Oncolytic Adenovirus-sTGFbetaRIIFc Targeting Breast Cancer Bone Metastasis

溶瘤腺病毒-sTGFbetaRIIFc靶向乳腺癌骨转移

• 批准号: 8025982
• 负责人: PREM SETH
• 金额: $ 28.01万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-09 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8025982
• 关键词: Adenovirus Vector; Adenoviruses; Attenuated; Binding; Biochemical Markers; Blood; Breast Cancer Cell; Calcitonin Receptor; Cancer Patient; Cells; Clinical Trials; Diagnosis; Diagnostic radiologic examination; EP300 gene; Enzymes; Evaluation; Gene Expression; Genes; Genetic; Goals; Human; In Vitro; Injection of therapeutic agent; Interleukin-11; Intravenous; Liver; Mammary Neoplasms; Measures; Mediating; Mesocricetus auratus; Metastatic Neoplasm to the Bone; Methods; Mission; Modeling; Morbidity - disease rate; Mus; National Cancer Institute; Neoplasm Metastasis; Normal Cell; Nude Mice; Oncolytic; Organ; Osteocalcin; Osteolytic; Pathway interactions; Patients; Phosphorylation; Primary Neoplasm; Production; Proteins; Research Personnel; Route; Safety; Scanning; Signal Transduction; TGFB1 gene; Testing; Therapeutic; Toxic effect; Transforming Growth Factors; United States; Viral; Virus; Woman; Work; adenoviral-mediated; base; bone; cancer cell; cathepsin K; chemokine; cytokine; gene therapy; human TERT protein; in vivo; malignant breast neoplasm; mitogen-activated protein kinase p38; mortality; mutant; neoplastic cell; novel strategies; osteoblast differentiation; osteoclastogenesis; parathyroid hormone-related protein; pre-clinical research; programs; promoter; receptor; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The majority of patients with advanced breast cancer develop bone metastases causing considerable morbidity and mortality. Thus, there is a tremendous need to develop novel approaches to treat breast cancer, and is one of the missions of National Cancer Institute. The goal of this proposal is to develop a therapeutic approach that will destroy the primary tumor, and simultaneously inhibit the breast cancer-associated bone metastasis. We will target the transforming growth factor-¿ (TGF¿) pathway because high levels of TGF¿ protein are known to contribute to the tumor progression, and are associated with bone metastasis in breast cancer patients. We will test whether oncolytic adenoviral vectors (dl01/07 based) expressing the soluble form of TGF¿ receptor II fused with human Fc lgG1 (Fc) (sTGF¿RIIFc) have anti- tumor effects. We constructed a dl01/07 based adenoviral vector expressing sTGF¿RIIFc (Ad.sT¿RFc). To further restrict viral replication in breast tumor cells, we have constructed mhTERTAd.sT¿RFc, a modified 01/07 based adenoviral vector expressing sTGF¿RIIFc gene, in which viral replication is under the control of a modified human telomerase reverse transcriptase (mhTERT) promoter. We will test the hypothesis that Ad.sT¿RFc and mhTERTAd.sT¿RFc will be oncolytic to the tumor cells, will produce sTGF¿RIIFc, and will cause minimum or no toxicity to the normal cells. We will also test the hypothesis that adenoviral-mediated production of sTGF¿RIIFc will abolish the effects of TGF¿ on tumor progression, osteoclastogenesis, and osteoblast differentiation together inhibiting the metastatic potential of the breast cancer cells. Following are the Specific Aims. Aim 1. To evaluate Ad.sT¿RFc and mhTERT Ad.sT¿RFc in vitro: Viral replication and sTGF¿RIIFc production. Aim 2. To evaluate sTGF¿RIIFc-mediated inhibition of TGF¿ functions in vitro: TGF¿ signaling, osteoclastogenesis, and osteoblast differentiation. Aim 3. To evaluate Ad.sT¿RFc and mhTERTAd.sT¿RFc in vivo: Virus distribution, replication, gene expression, safety, and toxicity. Aim 4. To evaluate Ad.sT¿RFc and mhTERT Ad.sT¿RFc in vivo: Tumor growth, metastasis, and osteolytic bone destruction. Nearly 200, 000 women are diagnosed with breast cancer each year in the United States. Most of the patients with advanced breast cancer develop bone metastases causing considerable morbidity and mortality. Thus, there is an urgent need to develop novel approaches to treat breast cancer. The goal of this project is to develop a new gene therapy method to treat breast cancer. The successful completion of the preclinical research proposed here is essential before clinical trials on breast cancer patients can be initiated.

描述（由申请人提供）：大多数晚期乳腺癌患者会发生骨转移，导致发病率和死亡率相当高，因此，非常需要开发治疗乳腺癌的新方法，这也是国家癌症中心的使命之一。研究所该提案的目标是开发一种治疗方法，能够破坏原发肿瘤，同时抑制乳腺癌相关的骨转移，我们将针对转化生长因子-¿ (TGF¿) 途径，因为高水平的 TGF¿已知 TGF 蛋白有助于肿瘤进展，并且与乳腺癌患者的骨转移相关。我们将测试溶瘤腺病毒载体（基于 dl01/07）是否表达可溶形式的 TGF¿与人Fc IgG1 (Fc) (sTGF¿RIIFc)融合的受体II具有抗肿瘤作用我们构建了表达sTGF¿的基于dl01/07的腺病毒载体。为了进一步限制乳腺肿瘤细胞中的病毒复制，我们构建了 mhTERTAd.sT¿ RFc，一种基于 01/07 的改良腺病毒载体，表达 sTGF¿ RIIFc 基因，其中病毒复制受修饰的人端粒酶逆转录酶 (mhTERT) 启动子控制。我们将检验 Ad.sT¿ 的假设。 RFc 和 mhTERTAd.sT¿ RFc 对肿瘤细胞具有溶瘤作用，会产生 sTGF¿ RIIFc，将对正常细胞造成最小的毒性或没有毒性，我们还将测试腺病毒介导的 sTGF 产生的假设。 RIIFc 将消除 TGF 的作用¿肿瘤进展、破骨细胞生成和成骨细胞分化共同抑制乳腺癌细胞的转移潜力。 具体目标 1. 评估 Ad.sT¿ RFc 和 mhTERT Ad.sT¿ RFc 体外：病毒复制和 sTGF¿目标 2. 评估 sTGF¿ RIIFc 介导的 TGF 抑制¿体外功能：TGF¿目标 3. 评估 Ad.sT¿ RFc 和 mhTERTAd.sT¿ RFc 体内：病毒分布、复制、基因表达、安全性和毒性。目标 4. 评估 Ad.sT¿ RFc 和 mhTERT Ad.sT¿ RFc 体内：肿瘤生长、转移和溶骨性骨破坏在美国，每年有近 200, 000 名女性被诊断患有乳腺癌，大多数晚期乳腺癌患者会发生骨转移，从而导致发病率和死亡率。迫切需要开发治疗乳腺癌的新方法，该项目的目标是开发一种新的基因治疗方法来治疗乳腺癌，在此提出的临床前研究的成功完成对于临床试验至关重要。对乳腺癌患者可以启动。

项目成果

Systemic delivery of a novel liver-detargeted oncolytic adenovirus causes reduced liver toxicity but maintains the antitumor response in a breast cancer bone metastasis model.

在乳腺癌骨转移模型中，全身递送新型肝脏去靶向溶瘤腺病毒可降低肝脏毒性，但维持抗肿瘤反应。

• DOI: 10.1089/hum.2011.003
• 发表时间: 2011-04-12
• 期刊: Human gene therapy
• 影响因子: 4.2
• 作者: Zhenwei Zhang;Jeffrey D. Krimmel;Zhiling Zhang;Zebin Hu;P. Seth
• 通讯作者: P. Seth

Ad5/48 hexon oncolytic virus expressing sTGFβRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases.

• DOI: 10.1038/mt.2014.80
• 发表时间: 2014-08-01
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy
• 作者: Weidong Xu;Zhenwei Zhang;Yuefeng Yang;Zebin Hu;Chi;Melanie Morgan;Ying Wu;R. Hutten
• 通讯作者: R. Hutten

A modified hTERT promoter-directed oncolytic adenovirus replication with concurrent inhibition of TGFbeta signaling for breast cancer therapy.

一种修饰的 hTERT 启动子引导的溶瘤腺病毒复制，同时抑制 TGFbeta 信号传导，用于乳腺癌治疗。

• 发表时间: 2010-04
• 影响因子: 6.4
• 作者: Hu, Z;Robbins, J S;Pister, A;Zafar, M B;Zhang, Z;Gupta, J;Lee, K J;Newman, K;Neuman, K;Yun, C;Guise, T;Seth, P
• 通讯作者: Seth, P

Intravenous administration of adenoviruses targeting transforming growth factor beta signaling inhibits established bone metastases in 4T1 mouse mammary tumor model in an immunocompetent syngeneic host.

静脉注射靶向转化生长因子β信号传导的腺病毒可抑制免疫活性同基因宿主的4T1小鼠乳腺肿瘤模型中已形成的骨转移。

• 发表时间: 2012-09
• 影响因子: 6.4
• 作者: Zhang, Z;Hu, Z;Gupta, J;Krimmel, J D;Gerseny, H M;Berg, A F;Robbins, J S;Du, H;Prabhakar, B;Seth, P
• 通讯作者: Seth, P

Oncolytic adenovirus expressing soluble TGFβ receptor II-Fc-mediated inhibition of established bone metastases: a safe and effective systemic therapeutic approach for breast cancer.

溶瘤腺病毒表达可溶性 TGFβ 受体 II-Fc 介导的骨转移抑制：一种安全有效的乳腺癌全身治疗方法。

• DOI: 10.1038/mt.2011.114
• 发表时间: 2011-09-01
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy
• 作者: Zebin Hu;Helen Gerseny;Zhenwei Zhang;Yun;A. Berg;Zhiling Zhang;S. Stock;P. Seth
• 通讯作者: P. Seth