Chitsike Lennox, Duerksen-Hughes Penelope J
Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, United States.
Front Oncol. 2021 Aug 17;11:730412. doi: 10.3389/fonc.2021.730412. eCollection 2021.
The treatment landscape of locally advanced HPV-oropharyngeal squamous cell carcinoma (OPSCC) is undergoing transformation. This is because the high cures rates observed in OPSCC are paired with severe treatment-related, long-term toxicities. These significant adverse effects have led some to conclude that the current standard of care is over-treating patients, and that de-intensifying the regimens may achieve comparable survival outcomes with lower toxicities. Consequently, several de-escalation approaches involving locally advanced OPSCC are underway. These include the reduction of dosage and volume of intensive cytotoxic regimens, as well as elimination of invasive surgical procedures. Such de-intensifying treatments have the potential to achieve efficacy and concurrently alleviate morbidity. Targeted therapies, given their overall safer toxicity profiles, also make excellent candidates for de-escalation, either alone or alongside standard treatments. However, their role in these endeavors is currently limited, because few targeted therapies are currently in clinical use for head and neck cancers. Unfortunately, cetuximab, the only FDA-approved targeted therapy, has shown inferior outcomes when paired with radiation as compared to cisplatin, the standard radio-sensitizer, in recent de-escalation trials. These findings indicate the need for a better understanding of OPSCC biology in the design of rational therapeutic strategies and the development of novel, OPSCC-targeted therapies that are safe and can improve the therapeutic index of standard therapies. In this review, we summarize ongoing research on mechanism-based inhibitors in OPSCC, beginning with the salient molecular features that modulate tumorigenic processes and response, then exploring pharmacological inhibition and pre-clinical validation studies of candidate targeted agents, and finally, summarizing the progression of those candidates in the clinic.
局部晚期人乳头瘤病毒相关性口咽鳞状细胞癌（OPSCC）的治疗格局正在发生变革。这是因为在OPSCC中观察到的高治愈率伴随着严重的治疗相关长期毒性。这些显著的不良反应导致一些人得出结论，认为当前的治疗标准对患者过度治疗，而降低治疗方案强度可能会在毒性较低的情况下实现相当的生存结果。因此，几种涉及局部晚期OPSCC的降阶梯治疗方法正在进行中。这些方法包括减少强化细胞毒性治疗方案的剂量和体积，以及取消侵入性手术程序。这种降低强度的治疗有可能实现疗效并同时减轻发病率。鉴于其总体毒性谱更安全，靶向治疗单独或与标准治疗联合使用时，也是降阶梯治疗的理想选择。然而，它们在这些努力中的作用目前有限，因为目前很少有靶向治疗用于头颈癌的临床治疗。不幸的是，在最近的降阶梯试验中，唯一获得美国食品药品监督管理局（FDA）批准的靶向治疗药物西妥昔单抗与放疗联合使用时，与标准放疗增敏剂顺铂相比，疗效较差。这些发现表明，在设计合理的治疗策略以及开发安全且能提高标准治疗的治疗指数的新型OPSCC靶向治疗时，需要更好地了解OPSCC生物学。在本综述中，我们总结了OPSCC中基于机制的抑制剂的正在进行的研究，首先介绍调节肿瘤发生过程和反应的显著分子特征，然后探讨候选靶向药物的药理抑制和临床前验证研究，最后总结这些候选药物在临床中的进展。
