Replicative Adenovirus and Anti-angiogenic Therapy

复制性腺病毒和抗血管生成治疗

• 批准号: 7629054
• 负责人: Chinghai Kao
• 金额: $ 28.79万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629054
• 关键词: Ablation; Acute; Adenoviruses; Affect; American; Androgens; Angiogenesis Inhibitors; Angiogenic Factor; Angiostatins; Animal Model; Animals; Ants; Arts; Basal Cell; Biodistribution; Biological; Biological Assay; Bioluminescence; Bone neoplasms; Cancer Etiology; Cells; Cessation of life; Chimeric Proteins; Clinic; Clinical; Clinical Trials; Cyan Fluorescent Protein; Cytomegalovirus; Data; Detection; Development; Diagnosis; Disease; Dynamic Enhanced CT; Early Diagnosis; Endostatins; Enhancers; Fiber; Firefly Luciferases; Future; Genes; Genetic Enhancer Element; Glutamate Carboxypeptidase II; Growth; Herpes Simplex Infections; Hormonal; Human; Hybrids; Image; In Vitro; Injection of therapeutic agent; Investigation; Label; Laboratories; Luciferases; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modality; Modeling; Monitor; Neoplasm Metastasis; Oncogenes; Organ; Osteocalcin; Patients; Photons; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Reporter; Reporting; Research Personnel; Safety; Second Primary Neoplasms; Structure of base of prostate; Structure of thyroid parafollicular cell; Symptoms; TK Gene; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Treatment Efficacy; United States; Upper arm; Vertebral column; Viral; Virus; Wound Healing; androgen independent prostate cancer; base; cancer cell; cancer recurrence; cancer therapy; cell type; clinical application; experience; gene therapy; hormone refractory prostate cancer; improved; in vivo; killings; men; novel; preclinical study; programs; promoter; red fluorescent protein; research study; response; tissue culture; treatment effect; tumor; tumor growth

DESCRIPTION (provided by applicant): Prostate cancer is the second most frequently diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. Despite recent advances in the early detection and treatment of organ-confined prostate cancer, treatment results for advanced prostate cancer remain quite disappointing. In particular, current treatment modalities for androgen-independent (Al) prostate cancer only relieve the symptoms temporarily. We recently developed a prostate-restricted replicative adenovirus (PRRA), AdE1aPESEE4, to treat Al prostate cancer. Ad E1aPSESE4 replicated as efficient as a wild-type adenovirus in PSA/PSMA positive prostate cancer cells, but not in any other cell types, in tissue culture. However, the therapeutic effect of AdE1aPSESE4 in an animal tumor model was only temporary, probably due to limited tumor targeting and insufficient viral replication and distribution inside the tumor. We subsequently improved our treatment modality by integrating a expression cassette for an anti-angiogenic factor, EndoAngio (an endostatin-angiostatin fusion protein), into our PRRA to make an ant-angiogenic PRRA, EndoAngio-Ad5/35PRRA which eliminated 7 of 10 treated tumors. The remaining tumors ceased to grow in the 10-week observation period. This proposal further refines and develops our antiangiogenic PRRA therapy. Specific aim 1 will develop and validate several antiangiogenic PRRAs which express EndoAngio, sFlk1 or sTie2 to target tumor vasculature via different mechanisms. We will explore two viral backbones, Ad5 and Ad5/35 hybrid virus, to construct anti-angiogenic PRRAs. This aim will also evaluate the biodistribution and safety of antiangiogenic PRRAs after intra-tumoral and systemic administration of the virus, and assay their effects on wound healing. These steps will facilitate eventual clinical application of this therapy. Specific Aim 2 will evaluate the therapeutic advantages of antiangiogenic PRRAs over PRRA itself on s.c. prostate tumors by intra-tumor injection, prostate cancer metastases by systemic injection, and s.c. hybrid tumors composed of both PSA/PSMA-positive and negative cells by intra-tumor injection. Androgen-independent prostate cancer cells will be labeled with reporters, such as Cyan fluorescent protein, red fluorescent protein, firefly luciferase and Renila luciferase, to facilitate the detection of metastasis and analysis of therapeutic efficacy. The antiangiogenic effects of treatment on tumor vasculature will be monitored by dynamic contrast-enhanced CT (DCE-CT) imaging. We will explore dual photon fluorescent imaging to compare effects on tumor vasculature between therapies. According to our preliminary data and recent reports by others, we believe that the combination of PRRA therapy and antiangiogenic therapy presents a novel promising modality for cancer treatment and deserves more extensive investigation and further development. The study proposed in this application can be translated into the clinic to treat patients with advanced prostate cancer in the near future.

描述（由申请人提供）：前列腺癌是美国男性中第二常见的恶性肿瘤，也是导致男性癌症相关死亡的第二大原因。尽管最近在器官局限性前列腺癌的早期检测和治疗方面取得了进展，但晚期前列腺癌的治疗结果仍然相当令人失望。特别地，目前针对雄激素非依赖性(Al)前列腺癌的治疗方式只能暂时缓解症状。我们最近开发了一种前列腺限制性复制腺病毒（PRRA）AdE1aPESEE4，用于治疗前列腺癌。在组织培养中，Ad E1aPSESE4 在 PSA/PSMA 阳性前列腺癌细胞中的复制效率与野生型腺病毒相同，但在任何其他细胞类型中则不然。然而，AdE1aPSESE4 在动物肿瘤模型中的治疗效果只是暂时的，可能是由于肿瘤靶向有限以及肿瘤内病毒复制和分布不足所致。随后，我们通过将抗血管生成因子 EndoAngio（一种内皮抑素-血管抑制素融合蛋白）的表达盒整合到我们的 PRRA 中，从而改进了我们的治疗方式，以制成抗血管生成 PRRA，EndoAngio-Ad5/35PRRA，消除了 10 例治疗中的 7 例肿瘤。其余肿瘤在 10 周的观察期内停止生长。该提案进一步完善和发展了我们的抗血管生成 PRRA 疗法。具体目标 1 将开发并验证几种表达 EndoAngio、sFlk1 或 sTie2 的抗血管生成 PRRA，以通过不同机制靶向肿瘤脉管系统。我们将探索两种病毒骨架，Ad5 和 Ad5/35 混合病毒，以构建抗血管生成 PRRA。该目标还将评估肿瘤内和全身注射病毒后抗血管生成 PRRA 的生物分布和安全性，并测定其对伤口愈合的影响。这些步骤将有助于该疗法的最终临床应用。具体目标 2 将评估皮下抗血管生成 PRRA 相对于 PRRA 本身的治疗优势。通过肿瘤内注射治疗前列腺肿瘤，通过全身注射治疗前列腺癌转移，以及皮下注射。通过肿瘤内注射由 PSA/PSMA 阳性和阴性细胞组成的混合肿瘤。雄激素非依赖性前列腺癌细胞将被标记青色荧光蛋白、红色荧光蛋白、萤火虫荧光素酶和海肾荧光素酶等报告基因，以方便检测转移和分析治疗效果。治疗对肿瘤脉管系统的抗血管生成作用将通过动态对比增强 CT (DCE-CT) 成像进行监测。我们将探索双光子荧光成像，以比较不同疗法对肿瘤血管系统的影响。根据我们的初步数据和其他人最近的报告，我们认为PRRA疗法和抗血管生成疗法的结合为癌症治疗提供了一种新的有前途的方式，值得更广泛的研究和进一步的发展。该申请中提出的研究可以在不久的将来转化为临床以治疗晚期前列腺癌患者。