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: 7610962
• 负责人: ELI J. GLATSTEIN
• 金额: $ 162.21万
• 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/7610962
• 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）：在我们的最初赠款中，我们提议优化腹膜内PDT来处理涉及腹膜表面的肿瘤。我们表明，对腹膜的IP-PDT是可行的，可耐受性的，具有可接受的毒性但有边际功效。我们证明IP-PDT具有狭窄的治疗比，反映了肿瘤与光蛋白的正常组织保留率相对较差。在此续约中，我们将通过阻断EGF受体来研究PDT过程的生物学和分子增强。临床前研究表明，EGFR与PDT结合使用可改善细胞毒性，而无需增加正常组织毒性。这表明，抑制PDT后的信号转导可以改善IP-PDT的治疗指数，并在没有毒性的情况下产生更多疗效。在项目1中，我们将通过使用第二代光敏剂（BPD）与Cetuximab结合使用Cetuximab来优化IP-PDT，以改变人类肿瘤中的信号转导，从而增强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组件来优化浆膜PDT。该项目将定义抑制EGF信号对BPD介导的卵巢和肺癌细胞PDT后细胞死亡机制的影响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受体和受体后信号传导途径。我们将研究PDT和生长因子途径抑制的序列和时机，以最大程度地发挥这种协同作用。项目3将研究PDT与靶向分子治疗的微环境效应。我们将定义肿瘤微环境与PDT结局之间的关系，并特别注意对Avastin，C225和Nelfinavir的Akt信号转导途径。在项目4中，我们将研究组织的实时光学诊断，以进行PDT剂量测定和处理，重点是表征生物学靶向带来的肿瘤微环境，同时评估我们的剂量法。我们添加了一个新的项目5，用于肺癌的肺癌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可以验证PDT治疗表面恶性肿瘤的概念。该计划项目赠款在很大程度上是转化的，并为涉及浆膜表面的癌症提供了一种新颖且潜在的疗法。