First-in-class TREM-1 inhibitors in combination therapy for pancreatic cancer

用于胰腺癌联合治疗的一流 TREM-1 抑制剂

• 批准号: 9984628
• 负责人: Alexander B Sigalov
• 金额: $ 0.21万
• 依托单位: SIGNABLOK, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9984628
• 关键词: Adenocarcinoma; Albumins; American Cancer Society; Amplifiers; Animal Model; Animal Testing; Animals; Antineoplastic Agents; Apolipoprotein A-I; Biological; Biological Assay; Biological Availability; Biological Models; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Chemistry; Colon Carcinoma; Combined Modality Therapy; Comparative Study; Complex; Data; Development; Dose; Drug Combinations; Evaluation; Excretory function; Female; Formulation; Future; Goals; Half-Life; High Density Lipoproteins; Histology; Human; Immunoblot Analysis; Immunohistochemistry; Immunotherapy; In Vitro; Infiltration; Inflammation; Interleukin-6; Investigational New Drug Application; Lesion; Ligands; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolism; Metastatic breast cancer; Molecular; Mus; Myeloid Cells; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Nude Mice; Operative Surgical Procedures; Organ; Oxides; Paclitaxel; Pancreas; Pancreatic carcinoma; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Play; Process; Radiation therapy; Randomized Clinical Trials; Regimen; Research; Risk; Role; Severity of illness; Site; Solubility; Supervision; Survival Analysis; Survival Rate; Testing; Tissues; Toxic effect; Toxicology; Tumor Promotion; Tumor-associated macrophages; United States; United States Food and Drug Administration; Vascular Endothelial Growth Factors; Water; Work; Xenograft Model; Xenograft procedure; absorption; advanced pancreatic cancer; alpha Tubulin; angiogenesis; anti-cancer; anti-cancer therapeutic; anticancer activity; base; cancer cell; cancer therapy; cancer type; chemotherapy; combinatorial; comparative; cytokine; cytotoxicity; drug candidate; drug development; gemcitabine; improved; in vivo; inhibitor/antagonist; lead series; macrophage; malignant breast neoplasm; mouse model; nanoparticle; nanosystems; neoplastic cell; novel; oncology; pancreatic cancer model; pancreatic cancer patients; peptide I; phase 1 study; receptor; reduce symptoms; sex; side effect; stathmin; targeted delivery; tumor; tumor growth; tumor progression; uptake

Project Summary/Abstract Carcinoma of the pancreas, or pancreatic cancer (PC), is the fourth leading cause of cancer-related death in the United States. According to the American Cancer Society, 55,300 new cases are expected in 2016. Despite advances in therapy, the 5-year survival rate is less than 4%. Current treatments of PC include surgery, radiation therapy, chemotherapy, and immunotherapy but they all only slightly prolong survival or relieve symptoms in patients with PC. Gemcitabine (GEM), first line therapy for advanced PC, is only modestly effective with a median survival of about 6 months in randomized clinical trials, The combination of GEM with different anticancer agents does not show significant survival advantage as compared with GEM alone. These limitations in efficacy of available treatments highlight the need for new treatments. Pancreatic inflammation is known to increase the risk of PC. High macrophage infiltration into the tumor mass correlates with the promotion of tumor growth and metastasis development. Triggering receptor expressed on myeloid cells (TREM-1), an inflammation amplifier, plays a role in PC progression. Expression of TREM-1 on tumor-associated macrophages (TAMs), is upregulated in patients with PC and correlates to disease severity. Recently, we demonstrated that a first-in-class TREM-1 inhibitory peptide GF9 in free form and bound to macrophage-targeted lipopeptide complexes that mimic human high density lipoproteins (GF9-HDL) inhibits tumor growth in animal models of PC. We also showed that blockade of TREM-1 inhibits release of cytokines and M-CSF in these animal models. The main hypothesis of this project is that a combination therapy that includes TREM-1 inhibitors and anticancer agents and targets cancer-related inflammation and tumor cells directly can synergistically improve survival of PC patients. We also hypothesize that this effect will be especially pronounced in PC patients with high intratumoral macrophage infiltration. Our preliminary studies strongly support this hypothesis. The long-term objective of the proposed project is to develop a novel combinatorial approach to efficiently target PC. The major goal of the Phase I study is to demonstrate that specific inactivation of TREM-1 with first-in-class inhibitory peptides in combination with GEM or nanoparticle albumin (nab)- bound paclitaxel (nab-PTX), another promising agent that directly targets cancer cells and is widely approved for the treatment of metastatic breast cancer (BC), synergistically suppresses PC tumor progression in animal model system and improves survival. Phase I specific aims are to: 1) evaluate effects and mechanisms of GF9-GEM and GF9-nab-PTX combinations in vitro, and 2) test GF9-GEM and GF9- nab-PTX combinations in two xenograft mouse models of PC. Non-toxic peptide GF9, which employs novel, ligand-independent mechanisms of TREM-1 inhibition, is anticipated to have less severe side effects. In order to increase peptide solubility, bioavailability and targeting to TAMs, we will utilize SignaBlok's proprietary HDL-based nanosystem for macrophage-targeted delivery of water insoluble and poorly water soluble drugs. We will use in vitro macrophage uptake assay to elucidate the molecular mechanisms of a putative receptor-mediated process of targeted delivery of GF9 to macrophages. We will optimize GF9 formulations based upon their stability, GF9 content, and macrophage uptake in vitro. We will use an in vitro cytotoxicity assay and immunoblot analysis to test proliferation of BxPC-3 and AsPC-1 cells as well as expression of phospho-stathmin and alpha-tubulin in the presence of GEM, nab-PTX or their combinations with GF9 formulations. We will use BxPC-3 and AsPC-1 mouse xenograft models to test the ability of GF9- GEM and GF9-nab-PTX combinations to synergistically inhibit tumor progression and promote survival as compared with GF9, GEM, and nab-PTX alone. Free GF9 and GF9-HDL will be tested. Comprehensive histology and immunohistochemistry studies will be performed to analyze angiogenesis, intratumoral macrophage infiltration, and potential non-specific toxicity for organ/tissues. It is anticipated that the proposed research will identify a novel anticancer combination approach that will set the stage for the development of new targeted combination therapies of PC, thereby leading to a higher survival rate of the patients. If successful, the Phase I will be followed in the Phase II by toxicology, absorption/ disposition/ metabolism/ excretion (ADME), pharmacology and chemistry/ manufacturing/ control (CMC) studies, filing an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) and subsequent evaluation in humans. Final product will be the stable TREM-1- targeted lipopeptide formulation that can be used in combination therapies of PC patients to prolong their survival. Importantly, our recent data demonstrate that blockade of TREM-1 suppresses in vivo progression of not only PC but also non-small cell lung cancer (NSCLC). Thus, successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable to a variety of inflammation- associated tumors such as NSCLC, BC, colon cancer, and others.

项目概要/摘要 胰腺癌或胰腺癌 (PC) 是癌症相关死亡的第四大原因 在美国。据美国癌​​症协会称，2016 年预计将出现 55,300 例新病例。 尽管治疗取得了进步，但 5 年生存率仍低于 4%。目前 PC 的治疗方法包括 手术、放射治疗、化疗和免疫治疗，但它们都只能稍微延长生存期或 缓解PC患者的症状。吉西他滨 (GEM) 是晚期 PC 的一线治疗药物，是唯一 在随机临床试验中，该组合具有一定的效果，中位生存期约为 6 个月 与不同的抗癌药物相比，GEM 并没有表现出显着的生存优势 创业板独。现有治疗功效的这些局限性凸显了对新治疗方法的需求。 众所周知，胰腺炎症会增加 PC 的风险。巨噬细胞大量浸润至肿瘤 质量与促进肿瘤生长和转移发展相关。触发受体 在骨髓细胞上表达的 (TREM-1) 是一种炎症放大器，在 PC 进展中发挥作用。 肿瘤相关巨噬细胞 (TAM) 上 TREM-1 的表达在 PC 和 PC 患者中上调 与疾病严重程度相关。最近，我们证明了一种首创的 TREM-1 抑制肽 游离形式的 GF9 与模拟人类高密度巨噬细胞靶向脂肽复合物结合 脂蛋白 (GF9-HDL) 抑制 PC 动物模型中的肿瘤生长。我们还表明，封锁 TREM-1 抑制这些动物模型中细胞因子和 M-CSF 的释放。 该项目的主要假设是包含 TREM-1 抑制剂和 抗癌药物并直接针对癌症相关炎症和肿瘤细胞可以协同作用 提高 PC 患者的生存率。我们还假设这种影响在 PC 中尤其明显 瘤内巨噬细胞浸润高的患者。我们的初步研究有力地支持了这一点 假设。拟议项目的长期目标是开发一种新颖的组合方法 有效地瞄准PC。第一阶段研究的主要目标是证明特定的失活 TREM-1 具有一流的抑制肽与 GEM 或纳米颗粒白蛋白 (nab) 的组合 - 结合型紫杉醇 (nab-PTX)，另一种有前景的药物，可直接靶向癌细胞，并被广泛应用 批准用于治疗转移性乳腺癌 (BC)，协同抑制 PC 肿瘤 动物模型系统的进展并提高生存率。第一阶段的具体目标是：1）评估效果 GF9-GEM 和 GF9-nab-PTX 组合的体外研究和机制，以及 2) 测试 GF9-GEM 和 GF9- 两种 PC 异种移植小鼠模型中的 nab-PTX 组合。无毒肽 GF9，采用新颖、 TREM-1 抑制的配体独立机制预计不会产生严重的副作用。在 为了提高肽的溶解度、生物利用度和针对 TAM 的靶向性，我们将利用 SignaBlok 的 基于 HDL 的专有纳米系统，用于巨噬细胞靶向输送水不溶性和难水性 可溶性药物。我们将使用体外巨噬细胞摄取实验来阐明巨噬细胞摄取的分子机制。 假定的受体介导的将 GF9 靶向递送至巨噬细胞的过程。我们将对GF9进行优化 根据其稳定性、GF9 含量和体外巨噬细胞摄取来确定制剂。我们将使用一个 in 体外细胞毒性测定和免疫印迹分析，以测试 BxPC-3 和 AsPC-1 细胞的增殖以及 在 GEM、nab-PTX 或其组合存在下磷酸-stathmin 和 α-微管蛋白的表达 采用 GF9 配方。我们将使用BxPC-3和AsPC-1小鼠异种移植模型来测试GF9-的能力 GEM 和 GF9-nab-PTX 组合可协同抑制肿瘤进展并促进生存 与单独使用 GF9、GEM 和 nab-PTX 相比。将测试免费的 GF9 和 GF9-HDL。综合的 将进行组织学和免疫组织化学研究来分析血管生成、瘤内 巨噬细胞浸润以及对器官/组织的潜在非特异性毒性。 预计拟议的研究将确定一种新的抗癌组合方法，该方法 将为开发新的 PC 靶向联合疗法奠定基础，从而导致 患者的生存率更高。如果成功，第一阶段将在第二阶段进行毒理学研究， 吸收/处置/代谢/排泄（ADME），药理学和化学/制造/ 对照（CMC）研究，向美国食品药品监督管理局提交研究性新药（IND）申请 给药（FDA）和随后的人体评估。最终产品将是稳定的 TREM-1- 靶向脂肽制剂，可用于 PC 患者的联合治疗，以延长其寿命 生存。重要的是，我们最近的数据表明，TREM-1 的阻断可抑制体内进展 不仅是PC，还包括非小细胞肺癌（NSCLC）。因此，第一阶段的顺利完成将 提供可能适用于各种炎症的假设的概念证明- 相关肿瘤，如 NSCLC、BC、结肠癌等。