Antiangiogenic Therapy for AIDS-Associated Lymphomas

艾滋病相关淋巴瘤的抗血管生成治疗

• 批准号: 7414557
• 负责人: ROSEMARY ROCHFORD
• 金额: $ 15.7万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414557
• 关键词: AIDS related cancer; AIDS therapy; AIDS-Related Burkitt' s Lymphoma; AIDS-Related Lymphoma; AIDS-Related Non-Hodgkin' s Lymphoma; Acquired Immunodeficiency Syndrome; Address; Adopted; Africa; Angiogenesis Inhibitors; Arts; B-Lymphocytes; Biological Markers; Blood Vessels; Burkitt Lymphoma; Cancer Patient; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Chronic; Clinic; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Country; Cytotoxic Chemotherapy; Cytotoxic agent; Daily; Development; Disease; Disease regression; Disease remission; Dose; Endothelial Cells; Engraftment; Epidemic; Goals; Green Fluorescent Proteins; HIV; Health; Human; Image; Injection of therapeutic agent; International; Kenya; Lentivirus Vector; Luciferases; Lymphomagenesis; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Mediating; Medical; Modeling; Monitor; Myelosuppression; Palliative Care; Patients; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Proliferating; Rate; Research; Resources; Retroviral Vector; SCID Mice; Schedule; Sorting - Cell Movement; Standards of Weights and Measures; Supportive care; System; Testing; Therapeutic; Therapy Evaluation; Thinking; Toxic effect; Uganda; Universities; Viral; Work; angiogenesis; base; cancer therapy; cellular transduction; chemotherapy; experience; in vivo; innovation; lung Carcinoma; malignant breast neoplasm; mortality; mouse model; novel; novel strategies; novel therapeutics; pre-clinical; response; time use; tumor; tumor growth; vector

DESCRIPTION (provided by applicant): The burden of the AIDS epidemic is highest in Africa where resources are limited for the treatment of HIV and for HIV-associated diseases. And as the AIDS epidemic continues to grow in Africa, AIDS-related malignancies are also increasing including AIDS-related Burkitt's lymphoma (BL). The current treatment paradigm relies on cytotoxic drugs given at the maximum tolerated dose. However, in the resource-constrained setting, there is a lack of supportive care available to patients undergoing these intensive combination chemotherapy regimens resulting in unacceptably high mortality rates. Alternative approaches to the treatment of BL and other AIDS-related non-Hodgkin's lymphomas are needed in resource-poor countries. A new alternative approach utilizes standard chemotherapeutic drugs but delivers them at a metronomic (chronic, continuous and low-dose) schedule. The metronomic scheduling of cytotoxic drugs is hypothesized to inhibit the development of endothelial cells within the tumor and block angiogenesis. Because of the lower doses of drugs, there is reduced myelosuppression and associated toxicities. The objectives of this application are to develop a preclinical model of AIDS- associated BL to test this new therapeutic approach and to test metronomic therapy in this model. We will develop a lentiviral vector to transduce primary AIDS-BL cell lines with luciferase to monitor tumor growth and response to treatment by bioluminescent imaging. The use of primary AIDS-BL lines engrafted into NOD/SCID mice intraperitoneally will generate an orthotopic model of BL that more closely resembles human clinical disease. Using this preclinical model of AIDS-BL, we will determine whether targeting of angiogenesis by adopting a metronomic schedule of chemotherapeutic drugs can induce remission and reduce toxicity. Our clinical hypothesis is that low-doses of combinations of cytotoxic agents given more frequently will inhibit the development of endothelial cells in primary AIDS-BL cell lines engrafted in NOD/SCID mice and result in long-lasting tumor regression. Our long-term goal is to develop mechanism-based therapies for the treatment of BL and other AIDS-related non-Hodgkin's lymphomas that address the unique needs in resource poor settings where supportive care is limited. The successful completion of this research will allow us to move forward to test metronomic dosing of cytotoxic drugs in the clinic. PROJECT NARRATIVE: The goal of the proposed research is to develop a preclinical model to test new chemotherapies for AIDS-associated lymphomas.

描述（由申请人提供）：非洲艾滋病流行的负担最为严重，那里用于治疗艾滋病毒和艾滋病毒相关疾病的资源有限。随着非洲艾滋病疫情的持续蔓延，与艾滋病相关的恶性肿瘤也在增加，其中包括与艾滋病相关的伯基特淋巴瘤（BL）。目前的治疗模式依赖于以最大耐受剂量给予细胞毒性药物。然而，在资源有限的环境下，接受这些强化联合化疗方案的患者缺乏支持性护理，导致死亡率高得令人无法接受。资源匮乏的国家需要治疗 BL 和其他与艾滋病相关的非霍奇金淋巴瘤的替代方法。一种新的替代方法利用标准化疗药物，但按节拍（慢性、连续和低剂量）时间表给药。细胞毒性药物的节律性调度被认为可以抑制肿瘤内内皮细胞的发育并阻止血管生成。由于药物剂量较低，因此骨髓抑制和相关毒性减少。本申请的目的是开发艾滋病相关 BL 的临床前模型，以测试这种新的治疗方法并在该模型中测试节拍疗法。我们将开发一种慢病毒载体，用荧光素酶转导原代 AIDS-BL 细胞系，通过生物发光成像监测肿瘤生长和对治疗的反应。使用腹腔内移植到 NOD/SCID 小鼠体内的原代 AIDS-BL 系将产生更接近人类临床疾病的 BL 原位模型。利用这种 AIDS-BL 的临床前模型，我们将确定通过采用化疗药物的节律性方案来靶向血管生成是否可以诱导缓解并降低毒性。我们的临床假设是，更频繁地给予低剂量的细胞毒性药物组合会抑制植入 NOD/SCID 小鼠的原代 AIDS-BL 细胞系中内皮细胞的发育，并导致持久的肿瘤消退。我们的长期目标是开发基于机制的疗法来治疗 BL 和其他与艾滋病相关的非霍奇金淋巴瘤，以满足支持性护理有限的资源匮乏地区的独特需求。这项研究的成功完成将使我们能够继续在临床上测试细胞毒性药物的节律剂量。项目叙述：拟议研究的目标是开发一种临床前模型来测试艾滋病相关淋巴瘤的新化疗方法。