Preclinical Development of Novel Targeted Therapeutics Against Pediatric Sarcoma

小儿肉瘤新型靶向治疗药物的临床前开发

• 批准号: 8350134
• 负责人: Liang Cao
• 金额: $ 19.83万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8350134
• 关键词: Animal Model; Antibodies; Biological Markers; Biological Models; CCR; Cell Death; Cell Line; Cells; Cessation of life; Childhood; Clinical Research; Clinical Trials; Complex; Cooperative Research and Development Agreement; Data; Dependence; Development; Drug resistance; Evaluation; Fc Receptor; IGF1R gene; In Vitro; Investigation; Journals; Malignant Neoplasms; Mediating; Mus; Oncogenes; Paper; Pharmacologic Substance; Platinum; Proto-Oncogene Proteins c-akt; Publications; Publishing; Rhabdomyosarcoma; Signal Transduction; Specificity; Surface; TNFRSF10A gene; TNFRSF10B gene; Therapeutic antibodies; Translating; Variant; Work; Xenograft procedure; cancer cell; caspase-8; in vivo; neoplastic cell; new therapeutic target; novel; pre-clinical; preclinical evaluation; receptor; response; sarcoma; tumor; tumor growth

Our previous results revealed a high degree of variation of IGF1R levels in cancers (Cao et al., Cancer Res. 68: 8039-48, 2008) showed a direct correlation between the levels of IGF1R in cancer cells and the anti-proliferative response to anti-IGF1R antibodies. Cancer cells expressing elevated IGF1R were very sensitive to IGF1R antibody. Our data suggested that tumor cells had a high degree of dependence on elevated IGF1R for maintaining high AKT signaling, both in vitro and in vivo. The inhibition of IGF1R with therapeutic antibodies resulted in a dramatic reduction of AKT signaling in tumor cells with elevated IGF1R. In our current study, we identified a model system in which IGF1R antibody selectively induced rapid tumor cell death in vitro and in vivo. Our results illustrate the mechanism of anti-IGF1R-induced cancer cell death mediated via AKT and BclxL. Tumor cells without elevated Bcl2 had a greater degree of dependence on IGF1R and AKT signaling, and thus, more susceptible to anti-IGF1R induced cell death. Our data further showed a dual function for IGF1R in tumor growth and survival. This work results in a paper in press for oncogene (Mayeenuddin et al., Oncogene. 2010). It wascited at the Platinum Publications (12/2010) and featured at In the Journal by CCR, NCI(9/2010). To identify novel agents with selective activity against sarcoma and biomarkers predictive of responses, we investigated a death receptor DR5 targeted antibody drozitumab in working with Genentech. We show that DR5, but not DR4, persisted at high levels and on the surface of all rhabdomyosarcoma (RMS) cells. DR5 antibody drozitumab was effective in vitro against the majority of RMS cell lines. There was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of the death-induced signaling complex and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent antitumor activity against established RMS xenografts with a specificity predicted from the in vitro analysis and with tumor-free status in half of the treated mice. Our study provides the first preclinical evaluation of the potency and selectivity of a death receptor antibody in RMS. Drozitumab is effective, in vitro, against the majority of RMS cell lines that express caspase-8 and, in vivo, may provide long-term control of RMS. The work was published in Clin Cancer Res (Kang et al., 2011). Our wrok led to the initiation of dissucions to develop a CRADA with a major pharmaceutical company. We are pursuing the possibility of bringing a DR5 targeted agent to NCI for clinical investigations. Our investigations into novel agents targeting sarcoma and selectivity of these agents are being translated into predictive biomarkers for clinical studies and agents for clinical trials.

我们先前的结果显示IGF1R水平在癌症中的高度变异(Cao等人，癌症研究68：8039-48,2008)表明癌细胞中的IGF1R水平与抗IGF1R抗体的抗增殖反应直接相关。高表达IGF1R的癌细胞对IGF1R抗体非常敏感。我们的数据表明，无论在体外还是在体内，肿瘤细胞都高度依赖IGF1R的升高来维持高AKT信号。治疗性抗体抑制IGF1R导致IGF1R升高的肿瘤细胞AKT信号显著减少。在我们目前的研究中，我们确定了一个模型系统，在该系统中IGF1R抗体选择性地在体外和体内诱导肿瘤细胞快速死亡。我们的结果阐明了抗IGF1R通过AKT和BclxL介导的癌细胞死亡的机制。不表达Bcl2的肿瘤细胞对IGF1R和AKT信号的依赖程度更高，因此更容易受到抗IGF1R诱导的细胞死亡的影响。我们的数据进一步表明IGF1R在肿瘤生长和生存中具有双重功能。这项工作的结果是发表了一篇关于癌基因的论文(Mayeenuddin等，Oncogene。2010)。它在白金出版物上发表(2010年12月)，并在NCI CCR期刊上发表(2010年9月)。为了确定对肉瘤具有选择性活性的新药物和预测反应的生物标记物，我们与基因泰克合作研究了死亡受体DR5靶向抗体Drozitumab。我们发现DR5，而不是DR4，在所有横纹肌肉瘤(RMS)细胞表面的高水平持续存在。DR5抗体Drozitumab在体外对大多数RMS细胞株有一定的抑制作用。Caspase-8的表达与Drozitumab的敏感性密切相关，Drozitumab导致死亡诱导的信号复合体的快速组装和caspase-8仅在敏感细胞中的裂解。更重要的是，caspase-8的催化活性是调节Drozitumab敏感性的必要条件和充分条件。此外，Drozitumab对已建立的RMS异种移植瘤具有强大的抗肿瘤活性，其特异性可从体外分析中预测，并且在一半治疗的小鼠中处于无瘤状态。我们的研究首次对死亡受体抗体在RMS中的效力和选择性进行了临床前评估。在体外，Drozitumab对大多数表达caspase-8的RMS细胞株有效，在体内，可能提供对RMS的长期控制。这项研究发表在《临床癌症研究》(Kang等人，2011年)上。我们的工作导致了吸毒者与一家大型制药公司共同开发CRADA。我们正在探索将DR5靶向药物带到NCI进行临床研究的可能性。我们对针对肉瘤的新型药物和这些药物的选择性的研究正在转化为临床研究的预测生物标记物和临床试验的试剂。