Chemopreventive Agent-Responsive Genes in Oral Cancer

描述（由申请人提供）：癌症化学预防被定义为使用天然或合成试剂，组合或单独使用，以抑制，延迟或逆转致癌过程，并被认为是癌症研究的一个非常有前途的领域。许多流行病学研究表明，经常食用新鲜水果和蔬菜与降低癌症风险之间存在很强的相关性。通过以食物为基础的癌症化学预防方法，重点放在整个食物中预防剂的复杂混合物抑制多种致癌过程的潜力上。为了支持这种方法，已经进行了几项临床前动物研究，证明了黑树莓对化学诱导的呼吸消化道肿瘤发展的显着化学预防活性，包括口腔，食道和结肠。虽然这种化学预防现象在癌症动物模型中引人注目，但黑树莓对人类癌症发展的化学预防潜力尚未研究。本提案本质上是翻译性的，并努力将这种水果的化学预防评估扩展到人类口腔癌的问题。我们的初步研究表明，冻干的黑树莓（LBR）提取物显着抑制来自人口腔鳞状细胞癌的细胞的体外增殖，这表明LBR成分在体内对口腔癌的化学预防是可能的。因此，我们假设LBR将调节与关键生物学途径相关的关键基因的表达，这可能最终导致致癌过程的抑制、延迟或逆转。我们将首先确定全球基因表达谱的变化，以响应黑树莓治疗的人口腔癌细胞在体外（具体目标1），然后确定黑树莓的能力，以调节类似的基因表达谱在原代人口腔癌细胞在体内通过1B期研究（具体目标2）。这些新的研究将是第一个研究天然食品对人类口腔肿瘤发生的化学预防和分子作用。此外，这些数据将提供一个合适的基础，从未来的化学预防研究，使用LBR或其他化学预防剂的目标响应基因将进行手术后的患者或那些与癌前病变。

DESCRIPTION (provided by applicant): Cancer chemoprevention is defined as the use of natural or synthetic agents, in combination or alone, to inhibit, delay, or reverse the carcinogenic process and is recognized as a very promising area of cancer research. Numerous epidemiological studies have shown the strong correlation between frequent consumption of fresh fruits and vegetables and a decreased cancer risk. With a food-based approach to cancer chemoprevention, emphasis is placed on the potential for complex mixtures of preventive agents in whole food to inhibit multiple processes of carcinogenesis. In support of this approach, several preclinical animal studies have been conducted that demonstrate the remarkable chemopreventive activity of black raspberries on chemically-induced aerodigestive tract tumor development, including oral, esophagus, and colon. While this chemopreventive phenomenon is striking in animal models of cancer, the chemopreventive potential of black raspberries on human cancer development remains unstudied. The present proposal is fundamentally translational in nature and strives to extend the chemopreventive assessment of this fruit to the problem of human oral cancer. Preliminary studies by us have shown that an extract of lyophilized black raspberries (LBR) dramatically inhibits the in vitro proliferation of cells derived from a human oral squamous cell carcinoma, suggesting that the chemoprevention of oral cancer by LBR components in vivo is possible. We therefore hypothesize that LBR will modulate the expression of critical genes associated with key biological pathways which may ultimately result in the inhibition, delay or reversal of the carcinogenic process. We will first identify changes in the global gene expression profiles in response to black raspberry treatment of human oral cancer cells in vitro (Specific Aim 1) and then determine the ability of black raspberries to modulate similar gene expression profiles in primary human oral cancer cells in vivo through a Phase 1B study (Specific Aim 2). These novel studies will be the first to examine the chemopreventive and molecular effects of a natural food product on human oral tumorigenesis. Additionally, these data will provide a suitable foundation from which future chemopreventive studies using LBR or other chemopreventive agents that target responsive genes will be conducted in post-surgical patients or those presenting with premalignant lesions.