Cell Reports Medicine:“伟哥”有助于食管癌治疗,即将进行临床试验

2022-06-23 王聪 “生物世界”公众号

食管癌主要分为食管鳞状细胞癌(ESCC)和食管腺癌(EAC),其中食管腺癌预后较差,5年生存率低于20%。这很大程度上是因为化疗耐药性,80%的患者对化疗没有反应。

据世界卫生组织国际癌症研究署(IARC)发布的2020年全球癌症负担数据,食管癌是世界年新增人数第8,年死亡人数第6的恶性肿瘤。而且,食管癌在中国尤为突出,全球每年新增和死亡的食管癌,均有超过一半在中国。

食管癌主要分为食管鳞状细胞癌(ESCC)和食管腺癌(EAC),其中食管腺癌预后较差,5年生存率低于20%。这很大程度上是因为化疗耐药性,80%的患者对化疗没有反应。

2022年6月21日,英国南安普顿大学医院的研究人员在 Cell 子刊 Cell Reports Medicine 上发表了题为:Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts 的研究论文。

该研究发现,PDE5抑制剂可以通过靶向肿瘤周围的癌症相关成纤维细胞(CAF),PDE5抑制剂联合化疗能够比单独进行化疗更好地抑制食管腺癌,逆转食管腺癌的化疗耐药性,而化疗耐药性是食管腺癌治疗面临的主要挑战之一。

该研究中使用的PDE5抑制剂是伐地那非,由拜耳和GSK公司开发,用于治疗男性勃起功能障碍(ED)。

食管癌的化疗耐药受肿瘤微环境的影响,例如癌症相关成纤维细胞(CAF),它们对肿瘤的生长很重要,为肿瘤提供营养,并可以发挥保护作用,阻止化疗药物产生效果。

在这项研究中,研究团队发现,与健康的食管组织相比,食管腺癌细胞中5-磷酸二酯酶(PDE5)显着高表达,而在肿瘤微环境中的癌症相关成纤维细胞(CAF)同样高表达 PDE5。同时,PDE5 的高表达与较差的总生存率相关,这表明 PDE5 可能是一个有效的食管腺癌治疗靶点。

随后,研究团队在食管癌肿瘤的 CAF 中测试了 PDE5 抑制剂(PDE5i)。结果显示,PDE5i 能够抑制 CAF 活性,使它们看起来更像正常的成纤维细胞。

接下来,研究团队从8名食管腺癌患者的15个组织活检样本中提取了肿瘤细胞样本,并进行培养,然后对这些体外培养的肿瘤进行 PDE5i+标准化疗的联合治疗试验。在12个临床中化疗反应较差的样本中,有9个通过 PDE5i 靶向 CAF 时的癌细胞对化疗重新变得敏感。

研究团队进一步使用人源肿瘤异种移植模型测试了这种联合治疗,结果表明这种联合治疗没有不良副作用,且能够比单独的化疗更好地抑制和缩小肿瘤。

使用 PDE5 抑制剂的一个好处是,它已经被证明是安全且耐受性良好的药物,在世界各地的患者中得到了广泛使用。包括西地那非(俗称伟哥)、伐地那非、阿伐那非、他达拉非等,都是PDE5 抑制剂,通过抑制 PDE5 来发挥治疗作用。

最早的 PDE5 抑制剂(PDE5i)是由辉瑞公司开发的西地那非(俗称伟哥),最初被开发用于治疗心血管疾病,但临床试验中并未达到预期的扩张血管、缓解心血管疾病的目的。1991年4月,西地那非的临床研究正式宣告失败。但研究人员奇怪地发现,参与研究的志愿者都不愿交回剩余的药物,追问之下,这些志愿者表示,这种药物对性生活有所改善。之后辉瑞公司的研究人员转变了研究方向,就西地那非对阴茎海绵体平滑肌的作用展开了研究。1998年西地那非获得FDA批准上市,用于治疗男性勃起功能障碍(ED)。此后,其他的 PDE5 抑制剂 伐地那非、阿伐那非、他达拉非陆续上市。

该研究的通讯作者、南安普顿大学的 Tim Underwood 教授表示,食管癌的化疗耐药性意味着许多患者即使接受的高强度化疗也仍然不起作用。而这项研究找到了一种已经被广泛使用的安全的药物,这可能是应对食管癌这种难治性疾病的巨大进步。

随着这些药物的安全性得到证实,以及该临床前研究的积极结果,研究团队表示,下一步将进行I/II期临床试验,测试 PDE5 抑制剂联合化疗治疗晚期食管癌患者。

如果临床试验成功的话,将挽救众多食管癌患者,此外,这项研究也可能为 PDE5 抑制剂在其他癌症类型中的应用铺平道路。

原始出处:

Benjamin P. Sharpe, et al. Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts. Cell Reports Medicine, 2022.

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    2022-12-01 维他命
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    2023-04-04 kalseyzl
  4. [GetPortalCommentsPageByObjectIdResponse(id=1872452, encodeId=3ac218e2452da, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Thu Nov 03 08:14:29 CST 2022, time=2022-11-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962780, encodeId=2dc91962e805f, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Dec 01 07:14:29 CST 2022, time=2022-12-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1774067, encodeId=53941e74067b5, content=<a href='/topic/show?id=5f014e1852' target=_blank style='color:#2F92EE;'>#CIN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4718, encryptionId=5f014e1852, topicName=CIN)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a9a038523631, createdName=kalseyzl, createdTime=Tue Apr 04 22:14:29 CST 2023, time=2023-04-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1859269, encodeId=49971859269c6, content=<a href='/topic/show?id=e0a9593596' target=_blank style='color:#2F92EE;'>#DIC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5935, encryptionId=e0a9593596, topicName=DIC)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6f7770, createdName=jeanqiuqiu, createdTime=Fri Jul 29 02:14:29 CST 2022, time=2022-07-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1228723, encodeId=081a1228e2337, content=那阴茎勃起不是又成副作用了 , beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b7585483820, createdName=ms3000000731310237, createdTime=Sun Jun 26 09:46:18 CST 2022, time=2022-06-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1437747, encodeId=790e143e74736, content=<a href='/topic/show?id=0e311010591a' target=_blank style='color:#2F92EE;'>#食管#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=101059, encryptionId=0e311010591a, topicName=食管)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Sat Jun 25 05:14:29 CST 2022, time=2022-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577902, encodeId=9d9615e79027c, content=<a href='/topic/show?id=cda91148004' target=_blank style='color:#2F92EE;'>#Medicine#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11480, encryptionId=cda91148004, topicName=Medicine)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=54cd16396700, createdName=ms1692212821629096, createdTime=Sat Jun 25 05:14:29 CST 2022, time=2022-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1611627, encodeId=e16d161162e26, content=<a href='/topic/show?id=eb6b1145939' target=_blank style='color:#2F92EE;'>#Med#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11459, encryptionId=eb6b1145939, topicName=Med)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a19396740, createdName=ms3994565386320060, createdTime=Sat Jun 25 05:14:29 CST 2022, time=2022-06-25, status=1, ipAttribution=)]
    2022-07-29 jeanqiuqiu
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    2022-06-26 ms3000000731310237

    那阴茎勃起不是又成副作用了

    0

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    2022-06-25 zhouqu_8
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