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: 10578652
• 负责人: JENNY T MAO
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 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 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578652
• 关键词: A549; Adverse reactions; Aftercare; Antineoplastic Agents; Apoptosis; Arachidonate 15-Lipoxygenase; Biological Availability; Biological Markers; Biological Monitoring; Biopsy; Blood; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchoscopy; C-reactive protein; CASP3 gene; Cancer Etiology; Cancer Patient; Cause of Death; Cells; Cessation of life; Chest; Clinic; Clinical; Clinical Research; Clinical Trials; Colorectal Cancer; Common Terminology Criteria for Adverse Events; Complex; Consent; Country; Data; Development; Diagnosis; Diagnostic Procedure; Dinoprostone; Down-Regulation; Drug Kinetics; Early treatment; Eicosanoids; Enrollment; Epigenetic Process; Epoprostenol; Excision; Food Supplements; Future; Gene Expression Profile; Growth; Health Food; Human; Hydroxyeicosatetraenoic Acids; IGF Type 2 Receptor; Interleukin-10; Interleukin-12; Interleukin-6; Label; Lesion; 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; Qualifying; Questionnaires; RNA; 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; aspirate; 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; 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.

丰富的临床前数据表明，葡萄籽原花青素提取物（GSE）具有多方面的抗癌作用 特性. GSE已被证明有利于调节致癌机制，包括1）主要 类花生酸途径，如抑制环氧化酶（考克斯）-2/前列腺素（PG）E2，诱导 前列环素合酶（PTGIS）/PGI 2并增加15（S）-羟基-二十碳四烯酸（15-HETE）的产生; 2)下调oncomirs microRNA（miR）-19 a，-19 b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-2 R）和磷酸酶和张力蛋白同源物（PTEN）， 导致磷酸化（P）-AKT的减少，以及oncomir miR-106 b和miR-106 b的下调， 上调其靶点-肿瘤抑制因子P21。最近，我们发现口服白细胞选择性植物体 (LP)一种标准化的GSE与大豆磷脂复合，以提高生物利用度， 人肺癌异种移植物生长，降低支气管Ki-67标记指数（增殖的标志物），有利地 调节主要的类花生酸途径，并下调血清miR-19 a，-19b和-106b， 当前/以前吸烟者。因此，我们假设口服LP是安全的， 本发明涉及与肺癌化相关的机制，并且可用于肺癌治疗。测试这些 假设，将在30例患者中进行使用LP的单臂IIa期新辅助肺癌治疗研究， 新诊断的I期和II期可切除肺癌患者。 目的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）患者在切除术前口服LP。受试者将同意 研究参与和研究标本存档，包括血液、尿液和诊断样本 支气管镜检查[支气管肺泡灌洗（BAL）液和细胞、病变活检和淋巴结活检] 淋巴结（LN）采样]和/或经胸针吸活检（TTNA）（如有临床指征），用作术前 处理样品。诊断为可切除肺癌的合格受试者将入组并接受治疗 约2-3周，直至手术切除。在手术时，连续的临床标本，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，用于评估 PK/生物利用度、PD和作用机制（如适用）。将每周监测口服LP的安全性 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：确定口服LP在I/ II期肺癌患者中的治疗和机制作用。 将通过比较LP治疗前与治疗后的生物活性来评估LP的抗癌作用， 通过调节肿瘤病理反应、降级、Ki-67标记指数、活化半胱天冬酶3 （凋亡标志物）、考克斯-2、PTGIS、15-LOX、PTEN、P-AKT、IGF 2 R; 2）炎症和抗肿瘤标志物 免疫：BAL、血浆和/或中的PGE 2、PGI 2、15-HETE、白细胞介素（IL）-6、-10、-12、C反应蛋白（CRP） 肿瘤; 3）BAL细胞和肿瘤中的癌症相关、途径特异性基因表达谱; 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-19 a、-19 b和-106 b。 目的#3：验证miR-19 a、miR-19 b和miR-106 b在介导抗肿瘤作用中的作用。 GSE和血清miR-19 a、-19 b和-106 b作为治疗性终点生物标志物（SEBM）的效用 监测.在我们以前的研究中，我们发现GSE显著下调众所周知的肺癌 在人肺肿瘤细胞和裸鼠A549异种移植瘤中， 以及在重度当前/前吸烟者的血清中。 这些发现将为GSE/LP治疗肺癌的可行性和机制效应提供重要见解， 有助于识别SEBM，并为未来的验证性临床试验奠定基础。