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.
The studies outlined in this proposal will contribute to our basic understanding of cutaneous angiogenesis. In addition, insights gained from the studies described in this proposal may lead to novel therapeutic approaches to cutaneous disease through signal transduction modulation.
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|Arbiser, Jack L; Bonner, Michael Y (2016) Seborrheic Keratoses: The Rodney Dangerfield of Skin lesions, and Why They Should Get Our Respect. J Invest Dermatol 136:564-6|
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|Rajamanickam, Subapriya; Panneerdoss, Subbarayalu; Gorthi, Aparna et al. (2016) Inhibition of FoxM1-Mediated DNA Repair by Imipramine Blue Suppresses Breast Cancer Growth and Metastasis. Clin Cancer Res 22:3524-36|
|Kang, Hee-Bum; Fan, Jun; Lin, Ruiting et al. (2015) Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling. Mol Cell 59:345-58|
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|Weyemi, Urbain; Redon, Christophe E; Aziz, Towqir et al. (2015) NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease. Proc Natl Acad Sci U S A 112:2121-6|
|Amin, A R M Ruhul; Karpowicz, Phillip A; Carey, Thomas E et al. (2015) Evasion of anti-growth signaling: A key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds. Semin Cancer Biol 35 Suppl:S55-77|
|Pillai, Vinodkumar B; Samant, Sadhana; Sundaresan, Nagalingam R et al. (2015) Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun 6:6656|
|Mochin, Maria T; Underwood, Karen F; Cooper, Brandon et al. (2015) Hyperglycemia and redox status regulate RUNX2 DNA-binding and an angiogenic phenotype in endothelial cells. Microvasc Res 97:55-64|
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