Cutaneous Hemangiomas and Signal Transduction

描述(由申请人提供)：本申请侧重于使用在本提案的前一个周期中获得的信息来治疗血管瘤、血管畸形和恶性血管肿瘤。我们已经展示了三种不同的信号过程，它们是三类血管病变的基础，并提出了治疗这些病变的新方法。特别是，我们发现婴儿期的血管瘤使用了一条活性氧/Akt/Angiopoietin-2信号通路，并证明了该通路的抑制剂在治疗小鼠和人类的血管瘤方面都是有效的。第二，我们发现许多血管畸形使用Akt依赖但不依赖于活性氧的途径。鉴于诱导内质网应激(ER应激)的药物下调Akt，治疗性诱导内质网应激可能为血管畸形带来新的治疗方法。事实上，我们已经发现和厚朴酚，一种小分子血管生成抑制剂，是内质网应激的有效诱导者，也是ras信号转导的抑制剂。最后，我们发现了一种新的化合物，tris DBA钯，它通过阻断肉豆蔻酰化来阻断src家族的信号转导。重要的是，tris DBA钯在体内显示出抗肿瘤移植瘤的活性。鉴于血管瘤可能需要src家族激酶活性，而tris DBA钯通过抑制肉豆蔻酰化来阻止src家族激酶激活，tris DBA钯可能是一种治疗血管瘤的新方法。在上一次资助期间进行的研究表明，可以通过信号通路来区分血管瘤和血管畸形。有趣的是，心得安，一种β-受体阻滞剂，已经成为治疗婴儿大血管瘤的首选药物。心得安也是NADPH氧化酶的抑制剂，因此它的活性可能不依赖于β受体阻滞剂，因此，血管瘤的治疗可以完成，而不需要住院治疗与β受体阻滞剂副作用相关的婴儿。我们也许能够通过使用光学活性异构体来实现这一点，这些异构体作为β受体阻滞剂是无效的，但作为NADPH氧化酶抑制剂是活性的。有血管瘤和PHACE综合征(P-后颅窝异常、颈部面部H-血管瘤(S)、A-动脉脑血管异常、C-心缺陷、主动脉缩窄及其他主动脉异常、E眼异常)的患者中风的风险增加，因此一种不降低血压的药物将对这些儿童有很大的好处。假设：信号转导的差异可以指导体内血管内皮细胞肿瘤的治疗。具体目的1：评价β受体阻滞剂光学异构体作为抗血管瘤药物的活性。具体目的2：评价内质网应激和mTOR阻断对血管畸形模型的联合作用。具体目的3：确定肉豆蔻酰转移酶抑制体内血管瘤生长的作用。

DESCRIPTION (provided by applicant): This application focuses on using the information gained during the previous cycle of this proposal to the treatment of hemangiomas, vascular malformations and malignant vascular tumors. We have demonstrated three different signaling processes that underlie the three classes of vascular lesions, and have come up with novel approaches to treat these lesions. In particular, we have found that hemangiomas of infancy use a reactive oxygen/Akt/Angiopoietin-2 signaling pathway and have shown that inhibitors of this pathway are efficacious in the treatment of hemangiomas in both mice and humans. Second, we have found that many vascular malformations use an Akt dependent but reactive oxygen independent pathway. Given that agents that induce endoplasmic reticulum stress (ER stress) downregulate Akt, therapeutic induction of ER stress may lead to novel therapies for vascular malformations. Indeed, we have found that honokiol, a small molecule angiogenesis inhibitor, is a potent inducer of ER stress, as well as an inhibitor of ras signaling. Finally, we have found a novel compound, tris DBA palladium, which blocks src family kinase signaling by blocking myristoylation. Of importance, tris DBA palladium exhibits activity in vivo against tumor xenografts. Given that hemangiomas likely require src family kinase activity, and that tris DBA palladium prevents src family kinase activation through inhibition of myristoylation, tris DBA palladium might be a novel therapy for hemangiomas. Studies performed during the last funding period have suggested that hemangiomas and vascular malformations can be distinguished by signaling pathways. Interestingly, propranolol, a beta blocker, has become the treatment of choice for large hemangiomas of infancy. Propranolol is also an inhibitor of NADPH oxidase, thus its activity may be independent of beta blockade, and thus treatment of hemangiomas may be accomplished without the hospitalization associated with beta blockade side effects in infants. We may be able to accomplish this by using optically active isomers that are inactive as beta blockers but active as NADPH oxidase inhibitors. Patients with hemangiomas and PHACE (P - Posterior fossa abnormalities, H - Hemangioma(s) of the cervical facial region, A - Arterial cerebrovascular anomalies, C - Cardiac defects, aortic coarctation and other aortic abnormalities, E - Eye anomalies) syndrome are at increased risk of stroke, so an agent that doesn't lower blood pressure would be of great benefit to these children. Hypothesis: Differences in signal transduction can guide the treatment of endothelial neoplasms in vivo. Specific Aim 1: To evaluate the activity of optical isomers of beta blockers as antihemangioma agents. Specific Aim 2: To evaluate the combination of ER stress and mTOR blockade against vascular malformation models. Specific Aim 3: To determine the role of myristoyltransferase inhibition on hemangioma growth in vivo.