A new drug that inhibits the hedgehog signaling pathway has shown “remarkable” antitumor activity against basal cell carcinoma and medulloblastoma, according to two reports published online Sept. 2 in the New England Journal of Medicine.
The hedgehog signaling pathway regulates cell growth and differentiation during early development but is inactive in healthy adults. However, it appears that mutations in components of the pathway can cause malignant growth in some cases of medulloblastoma, the most common brain cancer in children, and in several cancers in adults, notably basal cell carcinoma.
The hedgehog pathway derived its name from its signaling molecule, a polypeptide ligand called Hedgehog [Hh] because the mutation it caused when it was first discovered in fruit flies produced stubby, hairy-looking larvae resembling hedgehogs.
The new oral agent, GDC-0449, was developed to selectively and potently inhibit hedgehog signaling without producing the adverse effects common with conventional chemotherapy. It appears to have done so in a phase I clinical trial of patients with advanced or metastatic basal cell carcinoma and in a single case study testing it against medulloblastoma refractory to all other treatments. Both studies were supported by Genentech Inc., developer of GDC-0449.
These results indicate that targeting the hedgehog signaling pathway may be a promising avenue for a whole new class of cancer therapies, Dr. Andrzej A. Dlugosz and Dr. Moshe Talpaz of the University of Michigan, Ann Arbor, said in an editorial comment accompanying the two reports.
“Although the total number of patients with advanced or metastatic basal cell carcinoma is small, these studies should ignite renewed interest in testing hedgehog pathway inhibitors in patients with typical basal cell carcinoma” as well as other cancers, they said.
“For patients at especially high risk for multiple basal cell tumors, an effective medical treatment would be a welcome alternative to repeated surgical procedures, which can be especially disfiguring when the tumors occur on the face,” Dr. Dlugosz and Dr. Talpaz said (N. Engl. J. Med. 2009; [doi 10.1056/NEJMe0906092]).
Alternatively, tumor debulking with the use of hedgehog inhibitors, followed by surgical excision, might prove beneficial in many patients, they added.
In the clinical trial, Dr. Daniel D. Von Hoff of the Translational Genomics Research Institute in Scottsdale, Arizona, and his associates assessed GDC-0449 in 18 patients with metastatic and 15 patients with locally advanced basal cell carcinoma that had been refractory to surgery, radiotherapy, and chemotherapy.
A total of 18 patients showed a clinical response, 11 showed stable disease for up to 10 months, and 4 had disease progression, Dr. Von Hoff and his colleagues said (N. Engl. J. Med. 2009 [doi.10.1056/NEJMoa0905360]).
The overall response rate was 55%. Dr. Dlugosz and Dr. Talpaz termed the 50% response rate among patients with metastatic disease “remarkable.”
There were no dose-limiting toxic effects or grade-5 adverse events during the study. One grade-4 event occurred (asymptomatic hyponatremia) and several patients reported a variety of problems that may or may not have been related to treatment, such as fatigue and weight loss. One patient discontinued treatment after 8 months, citing abdominal pain, fatigue, weight loss, anorexia, and dysgeusia.
In the case study, Dr. Charles M. Rudin of Johns Hopkins University, Baltimore, and his associates assessed GDC-0449 in a 26-year-old man with a 4-year history of medulloblastoma. The patient had undergone gross total resection of the tumor, craniospinal irradiation, extensive chemotherapy, autologous stem-cell transplantation, and additional systemic treatment with temozolomide and bevacizumab, but nevertheless had widespread skeletal and soft tissue metastases. With no alternative therapies left, he was offered CDC-0449.
Within 1 month, supraclavicular lymphadenopathy resolved, sternal masses regressed, and the patient reported that his intractable pain had resolved. After a few more weeks, more nodules regressed and the patient had returned to a normal level of activity. After a few more weeks, further metastases were markedly diminished or, in the case of a disabling epidural mass at C7, no longer detectable.
After 3 months of treatment, however, there was renewed tumor activity, including new lesions as well as regrowth of old lesions. The patient progressed rapidly, despite a series of subsequent therapies, and died.
“The tumor had a remarkable, although incomplete, and rapid, although transient, response to inhibition of the hedgehog pathway with GDC-0449,” Dr. Rudin and his colleagues said (N. Engl. J. Med. 2009 [doi:10.1056/NEJMoa0902903]).
“The regression is notable because of the tumor burden and the extent of metastasis in this patient, with substantial soft tissue and bony tissue involvement and clinically significant bone marrow compromise, and underscores the primary role that the hedgehog pathway played in maintaining and driving the growth of this patient’s tumor,” they added.
Examining the possibility of acquired resistance to hedgehog pathway inhibitors will be key in future studies, they said. In addition, the potential adverse effects of hedgehog pathway blockade in children must be delineated, as they are the largest population of patients with medulloblastoma.
Dr. Dlugosz reported receiving consulting fees from Merck and Co. and grant support from Pfizer Inc. Dr. Von Hoff reported receiving clinical research funding from Genentech Inc. Dr. Rudin reported receiving research funding and a BioOncology Grant Program Award from Genentech, as well as a clinical scientist award in translational research from Burroughs Wellcome Fund. Dr. Talpaz had no conflicts to report.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
据《新英格兰医学杂志》(New England Journal of Medicine)网络版9月2日刊发的2篇论文报道称：一种新型抑制hedgehog信号通路的药物显示出“显著的”抗基底细胞癌和髓母细胞瘤活性。
Hedgehog信号通路在早期发育过程中调节细胞的生长和分化，但在健康的成年人中呈静息状态。然而，该通路信号分子的突变似乎可导致部分肿瘤的恶性生长，其中包括儿童最常见的脑部恶性肿瘤髓母细胞瘤以及许多成年人肿瘤，尤其是基底细胞癌。
Hedgehog通路取自它的信号分子——一个称为“Hedgehog”(Hh)的多肽配体，首次在果蝇中发现该基因突变会导致幼虫体表出现许多短密的毛状凸起，形似刺猬(Hedgehog)，故而得名。
GDC-0449作为一种新型的口服靶向制剂，可有效地抑制hedgehog信号通路且不会产生常规化疗所常见的副作用。一项晚期或转移性基底细胞癌患者的临床I期试验以及一项难治性髓母细胞瘤患者的单病例研究均证实该药物有效。GDC-0449开发商基因泰克公司为上述2项研究提供了支持。
美国密歇根大学的Andrzej A. Dlugosz博士和Moshe Talpaz博士在上述2篇论文所附的编辑评论中写道：这些结果表明Hedgehog信号通路的靶向治疗有望成为一种全新的癌症治疗途径。
虽然晚期或转移性基底细胞癌患者为数不多，但这些研究将重新点燃研究人员尝试将hedgehog通路抑制剂用于治疗基底细胞癌及其他肿瘤患者的兴趣，他们说。
Dlugosz博士和Talpaz博士说，特别是对于多发性基底细胞癌的高危患者，他们更愿意用有效的药物治疗来代替多次手术，因为当肿瘤发生于面部时，手术可能会导致毁容。”(N.Engl.J.Med.2009;[doi 10.1056/NEJMe0906092])
他们补充说，此外，采用hedgehog抑制剂缩小肿瘤体积后再行手术切除，将使许多患者从中获益。
在上述临床试验中，美国亚利桑那州斯科茨代尔翻译基因组学研究院(Translational Genomics Research Institute，TGen)的Daniel D. Von Hoff博士和他的同事评估了GDC-0449在18例转移性肿瘤患者及15例对手术、放化疗耐受的局部晚期基底细胞癌患者中的疗效。
Von Hoff博士和他的同事说，出现临床缓解的患者总计有18例，疾病稳定达10个月的患者有11例，疾病进展4例(N.Engl.J.Med.2009[doi.10.1056/NEJMoa0905360])。
患者总缓解率为55%。Dlugosz博士和Talpaz博士将“显著”定义为50%的转移性肿瘤患者出现缓解。
实验当中未发生剂量限制性毒性反应或5级不良事件。发生过1起无症状性低钠血症的4级事件，还有数例患者报告称出现了一些可能与治疗相关或不相关的问题，如疲劳、体重下降等。仅有1例患者在8个月后因腹痛、乏力、消瘦、食欲不振和味觉障碍停止了治疗。
在上述单病例研究中，美国巴尔的摩市约翰霍普金斯大学Charles M. Rudin博士和他的同事评估了GDC-0449在一名患有4年髓母细胞瘤的26岁男性患者的疗效。该患者经肿瘤肉眼下全切、全脑全脊髓放疗、充分化疗、自体造血干细胞移植再加上替莫唑胺和贝伐单抗的全身治疗，但仍出现广泛的骨和软组织转移。历经所有其他治疗后，患者开始服用GDC-0449。
在1个月内，患者的锁骨上淋巴结转移消退、胸骨瘤块缩小，且报告称顽固性疼痛消失。数周后，多个癌灶消退，患者已可正常活动。再经数周后，转移灶进一步显著减少，且检查不到原先引起运动失能的C7硬膜外瘤块。
但经3个月的治疗后，肿瘤死灰复燃，包括出现新的转移灶以及原有癌灶再度生长。患者进展迅速，尽管随后进行了一系列治疗，但最终死亡。
Rudin 博士和他的同事说：“GDC-0449通过抑制hedgehog通路，使肿瘤出现显著却不完全、迅速而短暂的缓解。”(N. Engl. J. Med. 2009 [doi:10.1056/NEJMoa0902903])
“该患者肿瘤负荷重且出现广泛转移，包括大量的软和骨组织浸润以及临床上显著的骨髓受累，因此出现肿瘤消失值得关注，该现象也强调hedgehog通路在维持及促进肿瘤生长方面发挥主要作用。”他们说。
他们说，hedgehog通路抑制剂的获得性耐药性可能将成为今后的研究重点。此外，由于儿童是髓母细胞瘤的高危人群，因此必须阐明阻断hedgehog通路对儿童的潜在副作用。
Dlugosz博士称接受过默克公司咨询费以及辉瑞公司的基金资助。Von Hoff博士称接受了基因泰克公司的临床研究基金资助。Rudin博士报告称接受了基因泰克公司的“BioOncology基金项目奖”的研究基金资助以及Burroughs Wellcome基金会的转化型研究临床科学家奖。Talpaz博士称无相关的利益冲突。
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