Cutaneous Hemangiomas and Signal Transduction

皮肤血管瘤和信号转导

• 批准号: 8856496
• 负责人: JACK L ARBISER
• 金额: $ 34.32万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856496
• 关键词: Address; Adrenergic beta-Antagonists; Adverse effects; Agreement; Angiogenesis Inhibitors; Angiopoietin-2; Animals; Aortic coarctation; Behavior; Blood Vessels; Bradycardia; Brain; Cell model; Cells; Cervical; Child; Clinical; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Congenital Heart Defects; Cutaneous; Disease; Down-Regulation; Doxorubicin; Drug usage; Dyes; Endothelial Cells; Eosine Yellowish; Exhibits; Eye; FDA approved; Face; Funding; Glioblastoma; Growth; Health; Hemangioma; Hemangiosarcoma; Hospitalization; Human; Hypotension; In Vitro; Infant; Inhibitory Concentration 50; Isomerism; Kaposiform Hemangioendothelioma; Lead; Legal patent; Lesion; Licensing; Lymphangioma; Lymphatic; Malignant Vascular Neoplasm; Modeling; Mus; NADPH Oxidase; Neoplasms; Optics; Outpatients; Oxygen; Palladium; Paper; Pathologic Neovascularization; Pathway interactions; Patients; Pharmacologic Substance; Phosphotransferases; Posterior Fossa; Propranolol; Proteins; Ras Inhibitor; Rattus; Research; Risk; Role; SRC gene; Science; Signal Pathway; Signal Transduction; Sirolimus; Stroke; Syndrome; Therapeutic; angiogenesis; blood pressure reduction; cerebrovascular; endoplasmic reticulum stress; honokiol; human FRAP1 protein; human NOS3 protein; improved; in vivo; infancy; inhibitor/antagonist; insight; malformation; melanoma; member; mouse model; myristoylation; novel; novel strategies; novel therapeutic intervention; prevent; signal processing; small molecule; src-Family Kinases; translational medicine; triphenylmethane; tumor xenograft

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.

描述（由申请人提供）：本申请的重点是使用在本提案的前一个周期中获得的信息治疗血管瘤、血管畸形和恶性血管肿瘤。我们已经证明了构成三类血管病变基础的三种不同信号传导过程，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，并且已经表明该通路的抑制剂在小鼠和人类血管瘤的治疗中是有效的。其次，我们发现许多血管畸形使用Akt依赖性但不依赖活性氧的途径。鉴于诱导内质网应激（ER应激）的药物下调Akt，ER应激的治疗性诱导可能导致血管畸形的新疗法。事实上，我们已经发现，和诺明，一种小分子血管生成抑制剂，是一种有效的ER应激诱导剂，以及ras信号传导抑制剂。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家族激酶信号传导。重要的是，tris DBA钯表现出体内抗肿瘤异种移植物的活性。鉴于血管瘤可能需要src家族激酶活性，并且tris DBA钯通过抑制肉豆蔻酰化防止src家族激酶活化，tris DBA钯可能是血管瘤的新疗法。在上一个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β受体阻滞剂，已经成为治疗婴儿大血管瘤的首选。普萘洛尔也是NADPH氧化酶的抑制剂，因此其活性可能不依赖于β受体阻滞剂，因此可以完成血管瘤的治疗，而无需与婴儿β受体阻滞剂副作用相关的住院治疗。我们可以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受体阻滞剂是无活性的，但作为NADPH氧化酶抑制剂是有活性的。患有血管瘤和PHACE（P -后颅窝异常，H -颈面部区域血管瘤，A -动脉脑血管异常，C -心脏缺陷，主动脉缩窄和其他主动脉异常，E -眼异常）综合征的患者中风风险增加，因此不降低血压的药物对这些儿童非常有益。假设：信号转导的差异可以指导体内内皮肿瘤的治疗。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ER应激和mTOR阻断的组合对血管畸形模型的作用。具体目标3：确定肉豆蔻酰转移酶抑制对体内血管瘤生长的作用。