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: 7738712
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738712
• 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（由申请人提供）：传统的抗癌治疗通常被认为是不够有效和毒性过大。这促进了针对癌细胞中关键分子通路的特异性治疗的发展（“分子靶向治疗”）。许多癌症严重依赖于脂质合成上调（如脂肪酸合成酶（FAS））和/或饮食中循环脂质摄取增加（脂肪分解）。我们已经证明，斑点14 (S14； THRSP)，一个新的脂质合成的中央调节剂，是一个有吸引力的治疗靶点。在动物模型中，口服耐受剂量的共轭亚油酸（CLA）可以抑制S14的表达。共轭亚油酸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，CLA可以安全达到的水平，其分布和消除动力学目前尚不清楚。因此，开发CLA作为一种潜在的抗癌治疗方法的第一步是确定一个安全适当的剂量用于临床疗效试验。因此，我们将验证耐受剂量的CLA抑制正常人类脂肪细胞和晚期实体瘤患者肿瘤活检中S14 mRNA表达的假设。有两个具体目的：(1)确定最大限度地抑制脂肪细胞中S14表达的CLA的耐受剂量；(2)确定该剂量是否能抑制可能对脂肪生成抑制敏感的肿瘤类型的肿瘤活检标本中S14 mRNA的表达。CLA口服，每日一次。使用加速滴定方案增加剂量（单个患者队列），一旦观察到S14表达抑制或临床毒性，就扩大到常规队列大小（3-6例患者）。剂量滴定继续进行，直到观察到S14反应达到平台，除非临床毒性或药代动力学要求在此之前停止。研究设计旨在确定后续II期试验（RP2D）的推荐剂量，该剂量是可耐受的，并且可以看到最大的S14反应（反应定义为S14 m RNA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相关）。在第1天和第15天进行药代动力学取样和活组织检查，用银离子高效液相色谱法定量血浆CLA水平。分子药效学（PD）终点通过RT-PCR和/或免疫组织化学检测。次要分子终点包括其他脂质生成和脂质分解酶（如FAS）、SREBP1、磷酸化akt、细胞周期/增殖生物标志物（Ki67、geminin）和凋亡（cleaved caspase 3）。这一原理验证试验——有史以来第一次针对癌症患者的脂肪生成，使用任何药物——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。将这种疗法快速转化为临床有可能改善晚期癌症患者的护理，这是我们的最终目标。公共卫生相关性：很明显，许多癌症的持续生长依赖于特定的脂肪（脂质）。共轭亚油酸（CLA）是一种安全、受欢迎、耐受性良好的膳食补充剂，有助于减肥和减脂。CLA最近被证明可以抑制某些癌症生长所需的脂质的吸收和产生，从而抑制癌细胞的生长和杀死癌细胞。我们提出了一项临床试验，以测试口服CLA是否会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用于设计以后的试验，测试CLA对不同类型癌症的有效性。靶向脂质是一种很有前途的癌症治疗新方法，它有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）的患者受益。因此，成功完成拟议的研究可能转化为公共卫生方面的重大改善。