|
1946年，现代广告之父阿尔伯特·拉斯克创办了拉斯克奖（包括基础医学研究奖、临床医学研究奖、公共卫生服务奖、医学特殊贡献奖）以奖励那些对医学基础研究、诊断、预防、治疗或康复有重大贡献者。拉斯克奖被认为是医学界的最高奖，其中基础医学研究奖和临床医学研究奖被认为是仅次于诺贝尔生理学或医学奖的医学界最高荣誉。拉斯克临床医学研究奖于2008年心脏搭桥手术大师迈克尔·埃利斯·狄贝基逝世后改名为：拉斯克-狄贝基临床医学研究奖，以纪念狄贝基对心脏手术的开创贡献和终生成就。拉斯克奖评选结果通常于9月公布，而诺贝尔奖通常于10月公布，因此拉斯克奖又被医学界称为诺贝尔奖风向标，又有美国诺贝尔奖之美誉，是美国最具声望的生物医学奖项，也是医学界仅次于诺贝尔奖的大奖。拉斯克奖各项奖金为25万美元。 过去三十年以来，由于筛查、早期治疗以及更多有效且副作用更少的治疗方法，尤其术后辅助治疗，美国的乳腺癌死亡风险减少了将近一半。因此，2019年9月10日，拉斯克-狄贝基临床医学研究奖被授予三位科学家（德国生物化学家阿克塞尔·乌尔里希、美国肿瘤学家丹尼斯·约瑟夫·斯拉蒙、美国药学家迈克尔·谢泼德）应该不足为奇，而是极度欣喜和愉悦。人类表皮生长因子受体HER2对于乳腺癌，确实开创了肿瘤学临床研究和实践的新时代。 迈克尔·谢泼德 丹尼斯·约瑟夫·斯拉蒙 阿克塞尔·乌尔里希 2019年9月10日，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》在线发表密歇根大学罗杰尔癌症中心丹尼尔·弗莱明·海耶斯教授的述评：HER2与乳腺癌——非凡的成功故事。 1980年，仅有两类可以用于乳腺癌的全身治疗：化疗、对于雌激素受体阳性乳腺癌患者的抗雌激素治疗（更恰当地应该称为“内分泌”治疗）。20世纪70年代末和80年代，分子生物学新技术的迅猛发展，促进了对各种类固醇和肽类激素生长因子及其受体的生物学认识和基因克隆，为治疗药物开发带来了希望。其中，表皮生长因子EGF及其受体EGFR被发现，现在已知属于包括其他三种受体的人类表皮受体HER家族。该家族的三个成员EGFR又称HER1、HER3和HER4与至少11种已知的肽类配体结合，导致这些受体之间的两两结合（同类二聚化或异类二聚化）以及随后下游酪氨酸激酶信号转导连锁反应。这些信号连锁反应随后刺激细胞的繁殖、转移、浸润和生存，成为癌症的特征。HER2并无已知配体，但却是其他三种受体的优先二聚化搭档。HER2编码基因ERBB2又称neu被发现扩增并过表达于大约20%的新诊断乳腺癌之后，学术界和制药界进行了鼓舞人心的研究，改变了乳腺癌的面貌。这些研究主要由三位拉斯克-狄贝基临床医学研究奖获得者领导。 发现ERBB2过度表达于乳腺癌之后不久，一些临床前研究表明，此类肿瘤的恶性程度较高、攻击能力较强。乌尔里希、斯拉蒙与德克萨斯大学圣安东尼奥医学中心的已故肿瘤学家威廉·麦圭尔一起，首先发表研究论文报告了ERBB2的扩增和过表达与乳腺癌女性预后较差相关。同时，基因泰克已经开发了一系列针对该蛋白质的小鼠单克隆抗体。其中，MoAb4D5被乌尔里希和谢泼德等人的临床前研究证实，可以有效减少HER2阳性乳腺癌细胞的繁殖和生存。不过，主要障碍仍然有待克服，需要开发出可以安全、重复地给予HER2阳性乳腺癌患者的“人源化”小鼠单克隆抗体。谢泼德领导的团队成功地将小鼠抗原结合区移植入人类免疫球蛋白骨架，为随后的临床研究打开了大门。 1994年，笔者接到了斯拉蒙博士的电话称人源化单克隆抗体4D5（现在被称为曲妥珠单抗）单药一期临床研究获得了非凡的效果，他邀请笔者参加按计划进行的抗体＋化疗二期临床研究。笔者难以忘记入组该研究的首例患者：骨、肝、肺转移的HER2阳性乳腺癌中年女性，对各种化疗无效恶化。曲妥珠单抗对她的效果非常神奇：肺转移和肝转移完全消除、生活质量改善。笔者还记得兴奋地告诉同事：有药可救了！ 此后，一些临床研究表明，曲妥珠单抗可以改善HER2阳性晚期乳腺癌患者的总生存，甚至可以减少HER2阳性早期乳腺癌患者术后辅助治疗的死亡。随后开发的抗HER2药物，包括另一种单克隆抗体（帕妥珠单抗）、若干HER2酪氨酸激酶抑制剂（拉帕替尼、奈拉替尼、帕唑帕尼）以及抗体与化疗药缀合物曲妥珠单抗恩特星T-DM1，甚至可以进一步改善HER2阳性乳腺癌患者的生存。 图、人类表皮受体（HER）家族及其靶向药物 如图A所示，HER家族由四个成员组成：HER1，又称表皮生长因子受体（EGFR）；HER2，由ERBB2（又称neu）基因编码；HER3；HER4。至少11种已知的肽类生长因子（配体）可以结合至HER1（表皮生长因子EGF，肝素结合EGF样生长因子HBEGF，β细胞素，转化生长因子TGFα，双向调节因子或双调蛋白，上皮丝裂因子或上皮促有丝分裂原，上皮调节因子或上皮调节蛋白）、HER3（神经调节蛋白1和2）、HER4（神经调节蛋白1、2、3、4，β细胞素，HBEGF，上皮调节蛋白）。HER2并无与配体结合的结构区，但是似乎充当了该家族作用机制的守门人。HER1、HER3或HER4的结合，可以诱发与其自身或其他三种受体之一的二聚化。EGFR、HER2和HER3各自具有酪氨酸激酶结构区，其二聚化时被激活，并将信号级联传递至接受基因，诱发细胞的繁殖、浸润、转移或生存，成为癌症的特征。HER3的酪氨酸激酶结构区受损。图B显示了抗HER2疗法的细胞结合区。曲妥珠单抗、帕妥珠单抗、曲妥珠单抗恩特星（抗体与化疗药的缀合物）可以与HER2的细胞外结构区结合。曲妥珠单抗和帕妥珠单抗可以改变正常的酪氨酸激酶信号转导，或诱发抗体依赖型补体介导的细胞毒性（ADCC）。曲妥珠单抗恩特星被HER2结合以后，恩特星与曲妥珠单抗之间的连接被酶解，于是恩特星直接对细胞发挥细胞毒性，引起细胞死亡。酪氨酸激酶抑制剂拉帕替尼、奈拉替尼、帕唑帕尼可以穿过细胞膜，直接抑制细胞内的酪氨酸激酶结构区活性。 肿瘤学传统观念一直认为转移性乳腺癌女性无法治愈。不过，笔者和专门治疗该疾病的同事都有一些患者长期无病生存，挑战了这种传统观念。无论如何，即使对于许多未被治愈的HER2阳性转移性乳腺癌患者，抗HER2治疗也可显著而持久地改善生活质量和总生存。抗HER2治疗领域甚至仍有更新的药物正被不断开发。新型抗体与化疗药缀合物和酪氨酸激酶抑制剂的临床研究正在进行，抗HER2疗法与免疫检查点抑制剂等其他创新药物组合的临床研究也正在进行。此外，曲妥珠单抗现已被证明对其他HER2阳性非乳腺癌，尤其胃癌具有活性。 不过，此类治疗药物非常昂贵，并且需要专家指导用药，这些因素限制了医疗保险不足或低收入国家的患者获得治疗。正在进行的研究可以扩大抗HER2治疗获得范围，包括抗HER2抗体的非专利生物仿制药、皮下而非静脉注射曲妥珠单抗。 肿瘤医学界以及我们的患者，应该感谢乌尔里希、谢泼德和斯拉蒙以及众多其他实验室、转化研究和临床研究人员对这个非凡故事发挥了重要作用。我们还必须感谢已经参加和正在参加我们治疗HER2阳性癌症临床研究的勇敢女性。该领域正在进行和计划进行的研究将继续引领我们走向未来，其中更多HER2阳性乳腺癌女性将活得更久或甚至被治愈。“游戏规则改变者”和“重磅炸弹”这两种说法虽然已经过时，但是这些合作者的聪明才智、远见卓识和坚持不懈地证明了他们名至实归。 对此，国际四大医学期刊之一《美国医学会杂志》正刊在线发表此次拉斯克-狄贝基临床医学研究奖获得者、基因泰克生物肿瘤学顾问迈克尔·谢泼德博士的述评：生物标志推动癌症药物开发——曲妥珠单抗的开发；全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表报道：免疫细胞先驱赢得著名的拉斯克医学奖；全球自然科学三大旗舰期刊之一、美国《细胞》正刊在线发表霍华德休斯医学研究所、纽约纪念医院斯隆凯特林癌症中心查尔斯·索耶斯研究员的述评：赫赛汀——对癌基因的首次进攻引发了一场革命，以及《细胞》编辑部对此次拉斯克-狄贝基临床医学研究奖获得者、美国洛杉矶加利福尼亚大学丹尼斯·约瑟夫·斯拉蒙教授的访谈：将癌症遗传学转化为临床疗法。 相关阅读 N Engl J Med. 2019 Sep 10. [Epub ahead of print] HER2 and Breast Cancer — A Phenomenal Success Story. Daniel F. Hayes. University of Michigan Rogel Cancer Center, Ann Arbor. During the past three decades, the risk of dying from breast cancer in the United States has declined by nearly half, thanks to a combination of screening and early therapy as well as more treatments that are effective with fewer side effects, especially in the adjuvant setting. Therefore, it should come as no surprise, but rather with a great deal of satisfaction and happiness, that the 2019 Lasker-DeBakey Clinical Medical Research Award goes to three scientists (Axel Ullrich, Dennis Slamon, and Michael Shepard) whose work on the human epidermal growth factor receptor 2 (HER2) in breast cancer launched a new era in clinical research and the practice of oncology. In 1980, there were two classes of systemic therapies available for breast cancer: chemotherapy and, for patients with cancers rich in estrogen receptor, antiestrogen therapy (more properly termed "endocrine" therapy). In the late 1970s and 1980s, the explosion of new technologies in molecular biology led to genetic cloning and biologic understanding of a variety of steroid and peptide hormone growth factors and their receptors, stoking hopes of their therapeutic exploitation. Among these discoveries was the identification of the epidermal growth factor (EGF) and its receptor (EGFR), which we now know belongs to a family containing three other receptors, known as the human epidermal receptors, or HERs. Three members of this family, EGFR (also known as HER1), HER3, and HER4, bind to at least 11 known peptide ligands, which results in homodimerization and heterodimerization among these receptors and subsequent downstream tyrosine kinase signaling cascades. These signaling cascades stimulate subsequent cell proliferation, migration, invasion, and survival, all hallmarks of cancer. HER2 has no known ligand but is a preferred dimerization partner of the other three receptors. The gene that encodes HER2 (ERBB2, formerly known as neu) is amplified and overexpressed in approximately 20% of newly diagnosed breast cancers. This observation, followed by inspired and dogged research in both academia and pharma, has changed the face of breast cancer. These investigations have been led in particular by the three Lasker-DeBakey awardees. Soon after the observation that ERBB2 overexpression occurs frequently in breast cancers, preclinical studies from several investigators showed that tumors that have this aberration are more aggressive than those that do not have it. Working with the late William McGuire and others, Drs. Ullrich and Slamon were the first to report that amplification and overexpression of ERBB2 is associated with a worse prognosis for women with breast cancer. At the same time, investigators at Genentech had generated a set of mouse monoclonal antibodies against the protein. One of these, designated "MoAb 4D5", was shown in preclinical studies by Drs. Ullrich and Shepard and their colleagues to be particularly potent in reducing the proliferation and survival of HER2-positive breast-cancer cell lines. However, a major obstacle remained to be overcome — the development of a "humanized" murine monoclonal antibody that could be safely and repeatedly administered to patients with HER2-positive breast cancer. Dr. Shephard led a team of colleagues that successfully grafted the murine antigen-binding domain into a human immunoglobulin backbone, opening the door for subsequent clinical trials. In 1994, I received a telephone call from Dr. Slamon, in which he described phenomenal responses in a phase 1, single-agent trial testing the toxicities of the humanized monoclonal antibody 4D5, now designated trastuzumab. He invited me to participate in a planned phase 2 trial of the antibody plus chemotherapy. I will not forget my first patient involved in this trial — a middle-aged woman with metastatic HER2-positive breast cancer in bone, liver, and lung that had progressed on every chemotherapy then known to have activity in the disease. She had a nearly miraculous response, with complete resolution of her pulmonary and hepatic metastases and dramatic improvement in her quality of life. I recall telling a colleague, "This is a drug!" Since then, several clinical trials have shown that trastuzumab improves overall survival in patients with HER2-positive metastatic breast cancer and, even more dramatically, that it reduces mortality when delivered in the adjuvant setting. Subsequently developed anti-HER2 agents have even further improved survival in patients with HER2-positive breast cancer, including another monoclonal antibody (pertuzumab), several HER2 tyrosine kinase inhibitors (lapatinib, neratinib, and pazopanib), and an antibody-drug conjugate, trastuzumab emtansine. The Human Epidermal Receptor (HER) System and Ways to Target It. As shown in Panel A, the HER system consists of four family members, designated HER1 (also known as epidermal growth factor receptor [EGFR]), HER2 (encoded by ERBB2, formerly known as neu), HER3, and HER4. At least 11 known peptide growth factors bind to HER1 (epidermal growth factor [EGF], heparin-binding EGF-like growth factor [HBEGF], β-cellulin, transforming growth factor α [TGF-α], amphiregulin, epigen, and epiregulin), HER3 (neuregulins 1 and 2), and HER4 (neuregulins 1, 2, 3, and 4; β-cellulin; HBEGF; and epiregulin). HER2 has no ligand-binding domain but appears to act as a gatekeeper for the mechanism of action of the family. Binding of HER1, HER3, or HER4 induces dimerization with itself or one of the other three receptors. EGFR, HER2, and HER3 each has a tyrosine kinase domain that is activated on dimerization and transmits a signal cascade to a receptive gene, which induces cell proliferation, invasion, migration, or survival, the hallmarks of cancer. HER3 has an impaired tyrosine kinase domain. Panel B shows the cellular binding regions of anti-HER2 therapies. Trastuzumab, pertuzumab, and the antibody-drug conjugate trastuzumab emtansine bind to the extracellular domain of HER2. Trastuzumab and pertuzumab either alter normal tyrosine kinase signaling or induce antibody-dependent complement-mediated cytotoxicity (ADCC). Trastuzumab emtansine is internalized, and the chemotherapeutic agent is enzymatically cleaved, which leads to cytotoxic cell death. The tyrosine kinase inhibitors lapatinib, neratinib, and pazopanib cross the cell membrane and inhibit the intracellular tyrosine kinase domain activities. Oncologic dogma maintains that women who have metastatic breast cancer will not be cured. However, my colleagues and I who specialize in the treatment of this disease all have a few such patients who have been rendered disease-free for prolonged periods of time — challenging that dogma. Regardless, even for the many patients who have HER2-positive metastatic breast cancer who are not cured, anti-HER2 therapy results in considerable and long-lasting improvement in quality of life and overall survival. In this regard, even newer advances in the field of anti-HER2 therapy are being tested. Novel antibody-drug conjugates and tyrosine kinase inhibitors are in clinical trials, as are innovative combinations of anti-HER2 therapies with other strategic approaches, such as immune checkpoint inhibitors. Moreover, trastuzumab has now been shown to be active in other, nonbreast HER2-positive cancers, particularly gastric cancers. However, to sing a familiar tune in oncology, these treatments are expensive and require some expertise in delivery, factors that limit their availability for patients without adequate health insurance and those in lower-income countries. Ongoing investigations are leading to more widespread availability of anti-HER2 therapies, including use of generic biosimilar anti-HER2 antibodies and subcutaneous, rather than intravenous, delivery of trastuzumab. The oncologic medical community and, more importantly, our patients owe Drs. Ullrich, Shepard, and Slamon and the numerous other laboratory, translational, and clinical investigators who have played a role in this remarkable story a great debt of appreciation. We must also acknowledge the courageous women who have participated, and continue to do so, in the clinical trials that have gotten us where we are in the treatment of HER2-positive cancers. The ongoing and planned areas of research in this field will continue to lead us into the future in which even more women with HER2-positive breast cancer will live longer or even be cured. The terms "game changer" and "blockbuster" are worn, but in this case the ingenuity, vision, and persistence of these collaborators justify these superlatives. DOI: 10.1056/NEJMcibr1909386
|
|
|
