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

摘要表皮生长因子受体（EGFR）抑制剂是头颈部鳞状细胞癌（HNSCC）的标准治疗方法，但疗效较低，耐药（原发性或获得性）几乎普遍存在。我们建立了一种独特的HNSCC直接患者肿瘤模型（DPTM），该模型最适合研究癌症干细胞（CSC）。我们发现假定的CSC在治疗后在肿瘤中富集，在分选和植入后能够产生肿瘤，并且在与CSC相关的hedgehog通路中具有非常强烈的信号。我们的首要目标是识别和描述CSC以及它们可能具有的漏洞。在本研究计划中，我们计划确定CSC及其通过hedgehog基因信号传导在对常规疗法，特别是EGFR抑制剂的抗性中的作用。首先，我们将确定真正的CSC，并将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抑制的合理组合。最后，我们将在接受常规治疗的HNSCC患者样本中验证上述观察结果。这些研究的意义在于，它们将帮助我们了解对目前使用的治疗方法产生耐药性的基础。本项目测试了hedgehog信号在CSC中的相关性以及hedgehog通路在HNSCC中的相关性。如果结果是积极的，这些数据将为在临床试验中探索hedgehog基因抑制剂在HNSCC中的应用提供依据，为这些患者增加新的潜在途径。两者都是相关的未满足需求。

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.