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.

我们先前的结果表明，癌症中IGF1R水平的高度变化（Cao等，CancerRes。68：8039-48，2008）表明，癌细胞中IGF1R水平与抗增殖性反应之间的直接相关性与抗IGF1R抗体的反应之间存在直接相关性。表达IGF1R升高的癌细胞对IGF1R抗体非常敏感。我们的数据表明，肿瘤细胞对IGF1R的升高具有高度的依赖性，用于在体外和体内维持高AKT信号传导。用治疗性抗体对IGF1R的抑制作用导致IGF1R肿瘤细胞中Akt信号传导的急剧减少。在当前的研究中，我们确定了一个模型系统，其中IGF1R抗体在体外和体内选择性诱导快速肿瘤细胞死亡。我们的结果说明了通过AKT和BCLXL介导的抗IGF1R诱导的癌细胞死亡的机制。没有升高BCl2的肿瘤细胞对IGF1R和AKT信号的依赖程度更大，因此，对抗IGF1R诱导的细胞死亡更容易受到影响。我们的数据进一步显示了IGF1R在肿瘤生长和存活中的双重功能。 这项工作导致了一篇论文，以抗癌（Mayeenuddin等，Oncogene。2010）。它在Platinum Publications（12/2010）中被引入，并在CCR，NCI（9/2010）的《杂志》中出现。为了鉴定具有针对肉瘤和生物标志物的选择性活性的新型药物，我们研究了与GenEntech合作的死亡受体DR5靶向抗体Drozitumab。 我们表明，DR5（而不是DR4）一直持续到所有横平和所有横幅性肉瘤（RMS）细胞的表面。 DR5抗体Drozitumab对大多数RMS细胞系有效。 caspase-8表达与对Drozitumab的敏感性之间存在很强的相关性，这诱导了死亡诱导的信号传导复合物的快速组装与仅在敏感细胞中的caspase-8的裂解。更重要的是，caspase-8催化活性既需要介导对drozitumab的敏感性，既需要且足够。此外，drozitumab具有对已建立的RMS异种移植物具有有效的抗肿瘤活性，其特异性是根据体外分析预测的，并且在一半治疗的小鼠中具有无肿瘤状态。我们的研究提供了RMS中死亡受体抗体的效力和选择性的首次临床前评估。 Drozitumab在体外是有效的，对表达caspase-8和体内表达caspase-8的大多数RMS细胞系可能会提供对RMS的长期控制。这项工作发表在Clin Cancer Res（Kang等，2011）。我们的Wrok引发了分解，以与一家大型制药公司开发Crada。我们正在追求将DR5靶向代理带到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用于临床研究的预测生物标志物，用于临床试验的药物。