Novel Therapeutic Strategy for Gliomas

描述（由申请人提供）：恶性胶质瘤的特点是其能够迅速和弥漫性地从原发灶侵入周围正常的脑实质，使其无法通过手术治愈。未能控制细胞的侵袭亚群可能是肿瘤根治后局部胶质瘤复发的关键原因。目前可用的治疗策略效果不佳，有效的解决方案可能需要攻击这些恶性细胞的多种异常机制。Onconova正在开发一种基于机制的新型治疗药物，这种药物对正常细胞和癌细胞有不同的作用。对癌细胞的影响是多方面的，包括抑制细胞生长和激活细胞凋亡。正常细胞，如参与血管生成的内皮细胞，生长受到抑制，但不诱导凋亡。我们的假设是筛选这一系列化合物，这些化合物对参与细胞生长、侵袭和血管生成的各种基因有广泛的影响。初步数据表明，这种用小分子药物影响双生长/死亡机制的策略是有希望的。具体目的是：1)扩大药物的化学结构和活性关系；2)研究Onconova系列化合物ON 01060、ON 01330、ON 01370、ON 01500、ON 01590和ON 01910对体外模型胶质瘤生长、粘附、迁移和血管生成的影响。这些研究可能为这些化合物在肿瘤细胞粘附、侵袭和血管生成中的作用提供有价值的信息。

DESCRIPTION (PROVIDED BY APPLICANT): Malignant gliomas are characterized by their ability to swiftly and diffusely invade from their primary foci into the surrounding normal brain parenchyma, making them surgically incurable. The failure to control invasive subpopulations of cells may be the key cause of local glioma recurrence after radical tumor resection. Currently available therapeutic strategies have poor outcome and an effective solution may require attack on multiple aberrant mechanisms in these malignant cells. Onconova is developing novel, mechanism based, therapeutic agents that have differential effects on normal and cancer cells. The effect on cancer cells is pleiotropic and involves inhibition of cell growth as well as activation of apoptosis. Normal cells, such as endothelial cells involved in angiogenesis, are growth inhibited without induction of apoptosis. Our hypothesis is to screen this series of compounds that exhibit a broad range of effects on various genes that are involved in cell growth, invasion and angiogenesis. Preliminary data suggests that this strategy of impacting dual growth/death mechanisms with a small molecule drug is promising. The specific aims are 1) to expand the chemical structure and activity relationship of the drug and 2) to study the effect of Onconova Series compounds ON 01060, ON 01330, ON 01370, ON 01500, ON 01590 and ON 01910 on glioma growth, adhesion, migration and angiogenesis in in vitro models. The studies may provide valuable information about the role of these compounds in tumor cell adhesion, invasion and angiogenesis.