Rational combination of EGFR and Hedgehog inhibitors in head and neck cancer

描述（由申请人提供）：表皮生长因子受体（EGFR）抑制剂可改善头颈部鳞状细胞癌（HNSCC）患者的生存率，但总体疗效有限，特别是当用于其适应症之一时（西妥昔单抗单药治疗化疗难治性HNSCC），反应较低，预后较差。癌症干细胞（CSC）与抗癌疗法的耐药性有关。使用晚期患者来源的异种移植HNSCC模型，我们已经记录了EGFR抑制剂后CSC亚群的积累，并假设CSC因此负责肿瘤复发。与非CSC增殖细胞相比，这些CSC显示Hedgehog途径的500倍过表达。此外，我们观察到西妥昔单抗诱导SIP 1/ZEB 2和TWIST，它们是上皮向间充质转化（EMT）的启动子，也与HNSCC对EGFR抑制剂的耐药性相关。最后，我们在体内确定EGFR和Hedgehog抑制剂的组合减少CSC群体，阻断EMT，并防止HNSCC肿瘤的再生长。本提案的目的是在难治性HNSCC患者中进行EGFR和Hedgehog抑制剂的合理驱动联合I期研究。该试验将包括为期两周的西妥昔单抗导入期，然后从第3周开始西妥昔单抗+IPI-926的组合。通过进行三次连续肿瘤活检（治疗前[d 0]、导入后[C1 D14]和联合治疗后[C1 D28]），我们将检验我们的假设：1）常规治疗后CSC蓄积，2）EGFR抑制剂诱导EMT，3）EGFR和Hedgehog抑制剂联合治疗通过抑制增殖细胞和CSC并预防EMT诱导抗肿瘤作用。候选人是理想的定位，以推动这种翻译从板凳到诊所，因为他参与了IPI-926的首次人体研究的主要研究者，他在CSC领域的经验和他独特的专业知识，在进行研究与多种肿瘤试验与药效学终点。 公共卫生相关性：我们的目标是在头颈癌患者中进行EGFR和Hedgehog抑制剂联合治疗的转化I期研究。我们建议调查从这些患者中连续活检的分子事件，这将阐明增殖和癌症干细胞治疗引起的变化。该项目是基于在申请人的实验室进行的临床前工作，该实验室确定了癌症干细胞对抗EGFR治疗产生耐药性。为此，他利用了一种新的直接患者肿瘤模型，他设计了将患者头颈癌植入小鼠体内。然后对这些干细胞进行分子表征，并与非祖细胞进行比较，这导致Hedgehog途径在这些祖细胞中的表达增加了500倍。含有抑制该途径的药物（IPI- 926）的组合在动物模型中实现了肿瘤治愈和前体细胞数量的减少。这支持将这些发现转化为临床。该提议的第一个独特特征是利用直接患者肿瘤模型，其允许保留构成肿瘤的所有隔室。第二个是实验室观察和临床研究的整合，因为申请人在他的实验室中使用IPI-926，并领导了IPI-926在实体瘤患者中的首次人体I期研究。正是这种整合允许有效的翻译，如这种癌症干细胞特异性治疗。这项拟议的临床试验代表了真正的假设驱动的药物开发和应用转化科学。

DESCRIPTION (provided by applicant): Epidermal growth factor receptor (EGFR) inhibition improves survival of head and neck squamous cell carcinoma (HNSCC) patients, but the overall efficacy is limited, and particularly when given in one of its indications (cetuximab single-agent in chemotherapy-refractory HNSCC) responses are low and prognosis is dismal. Cancer stem cells (CSC) have been implicated in resistance to anticancer therapies. Using an advanced patient-derived xenograft HNSCC model we have documented accumulation of CSC subpopulations after EGFR inhibitors, and have hypothesized that CSC are thus responsible for tumor recurrence. These CSC showed 500-fold over expression of the Hedgehog pathway compared with the non-CSC, proliferating cells. In addition, we observed that cetuximab induced SIP1/ZEB2 and TWIST that are promoters of epithelial to mesenchymal transition (EMT), also associated to resistance to EGFR inhibitors in HNSCC. Finally, we determined in vivo that a combination of EGFR and Hedgehog inhibitors decreased the CSC population, blocked EMT, and prevented re-growth of HNSCC tumors. The goal of this proposal is to conduct a rationally- driven combination Phase 1 study of EGFR and Hedgehog inhibitors in refractory HNSCC patients. The trial will include a cetuximab lead-in period of two weeks, followed by the combination of cetuximab plus IPI-926 starting in week 3. By conducting three seriated tumor biopsies (pre-treatment [d0], post-lead-in [C1D14], and post-combination [C1D28]) we will test our hypotheses that 1) CSC accumulate after conventional therapy, 2) EGFR inhibitors induce EMT, and 3) the combination of EGFR and Hedgehog inhibitors induces an antitumor effect by inhibiting both proliferating cells and CSC, and preventing EMT. The candidate is ideally positioned to drive this translation from the bench to the clinic given his involvement as principal investigator in the first-in- human study of IPI-926, his experience in the field of CSC and his unique expertise in conducting studies with multiple tumor testing with pharmacodynamic endpoints. PUBLIC HEALTH RELEVANCE: Our goal is to conduct a translational Phase 1 study combining EGFR and Hedgehog inhibitors in patients with head and neck cancer. We propose to investigate the molecular events in sequential biopsies taken from these patients, which will elucidate the variations induced by therapy in proliferating and cancer stem cells. This project is based on preclinical work conducted in the applicant's laboratory that identified cancer stem cells as responsible for resistance to anti-EGFR therapy. For this he utilized a novel direct patient tumor model he has devised implanting patient head and neck cancers in mice. These stem cells were then characterized molecularly and compared to non-progenitor cells, which led to the identification of the Hedgehog pathway as 500-fold more expressed in these progenitor cells. A combination containing a drug inhibiting this pathway (IPI- 926) achieved tumor cures and a reduction in the number of precursor cells in animal models. This supports translating these findings to the clinic. The first unique feature of this proposal is the utilization of a direct patient tumor model that allows the preservation of all the compartments that constitute a tumor. The second is the integration of laboratory observations and clinical research, since the applicant works with IPI-926 in his laboratory as well as leading the first-in-human Phase 1 study of IPI-926 in patients with solid tumors. It is that integration that permits an efficient translation such as this cancer stem cell-specific therapy. This proposed clinical trial represents truly hypothesis-driven drug development and applied translational science.