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.

摘要：胰腺导管腺癌（PDAC）是最具破坏性的人类癌症之一。它是 每年是美国癌症相关死亡的第四大原因，5 年生存率 <7%。尽管 FDA 批准的治疗方案以及医疗和外科护理方面的显着改善，没有显着 对 PDAC 患者生存的影响已经实现。 2017 年，预计将有约 53,000 名美国人 确诊，预计约有 43,000 人死于 PDAC。越来越多的证据表明大多数实体瘤 例如 PDAC 具有称为肿瘤干细胞 (TSC) 的肿瘤起始细胞亚群，它们参与其中 通过称为上皮间质转化（EMT）的过程参与癌症侵袭/转移。此外， 研究表明，DCLK1 在 Apcmin/+ 小鼠肠道肿瘤模型中标记 TSC。 COARE 表明 TSC 标记 DCLK1 在 PDAC 中上调，并且是关键的中央调节器 致癌、多能性途径和 EMT。此外，Dclk1 在 PDAC 启动中的作用通过 谱系追踪和 TSC 启动小鼠模型。 COARE 的临床前数据表明，靶向细胞 过度表达 DCLK1 可抑制异种移植肿瘤的生长。使用 DCLK1 特异性 siRNA 抑制 DCLK1 信号传导 通过 PLGA 纳米颗粒 (NP) 传递，触发几种关键内源性肿瘤的诱导和激活 抑制途径，进而调节致癌途径和 EMT 相关转录因子。 COARE 与 Bioneer Inc. 合作开发了 CBT-411E（封装在 DCLK1 siRNA 中） SAMiRNATM 与 EGFR 抗体缀合），与 PLGA NP 相比具有多种优势，包括 增强功效、减少脱靶毒性、增加 siRNA 半衰期，并最大限度地减少细胞因子或干扰素 人类 PBMC 中的诱导。该快速通道 SBIR 项目的潜在成果是改善对 PDAC 以及人体临床试验和商业化的准备。我们将追求四个第一/第二阶段的目标： 快速通道第一阶段：目标 1：制定 CBT-411E 并使其标准化。目标 2：展示 CBT 的有效性 411E 在体外和体内针对 PDAC。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-411E 在患者源性药物中的持续临床前疗效 PDAC肿瘤异种移植模型。目标 4：对 CBT 进行 IND 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、癌基因（NOTCH、 MYC、VEGF 和 COX2) 和 DCLK1 表达)；持续的临床前疗效，包括。减少 3 倍以上 源自患者的肿瘤发生模型；合适的 PK/PD，SDR 和 NHP 中可测量的毒性 <5%。 预期成果：第一/第二阶段 SBIR 的成功将提供私营部门参与所需的结果和数据 投资者/合作伙伴为 PDAC 患者临床试验所需的监管批准提供资金。成功将会 导致 CBT-411E 作为第一个 PDAC 治疗药物上市，显着提高患者生存率。