Inhibitors of Hedgehog Signaling For Brain Cancer Chemotherapy

脑癌化疗的 Hedgehog 信号抑制剂

基本信息

批准号：
7654776
负责人：
Nadia Dahmane
金额：
$ 43.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7654776
关键词：
Acids Adult Adverse effects Alkaloids Androstanes Biological Biological Factors Biological Models Biological Testing Blood - brain barrier anatomy Brain Neoplasms Cancer Biology Cellular Assay Chemotherapy-Oncologic Procedure Cholanes Cholic Acids Clinical Critiques Cytoplasmic Granules Development Developmental Biology Diagnosis Erinaceidae Estrone Ethers Evaluation Glioblastoma Glioma Goals Growth Homo Hydroxyl Radical In Vitro Institutes Intervention Laboratories Malignant - descriptor Malignant neoplasm of brain Mediating Mesenchymal Stem Cells Metabolic Molecular Target Mus Neurons Operative Surgical Procedures Organic Chemistry Patients Pennsylvania Radiation therapy Research Role Scheme Screening procedure Signal Pathway Sonic Hedgehog Pathway Steroids Structure Survival Rate System Testing United States Universities analog base cell growth chemotherapeutic agent chemotherapy cyclopamine design drug candidate in vitro testing in vivo inhibitor/antagonist innovation killings medulloblastoma neoplastic cell novel precursor cell programs response scaffold smoothened signaling pathway tool tumor growth

项目摘要

The overarching goal of this research program is the development of new chemotherapeutic agents for the treatment of brain cancer. Approximately 10,000 cases of glioma are diagnosed each year in the United States and only about half of those patients survive one year. For adults, high-grade glioma or glioblastoma multiforme (GBM) is the most malignant and invasive brain tumor. Treatments include surgery, radiotherapy, and chemotherapy, yet survival rarely exceeds one year after diagnosis. New molecular targets and approaches for clinical intervention are thus desperately needed to increase the survival rate and reduce side effects. Glioblastoma multiforme (GBM) requires Sonic Hedgehog (SHH) signaling for its growth. Our hypothesis is that blockade of SHH signaling constitutes a promising strategy for brain cancer chemotherapy. Cyclopamine, a naturally occurring alkaloid that inhibits the SHH pathway, reduces growth of tumors with activated SHH signaling in vivo, and has been shown to cross the blood brain barrier. However, the metabolic instability of cyclopamine precludes its use as a chemotherapeutic agent. We propose that structurally simplified, metabolically stable cyclopamine-like SHH signaling inhibitors can be prepared from commercially available steroidal precursors (estranes, androstanes and cholanes). The steroidal framework enables the facile synthesis of analogs for in vitro biological testing and for the optimization of biological potency and selectivity. Importantly, our preliminary results have established the validity of this scenario. The studies outlined herein therefore hold the promise of developing important new tools in cancer biology and new drug candidates for the treatment of brain cancers.

该研究计划的总体目标是开发用于治疗脑癌的新型化疗药物。美国每年诊断出约 10,000 例神经胶质瘤病例，其中只有约一半患者能存活一年。对于成年人来说，高级别胶质瘤或多形性胶质母细胞瘤（GBM）是最恶性和最具侵袭性的脑肿瘤。治疗方法包括手术、放疗和化疗，但诊断后生存期很少超过一年。因此，迫切需要新的临床干预分子靶点和方法来提高生存率并减少副作用。多形性胶质母细胞瘤 (GBM) 的生长需要 Sonic Hedgehog (SHH) 信号传导。我们的假设是，阻断 SHH 信号传导是脑癌化疗的一种有前景的策略。环巴明是一种天然存在的生物碱，可抑制 SHH 通路，通过体内激活的 SHH 信号传导来减少肿瘤的生长，并已被证明可以穿过血脑屏障。然而，环巴明的代谢不稳定性妨碍了其作为化疗剂的用途。我们建议，结构简化、代谢稳定的环杷明样 SHH 信号抑制剂可以由市售的甾体前体（雌烷、雄甾烷和胆烷）制备。类固醇框架使得能够轻松合成类似物，用于体外生物测试以及生物效力和选择性的优化。重要的是，我们的初步结果已经证实了这种情况的有效性。因此，本文概述的研究有望开发癌症生物学中重要的新工具和治疗脑癌的新候选药物。