Leucoselect Phytosome for Neoadjuvant Treatment of Early Stage Lung Cancer

Leucoselect Phytosome 用于早期肺癌新辅助治疗

• 批准号: 10316152
• 负责人: JENNY T MAO
• 金额: --
• 依托单位: ALBUQUERQUE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316152
• 关键词: A549; Adverse reactions; Aftercare; Antineoplastic Agents; Apoptosis; Arachidonate 15-Lipoxygenase; Biological Availability; Biological Markers; Biological Monitoring; Biopsy; Blood; Bronchoalveolar Lavage; Bronchoscopy; C-reactive protein; CASP3 gene; Cancer Etiology; Cancer Patient; Cause of Death; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Colorectal Cancer; Common Terminology Criteria for Adverse Events; Consent; Country; Crude Extracts; Data; Development; Diagnosis; Diagnostic Procedure; Dinoprostone; Down-Regulation; Drug Kinetics; Early treatment; Eicosanoids; Eicosatetraenoic Acids; Enrollment; Epigenetic Process; Epoprostenol; Excision; Food Supplements; Future; Gene Expression Profile; Growth; Health Food; Human; Hydroxyeicosatetraenoic Acids; IGF Type 2 Receptor; IGF2R gene; Interleukin-10; Interleukin-12; Interleukin-6; Label; Lead; Lesion; Liquid substance; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Mediating; MicroRNAs; Monitor; Needles; Neoadjuvant Therapy; Newly Diagnosed; Non-Small-Cell Lung Carcinoma; Nude Mice; Operative Surgical Procedures; Oral; Oral Administration; Outcome; PTEN gene; Participant; Pathologic; Pathway interactions; Patients; Pharmacodynamics; Phase; Phospholipids; Phosphorylation; Physiological; Pilot Projects; Plasma; Probability; Procyanidins; Production; Proliferation Marker; Property; Prostaglandins I; Proto-Oncogene Proteins c-akt; Questionnaires; Recurrence; Resectable; Role; Safety; Sampling; Serum; Smoking; Specimen; Standardization; Structure of parenchyma of lung; Surrogate Endpoint; Telephone; Testing; Therapeutic; Time; Tissues; Toxic Environmental Substances; Tumor Immunity; Tumor Suppressor Proteins; Up-Regulation; Urine; Veterans; Visit; Xenograft procedure; anti-cancer; arm; base; biological specimen archives; cancer chemoprevention; cancer therapy; capsule; carcinogenicity; cardiovascular health; confirmatory clinical trial; confirmatory trial; effective therapy; follow-up; former smoker; grape seed; high risk; improved; indexing; inflammatory marker; insight; lymph nodes; malignant breast neoplasm; neoplastic cell; oncoprotein p21; pharmacokinetics and pharmacodynamics; pre-clinical; predict responsiveness; recruit; response; safety and feasibility; soy; treatment strategy; tumor; tumor xenograft

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.

充足的临床前数据表明，葡萄种子procyanidin提取物（GSE）具有多方面的抗癌 特性。 GSE已显示经常调节致癌机制，包括1）主要 类花生酸途径，例如对环氧酶（COX）-2/Prostaglandin（PG）E2的抑制作用，诱导 前列环蛋白合酶（PTGIS）/PGI2并增加15（S） - 羟基 - Eicosatetraenoic Acid（15-HETE）的产生； 2）oncomirs microRNA（mir）-19a，-19b的下调及其下游目标的上调 - 肿瘤 补充剂类胰岛素样生长因子II受体（IGF-2R）以及磷酸酶和Tensin同源物（PTEN）， 导致磷酸化（p）-akt的降低，以及oncomir miR-106b和 其靶标的上调 - 肿瘤抑制剂P21。最近，我们发现口服白许植物体 （LP）是一种与大豆磷脂相络合以增强生物利用度的标准化GSE，可显着抑制 人肺癌异种移植生长，减少支气管KI-67标记指数（增殖标记），有利 调节重的类固醇途径，并下调血清miR -19a，-19b和-106b 当前/前吸烟者。因此，我们假设口服LP是安全的，可以很好地调节 与肺癌相关的机制，可用于肺癌治疗。测试这些 假设是使用LP的单臂，IIA新辅助肺癌治疗研究，将在30中进行 新诊断，I期和II期可切除的肺癌的患者。 目标＃1：将确定2-3周的安全性，可行性和药代动力学（PK）/药效学（PD） 切除前I或II期非小细胞肺癌（NSCLC）患者的口服LP。受试者将同意 研究参与和档案的研究标本，包括血液，尿液和诊断 程序，例如支气管镜[支气管肺泡灌洗（BAL）流体和细胞，病变活检和淋巴 节点（LN）采样]和/或经胸针抽吸（TTNA）如临床上所示，可用作前 治疗样本。被诊断为可切除肺癌的合格受试者将被招募和治疗 约2-3周，直到手术切除。在手术时，包括BAL，LN，肺 肿瘤/邻近组织，血液和尿液将作为治疗样品收集以进行评估 适用时PK/生物利用度，PD和动作机制。口服LP的安全将每周监控 具有不良事件的NCI常见术语标准5.0版和不良反应问卷。 AIM＃2：确定I/ II期肺癌患者口服LP的抗肿瘤和机械作用。 LP的抗癌作用将通过比较其生物活性前与处理后的生物活性来评估 通过肿瘤病理反应的调制，降级，KI-67标记指数，激活的caspase 3 （凋亡标记），COX-2，PTGIS，15-LOX，PTEN，P-AKT，IGF2R； 2）炎症和抗肿瘤的标记 免疫力：PGE2，PGI2，15 -HETE，白介素（IL）-6，-10，-12，C反应蛋白（CRP），BAL，血浆和/或 肿瘤； 3）与癌症相关的BAL细胞和肿瘤中的特定基因表达谱； 4）表观遗传学 BAL细胞和肿瘤中的miRNA谱； 5）血清和肿瘤中的miR -19a，-19b和-106b。 AIM＃3：将验证miR-19a，miR-19b和miR-106b在介导的抗塑性效应中的作用 GSE和血清miR -19a，-19b和-106b作为替代端点生物标志物（SEBM）的实用性用于治疗 监视。在我们先前的研究中，我们发现GSE显着下调了众所周知的肺癌 人肺肿瘤细胞中的oncomirs miR -19a，-19b和-106b在裸小鼠中 以及在重量流域/前吸烟者的精华液中。 发现将为GSE/LP对肺癌的可行性和机械影响提供重要见解， 帮助识别SEBM并为将来的确认临床试验奠定了基础。