Preclinical Development of iRGD for Pancreatic Cancer

iRGD 治疗胰腺癌的临床前开发

• 批准号: 8199138
• 负责人: Miguel Garcia-Guzman
• 金额: $ 41.66万
• 依托单位: ASPYRIAN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-12 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199138
• 关键词: Antineoplastic Agents; Applications Grants; Award; Biodistribution; Biopsy; Caring; Cities; Clinical; Data; Desmoplastic; Detection; Development; Disease; Dose; Drug Kinetics; Drug resistance; Evaluation; Extracellular Matrix; Frequencies; Funding; Future; Goals; Grant; Human; Intercellular Fluid; Investigational New Drug Application; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Mus; Outcome; Penetration; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Probability; Process; Property; Protocols documentation; Publications; Regimen; Relapse; Research Institute; Research Personnel; Research Support; Safety; Science; Small Business Innovation Research Grant; Therapeutic; Time; Toxicology; Translations; United States Food and Drug Administration; Validation; Xenograft Model; base; cancer therapy; chemotherapeutic agent; density; gemcitabine; improved; in vivo; mouse model; new technology; novel; pancreatic neoplasm; pre-clinical; preclinical efficacy; preclinical study; pressure; safety study; standard of care; tumor

DESCRIPTION (provided by applicant): The goal of this phase I SBIR proposal is to generate the pharmacokinetic and pharmacodynamic data required to support the filing of an Investigational New Drug application (IND) to the Food and Drug Administration (FDA), of the tumor-penetrating peptide iRGD, in combination with gemcitabine as a new treatment for pancreatic cancer. Pancreatic cancer is a key funding priority for the NCI in 2011. iRGD, increases drug accumulation and penetration specificaly into tumors, when co-administered with chemotherapeutic agents, enhancing anti-tumoral activity and tolerability. Pancreatic cancers are characterized by a dense extracellular matrix and stroma that together with high tumor interstitial fluid pressure, acts as a physical barrier inhibiting drug access to the tumor. Increasing drug access deep into the tumor is essential for improving the clinical outcome of both current and future therapies. Preliminary data show that co-administration of iRGD with gemcitabine, the first-line treatment for pancreatic cancer, augments anti-tumoral activity in a xenograft model of pancreatic cancer. The goal of this proposal is to complete the pharmacokinetic and preclinical efficacy studies required to enable filing of an IND for iRGD in combination with gemcitabine as follows: Phase I Aims: 1. Biodistribution studies and optimization of iRGD dosing in combination with gemcitabine. 2. Demonstrate enhanced anti-tumoral activity of gemcitabine co-administered with iRGD in a mouse model of pancreatic cancer. Phase II of this proposal will focus on completion of the required toxicology studies necessary to support filing of an Investigational New Drug application with the Food and Drug Administration. We expect iRGD- based therapies to define the new standard-of-care in pancreatic cancer. The clinical validation of iRGD as a method to enhance anti-tumoral activity of drugs, will support a broader effort to combine iRGD with other anti- cancer therapies. PUBLIC HEALTH RELEVANCE: Poor penetration of drugs into tumors has recently been recognized as a significant contributing factor to cancer drug resistance. This is particularly true of malignancies such as pancreatic cancer which are characterized by a desmoplastic microenvironment of low microvascular density. Our collaborators have discovered a way of overcoming the drug penetration problem. The goals of this Phase I SBIR proposal is to conduct pre-clinical studies aimed at applying this new technology to the treatment of pancreatic cancer, and in the process, define a new standard of care for this deadly disease.

描述(由申请人提供)：此第一阶段SBIR提案的目标是生成所需的药代动力学和药效学数据，以支持向食品和药物管理局(FDA)提交肿瘤穿透肽IRGD与吉西他滨联合作为胰腺癌新疗法的研究新药申请(IND)。胰腺癌是NCI 2011年的关键资金重点。IRGD，当与化疗药物联合给药时，增加药物的累积和对肿瘤的特异性渗透，增强抗肿瘤活性和耐受性。胰腺癌的特点是致密的细胞外基质和间质，与高肿瘤间质液体压力一起，起到物理屏障的作用，阻止药物进入肿瘤。增加进入肿瘤深处的药物对于改善当前和未来治疗的临床结果至关重要。初步数据显示，作为治疗胰腺癌的一线药物，IRGD与吉西他滨联合应用可增强胰腺癌异种移植模型的抗肿瘤活性。这项建议的目标是完成以下所需的药代动力学和临床前疗效研究，以便将IND与吉西他滨联合用于IRGD：第一阶段的目标是：1.与吉西他滨联合使用的IRGD的生物分布研究和剂量优化。2.证明吉西他滨与IRGD联合应用在小鼠胰腺癌模型中的抗肿瘤活性增强。该提案的第二阶段将侧重于完成必要的毒理学研究，以支持向食品和药物管理局提交调查性新药申请。我们期望以IRGD为基础的治疗将定义胰腺癌治疗的新标准。IRGD作为一种增强药物抗肿瘤活性的方法的临床验证，将支持将IRGD与其他抗癌治疗相结合的更广泛的努力。 与公共卫生相关：药物对肿瘤的渗透性差最近被认为是癌症耐药性的一个重要因素。这对于胰腺癌这样的恶性肿瘤尤其如此，它们的特点是结缔组织增生性微环境的微血管密度较低。我们的合作者已经发现了一种克服药物渗透问题的方法。这项第一阶段SBIR提案的目标是进行临床前研究，旨在将这项新技术应用于胰腺癌的治疗，并在此过程中，确定这种致命疾病的新护理标准。