Inhibiting TGF-β to increase response rates to chemoradiotherapy in rectal cancer.
Inhibiting TGF-β to increase response rates to chemoradiotherapy in rectal cancer.
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抑制 TGF-β 可提高直肠癌放化疗的反应率。
DOI：
10.1016/s1470-2045(22)00504-6
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Smith,JJoshua
中科院分区：
文献类型：
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作者：
Romesser,PaulB;Smith,JJoshua
随着年轻人直肠癌发病率的迅速增加，1对器官保存作为一种肿瘤学安全2，3和成本效益高的策略以改善患者生活质量的兴趣也在增长。4评估直肠癌新型放射增敏剂的研究受到关注，因为需要开发个性化治疗策略以提高反应率，同时促进器官保护。几十年来，TGF-β通路引起了科学家和临床医生的兴趣，5靶向这个复杂的信号网络现在被认为是改善对放射治疗反应的潜在方法。6然而，数十年来对TGF-β受体的研究--无论是作为单一疗法还是与放射疗法联合使用--都显示出混合的临床疗效，这可能是由于TGF-β的复杂生物学特性及其抑制的环境依赖性效应。6，7在《柳叶刀肿瘤学》中，Tomoko Yamazaki及其同事8报告了一项由化疗药物启动的、单臂、II期试验的结果，该试验评估了galunisertib（一种TGF-β抑制剂）作为放射增敏剂治疗局部晚期或寡转移性直肠癌患者的效果。患者接受galunisertib诱导治疗，随后接受galunisertib长期化疗和放疗。在放化疗完成后5-9周进行临床和放射学重新评估。试验符合其主要终点：38例入组患者中有12例（32%[单侧95% CI≥ 19%]）的病理或临床完全缓解持续至少1年，超过了拒绝零假设的10例患者完全缓解的最低要求。Galunisertib耐受性良好，仅发生1-2级毒性反应，因此符合安全性共同主要终点。这项试验的优势包括使用一种新的放射增敏剂，收集治疗中的活检
With the rapid increase in the incidence of rectal cancer in young adults, 1 interest in organ preservation as an oncologically safe2, 3 and cost-effective strategy to improve patients’ quality of life has also been growing. 4 Studies evaluating novel radiosensitisers in rectal cancer are receiving attention as a consequence of the need to develop personalised treatment strategies to increase response rates while also facilitating organ preservation. The TGF-β pathway has intrigued scientists and clinicians for decades, 5 and targeting this complex signalling network has now been implicated as a potential way to improve response to radiotherapy. 6 However, decades of research into TGF-β inhibitors—both as a monotherapy and in combination with radio therapy—have shown mixed clinical efficacy, probably due to the complex biology of TGF-β and the context-dependent effects of its inhibition. 6, 7In The Lancet Oncology, Tomoko Yamazaki and colleagues8 report the results of an investigator-initiated, single-arm, phase 2 trial evaluating galunisertib, a TGF-β inhibitor, as a radiosensitiser in patients with locally advanced or oligometastatic rectal cancer. Patients received galunisertib induction followed by long-course chemo radiotherapy with galunisertib. Clinical and radio graphic reassessment was done 5–9 weeks after chemoradiotherapy completion. The trial met its primary endpoint: 12 (32%[one-sided 95% CI≥ 19%]) of 38 enrolled patients had a pathological or clinical complete response sustained for at least 1 year, exceeding the minimum requirement of ten patients having a complete response to reject the null hypothesis. Galunisertib was well tolerated, with only grade 1–2 attributable toxic effects, and thus meeting the safety coprimary endpoint. The strengths of this trial include the use of a novel radiosensitiser, the collection of on-treatment biopsy