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（由申请人提供）：胰腺导管腺癌（PDAC）是实体瘤，是美国与癌症相关死亡的第四个主要原因，其受害者的5年生存率<5％。越来越多的证据表明，大多数实体瘤的肿瘤发射细胞的亚群称为“癌症干细胞”（CSC）。假定这些CSC的无法消除是对当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CSC的存在外，打击实体瘤的关键问题是肿瘤微环境中细胞类型的异质性。上皮 - 间质转变（EMT）使这种异质性更加复杂，该过程在癌症侵袭和转移中起关键作用。因此，胰腺癌的成功治疗需要开发可以同时攻击多种亲瘤途径的治疗剂。 COARE团队已经证明了推定的干细胞蛋白DCLK1是关键干细胞和致癌PDAC途径和EMT的中心调节剂。 Coare的临床前实验数据表明，过表达DCLK1的细胞的治疗靶向可阻止动物模型中的肿瘤生长。 DCLK1信号抑制作用触发了肿瘤内几种关键内源性肿瘤抑制途径的诱导/激活，进而调节几种下游癌基因和癌症生长调节途径以及过程以及EMT相关的转录因子。 DCLK1在许多实体瘤中过表达。 COARE产生了抗human-DCLK1 mAb，在结合后抑制DCLK1功能。因此，在此I阶段I SBIR项目中，我们建议证明优化以DCLK1为目标的CBT-1111的可行性，以消除PDAC。我们将追求三个具体目标。目标1：证明我们可以确定安全有效的CBT-1111。 AIM 2：通过MAB修改评估我们是否可以有效地将CBT-1111传递给动物和细胞。 AIM 3：证明使用人胰腺癌细胞在异种移植模型中CBT-1111对抑制原发性和转移性肿瘤生长的影响，并评估对体内候选基因表达的影响。可行性的测试：CBT-1111应在体外和体内击倒至少50％的DCLK1 mRNA和蛋白质及其下游致癌信号传导蛋白，具有最小的/NO毒性效应。使用全身和细胞活成像在动物/细胞中注射时，应跟踪用CY7标记的CBT-1111。此外，我们必须观察到肿瘤中的显着降低（> 3倍） CBT-1111治疗的肿瘤与对照组的大小。在用CBT1111治疗后，我们必须观察到肺和肝脏中转移性肿瘤摄取的减少。最后，我们必须观察到候选肿瘤抑制microRNA的增加2倍，而在用CBT-1111治疗后，在蛋白质和异种移植物残留肿瘤中，下游靶标的降低> 40％。第一阶段的成功将导致后续II期验证项目和最终III期商业化。