Novel SCD1 inhibitors for treatment of cancer

 描述(申请人提供)：转移性肾透明细胞癌(MCCRCC)是一种不能治愈的癌症，5年生存率低于10%，迫切需要开发新的治疗药物。众所周知，它对化疗和放射具有抵抗力。虽然分子靶向治疗已经导致了生存的改善，但由于最终会产生耐药性，其益处是相当有限的。我们发现，硬脂酰辅酶A去饱和酶1(SCD1)基因在所有被检查的患者肾细胞癌组织中异常和特异地过表达，包括转移性疾病(&gt；125)，而在正常肾上皮细胞中没有任何表达。我们已经发表了SCD1作为癌基因来调节生存和增殖。沉默ccRCC中的SCD1可导致内质网(ER)介导的细胞凋亡。SCD1抑制剂与FDA批准的mTOR抑制剂替西罗莫斯联合使用，在细胞培养和ccRCC小鼠模型中提供了抗肿瘤协同作用。重要的是，SCD1的表达已被证明在许多癌症中升高，并与不良预后相关。因此，我们在MCCRCC中确定了一种新的信号和靶向通路，可能会改善患者的预后。此外，我们最近开发了高度特异的小分子SCD1抑制剂，目的是将这些化合物开发为临床试验药物，与mTOR抑制剂联合治疗转移性肾细胞癌。我们现在展示了我们的主要SCD1抑制剂的出色生物利用度。在AIM 1(Hazlehurst，调制治疗公司)中，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实验室将使用ccRCC转移肿瘤模型和患者来源的异种移植(PDX)肿瘤模型，展示我们的领先SCD1抑制剂与mTOR抑制剂联合使用的单剂量疗效和抗肿瘤协同作用。综上所述，我们已经从发现患者临床样本中SCD1表达升高到开发具有显著生物利用度的新型SCD1抑制剂。重要的是，我们的数据表明，当SCD1抑制剂与FDA批准的mTOR抑制剂联合使用时，可产生协同抑制肿瘤生长的作用。我们预计，到第一阶段申请完成时，我们将获得足够的数据，以便举行IND前会议。第二阶段STTR应用的目标将是完成IND应用并启动第一阶段临床试验。

 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.