Cutaneous Hemangiomas and Signal Transduction

描述（由申请人提供）：本申请的重点是利用本申请前一个周期获得的信息来治疗血管瘤、血管畸形和恶性血管肿瘤。我们已经证明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，我们发现婴儿期血管瘤使用活性氧/Akt/血管生成素-2信号通路，并表明该通路的抑制剂在小鼠和人类的血管瘤治疗中都有效。其次，我们发现许多血管畸形使用Akt依赖但不依赖活性氧的途径。考虑到诱导内质网应激（ER应激）的药物下调Akt，内质网应激的治疗性诱导可能会导致血管畸形的新疗法。事实上，我们已经发现，一种小分子血管生成抑制剂——厚朴酚，是内质网应激的有效诱诱剂，也是ras信号的抑制剂。最后，我们发现了一种新的化合物，tris DBA palladium，它通过阻断肉豆蔻酰化来阻断src家族激酶信号传导。重要的是，tris DBA钯在体内表现出抗肿瘤异种移植的活性。鉴于血管瘤可能需要src家族激酶活性，而tris DBA钯通过抑制豆蔻酰化来阻止src家族激酶的激活，tris DBA钯可能是一种新的血管瘤治疗方法。在上一次资助期间进行的研究表明，血管瘤和血管畸形可以通过信号通路来区分。有趣的是，普萘洛尔，一种受体阻滞剂，已经成为治疗婴儿大血管瘤的首选。心得安也是NADPH氧化酶的抑制剂，因此其活性可能独立于β阻断剂，因此婴儿血管瘤的治疗可以在没有住院治疗的情况下完成，而住院治疗与β阻断剂的副作用有关。我们也许可以通过使用光活性同分异构体来实现这一点，这些同分异构体作为受体阻滞剂是无活性的，但作为NADPH氧化酶抑制剂是有活性的。血管瘤和PHACE （P -后窝异常、H -颈面血管瘤、A -脑血管动脉异常、C -心脏缺损、主动脉缩窄等主动脉异常、E -眼异常）综合征的患者卒中风险增加，因此一种不降血压的药物对这些儿童有很大的益处。假设：体内信号转导的差异可以指导内皮肿瘤的治疗。特异性目的1：评价-受体阻滞剂光学异构体作为抗血管瘤药物的活性。目的2：评价内质网应激联合mTOR阻断对血管畸形模型的影响。特异性目的3：确定肉豆蔻酰基转移酶抑制在体内血管瘤生长中的作用。

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.