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

描述（由申请人提供）：通常认为常规抗癌疗法疗效不足且毒性过大。这促进了靶向癌细胞中的关键分子途径的特异性疗法（“分子靶向疗法”）的发展。许多癌症严重依赖于上调的从头脂质合成（如脂肪酸合成酶（FAS））和/或增加的来源于饮食的循环脂质的摄取（脂解）。我们已经表明，斑点14（S14; THRSP），从头脂质合成的中央调节器，是一个有吸引力的治疗靶点。在动物模型中，S14表达被可耐受的口服剂量的共轭亚油酸（CLA）抑制，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。尽管在人类和动物中广泛使用，但CLA尚未在临床试验中作为抗癌剂进行测试。此外，目前还不清楚CLA的安全水平、分布和消除动力学。因此，开发CLA作为潜在抗癌治疗的第一步是确定临床疗效试验的安全和适当剂量。因此，我们将测试的假设，可耐受剂量的CLA抑制S14 mRNA在正常人脂肪细胞和晚期实体瘤患者的肿瘤活检组织中的表达。有两个具体目标：（1）确定最大程度抑制脂肪细胞中S14表达的CLA的耐受剂量;和（2）确定该剂量是否抑制对抑制脂肪生成潜在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（单个患者队列）递增剂量，一旦观察到S14表达抑制或临床毒性，则扩展至常规队列大小（3-6名患者）。剂量滴定持续至观察到S14反应的平台期，除非临床毒性或药代动力学需要在该点之前停止。研究设计旨在确定后续II期试验（RP 2D）的推荐剂量，该剂量可耐受且可观察到最大S14反应（反应定义为S14 m RNA表达抑制40%，该水平与相关动物模型中脂肪生成的显著抑制相关）。在第1天和第15天进行药代动力学取样和活组织检查，通过银离子HPLC定量血浆CLA水平。通过RT-PCR和/或免疫组织化学分析分子药效学（PD）终点。次要分子终点包括其他脂肪生成酶和脂解酶（如FAS）、SREBP 1、磷酸化AKT、细胞周期/增殖生物标志物（Ki 67、双生蛋白）和细胞凋亡（裂解的半胱天冬酶3）。这项原理验证试验是有史以来第一次使用任何药物针对癌症患者的脂肪生成的试验，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型疗法的一个例子。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，许多癌症依赖于特定的脂肪（脂质）来持续生长。共轭亚油酸（CLA）是一种安全，流行，耐受性良好的膳食补充剂，可促进减肥和脂肪损失。最近已显示CLA抑制某些癌症生长所需的脂质的摄取和产生，导致生长抑制和杀死癌细胞。我们提出了一项临床试验，以测试是否口服共轭亚油酸块的生产和摄取的脂质在肿瘤晚期癌症患者。从这些研究中获得的信息将用于设计后续试验，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，有可能使许多常见癌症（乳腺癌、前列腺癌、肺癌、卵巢癌和某些白血病）患者受益。因此，成功完成拟议的研究可能会大大改善公共卫生。

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.