Enhancing Photodynamic Therapy for Treating Kaposi's Sarcoma

加强光动力疗法治疗卡波西肉瘤

• 批准号: 7120420
• 负责人: CHARLES Joseph GOMER
• 金额: $ 11.57万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120420
• 关键词: AIDS; Kaposi' s sarcoma; human; model; neoplasm /cancer; receptor; skin; tissues; xenotransplantation

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS) continues to be a major medical challenge in HIV-AIDS patients even with the extensive use of highly active antiretroviral therapy. This malignancy can have both psychological and physically debilitating affects that negatively impact quality of life. A variety of treatment approaches are being used but unfortunately effective long term palliation of KS remains difficult to achieve. Photodynamic therapy (PDT) has been used in the treatment of KS and has been reported to be effective in part because the procedure can be repeated and is not associated with either immunosuppressive activity or significant systemic toxicity. However, results from previous PDT clinical trials for KS demonstrated that the procedure has not been optimized and recurrences can occur. We propose a novel exploratory project designed specifically to enhance the local tumoricidal response of PDT using angiogenic inhibitors. This application builds upon our recent discovery that PDT induces overexpression of vascular endothelial growth factor (VEGF) and that angiogenic inhibitors can improve PDT responsiveness in murine carcinomas. We also have new preliminary data documenting that PDT also increases VEGF levels in a human KS xenograft model. We hypothesize that PDT induced expression of VEGF decreases treatment efficacy and that a combined modality approach employing PDT and angiogenic inhibitors will be effective in treating KS without inducing a concomitant increase in normal tissue toxicity. The goal of our R21 application is to determine whether drugs selectively inhibiting various components of VEGF signaling will improve the treatment of human KS tumors using PDT. This will be accomplished through in-vivo analysis of treatment responsiveness of human KS tumors transplanted in nude mice. Anti-angiogenic agents that target VEGF (Avastin), VEGF receptor-2 (DC101), or the receptor tyrosine kinase [ZD6474] will be evaluated in experiments designed to examine tumor and normal tissue response. The overall objective of this research is to obtain translational data justifying a novel clinical approach to improve the efficacy of PDT for treating KS. The successful completion of this objective would result in an improved treatment option for KS that exhibits minimal toxicity and which can be used repeatedly and following chemotherapy and/or radiation therapy.

描述（由申请人提供）：即使广泛使用高效抗逆转录病毒疗法，卡波西肉瘤（KS）仍然是 HIV-AIDS 患者面临的主要医学挑战。这种恶性肿瘤可能会造成心理和身体衰弱，从而对生活质量产生负面影响。目前正在使用多种治疗方法，但不幸的是，仍难以实现有效的长期缓解 KS 的效果。光动力疗法 (PDT) 已用于治疗 KS，据报道其有效部分是因为该过程可以重复，并且与免疫抑制活性或显着的全身毒性无关。然而，之前针对 KS 的 PDT 临床试验结果表明，该程序尚未优化，并且可能会发生复发。我们提出了一个新的探索性项目，专门设计用于使用血管生成抑制剂增强 PDT 的局部杀肿瘤反应。该应用基于我们最近的发现，即 PDT 会诱导血管内皮生长因子 (VEGF) 过度表达，并且血管生成抑制剂可以改善小鼠癌症中的 PDT 反应性。我们还有新的初步数据证明 PDT 还可以提高人类 KS 异种移植模型中的 VEGF 水平。我们假设 PDT 诱导的 VEGF 表达会降低治疗效果，并且采用 PDT 和血管生成抑制剂的联合治疗方法将有效治疗 KS，而不引起正常组织毒性的伴随增加。我们 R21 申请的目标是确定选择性抑制 VEGF 信号传导各种成分的药物是否会改善使用 PDT 治疗人类 KS 肿瘤。这将通过对移植到裸鼠体内的人类 KS 肿瘤的治疗反应进行体内分析来完成。靶向 VEGF (Avastin)、VEGF 受体 2 (DC101) 或受体酪氨酸激酶 [ZD6474] 的抗血管生成药物将在旨在检查肿瘤和正常组织反应的实验中进行评估。本研究的总体目标是获得转化数据，证明一种新的临床方法的合理性，以提高 PDT 治疗 KS 的疗效。这一目标的成功完成将导致 KS 的治疗方案得到改进，其毒性最小，并且可以在化疗和/或放疗后重复使用。