Novel SCD1 inhibitors for treatment of cancer

用于治疗癌症的新型 SCD1 抑制剂

基本信息

批准号：
9048181
负责人：
John A. Copland
金额：
$ 27.9万
依托单位：
MODULATION THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-05 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9048181
关键词：
Address Adverse effects Affinity Apoptosis Attenuated Biological Assay Biological Availability Biological Markers Cell Culture Techniques Cell Line Cell Proliferation Cell Survival Cells Chronic Disease Clear Cell Clinical Clinical Trials Data Dependence Development Disease Dose Drug Kinetics Drug resistance Endoplasmic Reticulum Epithelial Cell Proliferation Epithelial Cells FDA approved Fibrous capsule of kidney Gene Expression Profile Genes Goals Growth Human Immune Implant In Vitro Kidney Laboratories Lead Legal patent Link Luciferases Lung Malignant Neoplasms Maximum Tolerated Dose Measurement Mediating Messenger RNA Metabolic Pathway Metastatic to Modeling Mono-S Monounsaturated Fatty Acids Mus Neoplasm Metastasis Oncogenes Outcome Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Principal Investigator Proteins Publications Publishing Quality of life Radiation Renal Cell Carcinoma Renal Tissue Resected Resistance Sampling Saturated Fatty Acids Signal Pathway Signal Transduction Small Business Technology Transfer Research Specimen Staging Stearoyl-CoA Desaturase Testing Therapeutic Therapeutic Agents Tissues Toxic effect Toxicokinetics Toxicology Tumor Biology Tumor Tissue Xenograft Model Xenograft procedure advanced disease cancer cell cancer therapy chemotherapy combinatorial desaturase design effective therapy efficacy testing endoplasmic reticulum stress experience improved in vivo inhibitor/antagonist innovation lipid biosynthesis mTOR Inhibitor meetings molecular marker mouse model novel novel strategies novel therapeutics outcome forecast overexpression pre-clinical public health relevance response small hairpin RNA small molecule targeted treatment therapeutic evaluation therapy design tool tumor tumor growth tumor microenvironment tumor xenograft tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Metastatic clear cell renal cell carcinoma (mccRCC) is an incurable cancer with a 5 year survival of less than 10%, for which novel therapeutic agents need to be developed urgently. It is notoriously resistant to chemotherapy and radiation. Although molecularly targeted therapies have led to an improvement in survival, the benefit is rather limited due to eventual development of drug resistance. We have discovered a gene, stearoyl CoA desaturase 1 (SCD1) to be aberrantly and specifically overexpressed in all patient ccRCC tissues examined to date including metastatic disease (>125) without any expression in normal renal epithelial cells. We have published that SCD1 acts as an oncogene to mediate survival and proliferation. Silencing SCD1 in ccRCC leads to endoplasmic reticulum (ER) mediated apoptosis. An SCD1 inhibitor combined with FDA approved mTOR inhibitor, temsirolimus, provided antitumor synergy in cell culture and a ccRCC mouse model. Importantly SCD1 expression has been shown to be elevated in numerous cancers and correlated with poor outcome. Thus, we have identified a novel signaling and targetable pathway in mccRCC that may improve patient outcomes. Furthermore, we have recently developed highly specific small molecule SCD1 inhibitors with the intent to develop these compounds as drugs to be tested in clinical trials in combination with mTOR inhibitors for metastatic ccRCC. We now demonstrate excellent bioavailability of our lead SCD1 inhibitor. In Aim 1 (Hazlehurst, Modulation Therapeutics Incorporated), in vivo Non-GLP toxicology and toxicokinetic characterization of the two lead SCD1 inhibitors will be determined. In Aim 2, the Copland laboratory will demonstrate single dose efficacy and antitumor synergy of our lead SCD1 inhibitor in combination with an mTOR inhibitor using a ccRCC metastatic tumor model and a patient derived xenograft (PDX) tumor model derived from a patient with metastatic disease. In summary, we have progressed from discovery of elevated SCD1 expression in patient clinical samples to the development of novel SCD1 inhibitors with remarkable bioavailability. Importantly, our data indicate that SCD1 inhibitors cause synergistic inhibition of tumor growth when combined with FDA approved mTOR inhibitors. We anticipate by the completion of this phase I application we will have obtained sufficient data to have a pre-IND meeting. The goal of the Phase II STTR application will be to complete the IND application and initiate the Phase I clinical trial.

描述（申请人提供）：转移性透明细胞肾细胞癌（mccRCC）是一种无法治愈的癌症，其 5 年生存率低于 10%，迫切需要开发新的治疗药物。众所周知，它对化疗和放疗具有耐药性。尽管分子靶向治疗已提高了生存率，但由于最终会产生耐药性，其益处相当有限。我们发现了一种基因，即硬脂酰辅酶A去饱和酶 1 (SCD1)。在迄今为止检查的所有患者 ccRCC 组织中，包括转移性疾病 (>125)，SCD1 均异常且特异性地过度表达，而在正常肾上皮细胞中没有任何表达。内质网 (ER) 介导的细胞凋亡。重要的是，SCD1 表达在多种癌症中均升高，并且与不良预后相关，因此，我们在 mccRCC 中发现了一种新的信号传导和靶向途径，可以改善患者的预后。高度特异性的小分子 SCD1 抑制剂，旨在将这些化合物开发为与 mTOR 抑制剂联合治疗转移性 ccRCC 的药物。目标 1（Hazlehurst，Modulation Therapeutics Incorporated）将确定两种主要 SCD1 抑制剂的体内非 GLP 毒理学和毒代动力学特征。在目标 2 中，Copland 实验室将证明我们的主要 SCD1 抑制剂的单剂量功效和抗肿瘤协同作用。使用 ccRCC 转移性肿瘤模型和源自转移性患者的患者衍生异种移植 (PDX) 肿瘤模型与 mTOR 抑制剂组合总之，我们已经从发现患者临床样本中的 SCD1 表达进展到开发具有显着生物利用度的新型 SCD1 抑制剂。重要的是，我们的数据表明，SCD1 抑制剂与 FDA 批准的 mTOR 抑制剂联合使用时会产生协同抑制肿瘤生长的作用。预计在完成第一阶段申请后，我们将获得足够的数据来召开 IND 前会议。第二阶段 STTR 申请的目标是完成 IND 申请并启动第一阶段临床试验。