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: 9553404
• 负责人: Sripathi M Sureban
• 金额: $ 29.88万
• 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 2021-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9553404
• 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; Gene Targeting; 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; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Operative Surgical Procedures; Organ; Outcome; PTGS2 gene; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Permeability; 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 Initiators; Tumor Stem Cells; Tumor Suppressor Proteins; Tumor-Derived; Vascular Endothelial Growth Factors; Work; Xenograft Model; base; cancer cell; cancer initiation; commercialization; cytokine; gemcitabine; immunogenicity; improved; in vivo; innovation; knock-down; migration; mouse model; nanoparticle; nonhuman primate; novel; novel therapeutics; overexpression; pluripotency; pre-clinical; preclinical efficacy; prevent; response; 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.

翻译后摘要：胰腺导管腺癌（PDAC）是最具破坏性的人类癌症之一。是 在美国每年癌症相关死亡的第四大原因，5年生存率<7%。尽管 FDA批准的治疗方案和医疗和手术护理的显著改善，无显著性差异 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 预计约有43，000人将死于PDAC。越来越多的证据表明，大多数实体瘤 例如具有称为肿瘤干细胞（TSCs）肿瘤起始细胞亚群的PDAC 在癌症侵袭/转移中通过称为上皮-间充质转化（EMT）的过程。此外，本发明还 研究已经证明DCLK 1标记肠肿瘤形成的Apcmin/+小鼠模型中的TSC。 COARE已经表明TSC标记物DCLK 1在PDAC中上调，并且是关键的调节因子， 致癌、多能性途径和EMT。此外，Dclk 1在PDAC启动中的作用被证实为： 谱系追踪和TSC起始小鼠模型。COARE的临床前数据显示， 过表达DCLK 1抑制异种移植肿瘤生长。使用DCLK 1特异性siRNA抑制DCLK 1信号传导 通过PLGA纳米颗粒（NP）递送的药物引发了几种关键的内源性肿瘤的诱导和激活， 抑制途径，反过来又调节致癌途径和EMT相关的转录因子。 COARE与Bioneer Inc.合作，开发了CBT-411 E（DCLK 1 siRNA封装在 SAMiRNATM与EGFR抗体缀合），其具有优于PLGA NP的几个优点，包括 增强的功效、降低脱靶毒性、增加siRNA半衰期和最小的细胞因子或干扰素 人PBMC中的诱导。这个快速通道SBIR项目的潜在结果是改善对 PDAC和用于人体临床试验和商业化的制剂。我们将实现第一/第二阶段的四个目标： 快速通道第一阶段：目标1：制定和标准化CBT-411 E。目标2：证明CBT的有效性- 411 E对PDAC的体外和体内作用。快速通道II期：目标3：获得最佳药代动力学（PK） 和药效学（PD）特性，以及CBT-411 E在患者源性 PDAC的肿瘤异种移植模型。目的4：对CBT进行IND使能毒性和免疫原性研究- Sprague-Dawley大鼠（SDR）和非人灵长类动物（NHP）中的411 E。军事：CBT-411 E将显示>40% 抑制DCLK 1活性（10 nM）; DCLK 1 MOA（EMT因子，癌基因（NOTCH， MYC、VEGF和COX 2）和DCLK 1表达）;持续临床前疗效，包括a减少3倍以上 患者来源的模型肿瘤发生;合适的PK/PD，以及SDR和NHP中<5%的可测量毒性。 预期成果：SBIR第一/第二阶段的成功将提供吸引私营部门参与所需的结果和数据 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CBT-411 E作为首个PDAC治疗药物上市，显著提高患者生存率。