Enhancing Photodynamic Therapy for Treating Kaposi's Sarcoma

描述（由申请人提供）：即使广泛使用高活性抗逆转录病毒疗法，卡波西肉瘤（KS）仍然是艾滋病毒-艾滋病患者的主要医学挑战。这种恶性肿瘤会造成心理和身体上的衰弱，对生活质量产生负面影响。各种治疗方法正在使用，但不幸的是，有效的长期姑息仍然难以实现。光动力疗法（PDT）已被用于治疗KS，据报道，其有效的部分原因是该过程可以重复，并且与免疫抑制活性或显着的全身毒性无关。然而，先前针对KS的PDT临床试验结果表明，该手术尚未优化，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的局部肿瘤杀伤反应。这项应用建立在我们最近的发现之上，即PDT诱导血管内皮生长因子（VEGF）的过度表达，血管生成抑制剂可以改善PDT在小鼠癌中的反应性。我们也有新的初步数据证明PDT也增加了人类KS异种移植模型中的VEGF水平。我们假设PDT诱导的VEGF表达降低了治疗效果，使用PDT和血管生成抑制剂的联合模式方法将有效治疗KS，而不会引起正常组织毒性的增加。我们R21申请的目的是确定药物选择性抑制VEGF信号的各种成分是否会改善使用PDT治疗人类KS肿瘤。这将通过对裸鼠移植的人类KS肿瘤治疗反应性的体内分析来完成。针对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翻译数据，证明一种新的临床方法可以提高PDT治疗KS的疗效。这一目标的成功完成将为KS提供一种改进的治疗方案，该方案毒性最小，可在化疗和/或放疗后反复使用。

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.