Clinical evaluation of a bioadhesive gel for oral cancer chemoprevention.

描述(申请人提供)：晚期口腔鳞状细胞癌(口腔SCCs)的预后仍然是实体肿瘤中最低的。显然，早期发现口腔鳞癌的前驱病变，即口腔上皮异型增生，结合局部干预策略，如化学预防，可以显著改善临床结果。虽然口腔癌的化学预防是一个有吸引力的概念，但迄今为止尝试的治疗主要依赖于全身给药，已被证明在很大程度上是无效的。我们已经证明了冷冻干燥的黑树莓(FBR)在体外和体内水平上都具有预防癌症的特性。此外，我们的实验室最近完成了一项试点I/II期临床试验，要求将含有10%FBR的生物黏附凝胶局部应用于口腔发育不良皮损(0.5克，每天4次，持续6周)。实验数据显示，凝胶应用显著减少了与肿瘤抑制基因相关的基因的杂合性指数(LOH)，降低了皮损上皮的组织学分级，减少了与RNA加工、生长因子循环和抑制细胞凋亡相关的基因的表达，减少了皮损血管的生成，并显著降低了皮损上皮环氧合酶2(COX-2)的水平。此外，与使用天然产品一致，在10名正常对照参与者或20名患有口腔癌前病变的参与者中都没有观察到有害影响。虽然这些数据是有希望的，但这是一项试验性研究，需要较短的治疗时间(6周)，并且只评估了活性凝胶配方。一项持续时间更长的、安慰剂对照的多中心研究是推进这一化学预防项目的合乎逻辑和必要的步骤。尽管切除了显微镜下清晰的手术切缘，大约30%的口腔发育不良病变仍会复发。此外，尽管大约33%的口腔癌前病变会进展为口腔鳞状细胞癌，但我们目前无法预测哪些病变将发生恶变。识别无毒、有效的化学预防化合物，为口腔发育不良病变提供治疗相关水平的制剂，有可能对临床结果产生积极影响。根据我们的体外、体内和临床数据，我们认为较长的治疗时间(3个月)将增强10%FBR凝胶的化学预防效果。因此，我们提出了以下具体目标：具体目标1：通过评估选定的临床相关、易于量化的评估参数，评估局部应用10%FBR凝胶(0.5克，每天4次，持续3个月)对显微镜下记录的口腔上皮异常增生性病变的化学预防效果。具体目标2：确定局部应用安慰剂凝胶(相同的凝胶基质，没有FBR，相同的应用程序)对显微镜确认的口腔上皮异常增生性病变的影响。将评估相同的评估参数。 公共卫生意义：鳞状细胞癌是头颈部的主要癌症，2009年将影响超过35,000名美国人，导致约7,600人死亡。此外，尽管许多癌症的治疗取得了显著进展，但被诊断患有头颈癌的个人的总体预后仍然是所有实体肿瘤中最低的。为了帮助解决这一担忧，我们建议进行一项安慰剂对照临床试验，以测试一种基于天然产品的生物黏附凝胶的预防口腔癌效果，该凝胶在我们之前的试点研究中证明了有希望的结果。

DESCRIPTION (provided by applicant): The prognosis for advanced stage oral squamous cell carcinomas (oral SCCs) remains among the lowest of solid tumors. Clearly, early detection of the precursor lesion for oral SCC i.e. oral epithelial dysplasia combined with local intervention strategies, such as chemoprevention, could dramatically improve clinical outcomes. While oral cancer chemopreventive is an attractive concept, the treatments attempted to date, which relied primarily on systemic agent administration, have proven to be largely ineffective. We have demonstrated that freeze dried black raspberries (FBR) possess cancer preventing properties at both the in vitro and in vivo levels. Further, our laboratories recently completed a pilot Phase I/II clinical trial that entailed topical application of a bioadhesive gel that contained 10% FBR to oral dysplastic lesions (0.5 gm 4-times per day for 6 weeks). Trial data show that gel application significantly reduced loss of heterozygosity indices (LOH) at loci associated with tumor suppressor genes, decreased histologic grades of lesional epithelium, reduced expression of genes associated with RNA processing, growth factor recycling and inhibition of apoptosis, decreased lesional angiogenesis and significantly reduced lesional epithelial cyclooxygenase 2 (COX-2) levels. Furthermore, consistent with the use of a natural product, no deleterious effects were observed in either the 10 normal control participants or the 20 participants with premalignant oral lesions. While these data are promising, this was a pilot study which entailed short treatment duration (6 weeks) and only evaluated the active gel formulation. A longer duration, placebo-controlled, multicenter study is the logical and necessary step to move this chemopreventive project forward. Approximately 30% of oral dysplastic lesions recur despite excision with microscopically clear surgical margins. Further, although approximately 33% of premalignant oral lesions will progress to oral SCC, we are unable at this time to predict which lesions will undergo malignant transformation. Identification of nontoxic, effective chemopreventive compounds delivered in formulations that provide therapeutically relevant levels to oral dysplastic lesions, has the potential to positively impact clinical outcomes. Based on our in vitro, in vivo and clinical data we propose that longer treatment duration (3 months) will augment the chemopreventive efficacy of the 10% FBR gel. Accordingly, we propose the following Specific Aims: Specific Aim 1: Assess chemopreventive efficacy of topical application of a10% FBR gel (0.5 gm, four times a day, for 3 months) on microscopically documented oral epithelial dysplastic lesions by evaluating effects on selected clinically relevant, readily quantifiable, evaluative parameters. Specific Aim 2: Determine the effects of topical application of a placebo gel (identical gel base, absence of FBR, same application schedule) on microscopically confirmed oral epithelial dysplastic lesions. Identical evaluative parameters will be assessed. PUBLIC HEALTH RELEVANCE: Squamous cell carcinoma, which is the primary cancer that develops in the head and neck region, will affect over 35,000 Americans in 2009, resulting in approximately 7,600 American deaths. Further, despite marked treatment advances for many cancers, the overall prognosis for individuals diagnosed with head and neck cancer remains among the lowest of all solid tumors. To help address this concern, we propose to conduct a placebo-controlled clinical trial to test the oral cancer preventing effects of a natural product based bioadhesive gel that demonstrated promising results in our previous pilot study.