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: 9407074
• 负责人: Alexander B Sigalov
• 金额: $ 22.47万
• 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/9407074
• 关键词: Adenocarcinoma; Adverse effects; 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; Controlled Study; 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; United States; United States Food and Drug Administration; Water; Work; Xenograft Model; Xenograft procedure; absorption; alpha Tubulin; angiogenesis; 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; peptide I; phase 1 study; receptor; reduce symptoms; sex; 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.

项目总结/摘要 胰腺癌或胰腺癌（PC）是癌症相关死亡的第四大原因 在美国根据美国癌症协会的数据，预计2016年将有55，300例新病例。 尽管治疗取得了进展，但5年生存率不到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， 缓解PC患者的症状。吉西他滨（GEM）是晚期PC的一线治疗药物， 在随机临床试验中，中位生存期约为6个月， GEM与不同抗癌药物的联合使用与对照组相比， 单独使用GEM。现有治疗方法的这些疗效局限性突出了对新治疗方法的需求。 胰腺炎是已知的增加PC的风险。高巨噬细胞浸润到肿瘤中 肿块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（炎症放大器）在PC进展中起作用。 TREM-1在肿瘤相关巨噬细胞（TAM）上的表达在PC患者中上调， 与疾病严重程度相关。最近，我们证明了一类TREM-1抑制肽， 游离形式的GF 9与模拟人高密度的巨噬细胞靶向脂肽复合物结合 脂蛋白（GF 9-HDL）抑制PC动物模型中的肿瘤生长。我们还发现， 在这些动物模型中，TREM-1抑制细胞因子和M-CSF的释放。 该项目的主要假设是，包括TREM-1抑制剂和TREM-2抑制剂的联合治疗可以改善患者的预后。 抗癌剂和靶向癌症相关的炎症和肿瘤细胞直接可以协同作用 提高PC患者的生存率。我们还假设这种效应在PC中尤其明显 高肿瘤内巨噬细胞浸润的患者。我们的初步研究强烈支持这一点 假说.拟议项目的长期目标是开发一种新的组合方法 有效地瞄准PC。第一阶段研究的主要目标是证明特异性失活 TREM-1与同类第一抑制肽与GEM或纳米粒白蛋白（nab）的组合 结合紫杉醇（nab-PTX），另一种有前途的药物，直接靶向癌细胞，并广泛 批准用于治疗转移性乳腺癌（BC），协同抑制PC肿瘤 在动物模型系统中的进展并改善存活率。第一阶段的具体目标是：1）评估效果 和机制，以及2）测试GF 9-GEM和GF 9-nab-PTX组合， nab-PTX组合在PC的两种异种移植小鼠模型中的应用。无毒肽GF 9，其采用新的， TREM-1抑制的配体非依赖性机制，预期具有较不严重的副作用。在 为了增加肽的溶解度、生物利用度和对TAM的靶向，我们将利用SignaBlok的 专有的基于HDL的纳米系统，用于巨噬细胞靶向递送水不溶性和水溶性差的药物 可溶性药物我们将使用体外巨噬细胞摄取试验来阐明 假定的受体介导的将GF 9靶向递送至巨噬细胞的过程。我们将优化GF 9 基于它们的稳定性、GF 9含量和体外巨噬细胞摄取来确定它们的制剂。我们将使用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或它们的组合存在下磷酸-stathmin和α-微管蛋白的表达 GF 9配方。我们将使用BxPC-3和AsPC-1小鼠异种移植物模型来测试GF 9 - 1在小鼠体内表达的能力。 GEM和GF 9-nab-PTX组合协同抑制肿瘤进展并促进存活， 与单独的GF 9、GEM和nab-PTX相比。将检测游离GF 9和GF 9-HDL。全面 将进行组织学和免疫组织化学研究以分析血管生成、肿瘤内 巨噬细胞浸润和对器官/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， 将为PC的新靶向组合疗法的开发奠定基础，从而导致 患者生存率较高。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/生产/ 对照（CMC）研究，向美国食品药品监督管理局（FDA）提交研究性新药（IND）申请 在人类中进行的给药（FDA）和后续评价。最终产品将是稳定的TREM-1- 靶向脂肽制剂，其可用于PC患者的联合治疗以延长其 生存重要的是，我们最近的数据表明，阻断TREM-1抑制体内进展， 不仅是PC，而且是非小细胞肺癌（NSCLC）。因此，第一阶段的成功完成将 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。