Clinical evaluation of a bioadhesive gel for oral cancer chemoprevention.

描述（由申请人提供）：晚期口腔鳞状细胞癌（oral SCCs）的预后仍然是实体肿瘤中最低的。显然，早期发现口腔鳞状细胞癌的前体病变，即口腔上皮异常增生，并结合局部干预策略，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，冷冻干燥的黑覆盆子（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验性I/II期临床试验，该试验涉及将含有10% FBR的生物粘合剂凝胶局部应用于口腔发育不良病变（每天4次，每次0.5克，持续6周）。试验数据显示，凝胶应用可显著降低肿瘤抑制基因相关位点杂合度指数（LOH）的损失，降低病变上皮的组织学分级，降低与RNA加工、生长因子循环和细胞凋亡相关基因的表达，减少病变血管生成，显著降低病变上皮环氧化酶2 （COX-2）水平。此外，与使用天然产品一致，在10名正常对照参与者和20名患有癌前口腔病变的参与者中均未观察到有害影响。虽然这些数据很有希望，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制剂。更长时间、安慰剂对照、多中心的研究是推动这一化学预防项目向前发展的合乎逻辑和必要的步骤。大约30%的口腔发育不良病变，尽管在显微镜下切除了清晰的手术边缘，仍会复发。此外，尽管大约33%的口腔癌前病变会发展为口腔SCC，但我们目前还无法预测哪些病变会发生恶性转化。鉴别出无毒、有效的化学预防化合物，这些化合物在配方中提供治疗相关水平的口腔发育不良病变，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，我们建议延长治疗时间（3个月）将增加10% FBR凝胶的化学预防效果。因此，我们提出以下具体目标：具体目标1：通过评估对选定的临床相关的、易于量化的评估参数的影响，评估局部应用10% FBR凝胶（0.5 gm，每天4次，连续3个月）对显微镜下记录的口腔上皮发育不良病变的化学预防效果。特定目标2：确定局部应用安慰剂凝胶（相同的凝胶基，不含FBR，相同的应用程序）对显微镜下确认的口腔上皮发育不良病变的影响。将评估相同的评价参数。

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.