Cancer Initiating Cells and Treatment Resistance

 描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)是第六种最常见的癌症，每年全球发病率约为60万例(1)。在过去的几十年里，HNSCC的诊断和治疗取得了进展，然而，5年生存率一直保持在50%左右。化疗耐药、局部复发和远处转移是HNSCC患者发病和死亡的主要原因。癌症起始细胞(CICs)或癌症干细胞是肿瘤内的一小部分癌细胞，具有分裂和扩大CIC池或分化为构成肿瘤主体的异质非致瘤细胞的独特能力。有新的证据表明，CICs对化疗和放射治疗无效，并与疾病的复发和进展有关。因此，消除CICs将对HNSCC患者的生存产生巨大的积极影响。人乳头状瘤病毒(HPV)被认为是HNSCC，尤其是口咽部SCC的危险因素。HPV16是最常见的亚型，约占HPV阳性HNSCC的90%。与HPV阴性的HNSCC患者相比，HPV16阳性的HNSCC患者往往因更多的结节受累而出现更晚期的疾病。矛盾的是，有相当多的证据表明，与以铂为基础的方案治疗HPV阴性的HNSCC相比，HPV16阳性的HNSCC具有更好的预后。在HNSCC研究CIC生物学的同时，我们积累了有趣的实验证据来解释这些看似自相矛盾的临床观察。我们发现HPV16阳性和HPV阴性的HNSCC细胞在数量和表型上有显著差异。HPV16阳性的HNSCC比HPV阴性的HNSCC具有更高的固有CIC池。令人惊讶的是，HPV16阳性的CIC对顺铂治疗的反应显著高于HPV阴性的CIC。这一发现违反了CIC假说，即CIC对传统疗法普遍耐药，并提供了有趣的证据，表明CIC对标准化疗药物顺铂的反应是不同的。在这项应用中，我们将利用我们的初步数据来研究与HNSCC的CIC生物学相关的临床问题。HPV16如何调节CICs对顺铂和/或辐射的反应？P300在调节HNSCC CICs治疗反应中的作用是什么？我们如何对HPV阴性的HNSCC CIC重新编程，以对传统治疗方式做出反应？在这项拟议的工作结束时，我们将为CIC生物学提供新的见解，可能导致创新疗法的进步，以消融治疗耐药的HPV阴性HNSCC CIC人群。

 DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer with an annual incidence of approximately 600,000 cases worldwide (1). Over the last several decades, diagnosis and management of HNSCC have advanced; however, the 5-year survival rate has remained static at around 50%. Treatment resistance, local-regional recurrence and distant metastasis are the major causes of morbidity and mortality in HNSCC patients. Cancer initiating cells (CICs) or cancer stem cells are a small sub-set of cancer cells within the tumor with the exclusive capacity to divide and expand the CIC pool or to differentiate into heterogeneous non-tumorigenic cells that constitute the bulk of the tumor. There is emerging evidence that CICs are refractory to chemotherapy and radiation and responsible for disease recurrence and progression. Therefore, elimination of CICs will have a dramatic positive impact on the survival of HNSCC patients. Human papillomavirus (HPV) is recognized as a risk factor for the development of HNSCC in particular oropharyngeal SCC. HPV16 is the most prevalent subtype and accounts for ~90% of HPV-positive HNSCC. Patients with HPV16-positive HNSCC tend to present to the clinic with more advanced disease due to increased nodal involvement than patients with HPV-negative HNSCC. Paradoxically, there is considerable evidence that HPV16-positive HNSCC has superior outcome compared to HPV-negative HNSCC treated with platinum- based regimens. While working on CIC biology in HNSCC, we accumulated intriguing experimental evidence to explain these seemingly paradoxical clinical observations. We found a striking difference in the number and phenotype between HPV16-positive and HPV-negative HNSCC CICs. HPV16-positive HNSCC has a higher intrinsic CIC pool than HPV-negative HNSCC. Surprisingly, HPV16-positive CICs are dramatically more responsive to cis-platinum treatment then HPV-negative CICs. This finding contradicts the "CIC hypothesis" postulate that CICs are universally resistant to conventional therapies and provide intriguing evidence that CICs are heterogeneous in response to a standard chemotherapeutic, cis-platinum. In this application, we will leverage our preliminary data to study clinically relevant questions regarding CIC biology in HNSCC. How does HPV16 modulate CICs to respond to cis-platinum and/or radiation? What is the role of p300 in modulating treatment response in HNSCC CICs? And how do we reprogram HPV-negative HNSCC CICs to respond to conventional treatment modalities? At the conclusion of this proposed work, we will provide novel insights into CIC biology that may lead to the advancement of innovative therapeutics to ablate the treatment-resistant HPV-negative HNSCC CIC population.