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(申请人提供)：卡波西肉瘤(KS)仍然是艾滋病毒-艾滋病患者面临的主要医学挑战，即使广泛使用高效的抗逆转录病毒治疗。这种恶性疾病可能会对心理和身体造成负面影响，对生活质量产生负面影响。目前正在使用各种治疗方法，但不幸的是，KS的长期有效姑息治疗仍然难以实现。光动力疗法(PDT)已被用于治疗KS，据报道是有效的，部分原因是该过程可重复进行，且与免疫抑制活性或显著的全身毒性无关。然而，以往光动力疗法治疗KS的临床试验结果表明，该程序尚未得到优化，可能会复发。我们提出了一个新的探索性项目，专门设计用血管生成抑制剂来增强PDT的局部杀瘤反应。这一应用建立在我们最近的发现基础上，即PDT诱导血管内皮生长因子(VEGF)的过度表达，以及血管生成抑制剂可以改善小鼠癌症的PDT反应性。我们也有新的初步数据证明，光动力疗法也增加了人类KS异种移植模型中的血管内皮生长因子水平。我们假设PDT诱导的血管内皮生长因子的表达降低了治疗效果，使用PDT和血管生成抑制剂的联合治疗方法将有效地治疗KS，而不会导致正常组织毒性的增加。我们应用R21的目的是确定选择性抑制血管内皮生长因子信号的各种成分的药物是否会改善使用PDT治疗人类KS肿瘤的效果。这将通过体内分析移植到裸鼠体内的人KS肿瘤的治疗反应性来实现。针对血管内皮生长因子(阿瓦斯丁)、血管内皮生长因子受体-2(DC101)或受体酪氨酸激酶[ZD6474]的抗血管生成药物将在旨在检测肿瘤和正常组织反应的实验中进行评估。这项研究的总体目标是获得翻译数据，以证明一种新的临床方法的合理性，以提高光动力疗法治疗KS的疗效。这一目标的成功完成将导致改善KS的治疗选择，其毒性最小，可重复使用，并可在化疗和/或放射治疗后使用。