Development of Monoclonal Antibodies To Treat Pancreatic Cancer

开发治疗胰腺癌的单克隆抗体

• 批准号: 8589430
• 负责人: Panayotis Pantazis
• 金额: $ 22.01万
• 依托单位: COARE BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8589430
• 关键词: Address; Animal Model; Animals; Antibodies; Antineoplastic Agents; Area; Binding; Biology; C-terminal; Cancer Etiology; Candidate Disease Gene; Caring; Cell Line; Cells; Cessation of life; Data; Development; Disease; Dose; Drug or chemical Tissue Distribution; Epithelial; Esters; Extracellular Domain; FDA approved; Gene Expression; Goals; Growth; Heterogeneity; Human; Image; Immunohistochemistry; In Vitro; International; Investments; Lead; Life; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Medical; Mesenchymal; Messenger RNA; MicroRNAs; Modification; Monoclonal Antibodies; Morphology; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Operative Surgical Procedures; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Play; Preparation; Primary Neoplasm; Private Sector; Process; Property; Proteins; RNA; Radiation; Recurrence; Regimen; Regulatory Pathway; Relapse; Residual Tumors; Resistance; Signal Transduction; Signaling Protein; Site; Small Business Innovation Research Grant; Solid Neoplasm; Stem cells; Survival Rate; T-cell acute lymphocytic leukemia 1 protein; Technology; Testing; Text; Therapeutic; Time; Tissues; Toxic effect; Treatment outcome; Tumor Suppressor Proteins; Validation; Work; Xenograft Model; Xenograft procedure; cancer stem cell; cell type; chemotherapy; combat; commercialization; effective therapy; epithelial to mesenchymal transition; experience; gemcitabine; high throughput screening; improved; in vivo; knock-down; next generation; novel; novel strategies; novel therapeutics; overexpression; pancreatic cancer cells; phase 2 study; pre-clinical; prevent; public health relevance; research and development; response; self-renewal; stem cell biology; success; therapeutic development; therapeutic target; transcription factor; tumor; tumor growth; tumor microenvironment; tumor progression; tumor xenograft; tumorigenic; uptake

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a solid tumor and is the fourth leading cause of cancer-related death in the U.S. The 5-year survival rate of its victims is <5%. There is increasing evidence that most solid tumors have a subpopulation of tumor-initiating cells termed "cancer stem cells" (CSCs). The inability to eradicate these CSCs is postulated to be the reason for tumor relapse and death following initial responses to the current standard therapeutic regimen. In addition to the existence of CSCs, a critical problem in combating solid tumors is the heterogeneity of cell types within the tumor microenvironment. This heterogeneity is further complicated by epithelial-mesenchymal transition (EMT), a process that plays a key role in cancer invasion and metastasis. Thus successful treatment of pancreatic cancer requires the development of therapeutics that can attack multiple pro-tumorigenic pathways simultaneously. The COARE team has demonstrated that the putative stem cell protein DCLK1 is a central regulator of key stem cell and oncogenic PDAC pathways and EMT. COARE's pre-clinical experimental data shows that therapeutic targeting of cells that overexpress DCLK1 arrests tumor growth in animal models. DCLK1 signaling inhibition triggers the induction/activation of several critical endogenous tumor-suppressor pathways within the tumor, which in turn regulate several downstream oncogenes and cancer growth regulatory pathways and processes and EMT-related transcription factors. DCLK1 is overexpressed in many solid tumors. COARE has generated anti-human-DCLK1 mAbs that inhibit DCLK1 function upon binding. Thus, in this Phase I SBIR project we propose to prove the feasibility of optimizing CBT-1111 that targets DCLK1 as a next-generation treatment for eradicating PDAC. We will pursue three Specific Aims. Aim 1: Prove that we can identify a safe and effective dose of CBT-1111. Aim 2: Assess via mAb modifications if we can effectively deliver CBT-1111 to the animals and cells. Aim 3: Demonstrate the effects of CBT-1111 on suppressing primary and metastatic tumor growth in xenograft models using human pancreatic cancer cells, and assess the effects on candidate gene expression in vivo. Test of Feasibility: CBT-1111 should knock down at least 50% of DCLK1 mRNA and protein and their downstream oncogenic signaling proteins in vitro and in vivo with minimal/no toxicity effects. CBT-1111 tagged with Cy7 should be tracked once injected in animals/cells using whole-body and cellular live imaging. Additionally, we must observe a significant reduction (>3 fold) in tumor size of the CBT-1111 treated tumors vs. controls. We must observe a reduction in metastatic tumor uptake in the lungs and liver following treatment with CBT1111. Finally, we must observe a 2-fold increase in candidate tumor suppressor microRNAs and a corresponding >40% reduction in downstream targets at the protein and mRNA level in xenograft residual tumors following treatment with CBT-1111. Phase I success will lead to a follow-on Phase II validation project and ultimate Phase III commercialization.

描述(申请人提供)：胰腺导管腺癌(PDAC)是一种实体瘤，是美国癌症相关死亡的第四大原因。其受害者的5年存活率为5%。越来越多的证据表明，大多数实体肿瘤都有一种称为“癌症干细胞”(CSCs)的肿瘤起始细胞亚群。无法根除这些CSCs被认为是目前标准治疗方案的初步反应后肿瘤复发和死亡的原因。除了CSCs的存在外，对抗实体肿瘤的一个关键问题是肿瘤微环境中细胞类型的异质性。上皮-间充质转化(EMT)使这种异质性变得更加复杂，这一过程在癌症的侵袭和转移中起着关键作用。因此，胰腺癌的成功治疗需要开发能够同时攻击多条促肿瘤途径的治疗方法。COARE团队已经证明，假定的干细胞蛋白DCLK1是关键干细胞和致癌PDAC途径和EMT的中央调节因子。COARE的临床前实验数据表明，对过度表达DCLK1的细胞进行治疗靶向可以阻止动物模型中的肿瘤生长。DCLK1信号抑制触发了肿瘤内几个关键的内源性肿瘤抑制通路的诱导/激活，这些通路反过来调节几个下游的癌基因、肿瘤生长调控途径和过程以及EMT相关的转录因子。DCLK1在许多实体瘤中过表达。COARE已经产生了抗人DCLK1单抗，在结合时抑制DCLK1的功能。因此，在这个第一阶段SBIR项目中，我们建议证明优化CBT-1111的可行性，该CBT-1111以DCLK1为靶点，作为根除PDAC的下一代治疗方法。我们将追求三个具体目标。目的1：证明可以确定CBT-1111的安全有效剂量。目的2：评价通过mAb修饰能否将CBT-1111有效地输送到动物和细胞中。目的：研究CBT-1111对人胰腺癌细胞移植瘤原发灶和转移瘤生长的抑制作用，并评价其对体内候选基因表达的影响。可行性试验：CBT-1111在体外和体内均能击倒至少50%的DCLK1mRNA和蛋白及其下游致癌信号蛋白，毒性作用最小/无。标记了Cy7的CBT-1111一旦注射到动物/细胞中，就应该使用全身和细胞活体成像进行跟踪。此外，我们必须观察到肿瘤显著减少(3倍)。 CBT-1111治疗的肿瘤与对照组的肿瘤大小。我们必须观察CBT1111治疗后转移性肿瘤在肺和肝脏的摄取减少。最后，我们必须观察到CBT-1111治疗后，在异种移植残留肿瘤中，候选抑癌基因microRNAs增加了2倍，下游靶标相应减少了40%。第一阶段的成功将导致第二阶段的后续验证项目和最终的第三阶段商业化。