Development of a DCLK1 siRNA Nanoparticle as Targeted Therapy to Treat Pancreatic Cancer

开发 DCLK1 siRNA 纳米颗粒作为治疗胰腺癌的靶向疗法

• 批准号: 10460621
• 负责人: Eliseu O. De Oliveira
• 金额: $ 94.56万
• 依托单位: COARE HOLDINGS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-22 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460621
• 关键词: Abraxane; American; Animal Model; Antibody-drug conjugates; ApcMin/+ mice; Apoptosis; Blood; Blood Circulation; Cancer Etiology; Caring; Cell Line; Cells; Cessation of life; Chemicals; Clinical Data; Clinical Trials; Collaborations; Data; Development; Diagnosis; Disease; Dose; Drug Kinetics; Effectiveness; Encapsulated; Epithelial; Epithelial Cells; FDA approved; Fc Receptor; Filtration; Funding; Genes; Goals; Growth; Growth Factor Receptors; Half-Life; Health; Human; Image; In Vitro; Interferons; Intestinal Neoplasms; Liposomes; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Marketing; Measures; Mediating; Medical; Mesenchymal; Micelles; MicroRNAs; Modeling; Molecular Target; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Operative Surgical Procedures; Organ; Outcome; PTGS2 gene; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Permeability; Persons; Pharmacodynamics; Phase; Phosphotransferases; Population; Preparation; Private Sector; Process; Property; Publishing; Pulmonary Fibrosis; RNA; Radiation therapy; Regimen; Relapse; Resistance; Role; Serum; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Small Interfering RNA; Solid Neoplasm; Sprague-Dawley Rats; Standardization; Stream; Structure; Supporting Cell; Surface; Survival Rate; Technology; Testing; Therapeutic; Tissues; Toxic effect; Tumor Stem Cells; Tumor Suppressor Proteins; Tumor-Derived; Vascular Endothelial Growth Factors; Work; Xenograft Model; base; cancer cell; cancer initiation; commercialization; cytokine; efficacy validation; gemcitabine; immunogenicity; improved; in vivo; innovation; knock-down; migration; mouse model; nanoparticle; nonhuman primate; novel; novel therapeutics; overexpression; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pharmacokinetics and pharmacodynamics; pluripotency; pre-clinical; preclinical efficacy; prevent; response; siRNA delivery; stem cell biomarkers; subcutaneous; success; targeted delivery; targeted treatment; therapeutic siRNA; transcription factor; tumor; tumor growth; tumor microenvironment; tumor xenograft; tumorigenesis

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating human cancers. It is the fourth leading cause of cancer-related deaths in the U.S. annually, with a <7% 5-year survival rate. Despite FDA-approved therapeutic regimens and marked improvements in medical and surgical care, no significant impact on PDAC patient survival has been achieved. In 2017, some 53,000 Americans are expected to be diagnosed, and ~43,000 are expected to die from PDAC. There is increasing evidence that most solid tumors such as PDAC have a subpopulation of tumor-initiating cells termed tumor stem cells (TSCs) that are involved in cancer invasion/metastasis through a process called epithelial-mesenchymal transition (EMT). Additionally, studies have demonstrated that DCLK1 marks TSCs in the Apcmin/+ mouse model of intestinal neoplasia. COARE has shown that the TSC marker DCLK1 is upregulated in PDAC and is a central regulator of key oncogenic, pluripotency pathways and EMT. Also, the Dclk1 role in PDAC initiation is demonstrated by lineage-tracing and TSC-initiating mouse models. COARE's pre-clinical data shows that targeting of cells that overexpress DCLK1 arrests xenograft tumor growth. DCLK1 signaling inhibition using DCLK1 specific siRNAs delivered via PLGA nanoparticles (NPs) triggers induction and activation of several critical endogenous tumor- suppressor pathways, which in turn regulate oncogenic pathways and EMT-related transcription factors. COARE, in collaboration with Bioneer Inc., has developed CBT-411E (DCLK1 siRNAs encapsulated into SAMiRNATM conjugated with EGFR antibodies), which has several advantages over PLGA NPs including enhanced efficacy, reduce off-target toxicity, increase siRNA half-life, and minimal cytokine or interferon induction in human PBMCs. The potential outcome of this Fast-Track SBIR project is improved inhibition of PDAC and preparation for human clinical trials and commercialization. We will pursue four Phase I/II Aims: Fast-Track Phase I: Aim 1: Formulate and standardize CBT-411E. Aim 2: Demonstrate effectiveness of CBT- 411E against PDAC in vitro and in vivo. Fast-Track Phase II: Aim 3: Obtain optimum pharmacokinetic (PK) and pharmacodynamic (PD) properties, and continued preclinical efficacy of CBT-411E in patient-derived tumor xenograft models of PDAC. Aim 4: Perform IND-enabling toxicity and immunogenicity studies for CBT- 411E in Sprague-Dawley rats (SDR) and non-human primates (NHPs). Milestones: CBT-411E will show >40% inhibition of DCLK1 activity (10 nM); a DCLK1 MOA (>50% reduction in EMT factors, oncogenes (NOTCH, MYC, VEGF, and COX2) and DCLK1 expression); continued preclinical efficacy incl. a >3-fold reduction in patient-derived model tumorigenesis; suitable PK/PD, and <5% measureable toxicity in SDR and NHPs. Desired Outcome: Phase I/II SBIR success will provide the results and data needed to engage private-sector investors/partners in funding the regulatory approval needed for clinical trials in PDAC patients. Success will lead to marketing CBT-411E as the first PDAC treatment for significantly increasing patient survival.

摘要：胰腺导管腺癌（PDAC）是人类最具破坏性的癌症之一。是 美国每年与癌症相关死亡的第四个主要原因，<7％的5年生存率。尽管 FDA批准的治疗方案和医疗和手术护理的明显改善，没有显着 已经实现了对PDAC患者生存的影响。 2017年，预计将有53,000名美国人 被诊断出，预计将死于PDAC。有越来越多的证据表明大多数实体瘤 诸如PDAC的肿瘤发射细胞被称为肿瘤干细胞（TSC）的亚群 通过称为上皮 - 间质转变（EMT）的过程，在癌症入侵/转移中。此外， 研究表明，DCLK1标志着肠道肿瘤的APCMIN/+小鼠模型中的TSC。 Coare表明TSC标记DCLK1在PDAC中上调，是钥匙的中心调节器 致癌，多能途径和EMT。同样，DCLK1在PDAC启动中的作用也通过 谱系追踪和TSC定位小鼠模型。 Coare的临床前数据表明，针对细胞的靶向 过表达的DCLK1阻止了异种移植肿瘤的生长。使用DCLK1特定siRNA的DCLK1信号抑制 通过PLGA纳米颗粒（NPS）触发和激活几个关键内源性肿瘤的激活 抑制途径又调节致癌途径和与EMT相关的转录因子。 Coare与Bioneer Inc.合作开发了CBT-411E（DCLK1 sirnas封装在 samirnatm与EGFR抗体结合），该抗体具有比PLGA NP的几个优点 增强功效，降低脱靶毒性，增加siRNA半衰期以及最小的细胞因子或干扰素 人类PBMC的诱导。这个快速轨道SBIR项目的潜在结果得到了改善的抑制作用 PDAC和人类临床试验和商业化的准备。我们将追求四个I/II阶段的目标： 快速轨道I期：AIM 1：制定和标准化CBT-411E。目标2：证明CBT-的有效性 411E在体外和体内针对PDAC。快速轨道II期：目标3：获得最佳药代动力学（PK） CBT-411E在患者衍生方 PDAC的肿瘤异种移植模型。 AIM 4：对CBT-执行毒性和免疫原性研究 Sprague-Dawley大鼠（SDR）和非人类灵长类动物（NHP）中的411E。里程碑：CBT-411E将显示> 40％ 抑制DCLK1活性（10 nm）； DCLK1 MOA（EMT因子降低了50％，癌基因（Notch，Notch， MYC，VEGF和COX2）和DCLK1表达式）;继续临床前功效。降低> 3倍 患者衍生的模型肿瘤发生；合适的PK/PD，在SDR和NHP中<5％可测量的毒性。 预期的结果：I/II阶段SBIR成功将提供参与私营部门所需的结果和数据 投资者/合作伙伴资助PDAC患者临床试验所需的监管批准。成功将 导致营销CBT-411E作为第一次大大增加患者生存的PDAC治疗方法。