Hedgehog signaling in head and neck cancer stem cells, and its role in resistance

描述（由申请人提供）：头颈癌干细胞中的Hedgehog信号传导及其在EGFR抑制剂抗性中的作用摘要表皮生长因子受体（EGFR）抑制剂是头颈鳞状细胞癌（HNSCC）的标准治疗，但功效低且抗性（原发性或获得性）几乎是普遍的。我们已经产生了一个独特的HNSCC直接患者肿瘤模型（DPTM），这是研究癌症干细胞（CSC）的最佳选择。我们已经发现了假定的CSC，其在治疗后在肿瘤中富集，并且能够在分选和植入后产生肿瘤，并且在与CSC相关的刺猬途径中具有非常强烈的信号传导。我们的首要目标是识别和描述CSC及其可能存在的漏洞。在这项研究计划中，我们计划确定CSC及其信号转导通过刺猬在抵抗常规疗法，特别是EGFR抑制剂中的作用。首先，我们将确定真正的CSC，并通过遗传手段敲除该途径。然后，我们将进行先进的动物研究，测试常规治疗与药物hedgehog抑制的合理组合。最后，我们将在接受常规治疗的HNSCC患者的样本中测试上述观察结果中的一些作为验证。这些研究的意义在于，它们将帮助我们了解对目前使用的疗法产生耐药性的基础。该项目测试CSC中hedgehog信号传导和HNSCC中hedgehog通路的相关性。如果是阳性的，这些数据将为在临床试验中探索HNSCC中的hedgehog抑制剂提供依据，为这些患者增加新的潜在途径。两者都是未满足的相关需求。 公共卫生相关性： 该项目的总体目标是表征负责头颈癌治疗失败的前体或癌症干细胞，并确定其易感性。我们将使用直接来自患者肿瘤的头颈癌模型。虽然比其他更简单的模型更麻烦，但这些肿瘤更忠实地代表了癌症的不同组成部分，因此信息量更大。我们已经发现，一种特殊的途径参与了这些储备细胞在治疗中的存活，由于我们有可用的抑制剂，我们计划单独测试它们的疗效，并与常规化疗一起使用。因为我们的团队也在患者身上测试相同的药物，如果我们有任何相关的发现，我们将处于一个非常有利的位置，开始在头颈癌患者身上进行测试。我们还将寻求方法来确定哪些患者将从这些药物中受益，以个性化癌症治疗。

DESCRIPTION (provided by applicant): Hedgehog signaling in head and neck cancer stem cells, and its role in resistance to EGFR inhibitors Abstract Epidermal growth factor receptor (EGFR) inhibitors are standard of care in head and neck squamous cell cancer (HNSCC) but the efficacy is low and resistance (primary or acquired) is almost universal. We have generated a unique direct patient tumor model (DPTM) of HNSCC that is optimal to study cancer stem cells (CSC). We have found putative CSC that are enriched in tumors after therapy and are able to generate tumors after sorting and implantation, and that have very intense signaling in the hedgehog pathway that is associated with CSC. Our overarching goal is to identify and characterize CSC and what vulnerabilities they may have. In this research proposal we plan to ascertain the role of CSC and their signaling through hedgehog in resistance to conventional therapies, particularly EGFR inhibitors. First we will identify bona fide CSC, and will knockdown the pathway by genetic means. Then, we will conduct advanced animal studies testing rational combinations of conventional therapy with pharmacological hedgehog inhibition. Finally we will test some of the above observations in samples from HNSCC patients undergoing conventional therapy as validation. The significance of these studies is that they will help us understand the basis of resistance to therapies that are in current use. This project tests both the relevance of hedgehog signaling in CSC and of the hedgehog pathway in HNSCC. If positive, these data will provide the rationale to explore hedgehog inhibitors in HNSCC in clinical trials, adding a new potential avenue for these patients. Both are relevant unmet needs. PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to characterize the precursor or cancer stem cells that are responsible for treatment failures in head and neck cancer, and identify their susceptibility. We will use a model of head and neck cancer that is derived directly from patient's tumors. Although more cumbersome to work with than other simpler models, these tumors more faithfully represent the different components of a cancer, and thus are more informative. We have found that a particular pathway is involved in allowing those reserve cells to survive treatment, and since we have inhibitors available we plan to test their efficacy alone, and with regular chemotherapy. Because our group is also testing the same drugs in patients, if we make any relevant discovery we will be in a very good position to initiate testing in head and neck cancer patients. We will also seek ways to determine what patients will benefit from these drugs, to individualize caner therapy.