Leucoselect Phytosome for Neoadjuvant Treatment of Early Stage Lung Cancer

大量的临床前数据表明，葡萄籽原花青素提取物(GSE)具有多方面的抗癌作用 属性。GSE已被证明有利地调节致癌机制，包括1)主要 二十烷类化合物途径，如抑制环氧合酶(COX)-2/前列腺素(PG)E2，诱导 前列环素合成酶/前列腺素I_2，增加15-羟基二十碳四烯酸(15-HETE)的产量； 2)抑癌基因microRNA(MiR)-19a、-19b的下调及其下游靶点-肿瘤的上调 抑制胰岛素样生长因子II受体(IGF-2R)和磷酸酶及紧张素同源物(PTEN)， 导致磷酸化(P)-AKT减少，以及oncomiR miR-106b和 上调其靶点--肿瘤抑制因子P21。最近，我们发现口服亮氨酸选择植物小体 (LP)，一种与大豆磷脂复合以提高生物利用度的标准化GSE，显著抑制 人肺癌移植瘤生长良好，支气管Ki-67标记指数(增殖标志)降低 调节主要二十烷类化合物通路，下调重型患者血清miR-19a、-19b和-106b 现在/以前吸烟者。因此，我们假设口服LP是安全的，可以有利地调节 与肺癌癌变相关的机制，并可用于肺癌的治疗。为了测试这些 假设，使用LP的单臂IIa期新辅助肺癌治疗研究将于30年内进行。 新诊断、I期和II期可切除肺癌的患者。 目的1：确定2-3周的安全性、可行性和药代动力学(PK)/药效学(PD) I期或II期非小细胞肺癌(NSCLC)患者手术前口腔LP的变化。受试者将同意 用于研究的样本的研究参与和存档，包括血液、尿液和诊断 程序，如支气管镜检查[支气管肺泡灌洗(BAL)液和细胞，病变活检和淋巴 结节(LN)采样]和/或临床指征的经胸针吸(TTNA)，用作前 处理样本。被诊断为可切除肺癌的合格受试者将被纳入并接受治疗。 持续2-3周，直到手术切除。手术时取一系列临床标本，包括BAL、LN、肺 将采集肿瘤/邻近组织、血液和尿液作为治疗后样本进行评估 PK/生物利用度、PD和作用机制(如果适用)。每周对口服LP的安全性进行监测 使用NCI不良事件通用术语标准5.0版和不良反应问卷。 目的#2：探讨口服LP对I/II期肺癌患者的抗肿瘤作用及其机制。 LP的抗癌效果将通过比较其治疗前后的生物活性来评估。 通过调控肿瘤病理反应、下调分期、Ki-67标记指数、活化的caspase-3 (2)炎症和抗肿瘤标记物 免疫：BAL、血浆和/或BAL中PGE2、PGI2、15-HETE、IL-6、-10、-12、C反应蛋白 肿瘤；3)BAL细胞和肿瘤中与癌症相关的通路特异性基因表达谱；4)表观遗传学 BAL细胞和肿瘤的miRNA图谱；5)血清和肿瘤的miR-19a、-19b和-106b。 目的#3：将验证miR-19a、miR-19b和miR-106b在介导MIR-19a、miR-19b和miR-106b抗肿瘤效应中的作用 GSE和血清miR-19a、-19b和-106b作为替代终点生物标志物(SEBM)在治疗中的应用 监控。在我们之前的研究中，我们发现GSE显著下调了众所周知的肺癌的表达 人肺肿瘤细胞和A549裸鼠移植瘤中的oncomir miR-19a、-19b和-106b 在大量吸烟者的血清中也是如此。 这些发现将为GSE/LP抗肺癌的可行性和机制效应提供重要的见解。 帮助确定SEBM，并为未来的验证性临床试验奠定基础。

Ample preclinical data suggests that grape seed procyanidin extract (GSE) possesses multi-faceted anticancer properties. GSE has been shown to favorably modulate carcinogenic mechanisms, including 1) major eicosanoids pathways, such as inhibitions of cyclocoxygenase (COX)-2/prostaglandin (PG)E2, induction of prostacyclin synthase (PTGIS)/PGI2 and increase production of 15(S)-hydroxy-eicosatetraenoic acid (15-HETE); 2) downregulation of oncomirs microRNA (miR)-19a, -19b and up-regulations of their downstream targets - tumor suppressors insulin-like growth factor II receptor (IGF-2R) and phosphatase and tensin homolog (PTEN), resulting in reduction of phosphorylated (P)-AKT, as well as downregulation of oncomir miR-106b and upregulation of its target – the tumor suppressor P21. Recently, we have found that oral leucoselect phytosome (LP), a standardized GSE complexed with soy phospholipid to enhance bioavailability, significantly inhibited human lung cancer xenograft growth, reduced bronchial Ki-67 labeling index (a marker of proliferation), favorably modulated major eicosanoids pathways, and downregulated serum miR-19a, -19b, and -106b in heavy current/former smokers. We therefore hypothesize that oral administration of LP is safe, can favorably modulate mechanisms associated with lung cancerization, and be useful for lung cancer treatment. To test these hypotheses, a single arm, phase IIa neoadjuvant lung cancer treatment study using LP, will be conducted in 30 patients with newly diagnosed, stage I and II resectable lung cancer. Aim #1: will determine the safety, feasibility and pharmacokinetics (PK)/pharmacodynamics (PD) of 2-3 weeks of oral LP in stage I or II nonsmall cell lung cancer (NSCLC) patients prior to resection. Subjects will consent to study participation and archive of specimens for research, including blood, urine, and from diagnostic procedures, such as bronchoscopy [bronchoalveolar lavage (BAL) fluid and cells, lesion biopsies and lymph node (LN) sampling] and/or transthoracic needle aspiration (TTNA) as clinically indicated, to be used as pre- treatment samples. Qualified subjects who are diagnosed with resectable lung cancer will be enrolled and treated for ~2-3 weeks until surgical resection. At the time of surgery, serial clinical specimens, including BAL, LN, lung tumor/adjacent tissue, blood and urine will be collected as post-treatment samples for assessing PK/bioavailability, PD and mechanism of actions when applicable. The safety of oral LP will be monitored weekly with the NCI common terminology criteria for adverse events Version 5.0 and adverse reaction questionnaires. Aim #2: To determine the antineoplastic and mechanistic effects of oral LP in stage I/ II lung cancer patients. The anticancer effects of LP will be assessed by comparing its bioactivity pre- vs. post-treatment, as measured by modulations of tumor pathological response, downstaging, Ki-67 labeling index, activated caspase 3 (apoptosis marker), COX-2, PTGIS, 15-LOX, PTEN, P-AKT, IGF2R; 2) markers of inflammation and antitumor immunity: PGE2, PGI2, 15-HETE, interleukin (IL)-6, -10, -12, C reactive protein (CRP) In BAL, plasma, and/or tumors; 3) cancer-relevant, pathway specific gene expression profile in BAL cells and tumors; 4) epigenetic miRNA profile in BAL cells and tumors; 5) miR-19a, -19b, and -106b in serum and tumors. Aim #3: will validate the roles of miR-19a, miR-19b, and miR-106b in mediating the anti-neoplastic effects of GSE and the utility of serum miR-19a, -19b, and -106b as surrogate endpoint biomarkers (SEBM) for therapeutic monitoring. In our previous studies, we found that GSE significantly down-regulated well-known lung cancer oncomirs miR-19a, -19b, and -106b in human lung neoplastic cells and A549 xenograft tumors in nude mice, as well as in the serum of heavy current/former smokers. Findings will provide important insights into the feasibility and mechanistic effects of GSE/LP against lung cancer, help identify SEBM and set the stage for future confirmatory clinical trials.