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点击蓝字 关注我们 引用本文：卢丽婷，王晰程，巴一．家族性腺瘤性息肉病的化学预防药物进展与展望[J/CD]．肿瘤综合治疗电子杂志，2024，10（4）：101- 108． 通信作者：王晰程 E-mail：xicheng_wang2024@163.com 家族性腺瘤性息肉病（familial adenomatous polyposis，FAP）是一种由APC基因胚系突变引起的常染色体显性遗传病，APC基因突变位置与结肠息肉病的发病年龄、严重程度、癌症风险等级及有无结肠外表现密切相关[1-2]。经典型FAP大多与发生在密码子169～1 393之间的突变相关，通常在青少年时期即出现数百甚至数千个结直肠腺瘤样息肉，未经治疗的患者会进一步发展为结直肠癌[3-4]。FAP患者也可能表现出多种结直肠外症状，如硬纤维瘤、十二指肠腺瘤、骨瘤、先天性视网膜色素上皮肥大、甲状腺癌、肝胆胰及上消化道恶性肿瘤等[5]。鉴于高发结直肠癌风险，2020年美国胃肠内镜学会指南推荐患者从10～12岁进行内镜下监测及息肉切除[6]。但内镜监测间隔期内仍有癌症发生的风险。目前，根据患者的腺瘤负荷和个人偏好，预防性手术如全结肠切除术＋回肠直肠吻合术（ileoanal anastomosis，IRA）或全结肠直肠切除术＋回肠储袋肛管吻合术（ileal pouch-anal anastomosis，IPAA）是标准治疗方案。与IRA相比，尽管IPAA降低了残余直肠癌变的风险，但二者均不能完全消除FAP相关肠外肿瘤发生风险，且2种术式患者术后肠功能障碍和硬纤维瘤发生率相当[7-9]。因此患者需终身进行内镜监测和进一步干预，严重影响生活质量。 化学预防旨在通过药物减少息肉数量和大小，从而延迟或避免手术，减少内镜检查和息肉切除的频率，降低手术相关并发症发生率，并防止癌症的进展。对于息肉负担尚未严重到需要进行结肠切除的青少年患者，化学预防可以减轻患者的心理和生理负担，使其达到更成熟的决策年龄[10]。此外，硬纤维瘤是FAP的第二大死因，与手术、创伤及雌激素相关[11-12]。对于APC基因突变位点更易发生硬纤维瘤的患者，通过化学预防延迟甚至避免手术有利于患者的生存[13]。更长时间的术前监测也有助于更清楚地了解腺瘤负荷，制订更好的个性化治疗方案。目前关于FAP的化学预防的探索已有40余年，但FAP的化学预防还处于早期阶段，尚无药物被批准。本文旨在对FAP化学预防的现有文献及研究进展作一综述，以期对其有全面了解并为未来开展临床试验提供方向。 1. 非甾体抗炎药 非甾体抗炎药（nonsteroidal anti-inflammatory drugs，NSAIDs）通过抑制环氧合酶（cyclooxygenase，COX），尤其是COX-2，减少前列腺素的合成，具有抗炎、镇痛和解热作用。COX-2的过表达与结直肠癌的增殖、侵袭、血管生成及抗凋亡等过程密切相关[14]。NSAIDs能抑制COX-2活性，减少前列腺素E2的生成，抑制息肉增生和血管生成，诱导癌细胞凋亡，影响Wnt/β-catenin信号通路。此外，COX-2的异常表达与APC基因突变相互影响[15]，表明COX抑制剂可能对FAP患者具有预防作用，其安全性和有效性已在临床试验中得到探究。 1.1 舒林酸 舒林酸是一种非选择性NSAIDs，可竞争性抑制COX-1和COX-2，是最早用于FAP化学预防研究的药物之一。1991年，Labayle等[16]的研究显示，在10例先前接受过结肠切除术的FAP患者中，服用舒林酸组（300 mg/d）与安慰剂组相比，息肉消退率比较差异有统计学意义（P＜ 0.01）。后续研究显示，舒林酸能显著减少未接受手术FAP患者的息肉数量和直径，但一旦停药，患者息肉数量、直径均增加[17]。低剂量舒林酸栓剂（50 mg/d）连续治疗33个月可使87%的直肠息肉患者腺瘤逆转，且安全性良好[18]。多项研究均表明，舒林酸治疗有效性不受APC基因突变位点影响，且对十二指肠息肉也有效果，但对壶腹周围息肉无效[19-20]。一项针对8～25岁APC突变携带者的研究结果显示，尽管舒林酸组黏膜前列腺素水平低于安慰剂组，但息肉直径和数量的获益无统计学意义[21]。此外，尽管在舒林酸治疗中进行密切内镜随访，但仍有患者进展为结直肠癌。这些研究均为小样本研究，且多数患者仅评估了直肠病变，其能否转变为临床获益尚需进一步研究证实。 舒林酸的代谢产物显示出一定的抑制肿瘤的潜力，但在一项研究中，6个月治疗后对息肉数量无显著影响，且因其肝脏毒性也限制了剂量增加[22]。 1.2 阿司匹林 阿司匹林作为广泛应用的非选择性NSAIDs，美国胃肠病学会指南建议50～69岁有心血管疾病风险的人群使用低剂量阿司匹林以降低结直肠癌和心血管疾病风险[23]。CAPP1研究纳入了206例10～21岁的FAP患者，发现阿司匹林片联合抗性淀粉组中位治疗17个月后，与安慰剂组相比，息肉负荷有减小趋势，差异无统计学意义，但阿司匹林组在用药超过1年后最大息肉直径显著减小（P＝0.02）[24]。日本一项研究[25]评估了阿司匹林（100 mg/d）与安慰剂的疗效，亚组分析显示，治疗前平均基线息肉直径为≤2 mm的受试者经阿司匹林干预后息肉直径和息肉数量均显著减少，但阿司匹林联合抗性淀粉组组有18%受试者出现严重不良反应。J-FAPP-Ⅳ研究[26]纳入104例患有超过100个大肠腺瘤性息肉且未接受结肠切除术的患者，在研究前，患者接受了内镜切除所有直径至少5 mm的结直肠息肉，结果显示，服用阿司匹林8个月的患者结肠息肉复发率显著降低，而美沙拉嗪组未见明显效果。但该研究入组患者中位年龄为30岁以上且无结直肠癌，可能为较轻表型，且阿司匹林仅给药8个月，长期使用的安全性仍是限制其广泛应用的主要问题。 1.3 塞来昔布 鉴于非选择性NSAIDs的胃肠道不良反应，塞来昔布作为一种选择性COX-2抑制剂在FAP中的化学预防作用得到广泛关注。Steinbach等[27]的研究将77例18～65岁的FAP患者分为安慰剂组、低剂量塞来昔布组（100 mg，2次/d）和高剂量塞来昔布组（400 mg，2次/d），与安慰剂组相比，6个月内高剂量塞来昔布组患者结直肠息肉总数减少了28% （P＝0.003），息肉直径之和下降30.7%（P＝0.001），各组间不良事件发生率相似。而低剂量塞来昔布组相对于安慰剂组无显著差异。进一步分析显示，对于初始十二指肠黏膜受累超过5%的患者，服用塞来昔布（400 mg，2次/d）可将十二指肠受累面积减少31%[28]。另一项Ⅰ期剂量递增试验评估了短期塞来昔布治疗FAP患儿的安全性和有效性，塞来昔布（16 mg/kg，1次/d）对FAP患儿是安全且耐受良好的，安慰剂组受试者在第3个月时息肉数量增加了39.1%，而最高剂量塞来昔布组患者中，息肉数量减少了44.2%（P＝0.01）[29]。Burke等[30]进行的CHIP研究，将10～17岁的FAP患儿随机分配至塞来昔布组（16 mg/kg，1次/d）或安慰剂组，持续干预5年。结果显示，塞来昔布组患儿疾病进展（最早出现≥20个直径＞2 mm息肉）的中位时间为2.1年，安慰剂组患儿为1.1年，无患者发展成结肠直肠癌。由于观察到的终点率低，长期影响尚不明确。对于高剂量塞来昔布长期治疗的安全性（尤其是心血管事件风险）和效果，以及与其他药物联合使用的潜在协同效应，仍需进一步的研究来确认。 1.4 基于NSAIDs药物的组合疗法 1.4.1 联合依氟鸟氨酸 多胺是一类含氨基的小分子代谢物，在细胞生长中发挥核心作用。在FAP患者中，多胺合成的关键酶鸟氨酸脱羧酶（ornithine decarboxylase，ODC）活性及黏膜多胺水平在正常和腺瘤组织中均显著升高[31]。依氟鸟氨酸是一种强效ODC抑制剂，在ApcMin/+小鼠中，依氟鸟氨酸联合NSAIDs可使肠道肿瘤数量减少超过80%（P＜0.000 1）；与单独使用舒林酸相比，其联合治疗可以显著减少高级别腺瘤的发生（P＝0.003）[32]。Ⅲ期临床试验评估了依氟鸟氨酸（750 mg/d）与舒林酸（150 mg/d）联合治疗与单药治疗在成人FAP患者的疗效和安全性[33]。该研究持续48个月，纳入171例患者，主要研究终点为疾病进展。结果显示，联合用药组并未显著降低疾病进展发生率[34]，但在延迟下消化道手术方面表现出显著优势（P＝0.02）[35]，但需要注意依氟鸟氨酸的耳毒性。另一项随机Ⅱ期试验显示，塞来昔布（400 mg，2次/d）联合或不联合依氟鸟氨酸在预防息肉病患者腺瘤方面无显著差异[36]。 1.4.2 联合厄洛替尼 体细胞APC失活和表皮生长因子受体（epidermal growth factor receptor，EGFR）信号转导可促进COX-2表达和随后的腺瘤-癌发展[37]。厄洛替尼是一种抗EGFR活性的口服酪氨酸激酶抑制剂。FAPEST研究显示，舒林酸（150 mg，2次/d）联合厄洛替尼（75 mg/d）可在6个月后显著降低FAP患者结直肠及十二指肠息肉负荷[38-39]。但联合治疗可能引发痤疮样皮疹等不良反应，长期使用还与心脏毒性相关[38-40]。一项Ⅱ期单臂试验评估了厄洛替尼（350 mg，1次/周）干预能否有效降低息肉负荷并改善不良事件状况。结果表明，厄洛替尼干预6个月后，十二指肠息肉负荷显著减轻，平均百分比变化为-29.6%，12%的患者Spigelman评分降级，且整体不良事件可接受，但仍需更多数据证实其长期安全性[41]。 1.4.3 其他  近年来研究表明，FAP患者的肠道菌群谱与正常人及腺瘤患者不同，致瘤菌群可能通过DNA损伤、慢性炎症等机制促进FAP进展[42]。一项舒林酸联合双歧杆菌三联活菌治疗FAP的临床试验表明，舒林酸联合双歧杆菌三联活菌组疗效优于单纯服用舒林酸组和双歧杆菌三联活菌组[43]。其原因可能与降低Bcl-2基因表达、减少对凋亡的抑制、改善肠内环境菌群等有关。以上研究表明，调节肠道菌群，维持肠道微生态平衡可能成为FAP预防的新途径。 2. 二十碳五烯酸 二十碳五烯酸（eicosapentaenoic acid，EPA）是ω-3多不饱和脂肪酸的一种，属于人体必需脂肪酸，主要来源于鱼油。临床前研究显示，EPA可减缓结直肠腺瘤病史患者的隐窝细胞增殖，促进正常结肠黏膜的细胞凋亡[44]。其作用机制可能涉及作为COX-2的替代底物减少前列腺素E2生成，改变T淋巴细胞与结肠细胞膜的脂筏功能并调节信号转导，以及增强氧化应激以促进细胞凋亡[45]。在多中心、随机seAFOod试验[46]中，28例接受过结肠切除术的FAP患者接受EPA（2 g/d）治疗6个月后，息肉数量平均减少22.4%（P＝0.012），息肉直径总和平均减少29.8%（P＝0.027），与选择性COX-2抑制剂塞来昔布的效果相似。同时EPA耐受性良好，不良事件发生率与安慰剂相似。EPA在结直肠腺瘤治疗中显示出潜在效益，特别是在减缓息肉生长方面。 3. 西罗莫司 西罗莫司是一种大环内酯类免疫抑制剂，仅抑制哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）C1的活性，不影响mTORC2。研究表明，西罗莫司可使ApcMin/+小鼠的肠道肿瘤细胞停止生长和分化，甚至可能导致息肉消退[47]。有病例报道了低剂量西罗莫司（0.05～0.1 mg/kg）在2例FAP患儿中的成功应用[48]。该病例治疗1年后，1例患儿显示壶腹周围息肉完全消退，结直肠息肉减小，黏膜发育异常程度降低；另1例患儿的结肠息肉负荷降低，但胃息肉负荷未发生变化，2例患儿均未出现严重不良反应。随后一项纳入5例FAP患者的前瞻性Ⅱ期临床试验显示，4例FAP患者接受西罗莫司治疗6个月后，直肠回肠袋息肉数量明显减少，但不良事件发生率高，1例患者因不能耐受中途退出试验[49]。考虑到西罗莫司的不良反应与血药浓度呈正相关，目前的ⅡA期试验使用封装西罗莫司，以更一致且更低剂量的药物探索其能否预防FAP患者的疾病进展（NCT04230499）。以上研究表明，西罗莫司及其衍生物在FAP化学预防中具有潜力，但其不良反应需要引起高度重视。 4. 二甲双胍 Meta分析显示，长期使用二甲双胍能够降低结直肠腺瘤及癌症风险[50]。Ⅲ期临床研究发现，对非糖尿病患者在息肉切除术后给予低剂量二甲双胍（250 mg/d）干预1年，可减少腺瘤或息肉复发[51]。然而，与一般人群的散发性腺瘤不同，FAP患者的腺瘤数量更多。一项纳入34例韩国FAP患者的随机研究表明，每日口服二甲双胍500 mg或1500 mg治疗7个月并未显著改变结直肠和十二指肠的总体息肉负荷[52]。我国学者发现，1年二甲双胍治疗FAP安全有效，与安慰组相比，试验组患者（每日口服250 mg二甲双胍）的息肉平均数和特定区域的平均息肉负荷显著减少（P＜0.05），且二甲双胍可能通过调节肠道菌群抑制FAP中腺瘤性息肉的发展[53]。在临床上，二甲双胍联合内镜检查被证实优于单独内镜检查治疗FAP。二甲双胍在非糖尿病患者中的应用显示了其在预防腺瘤复发方面的潜力，未来研究应在FAP患者中进一步探索调节肠道菌群与二甲双胍的联合作用，不同的膳食模式也可能对研究结果产生影响。 FAP化学预防随机对照试验汇总如表1所示。 5. 正在进行的试验 lorpucitinib（JNJ-64251330研究）是一种口服小分子泛Janus激酶（Janus kinase，JAK）抑制剂，可阻断信号转导和转录激活因子蛋白（signal transducer and activator of transcription，STAT）的磷酸化，从而抑制与炎症性疾病进展相关的基因转录。2023年美国临床肿瘤学会年度会议报告了lorpucitinib在FAP患者中的Ⅰb期研究（NCT05014360）结果，结果显示，lorpucitinib在FAP患者中表现出肠道选择性分布，虽然息肉负荷的减少在临床上并不显著，但lorpucitinib降低了几种血清炎症生物标志物的水平，有助于改善FAP相关的临床症状，且其具有良好的安全性和耐受性[54]。 REC-4881是一种人工智能辅助开发的口服MEK1和MEK2的非ATP竞争性的小分子别构抑制剂。据推测，REC-4881可能是通过抑制FAP腺瘤中异常的丝裂原激活蛋白激酶（mitogen activation protein kinase，MAPK）信号转导而使肿瘤消退或减慢其生长。目前，一项多中心的评估其在FAP患者中的疗效和安全性的Ⅰb～Ⅱ期试验正在进行（NCT 05552755）。 奥贝胆酸是一种经美国食品药品监督管理局批准用于治疗原发性胆汁性胆管炎的选择性胆汁酸受体激动剂，已显示出减轻炎症和纤维化的潜力[55]。一项Ⅱa期安慰剂对照随机研究正在招募，旨在评估奥贝胆酸干预6个月对FAP患者肠息肉负荷的影响（NCT05223036）。 锂在apcMin/+小鼠中显示出抑制肠干细胞扩增的作用，尽管尚无锂在FAP患者中的应用报道，但已有研究表明，其可降低双相情感障碍患者的结直肠癌和其他癌症发病率[56]。一项前瞻性Ⅱ期单臂试验正在探讨低剂量锂对FAP患者的干细胞动力学、息肉数量和大小的影响（NCT05402891）。 白细胞介素-23（interleukin-23，IL-23）通过激活JAK/STAT3通路维持结直肠癌进展的炎症特征已被证实[57]。一项针对FAP受试者的Ⅰb期临床研究评估靶向IL-23的guselkumab单抗的疗效已完成招募，结果尚未发布（NCT03649971研究）。 6. 总结与展望 FAP的治疗与预防是一项复杂的挑战，涉及基因、药物和肠道环境等多个层面。迄今为止，化学预防研究尚未在临床实践中常规使用，因为先前研究样本量有限且存在矛盾，同时常伴随不良事件。FAP主要与APC基因突变相关，不同的突变类型及位点对疾病表型有显著影响。精确的基因分型和全基因组测序对于实现个体化的风险评估和预防策略至关重要。此外，对于携带特定突变的患者，可以考虑更为针对性的药物干预，如针对特定突变的小分子抑制剂，以提高治疗的针对性和有效性。此外，肠道菌群的调节和特定炎症途径的药物干预也显示出预防FAP的潜力。未来研究需整合这些信息以优化治疗方案，实现个体化治疗，提高治疗的针对性和有效性。 参考文献 [1] HEINEN C D. 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MINNEAPOLIS, Oct. 31, 2024 (GLOBE NEWSWIRE) -- Panbela Therapeutics, Inc. (OTCQB: PBLA), (“Panbela”), a clinical stage company developing disruptive therapeutics for the treatment of patients with urgent unmet medical needs, today announced that it will host a conference call on November 14, 2024, at 4:30 PM Eastern Time to discuss results for its third quarter ended September 30, 2024. Conference Call InformationToll Free: 877-545-0320International: 973-528-0002Participant Access Code: 370494Webcast Link: https://www.webcaster4.com/Webcast/Page/2556/51548 Conference Call Replay InformationToll Free: 877-481-4010International: 919-882-2331Replay Passcode: 51548Webcast Replay: https://www.webcaster4.com/Webcast/Page/2556/51548 About Panbela’s PipelineThe pipeline consists of assets currently in clinical trials with an initial focus on familial adenomatous polyposis (FAP), first-line metastatic pancreatic cancer, neoadjuvant pancreatic cancer, colorectal cancer prevention and ovarian cancer. The combined development programs have a steady cadence of anticipated catalysts with programs ranging from pre-clinical to registration studies. Ivospemin (SBP-101)Ivospemin is a proprietary polyamine analogue designed to induce polyamine metabolic inhibition (PMI) by exploiting an observed high affinity of the compound for pancreatic ductal adenocarcinoma and other tumors. It has shown signals of tumor growth inhibition in clinical studies of metastatic pancreatic cancer patients, demonstrating a median overall survival (OS) of 14.6 months and an objective response rate (ORR) of 48%, both exceeding what is typical for the standard of care of gemcitabine + nab-paclitaxel suggesting potential complementary activity with the existing FDA-approved standard chemotherapy regimen. In data evaluated from clinical studies to date, ivospemin has not shown exacerbation of bone marrow suppression and peripheral neuropathy, which can be chemotherapy-related adverse events. Serious visual adverse events have been evaluated and patients with a history of retinopathy or at risk of retinal detachment will be excluded from future SBP-101 studies. The safety data and PMI profile observed in the previous Panbela-sponsored clinical trials provide support for continued evaluation of ivospemin in the ASPIRE trial. Flynpovi ™Flynpovi is a combination of CPP-1X (eflornithine) and sulindac with a dual mechanism inhibiting polyamine synthesis and increasing polyamine export and catabolism. In a Phase III clinical trial in patients with sporadic large bowel polyps, the combination prevented > 90% subsequent pre-cancerous sporadic adenomas versus placebo. Focusing on FAP patients with lower gastrointestinal tract anatomy in the recent Phase III trial comparing Flynpovi to single agent eflornithine and single agent sulindac, FAP patients with lower GI anatomy (patients with an intact colon, retained rectum or surgical pouch), showed statistically significant benefit compared to both single agents (p≤0.02) in delaying surgical events in the lower GI for up to four years. The safety profile for Flynpovi did not significantly differ from the single agents and supports the continued evaluation of Flynpovi for FAP. CPP-1XCPP-1X (eflornithine) is being developed as a single agent tablet or high dose powder sachet for several indications including prevention of gastric cancer, treatment of neuroblastoma and recent onset Type 1 diabetes. Preclinical studies as well as Phase I or Phase II investigator-initiated trials suggest that CPP-1X treatment may be well-tolerated and has potential activity. About PanbelaPanbela Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing disruptive therapeutics for patients with urgent unmet medical needs. Panbela’s lead assets are Ivospemin (SBP-101) and Flynpovi. Further information can be found at www.panbela.com. Panbela’s common stock is eligible for quotation on the OTCQB under the symbol “PBLA”. Cautionary Statement Regarding Forward-Looking StatementsThis press release contains “forward-looking statements,” including within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: “anticipate,” “believe,” “can,” “design,” “expect,” “focus,” “intend,” “looking forward,” “may,” “plan,” “positioned,” “potential,” and “will.” All statements other than statements of historical fact are statements that should be deemed forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations, and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results and financial condition may differ materially and adversely from the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results and financial condition to differ materially from those indicated in the forward-looking statements include, among others, the following: (i) our ability to obtain additional capital, on acceptable terms or at all, required to implement our business plan; (ii) our lack of diversification and the corresponding risk of an investment in our Company and the corresponding risk of potential deterioration of our financial condition and results due to failure to diversify; (iii) our ability to obtain and maintain our listing on a national securities exchange; (iv) results, progress and success of our randomized Phase Ia/Ib and Phase II/III clinical trials; (v) our ability to demonstrate the safety and effectiveness of our product candidates: ivospemin ( SBP-101 ), Flynpovi, and eflornithine (CPP-1X); (vi) potential delays or risks to the success of our randomized Phase II/III clinical trial resulting from a termination in our relationship with our CRO; (vii) our ability to obtain regulatory approvals for our product candidates, SBP-101, Flynpovi and CPP-1X in the United States, the European Union or other international markets; (viii) the market acceptance and level of future sales of our product candidates, SBP-101, Flynpovi and CPP-1X ; (ix) the cost and delays in product development that may result from changes in regulatory oversight applicable to our product candidates, SBP-101, Flynpovi and CPP-1X ; (x) the rate of progress in establishing reimbursement arrangements with third-party payors; (xi) the effect of competing technological and market developments; (xii) the costs involved in filing and prosecuting patent applications and enforcing or defending patent claims; and (xiii) such other factors as discussed in Part I, Item 1A under the caption “Risk Factors” in our most recent Annual Report on Form 10-K , any additional risks presented in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Any forward-looking statement made by us in this press release is based on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to publicly update any forward-looking statement or reasons why actual results would differ from those anticipated in any such forward-looking statement, whether written or oral, whether as a result of new information, future developments or otherwise. Contact Information: Investors:James CarbonaraHayden IR(646) 755-7412james@haydenir.com Media:Tammy GroenePanbela Therapeutics, Inc.(952) 479-1196IR@panbela.com