Oncolytic adenovector-mediated TRAIL gene therapy for cancers

溶瘤腺载体介导的 TRAIL 基因治疗癌症

• 批准号: 8018480
• 负责人: BINGLIANG FANG
• 金额: $ 30.51万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018480
• 关键词: Adenovirus Vector; Adverse effects; Animals; Apoptosis; Bystander Effect; Cancer cell line; Cells; Clinical; Clinical Research; Cytolysis; Fiber; Fibroblasts; Future; Gene Expression; Genes; Goals; Green Fluorescent Proteins; H1299; Human; Immune response; Immunocompetent; Immunocompromised Host; In Vitro; Individual; Induction of Apoptosis; Laboratories; Lead; Ligands; Malignant Neoplasms; Mediating; Mesocricetus auratus; Methods; Modeling; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; Oncolytic; Oncolytic viruses; Resistance; Safety; Solid; System; TNFSF10 gene; Telomerase; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; Tumor Necrosis Factor-alpha; Tumor Tissue; Viral; anticancer activity; base; cancer cell; cancer therapy; clinical application; cytotoxic; gene therapy; human TERT protein; in vivo; killings; neoplastic cell; novel therapeutics; oncolysis; oncolytic vector; preclinical study; promoter; subcutaneous; success; transduction efficiency; treatment strategy; tumor; tumor xenograft; vector

DESCRIPTION (provided by applicant): The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and oncolytic virus vectors have recently been investigated extensively for cancer therapy. However, preclinical and clinical studies have revealed that the clinical application of these two agents is hampered either by their weak anticancer activity or by their possible systemic toxicity. Therefore, strategies to maximize their anticancer activity and minimize their systemic toxicity are essential to the success of these agents in the treatment of cancers. The goal of this proposal is to determine the efficacy and safety of a tumor-specific replication-competent (oncolytic) adenovector expressing the TRAIL gene for the treatment of cancer. The hypothesis to be tested is that integration of virotherapy and TRAIL gene therapy into a single agent will enhance its in vivo transduction efficiency and apoptosis-induction capacity and that an oncolytic adenovector expressing both the TRAIL and E1A genes from the human telomerase reverse transcriptase (hTERT) promoter will target both virotherapy and TRAIL gene therapy to cancer, destroying tumor tissue but sparing normal tissue. Our preliminary studies showed that incorporating the TRAIL gene into an oncolytic adenovector enhanced viral replication and oncolysis in cancer cells, whether they were susceptible or resistant to the TRAIL gene, both in vitro and in vivo, with minimal replication activity and cytotoxic effects in normal human fibroblasts. Intralesional administration of the TRAIL-expressing oncolytic adenovector eliminated all subcutaneous xenograft tumors established from a human non-small cell lung cancer cell line in nu/nu mice, resulting in long-term tumor-free survival. To further test the hypothesis, we will determine the optimal adenovector systems for the delivery of hTERT-TRAIL to human and syngeneic Syrian hamster tumors by evaluating the therapeutic and side effects of hTERT-TRAIL delivered by an E1-deleted vector, an oncolytic vector, and a fiber-modified oncolytic vector in vitro and in vivo. We will also determine whether an immune response triggered by an adenovector will have any effect on either antitumor activity or side effects. Finally, we will determine the antitumor activity of the TRAIL-expressing oncolytic vector in both human and Syrian hamster syngeneic metastatic models established in both immunocompromised and immunocompetent animals. Completing the proposed studies will allow us to determine the optimal methods for delivery of hTERT- TRAIL and develop strategies for the treatment of metastasis. The results of these preclinical studies will also provide a solid scientific basis for future integration of TRAIL therapy and oncolytic virotherapy and may lead to new therapeutic agents for cancer therapy.

描述（由申请人提供）：最近已经对肿瘤坏死因子相关的凋亡诱导配体（TRAIL）和溶瘤病毒载体进行了广泛研究，以进行癌症治疗。但是，临床前和临床研究表明，这两种药物的临床应用会因其抗癌活性弱或可能的全身毒性而受到阻碍。因此，最大化其抗癌活性并最大程度地减少其全身毒性的策略对于这些药物在治疗癌症方面的成功至关重要。该提案的目的是确定肿瘤特异性复制（癌性）腺苷酸的功效和安全性，表达了用于治疗癌症的TRAIL基因。要检验的假说是，病毒疗法和越野基因治疗与单一药物的整合将提高其体内转导效率和凋亡诱导能力，并从表达TRAIL和E1A基因的鼻腺腺载炉从人类伸缩酶逆转录酶（HTERT）启动者的侵蚀剂群体侵蚀性疗法，从而破坏了病毒疗法的癌症，但会破坏癌症。我们的初步研究表明，将TRAIL基因纳入癌细胞中的癌细胞的肿瘤腺窝增强了病毒复制和肿瘤分解，无论它们在体外和体内都易感或抗性基因，对正常的人类成纤维成纤维组合体中的细胞毒性和细胞毒性影响最小。表达尾溶性腺苷酸的遗传内给药消除了NU/NU小鼠中人类非小细胞肺癌细胞系建立的所有皮下异种移植肿瘤，导致长期无肿瘤生存期。 To further test the hypothesis, we will determine the optimal adenovector systems for the delivery of hTERT-TRAIL to human and syngeneic Syrian hamster tumors by evaluating the therapeutic and side effects of hTERT-TRAIL delivered by an E1-deleted vector, an oncolytic vector, and a fiber-modified oncolytic vector in vitro and in vivo.我们还将确定腺窝触发的免疫反应是否会对抗肿瘤活性或副作用产生任何影响。最后，我们将确定在免疫功能低下和免疫能力的动物中建立的人和叙利亚仓鼠合成性转移模型中表达尾colytic型的抗肿瘤活性。完成拟议的研究将使我们能够确定提供HTERT-TRAIL的最佳方法，并制定用于治疗转移的策略。这些临床前研究的结果还将为未来的跟踪治疗和溶瘤病毒疗法的整合提供扎实的科学基础，并可能导致新的治疗剂进行癌症治疗。

项目成果

Identification of a small molecule with synthetic lethality for K-ras and protein kinase C iota.

• DOI: 10.1158/0008-5472.can-08-1449
• 发表时间: 2008-09-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Guo W;Wu S;Liu J;Fang B
• 通讯作者: Fang B

Analogues and derivatives of oncrasin-1, a novel inhibitor of the C-terminal domain of RNA polymerase II and their antitumor activities.

• DOI: 10.1021/jm101417n
• 发表时间: 2011-04-28
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Wu S;Wang L;Guo W;Liu X;Liu J;Wei X;Fang B
• 通讯作者: Fang B

Interruption of RNA processing machinery by a small compound, 1-[(4-chlorophenyl)methyl]-1H-indole-3-carboxaldehyde (oncrasin-1).

• DOI: 10.1158/1535-7163.mct-08-0839
• 发表时间: 2009-02
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Guo W;Wu S;Wang L;Wang RY;Wei X;Liu J;Fang B
• 通讯作者: Fang B

Introduction to this Special Issue: "Biomarker Discovery and Precision Medicine".

本期特刊简介：“生物标志物发现与精准医学”。

• DOI: 10.20517/2394-4722.2019.42
• 发表时间: 2020
• 期刊: Journal of cancer metastasis and treatment
• 作者: Fang,Bingliang

Coxsackie-adenovirus receptor as a novel marker of stem cells in treatment-resistant non-small cell lung cancer.

• DOI: 10.1016/j.radonc.2012.09.002
• 发表时间: 2012-11
• 期刊: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
• 作者: Zhang X;Fang B;Mohan R;Chang JY
• 通讯作者: Chang JY