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

EGFR与Hedgehog抑制剂合理联合治疗头颈癌

• 批准号: 8110769
• 负责人: Antonio Jimeno
• 金额: $ 31.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-08 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110769
• 关键词: Aftercare; Animal Model; Applications Grants; Biological Preservation; Biopsy; Cancer Etiology; Cell Count; Cells; Cessation of life; Cetuximab; Clinic; Clinical Research; Clinical Trials; Colon Carcinoma; Dose; Dose-Limiting; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erinaceidae; Event; Fine needle aspiration biopsy; Flow Cytometry; GLI gene; Gene Expression; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Implant; Laboratories; Lead; Malignant Squamous Cell Neoplasm; Malignant neoplasm of brain; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Modeling; Molecular; Mus; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phenotype; Population; Positioning Attribute; Principal Investigator; Proliferating; Receptor Inhibition; Recurrence; Refractory; Relapse; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Signal Transduction; Solid Neoplasm; Stem cells; Testing; Therapeutic; Tissues; Toxic effect; Transducers; Translating; Translational Research; Translations; Tumor-Derived; Uncertainty; Variant; Work; Xenograft procedure; aldehyde dehydrogenases; base; cancer stem cell; cancer therapy; chemotherapy; conventional therapy; drug development; epithelial to mesenchymal transition; experience; head and neck cancer patient; human study; improved; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; innovation; malignant breast neoplasm; melanoma; novel; open label; outcome forecast; phase 1 study; pre-clinical; precursor cell; prevent; promoter; prospective; receptor; response; smoothened signaling pathway; stem cell population; tumor; tumor initiation; tumorigenesis

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.

描述（由申请人提供）：表皮生长因子受体（EGFR）抑制可提高头颈鳞状细胞癌（HNSCC）患者的生存率，但总体疗效有限，特别是在其适应症之一（西妥昔单抗单药）中使用时在化疗难治性 HNSCC 中）反应较低，预后较差。癌症干细胞（CSC）与抗癌疗法的抵抗有关。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 是肿瘤复发的原因。与非 CSC 增殖细胞相比，这些 CSC 的 Hedgehog 通路表达量高出 500 倍。此外，我们观察到西妥昔单抗诱导 SIP1/ZEB2 和 TWIST，它们是上皮间质转化 (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 抑制剂的组合可以减少 CSC 数量，阻断 EMT，并防止 HNSCC 肿瘤的重新生长。该提案的目标是在难治性 HNSCC 患者中进行 EGFR 和 Hedgehog 抑制剂合理驱动的联合 1 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 周开始联合使用西妥昔单抗加 IPI-926。通过进行三个连续的肿瘤活检（治疗前 [d0]、导入后 [C1D14] ]，以及组合后[C1D28]）我们将测试我们的假设：1）常规治疗后 CSC 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并阻止EMT来诱导抗肿瘤作用。鉴于他作为 IPI-926 首次人体研究的主要研究者的参与、他在 CSC 领域的经验以及他在开展多项研究方面的独特专业知识，该候选人处于推动这种从实验室到临床转化的理想位置。具有药效学终点的肿瘤测试。 公共健康相关性：我们的目标是在头颈癌患者中开展一项结合 EGFR 和 Hedgehog 抑制剂的转化性 1 期研究。我们建议研究从这些患者身上采集的连续活检中的分子事件，这将阐明增殖和癌症干细胞治疗引起的变化。该项目基于申请人实验室进行的临床前工作，该工作确定癌症干细胞对抗 EGFR 疗法产生耐药性。为此，他利用了一种新颖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，从而确定 Hedgehog 通路在这些祖细胞中的表达量高出 500 倍。含有抑制该途径的药物 (IPI-926) 的组合实现了肿瘤治愈并减少了动物模型中前体细胞的数量。这支持将这些发现转化为临床。该提案的第一个独特特征是利用直接患者肿瘤模型，允许保存构成肿瘤的所有隔室。第二个是实验室观察和临床研究的结合，因为申请人在他的实验室中研究IPI-926，并领导了IPI-926在实体瘤患者中的首次人体1期研究。正是这种整合允许有效的翻译，例如这种癌症干细胞特异性疗法。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。