已被证明在克服顺铂耐药性方面是成功的，包括特异性靶向PARP、MDM 2或AKT/mTOR与顺铂的组合。最后，患者来源的异种移植物模型具有用于TC的机制研究和新型治疗策略的临床前验证的潜力。虽然研究靶向药物的临床试验令人失望，但化疗和靶向药物组合的临床前成功推动了在临床环境中进一步研究的需要。
Testicular cancer (TC) is the most common solid tumor among men aged between 15 and 40years. TCs are highly aneuploid and the 12p isochromosome is the most frequent chromosomal abnormality. The mutation rate is of TC is low, with recurrent mutations in KIT and KRAS observed only at low frequency in seminomas. Overall cure rates are high, even in a metastatic setting, resulting from excellent cisplatin sensitivity of TCs. Factors contributing to the observed cisplatin sensitivity include defective DNA damage repair and a hypersensitive apoptotic response to DNA damage. Nonetheless, around 10-20% of TC patients with metastatic disease cannot be cured by cisplatin-based chemotherapy. Resistance mechanisms include downregulation of OCT4 and failure to induce PUMA and NOXA, elevated levels of MDM2, and hyperactivity of the PI3K/AKT/mTOR pathway. Several pre-clinical approaches have proven successful in overcoming cisplatin resistance, including specific targeting of PARP, MDM2 or AKT/mTOR combined with cisplatin. Finally, patient-derived xenograft models hold potential for mechanistic studies and pre-clinical validation of novel therapeutic strategies in TC. While clinical trials investigating targeted drugs have been disappointing, pre-clinical successes with chemotherapy and targeted drug combinations fuel the need for further investigation in clinical setting.