Thermally Targeted Cell Cycle Inhibitors for the Treatment of Pancreatic Cancer

用于治疗胰腺癌的热靶向细胞周期抑制剂

• 批准号: 7896056
• 负责人: DRAZEN RAUCHER
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896056
• 关键词: Address; Adjuvant Chemotherapy; Adverse effects; Amino Acid Sequence; Animal Model; Apoptosis; Biopolymers; Blood Circulation; Cell Culture Techniques; Cell Cycle; Cell Cycle Inhibition; Cell Cycle Progression; Cell Proliferation; Cells; Code; Coupled; Data; Dose; Drug usage; Elastin; Engineering; Excision; Fever; Goals; Heating; In Vitro; Injection of therapeutic agent; Intravenous; Kinetics; Local Hyperthermia; Malignant neoplasm of pancreas; Measures; Mediating; Modality; Mus; Normal tissue morphology; Nude Mice; Operative Surgical Procedures; Peptides; Pharmaceutical Preparations; Physiological; Plasma; Quantitative Autoradiography; Radiation; Radiation therapy; Radiolabeled; Relative (related person); Research; Resistance; Rest; Site; Solid Neoplasm; Solutions; Specificity; Survival Rate; Technology; Temperature; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Transition Temperature; Treatment Efficacy; Tumor Volume; Xenograft Model; Xenograft procedure; aqueous; bactenecin; base; cancer cell; chemotherapy; cytotoxicity; design; improved; in vivo; inhibitor/antagonist; intraperitoneal; mouse model; neoplastic; neoplastic cell; new technology; oncoprotein p21; pancreatic neoplasm; polypeptide; public health relevance; radiotracer; subcutaneous; therapeutic target; tumor; tumor growth; tumor xenograft; uptake

DESCRIPTION (provided by applicant): Surgical resection, followed by chemotherapy and/or radiotherapy, is the most common therapeutic modalities used to treat pancreatic cancer. However, current treatment of localized pancreatic cancer is limited by normal tissue tolerance and/or inherent tumor resistance to radiation or chemotherapy, resulting in a low therapeutic index. To overcome these limitations, our goal is to develop a targeted therapeutic approach for localized pancreatic cancer that increases the specificity and efficacy of the therapy and reduces the cytotoxicity in normal tissues. We have designed a thermally responsive polypeptide which blocks cell cycle progression, induces apoptosis, and inhibits proliferation of pancreatic cancer in cell culture. The objective of the proposed research is to demonstrate that after systemic administration, these genetically engineered polypeptides can be targeted to the tumor site by applying local hyperthermia and can inhibit pancreatic tumor growth. The amino acid sequence of the thermally responsive polypeptides is based on elastin-like polypeptide (ELP) biopolymers, which are soluble in aqueous solution below physiological temperature (37 oC), but aggregate when the temperature is raised above 41 oC. A cell-penetrating peptide, Bactenecin (Bac), is conjugated to the ELP to facilitate cell entry, and a peptide derived from the cyclin-dependent kinase inhibitor p21 is added to inhibit the cell cycle. Our in vitro results demonstrate that Bac-ELP-p21 is a potent inhibitor of pancreatic cancer cell proliferation. Our hypothesis is that intravenously delivered Bac-ELP-p21 will be cleared from circulation under physiological conditions (37 oC), but will accumulate in pancreatic tumors grown in mice where externally induced local heat (42 oC) will be applied. The accumulated polypeptides will inhibit the cell cycle, induce apoptosis, and consequently inhibit proliferation of the cancer cells. In order to address this hypothesis, the following specific aims will be pursued: (1) measure the plasma kinetics and in vivo distribution of Bac-ELP-p21 in normal and neoplastic tissue and (2) evaluate the therapeutic efficacy of Bac- ELP-p21 in the treatment of pancreatic tumor xenografts in mice through repeated administration of the agent coupled with local hyperthermia. The successful completion of the proposed research will provide the in vivo data necessary to establish a new technology that has a competitive advantage over existing/alternate technologies for treatment of pancreatic cancer. Specific targeting of the proposed therapeutic polypeptides to pancreatic tumors by local hyperthermia would improve the efficacy and reduce the side effects relative to current drugs, and it would provide a means to substitute or augment present therapy for treatment of localized pancreatic cancer. PUBLIC HEALTH RELEVANCE: Current treatment of solid tumors is limited because only a small fraction of the administered drug dose reaches the tumor site while the rest of the drug is distributed throughout the body. This causes undesirable side effects to normal tissues when drugs are used in the doses required to eradicate cancer cells. Our long term goal is to overcome this limitation and reduce toxicity in normal tissues by developing an approach to specifically deliver therapeutics to the tumor site.

描述（由申请人提供）：手术切除，然后化疗和/或放疗，是用于治疗胰腺癌的最常见的治疗方式。然而，目前局部胰腺癌的治疗受到正常组织耐受性和/或固有的肿瘤对放射或化学疗法的抗性的限制，导致治疗指数低。为了克服这些局限性，我们的目标是开发一种针对局部胰腺癌的靶向治疗方法，提高治疗的特异性和有效性，并降低正常组织中的细胞毒性。我们已经设计了一种热响应多肽，其阻断细胞周期进程，诱导细胞凋亡，并抑制细胞培养中的胰腺癌增殖。所提出的研究的目的是证明在全身给药后，这些基因工程多肽可以通过应用局部热疗靶向肿瘤部位，并且可以抑制胰腺肿瘤生长。热响应多肽的氨基酸序列基于弹性蛋白样多肽（ELP）生物聚合物，其在低于生理温度（37 ° C）的水溶液中可溶，但当温度升高到41 ° C以上时聚集。将细胞穿透肽Bactenecin（Bac）与ELP结合以促进细胞进入，并加入衍生自细胞周期蛋白依赖性激酶抑制剂p21的肽以抑制细胞周期。我们的体外结果表明Bac-ELP-p21是胰腺癌细胞增殖的有效抑制剂。我们的假设是，静脉内递送的Bac-ELP-p21将在生理条件（37 ℃）下从循环中清除，但将在施加外部诱导的局部加热（42 ℃）的小鼠中生长的胰腺肿瘤中积累。积累的多肽将抑制细胞周期，诱导细胞凋亡，并因此抑制癌细胞的增殖。为了解决这一假设，将追求以下具体目标：（1）测量Bac-ELP-p21在正常和肿瘤组织中的血浆动力学和体内分布，和（2）通过重复施用与局部热疗结合的试剂，评价Bac-ELP-p21在治疗小鼠中的胰腺肿瘤异种移植物中的治疗功效。拟议研究的成功完成将提供必要的体内数据，以建立一种新技术，该技术与现有/替代技术相比具有竞争优势，用于治疗胰腺癌。通过局部热疗将所提出的治疗性多肽特异性靶向胰腺肿瘤将相对于当前药物提高功效并减少副作用，并且它将提供替代或增强用于治疗局部胰腺癌的当前疗法的手段。 公共卫生关系：目前对实体瘤的治疗是有限的，因为只有一小部分给药的药物剂量到达肿瘤部位，而其余的药物分布在整个身体。当药物以根除癌细胞所需的剂量使用时，这会对正常组织产生不良副作用。我们的长期目标是通过开发一种将治疗剂特异性地递送到肿瘤部位的方法来克服这种限制并降低正常组织中的毒性。