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: 10013949
• 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/10013949
• 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.

大量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 特性。 GSE 已被证明可以有利地调节致癌机制，包括 1) 主要 类二十烷酸途径，例如抑制环加氧酶 (COX)-2/前列腺素 (PG)E2、诱导 前列环素合酶 (PTGIS)/PGI2 并增加 15(S)-羟基二十碳四烯酸 (15-HETE) 的产生； 2) Oncomirs microRNA (miR)-19a、-19b的下调及其下游靶标——肿瘤的上调 抑制胰岛素样生长因子 II 受体 (IGF-2R) 以及磷酸酶和张力蛋白同源物 (PTEN)， 导致磷酸化 (P)-AKT 减少，以及 oncomir miR-106b 和 上调其靶标——肿瘤抑制因子 P21。最近，我们发现口服 leucoselect phytosome (LP)，一种与大豆磷脂复合的标准化 GSE，可提高生物利用度，显着抑制 人肺癌异种移植物生长，支气管 Ki-67 标记指数（增殖标记）降低，有利 调节主要类二十烷酸途径，并下调重度患者血清 miR-19a、-19b 和 -106b 当前/以前的吸烟者。因此，我们假设口服 LP 是安全的，可以有利地调节 与肺癌发生相关的机制，可用于肺癌的治疗。为了测试这些 假设，一项使用 LP 的单臂 IIa 期新辅助肺癌治疗研究将在 30 年进行 新诊断的 I 期和 II 期可切除肺癌患者。 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) I 期或 II 期非小细胞肺癌 (NSCLC) 患者切除前的口服 LP。受试者将同意 研究参与和研究样本存档，包括血液、尿液和诊断样本 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 根据临床指示，进行淋巴结（LN）取样]和/或经胸针吸活检（TTNA），用作预 处理样品。被诊断患有可切除肺癌的合格受试者将被纳入并接受治疗 约2-3周直至手术切除。手术时，一系列临床标本，包括 BAL、LN、肺 肿瘤/邻近组织、血液和尿液将被收集作为治疗后样本用于评估 适用时的 PK/生物利用度、PD 和作用机制。每周都会监测口服 LP 的安全性 符合 NCI 不良事件通用术语标准 5.0 版和不良反应调查问卷。 目标#2：确定口服 LP 对 I/II 期肺癌患者的抗肿瘤作用和机制作用。 LP 的抗癌作用将通过比较治疗前与治疗后测量的生物活性来评估 通过调节肿瘤病理反应、降期、Ki-67 标记指数、激活 caspase 3 (细胞凋亡标记物)、COX-2、PTGIS、15-LOX、PTEN、P-AKT、IGF2R； 2）炎症和抗肿瘤标志物 免疫：PGE2、PGI2、15-HETE、白细胞介素 (IL)-6、-10、-12、C 反应蛋白 (CRP) BAL、血浆和/或 肿瘤； 3) BAL 细胞和肿瘤中与癌症相关的途径特异性基因表达谱； 4）表观遗传 BAL 细胞和肿瘤中的 miRNA 谱； 5) 血清和肿瘤中的miR-19a、-19b和-106b。 目标#3：将验证 miR-19a、miR-19b 和 miR-106b 在介导抗肿瘤作用中的作用 GSE 以及血清 miR-19a、-19b 和 -106b 作为治疗替代终点生物标志物 (SEBM) 的用途 监控。在我们之前的研究中，我们发现 GSE 显着下调了众所周知的肺癌 人肺肿瘤细胞和裸鼠 A549 异种移植肿瘤中的 oncomirs miR-19a、-19b 和 -106b，如 以及重度吸烟者/戒烟者的血清中。 研究结果将为 GSE/LP 对抗肺癌的可行性和机制效应提供重要见解， 帮助识别 SEBM 并为未来的验证性临床试验奠定基础。