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

描述(申请人提供)：抑制表皮生长因子受体(EGFR)可提高头颈部鳞状细胞癌(HNSCC)患者的存活率，但总体疗效有限，尤其是在其适应症之一(化疗难治的HNSCC中给予西妥昔单抗)反应低且预后惨淡。肿瘤干细胞(CSC)与抗癌治疗的耐药有关。使用先进的患者来源的异种移植HNSCC模型，我们记录了EGFR抑制剂后CSC亚群的积累，并假设CSC因此与肿瘤复发有关。与非CSC相比，这些CSC显示Hedgehog通路的高表达500倍，增殖细胞。此外，我们观察到西妥昔单抗诱导SIP1/ZEB2和TWIST是上皮细胞向间充质转化(EMT)的促进剂，也与HNSCC对EGFR抑制剂的耐药有关。最后，我们在体内确定，EGFR和Hedgehog抑制剂的组合减少了CSC的数量，阻断了EMT，并防止了HNSCC肿瘤的再次生长。这项建议的目标是在难治性HNSCC患者中进行一项合理驱动的EGFR和Hedgehog抑制剂的联合第一阶段研究。该试验将包括为期两周的西妥昔单抗导入期，然后从第三周开始西妥昔单抗与IPI-926的联合应用。通过进行三次连续的肿瘤活检(治疗前[d0]、引入后[C1D14]和联合治疗后[C1D28])，我们将检验我们的假设，即1)CSC在常规治疗后积累，2)EGFR抑制剂诱导EMT，以及3)EGFR和Hedgehog抑制剂的组合通过抑制增殖细胞和CSC，以及预防EMT而诱导抗肿瘤作用。考虑到他作为IPI-926首个人类研究的首席研究员的参与、他在CSC领域的经验以及他在利用药效终点进行多肿瘤测试研究方面的独特专业知识，这位候选人处于推动这种从替补席到临床的理想位置。 公共卫生相关性：我们的目标是在头颈癌患者中进行一项结合EGFR和Hedgehog抑制剂的转化性第一阶段研究。我们建议研究这些患者连续活检中的分子事件，这将阐明在增殖和癌症干细胞治疗中诱导的变异。该项目是基于申请者实验室进行的临床前工作，该工作确定了癌症干细胞对抗EGFR治疗的耐药性。为此，他利用了他设计的一种新的直接患者肿瘤模型，将患者的头颈部癌症植入小鼠体内。然后对这些干细胞进行了分子特征分析，并与非祖细胞进行了比较，这导致了Hedgehog途径在这些祖细胞中的表达增加了500倍。一种含有抑制这一途径的药物(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应用。这一提议的第一个独特之处是利用了直接患者肿瘤模型，该模型允许保留构成肿瘤的所有隔室。第二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使用IPI-926，并领导了实体肿瘤患者的第一个人类IPI-926阶段研究。正是这种整合使这种癌症干细胞特异性疗法等有效转化成为可能。这项拟议的临床试验代表了真正的假说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.