Photodynamic therapy for neoplastic diseases involving serosal surfaces

涉及浆膜表面的肿瘤疾病的光动力疗法

• 批准号: 7760165
• 负责人: ELI J. GLATSTEIN
• 金额: $ 170.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-07 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760165
• 关键词: Photodynamic; therapy; neoplastic; diseases; involving

DESCRIPTION (provided by applicant): In our initial grant, we proposed to optimize intraperitoneal PDT to deal with tumors involving the peritoneal surface. We showed that IP-PDT to the peritoneum was feasible and tolerable, with acceptable toxicity but marginal efficacy. We demonstrated that IP-PDT has a narrow therapeutic ratio reflecting relatively poor ratios of tumor to normal tissue retention of Photofrin. In this renewal, we will study the biological and molecular enhancement of the PDT process by blocking EGF receptor. Preclinical studies show EGFR blockade in combination with PDT improves cytoxicity without increasing normal tissue toxicity. This suggests that inhibiting signal transduction after PDT can improve the therapeutic index of IP-PDT and yield more efficacy without toxicity. In Project 1, we will optimize IP-PDT by using a second generation photosensitizer (BPD) in combination with cetuximab to alter signal transduction in human tumors and thus enhance the therapeutic index of IP-PDT. Project 2 aims to optimize serosal PDT by inhibiting relevant components of signal transduction pathways. This project will define the impact of inhibiting EGF signaling on cytotoxicity and mechanisms of cell death following BPD mediated PDT of ovarian and lung cancer cells. We will use small molecules/antibody inhibitors and siRNA to inhibit EGF receptor and post-receptor signaling pathways. We will study both sequence and timing of PDT and growth factor pathway inhibition to maximize this synergistic effect. Project 3 will study the microenvironmental effects of PDT combined with targeted molecular therapy. We will define the relationship between tumor microenvironment and PDT outcome, with specific attention to the AKT signal transduction pathway looking at Avastin, C225 and nelfinavir. In Project 4, we will look at real-time optical diagnostics of tissue for PDT dosimetry and treatment with major emphasis on characterizing tumor microenvironment brought about by biological targeting while assessing our dosimetry. We have added a new Project 5, of IP-PDT for lung cancer presenting with pleural carcinomatosis. This work has gone on in parallel with our grant but not funded. Our clinical results appear to validate the concept of PDT for treatment of surface malignancies. This program project grant is largely translational and offers a novel and potentially effective therapy for cancers involving serosal surfaces.

描述（由申请人提供）：在我们的初始资助中，我们建议优化腹膜内 PDT 以治疗涉及腹膜表面的肿瘤。我们证明腹膜 IP-PDT 是可行且可耐受的，毒性可以接受，但疗效有限。我们证明 IP-PDT 的治疗比率较窄，反映出肿瘤与正常组织中 Photofrin 保留率相对较低。在本次更新中，我们将研究通过阻断 EGF 受体对 PDT 过程的生物学和分子增强作用。临床前研究表明，EGFR 阻断与 PDT 相结合可改善细胞毒性，而不增加正常组织毒性。这表明PDT后抑制信号转导可以提高IP-PDT的治疗指数，且疗效更佳且无毒副作用。在项目1中，我们将通过使用第二代光敏剂（BPD）与西妥昔单抗组合来优化IP-PDT，以改变人类肿瘤的信号转导，从而提高IP-PDT的治疗指数。项目2旨在通过抑制信号转导途径的相关成分来优化浆膜PDT。该项目将确定抑制 EGF 信号传导对卵巢癌细胞和肺癌细胞 BPD 介导的 PDT 后细胞毒性和细胞死亡机制的影响。我们将使用小分子/抗体抑制剂和siRNA来抑制EGF受体和受体后信号通路。我们将研究 PDT 和生长因子途径抑制的顺序和时间，以最大限度地发挥这种协同效应。项目3将研究PDT联合靶向分子治疗的微环境影响。我们将定义肿瘤微环境与 PDT 结果之间的关系，特别关注 Avastin、C225 和奈非那韦的 AKT 信号转导通路。在项目 4 中，我们将研究用于 PDT 剂量测定和治疗的组织实时光学诊断，重点是在评估我们的剂量测定时表征生物靶向带来的肿瘤微环境。我们增加了一个新的项目 5，即针对伴有胸膜癌病的肺癌进行 IP-PDT。这项工作与我们的赠款同时进行，但没有资助。我们的临床结果似乎验证了 PDT 治疗表面恶性肿瘤的概念。该计划项目拨款主要是转化性的，为涉及浆膜表面的癌症提供了一种新颖且潜在有效的疗法。