Inhibition of S14 by Conjugated Linoleic Acid in Advanced Solid Tumor Patients

共轭亚油酸对晚期实体瘤患者中 S14 的抑制作用

• 批准号: 7915780
• 负责人: RAYMOND P PEREZ
• 金额: $ 20.86万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915780
• 关键词: Adipocytes; Advanced Malignant Neoplasm; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Biological Markers; Biological Models; Biopsy; Biopsy Specimen; Body Weight decreased; Cancer Patient; Cattle; Cell Cycle; Cleaved cell; Clinic; Clinical; Clinical Trials; Conjugated Linoleic Acids; Data; Development; Diet; Disease; Dose; Drug Kinetics; Effectiveness; End Point Assay; Enzymes; Fatty Acids; Fatty acid glycerol esters; Fatty-acid synthase; Geminin; Genetic Transcription; Goals; Growth; High Pressure Liquid Chromatography; Histocytochemistry; Human; Ions; Kinetics; Lipids; Lipolysis; Lung; Malignant Neoplasms; Messenger RNA; Modeling; Molecular; Molecular Target; Mus; Oral; Oral Administration; Ovarian; Pathway interactions; Patient Care; Patients; Pharmacodynamics; Phase II Clinical Trials; Plasma; Production; Prostate; Public Health; Refractory; Research; Research Design; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Ruminants; Scheme; Silver; Solid Neoplasm; Spottings; Testing; Therapeutic; Titrations; Toxic effect; Translating; Translations; Up-Regulation; angiogenesis; anticancer treatment; bioactive food component; cancer cell; cancer therapy; cancer type; carcinogenesis; caspase-3; clinical efficacy; cohort; design; dietary supplements; efficacy trial; glucose metabolism; improved; inhibitor/antagonist; killings; leukemia; lipid biosynthesis; lipid metabolism; lipoprotein lipase; mRNA Expression; malignant breast neoplasm; novel; novel strategies; open label; overexpression; public health relevance; response; therapeutic target; therapy development; tumor; tumor progression; uptake

DESCRIPTION (provided by applicant): Conventional anticancer therapies are generally acknowledged to be insufficiently effective and excessively toxic. This has prompted development of specific therapies targeting critical molecular pathways in cancer cells ('molecular targeted therapies'). Many cancers critically depend upon upregulated de novo lipid synthesis (such as fatty acid synthase (FAS)), and/or increased uptake of circulating lipids derived from diet (lipolysis). We have shown that Spot 14 (S14; THRSP), a central regulator of de novo lipid synthesis, is an attractive therapeutic target. In animal models, S14 expression is inhibited by tolerable oral doses of conjugated linoleic acid (CLA), a popular dietary supplement and bioactive food component. Despite widespread use in humans and animals, CLA has not been tested as anticancer agent in clinical trials. In addition, levels of CLA that can be safely achieved, its distribution, and its elimination kinetics are currently unknown. Thus, the first step towards development of CLA as a potential anticancer treatment is to define a safe and appropriate dose for clinical efficacy trials. Therefore, we will test the hypothesis that tolerable doses of CLA inhibit expression of S14 mRNA in normal human adipocytes and in tumor biopsies from patients with advanced solid tumors. There are two specific aims: (1) to define a tolerable dose of CLA that maximally suppresses S14 expression in adipocytes; and (2) to determine whether this dose suppresses S14 mRNA expression in tumor biopsy specimens of tumor types potentially sensitive to inhibition of lipogenesis. CLA is administered orally, once daily. Doses are escalated using an accelerated titration scheme (single patient cohorts), with expansion to conventional cohort sizes (3-6 patients) once inhibition of S14 expression or clinical toxicity is observed. Dose titration continues until a plateau in S14 response is observed, unless clinical toxicities or pharmacokinetics require stopping before that point. The study design seeks to identify a recommended dose for subsequent phase II trials (RP2D) which is tolerable and where maximal S14 response is seen (response defined as suppression of S14 m RNA expression by e 40%, a level associated with significant inhibition of lipogenesis in relevant animal models). Pharmacokinetic sampling and biopsies are performed on days 1 and 15, with quantification of plasma CLA levels by silver- ion HPLC. Molecular pharmacodynamic (PD) endpoints are assayed by RT-PCR and/or immuno- histochemistry. Secondary molecular endpoints include other lipogenic and lipolytic enzymes (such as FAS), SREBP1, phospho-AKT, biomarkers of cell-cycle/proliferation (Ki67, geminin), and apoptosis (cleaved caspase 3). This proof-of-principle trial - the first ever targeting lipogenesis in cancer patients, with any agent - is an example of ongoing efforts by Dartmouth investigators to develop novel therapies targeting lipid metabolism in cancer cells. Rapid translation of such therapies into the clinic has the potential to improve care of patients with advanced cancer, which is our ultimate goal. PUBLIC HEALTH RELEVANCE: It has become apparent that many cancers depend on specific fats (lipids) for their continued growth. Conjugated linoleic acid (CLA) is a safe, popular, and well-tolerated dietary supplement that promotes weight loss and loss of fat. CLA has recently been shown to inhibit uptake and production of lipids required for growth of some cancers, resulting in growth inhibition and killing of cancer cells. We propose a clinical trial to test whether oral administration of CLA block production and uptake of lipids in tumors of patients with advanced cancers. Information gained from these studies will then be used to design later trials testing the effectiveness of CLA against different types of cancer. Targeting lipids is a promising, new approach to cancer therapy - one with the potential to benefit patients with many common cancers (breast, prostate, lung, ovarian, and some leukemias). Successful completion of the proposed studies could therefore potentially translate into significant improvements in public health.

描述(申请人提供)：传统的抗癌疗法被普遍认为是不够有效和毒性过大的。这促使了针对癌细胞中关键分子通路的特定疗法的开发(分子靶向疗法)。许多癌症严重依赖于新生脂肪合成的上调(如脂肪酸合成酶)，和/或来自饮食的循环脂肪的摄取增加(脂肪分解)。我们已经证明，点14(S14；THRSP)是从头合成脂质的中央调节因子，是一个有吸引力的治疗靶点。在动物模型中，S14的表达被口服可耐受剂量的共轭亚油酸(CLA)抑制，CLA是一种流行的膳食补充剂和生物活性食品成分。尽管CLA在人类和动物中广泛使用，但尚未在临床试验中作为抗癌剂进行测试。此外，目前尚不清楚可安全达到的共轭亚油酸水平、其分布和消除动力学。因此，开发CLA作为一种潜在的抗癌治疗的第一步是确定临床疗效试验的安全和适当的剂量。因此，我们将验证一个假设，即可耐受剂量的CLA抑制了正常人脂肪细胞和晚期实体瘤患者的肿瘤活检组织中S14 mRNA的表达。有两个特定的目的：(1)确定最大限度地抑制脂肪细胞S14表达的可耐受剂量的CLA；(2)确定该剂量是否抑制可能对抑制脂肪生成敏感的肿瘤类型的肿瘤活检标本中S14基因的表达。CLA是口服的，每天一次。使用加速滴定方案(单个患者队列)逐步增加剂量，一旦观察到S14的表达或临床毒性被抑制，就扩大到常规队列规模(3-6名患者)。持续剂量滴定，直到观察到S14反应的平台期，除非临床毒性或药代动力学需要在这一点之前停止。这项研究设计旨在确定后续II期试验(RP2D)的推荐剂量，该剂量可耐受且S14反应最大(反应定义为将S14 m RNA的表达抑制40%，这一水平与相关动物模型中显著抑制脂肪生成有关)。在第1天和第15天进行药代动力学采样和活组织检查，并用银离子高效液相色谱法测定血浆CLA水平。通过RT-PCR和/或免疫组织化学检测分子药效学(PD)终点。次级分子终点包括其他造脂和脂解酶(如Fas)、SREBP1、磷酸化AKT、细胞周期/增殖的生物标志物(Ki67、Ginin)和细胞凋亡(裂解的caspase 3)。这项原则验证试验是有史以来第一个针对癌症患者脂肪生成的任何药物的试验，是达特茅斯研究人员正在努力开发针对癌细胞脂质代谢的新疗法的一个例子。快速将这些疗法转化为临床，有可能改善对晚期癌症患者的护理，这是我们的最终目标。与公共健康相关：很明显，许多癌症依赖于特定的脂肪(脂)来持续生长。共轭亚油酸(CLA)是一种安全、流行和耐受性良好的膳食补充剂，可促进减肥和减脂。CLA最近被证明可以抑制某些癌症生长所需的脂类的摄取和产生，从而抑制和杀死癌细胞。我们建议进行一项临床试验，以测试口服共轭亚油酸是否能阻断晚期癌症患者肿瘤中脂质的产生和摄取。从这些研究中获得的信息将被用来设计后来的试验，测试共轭亚油酸对不同类型癌症的有效性。靶向脂类是一种有希望的癌症治疗新方法--一种可能使许多常见癌症(乳腺癌、前列腺癌、肺癌、卵巢癌和一些白血病)患者受益的方法。因此，拟议研究的成功完成可能转化为公共卫生方面的重大改善。