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）抑制作用可改善头颈鳞状细胞癌（HNSCC）患者的存活率，但总体功效受到限制，尤其是在其指示之一给出的（cetuximab单位抗体单位疗法中的单位疗法疗法疗法 - 重生HNSCC）的反应率低，并且较低。癌症干细胞（CSC）与对抗癌疗法的抗性有关。使用先进的患者衍生的异种移植HNSCC模型，我们记录了EGFR抑制剂后CSC亚群的积累，并假设CSC因此导致了肿瘤复发。与非CSC增殖细胞相比，这些CSC在刺猬途径的表达上显示出500倍。此外，我们观察到西妥昔单抗诱导的SIP1/ZEB2和扭曲是上皮启动子对间质转变（EMT）的启动子，也与HNSCC中对EGFR抑制剂的抗性有关。最后，我们在体内确定EGFR和刺猬抑制剂的组合减少了CSC群体，阻塞EMT并阻止了HNSCC肿瘤的重新生长。该提案的目的是对难治性HNSCC患者的EGFR和刺猬抑制剂进行合理驱动的组合1研究。该试验将包括两周的西素单抗铅铅，然后在第3周开始将西妥昔单抗加IPI-926组合。 EMT和3）EGFR和刺猬抑制剂的组合通过抑制增殖细胞和CSC并防止EMT来诱导抗肿瘤效应。鉴于他是IPI-926的首次研究，他在CSC领域的首次研究中，他作为首席研究员的参与，理想地将候选人从长凳上转变为诊所，以及他在通过药效端点进行多次肿瘤测试进行多次肿瘤测试方面的独特专业知识。 公共卫生相关性：我们的目标是进行翻译1研究，该研究结合了头颈癌患者的EGFR和刺猬抑制剂。我们建议研究从这些患者手中进行的顺序活检中的分子事件，这将阐明在增殖和癌症干细胞中治疗引起的变异。该项目基于申请人实验室中进行的临床前工作，该临床前研究确定癌症干细胞是抗抗EGFR治疗的抗性。为此，他利用了一种新型的直接患者肿瘤模型，他设计了将患者头部和颈部癌症植入小鼠。然后将这些干细胞分子表征并与非疾病细胞进行比较，这导致刺猬途径的鉴定为500倍，在这些祖细胞中表达了500倍。包含抑制该途径的药物的组合（IPI-926）可实现肿瘤治疗，并减少动物模型中的前体细胞数量。这支持将这些发现转化为诊所。该提案的第一个独特特征是利用直接患者肿瘤模型，该模型允许保存所有构成肿瘤的隔室。第二个是实验室观察和临床研究的整合，因为申请人在其实验室与IPI-926合作，并在实体瘤患者中领导IPI-926的第一阶段1期研究。正是这种融合允许进行有效的翻译，例如这种癌症干细胞特异性治疗。该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。