Chemoprevention of Oral Cancer with BBIC

描述(申请人提供)：这项建议的长期目标是确定从大豆中提取的蛋白酶抑制剂Bowman-Birk Inhibitor(BBI)浓缩物(C)是否可以导致口腔白斑的消退，以及某些候选中间标志物终点是否可以替代口腔白斑来预测疗效。这项研究的最终目标是预防人类癌症。 具体目标是： (1)应用BBIC对口腔白斑患者进行安慰剂对照、双盲、随机6个月期Lib癌化学预防试验。 (A)测定口腔白斑对BBIC的临床和组织学反应率。 (B)连续测量BBIC对中间标记终点(IME)的影响。 1)检测口腔黏膜细胞的蛋白分解活性(PA)、erb-B2(Neu)、维甲酸受体β(RAR-β)、bcl2和突变型P53蛋白的表达水平。 2)在口腔白斑病变的组织活检中，后四种蛋白也将 免疫组织化学方法检测。 3)在血清中，将连续测量neu蛋白的水平。 (C)探讨口腔白斑的临床和组织学反应与PA、erb-B2(Neu)、RAR-β、bcl2、突变型P53表达和血清neu水平的关系。 (D)确定BBIC的个人和群体副作用。 (2)对那些在最初6个月试验后达到PR或CR的患者进行长期(1年)随访 根据Ila期和LIB早期结果，我们估计大约25%-35%的患者 完成6个月的BBIC课程将属于这一类。将测量为特定目标1概述的相同参数。我们将特别注意依从性和毒性，因为我们最终希望将BBIC用于第二种恶性肿瘤预防的长期环境中。 这些第二阶段IME试验的所有方面都将通过NCI批准的数据安全和监测委员会(DSMB)并与NCI协调进行持续的本地评估来仔细监测合规性、安全性和毒性。这些研究的结果应该为头颈癌的大型III期随机降低风险试验提供实质性的生物学和治疗理论基础，并为进一步探索这些无毒化合物作为人类化学预防药物提供动力。

DESCRIPTION (provided by applicant): The long term objective of this proposal is to determine whether Bowman-Birk Inhibitor (BBI) Concentrate (C), a protease inhibitor extracted from soybeans, can cause regression of oral leukoplakia and whether certain candidate intermediate marker endpoints can predict response by serving as a surrogate for oral leukoplakia. The ultimate goal of this research is to prevent human cancer. The specific aims are: (1) To conduct a placebo-controlled, double-blind and randomized 6 month phase lib cancer control chemoprevention trial of BBIC in patients with oral leukoplakia. (a) To determine the clinical and histologic response rate of oral leukoplakia to BBIC. (b) To serially measure the effect of BBIC on intermediate marker endpoints (IME). 1) In oral mucosal cells the level of proteolytic activity (PA) and levels of erb-B2 (neu), retinoic acid receptor beta (RAR-beta), bcl-2, and mutant p53 protein will be measured. 2) In tissue biopsies of oral leukoplakia lesions the latter four proteins above will also be measured by immunohistochemistry. 3) In serum, the levels of the protein, neu, will be serially measured. (c) To correlate the clinical and histologic responses of oral leukoplakia to the effect on cellular levels of PA, erb-B2 (neu), RAR-beta, bcl-2, and mutant p53 expression, and serum levels of neu. (d) To determine the individual and group side-effects to BBIC. (2) To follow long term (one year) those patients who achieve a PR or CR afterthe initial 6 months trial Based on the phase Ila and early phase lib results we estimate that about 25-35% of patients completing the 6 months of BBIC will fall in this category. The same parameters outlined for specific aim 1 will be measured. Particular attention will be paid to adherence and toxicity as we eventually wish to use BBIC in the long term setting of second malignancy prevention. All aspects of these phase II IME trials will be carefully monitored for compliance, safety, and toxicity by continuous local evaluation by our NCI-approved Data Safety and Monitoring Board (DSMB) and in concert with the NCI. The results from these studies should provide a substantial biologic and therapeutic rationale for a large Phase III randomized risk reduction trial of head and neck cancer as well as provide impetus for further exploration of these non-toxic group of compounds as chemopreventive agents in humans.