Novel SCD1 inhibitors for treatment of cancer

项目摘要 代谢重编程在癌症的发生中起着关键作用，部分原因是它能够促进免疫。 肿瘤内的抑制特性。然而，目前尚不清楚是否抑制肿瘤中的脂肪酸代谢 会影响它们的免疫原性。在这里，我们首次证明了抑制硬脂酰辅酶A去饱和酶1(SCD1)， 脂肪酸合成中的限速酶--将饱和脂肪酸转化为单不饱和脂肪酸 脂肪酸(MUFAs)是人类癌症的潜在预后标记物，它增加了肿瘤的免疫原性 免疫原性低的肿瘤。我们的结果表明，抑制致癌的新生脂肪生成代表了一种 加强以T细胞为基础的癌症免疫治疗的新途径。在这样做的过程中，我们将评估我们的小说主角 SCD1抑制剂(SSI-4)单独使用，并与免疫检查点抑制剂联合使用具有免疫活性 小鼠模型，作为早期临床试验的前奏。我们还将优化疗效并寻求预测性 可能在临床上有用的生物反应标记物。SCD1在侵袭性癌症中普遍上调 并通过SSI-4在广泛的癌细胞系和肿瘤小鼠模型上的抗肿瘤活性进行了验证。 从机制上讲，成瘾癌细胞中MUFA的缺失导致内质网(ER)应激介导 细胞凋亡性死亡我们在免疫活性小鼠癌症模型中发现SSI-4激活了 内质网应激途径的钙网蛋白/PERK臂增强活化T细胞肿瘤的适应性免疫反应 从而促进抗PD1抗体的治疗。与抗PD1抑制剂联合使用，SSI-4增敏 肿瘤对免疫检查点抑制剂的治疗导致80%和30%的完全消退(CR)和长期 在两个HER2乳腺癌小鼠模型中，存活率被解释为治愈。根据这些数据，我们的中央 假说是异常的新生脂肪生成与肿瘤免疫原性的减弱有关。两个目标是 在此阶段2 STTR提案中提出。AIM 1将验证SCD1和免疫检查点的抗肿瘤协同作用 用免疫能力强的荷瘤小鼠模型来概括观察到的数据。《目标2》聚焦 在提交新药研究(IND)申请以获得FDA批准时，将执行以下任务 完成；i)测定SSI-4化合物的稳定性；ii)在大鼠和狗身上进行非GLP毒性研究 与FDA召开IND前会议，讨论监管战略四)进行GLP毒性研究，五) 设计I期临床试验和vi)完成IND应用。总而言之，我们设想SCD1是一个广泛 光谱抗癌靶标在侵袭性恶性肿瘤中过度表达。治疗有用，SSI-4增加 低免疫原性肿瘤的免疫原性从而对免疫检查点阻断敏感，导致 到戏剧性适应性免疫介导的肿瘤细胞杀伤。因此，这种联合治疗应该提高患者的 应答率和患者的耐受性良好。

Project Summary Metabolic reprogramming plays a critical role in carcinogenesis, in part due its ability to promote immune suppressive properties within tumors. However, it is unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicity. Here, we show for the first time that inhibition of stearoyl CoA desaturase 1 (SCD1), the rate limiting enzyme involved in fatty-acid synthesis converting saturated acids (SFA) to monounsaturated fatty acids (MUFAs) and a potential prognostic marker for human cancers, increases the immunogenicity of poorly immunogenic tumors. Our results indicate that inhibition of tumorigenic de novo lipogenesis represents a novel approach to enhance T cell based cancer immunotherapy. In so doing, we will evaluate our novel lead SCD1 inhibitor (SSI-4) singly, and in combination with immune checkpoint inhibitors using immune competent mouse models, as a prelude to an early phase clinical trial. We will also optimize efficacy and seek predictive biomarkers of response that could be clinically useful. SCD1 is universally upregulated in aggressive cancers and validated by SSI-4 antitumor activity across a broad range of cancer cell lines and tumor mouse models. Mechanistically, MUFA deprivation in addicted cancer cells leads to endoplasmic reticulum (ER) stress mediating apoptotic cell death. We discovered in immune competent mouse cancer models that SSI-4 activates the adaptive immune response via calreticulin/PERK arm of the ER stress pathway enhancing activated T cell tumor infiltration and thereby promoting anti-PD1 antibody therapy. Combined with anti-PD1 inhibitor, SSI-4 sensitizes tumors to immune checkpoint inhibitors leading to 80% and 30% complete regression (CR) and long-term survival interpreted as cures in two HER2 breast cancer mouse models. Based upon these data, our central hypothesis is that aberrant de novo lipogenesis is linked to attenuation of tumor immunogenicity. Two aims are proposed in this Phase 2 STTR proposal. Aim 1 will validate antitumor synergy of SCD1 and immune checkpoint blockade using immune competent breast mouse models to generalize the observed data to. Aim 2 is focused upon filing an application for investigation of new drug (IND) for FDA approval in which the following tasks will be accomplished; i) determine SSI-4 compound stability ii) perform non-GLP toxicity studies in rats and dogs iii) convene a pre-IND meeting with the FDA to discuss regulatory strategy iv) perform GLP toxicity studies, v) design the phase I clinical trial and vi) complete the IND application. In summary, we envision SCD1 as a broad spectrum anti-cancer target overexpressed in aggressive malignancies. Therapeutically useful, SSI-4 increases the immunogenicity of poorly immunogenic tumors thereby sensitizing to immune checkpoint blockade, leading to dramatic adaptive immune mediated tumor cell killing. Thus, this combination therapy should enhance patient response rates and be well tolerated in patients.