Novel Therapeutic Strategy for Gliomas

描述（申请人提供）：恶性神经胶质瘤的特征是能够从原发灶迅速弥漫性侵入周围正常脑实质，使其无法手术治愈。不能控制侵袭性细胞亚群可能是胶质瘤根治性切除术后局部复发的关键原因。目前可用的治疗策略具有较差的结果，并且有效的解决方案可能需要攻击这些恶性细胞中的多种异常机制。Onconova正在开发新的、基于机制的治疗药物，这些药物对正常细胞和癌细胞具有不同的作用。对癌细胞的作用是多效性的，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，生长受到抑制而不诱导凋亡。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表现出广泛的影响。初步数据表明，这种用小分子药物影响双重生长/死亡机制的策略是有希望的。具体目的是：1）拓展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在体外模型中对胶质瘤生长、粘附、迁移和血管生成的影响。这些研究为了解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了有价值的信息。

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.