Novel SCD1 inhibitors for treatment of cancer

 描述（由申请人提供）：转移性透明细胞肾细胞癌（mccRCC）是一种无法治愈的癌症，5年生存率低于10%，迫切需要开发新的治疗药物。众所周知，它对化疗和放疗有抵抗力。尽管分子靶向疗法改善了生存率，但由于最终出现耐药性，其益处相当有限。我们已经发现了一种基因，硬脂酰CoA去饱和酶1（SCD 1），在迄今为止检查的所有患者ccRCC组织中异常且特异性地过表达，包括转移性疾病（>125），而在正常肾上皮细胞中没有任何表达。我们已经发表了SCD 1作为癌基因介导生存和增殖。在ccRCC中沉默SCD 1导致内质网（ER）介导的细胞凋亡。SCD 1抑制剂与FDA批准的mTOR抑制剂替西罗莫司组合在细胞培养物和ccRCC小鼠模型中提供抗肿瘤协同作用。重要的是，已显示SCD 1表达在许多癌症中升高，并与不良结局相关。因此，我们已经确定了一种新的信号传导和靶向途径，在mccRCC，可能会改善患者的结果。此外，我们最近开发了高度特异性的小分子SCD 1抑制剂，目的是将这些化合物开发为与mTOR抑制剂联合用于转移性ccRCC的临床试验中测试的药物。我们现在证明了我们的主要SCD 1抑制剂具有出色的生物利用度。在目的1（Hazlehurst，Modulation Therapeutics Incorporated）中，将确定两种先导SCD 1抑制剂的体内非GLP毒理学和毒代动力学表征。在目标2中，Copland实验室将使用ccRCC转移性肿瘤模型和源自转移性疾病患者的患者来源的异种移植物（PDX）肿瘤模型证明我们的主要SCD 1抑制剂与mTOR抑制剂组合的单剂量功效和抗肿瘤协同作用。总之，我们已经从发现患者临床样品中升高的SCD 1表达进展到开发具有显著生物利用度的新型SCD 1抑制剂。重要的是，我们的数据表明，当与FDA批准的mTOR抑制剂组合时，SCD 1抑制剂引起肿瘤生长的协同抑制。我们预计，在完成本I期申请时，我们将获得足够的数据，以进行IND前会议。II期STTR申请的目标是完成IND申请并启动I期临床试验。

 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.