Faculty Bibliography

Most metastatic melanomas are refractory to current available therapy, underscoring the need to identify new effective treatments. Sorafenib, a multikinase inhibitor of the mitogen-activated protein kinase signaling pathway, showed promise in earlier stages of clinical development, but ultimately failed to demonstrate efficacy as a single agent in the treatment of melanoma. In order to enhance the efficacy of sorafenib in the treatment of melanoma, we tested over 2,000 naturally occurring compounds and marketed drugs in the presence of sorafenib in chemoresistant human melanoma cell lines also resistant to sorafenib-induced apoptosis. Of the 9 compounds identified as sorafenib sensitizers, we prioritized the cholesterol-lowering agent fluvastatin, based on its favorable pharmacokinetics and safety profile. Our results demonstrate that fluvastatin at 1 muM, a level safely achieved through oral administration, dramatically enhances the growth-inhibitory activity of clinically achievable concentrations of sorafenib in M14 and SKM-173 melanoma cells, with a 3.2- and 3.6-fold reduction in sorafenib 50% growth inhibition (GI50), respectively. Similar effects were observed for other melanoma cell lines. Combination indices analysis revealed a synergistic relationship between the two agents. Fluvastatin enhances sorafenib-mediated apoptosis as revealed through enhanced cleavage of poly (ADP-ribose) polymerase. In combination with sorafenib, fluvastatin treatment results in reduced levels of activated murine thymoma viral oncogene homolog along with enhanced levels of activated c-Jun N-terminal kinase. Sensitization to sorafenib is unique to fluvastatin, as other statins (pravastatin and simvastatin) do not enhance sorafenib-mediated growth inhibition. These promising results warrant further investigation into the clinical applicability of fluvastatin as an agent for enhancing the efficacy of sorafenib in the treatment of melanoma

BACKGROUND: Psoriasis adversely affects health-related quality of life (HRQoL) in adults; however, little information exists about its impact on children and adolescents. OBJECTIVE: The effect of etanercept therapy on HRQoL compared with placebo was evaluated in children and adolescents with moderate to severe plaque psoriasis. METHODS: HRQoL data were collected from patients 4 to 17 years of age in a randomized, double-blind, placebo-controlled, North American, phase III study of etanercept. Instruments for assessing HRQoL included the Children's Dermatology Life Quality Index (CDLQI), Pediatric Quality of Life Inventory (PedsQL), Stein Impact on Family Scale, and Harter Self-Perception Profile for Children. RESULTS: Baseline CDLQI and PedsQL scores revealed reduced HRQoL in patients with psoriasis relative to comparative populations. Patients treated with etanercept demonstrated significantly higher mean percentage improvement in total CDLQI scores from baseline to week 12 compared with those treated with placebo (52.3% etanercept vs 17.5% placebo [P = .0001]). At week 12, patients who achieved 75% improvement in their Psoriasis Area and Severity Index score had higher percentage improvements from baseline in total CDLQI scores than those who did not have 75% improvement in Psoriasis Area and Severity Index score. LIMITATIONS: The PedsQL, Stein scale, and Harter profile demonstrated limited improvement in patients' HRQoL, suggesting that these scales may not be sensitive to issues that are relevant to children with psoriasis and their families. CONCLUSION: Etanercept therapy had a clinically and statistically meaningful impact on disease-specific quality of life (CDLQI) and a clinically meaningful impact on general quality of life (PedsQL) in children and adolescents with moderate to severe plaque psoriasis

Oculocutaneous albinism (OCA) is a group of genetic disorders characterized by hypopigmentation of the skin, hair, and eyes. Affected individuals experience reduced visual acuity and substantially increased skin cancer risk. There are four major types of OCA (OCA1-OCA4) that result from disruption in production of melanin from tyrosine. Current treatment options for individuals with OCA are limited to attempts to correct visual problems and counseling to promote use of sun protective measures. However, Onojafe et al., reporting in this issue of the JCI, provide hope for a new treatment approach for OCA, as they demonstrate that treating mice that model OCA-1b with nitisinone, which is FDA approved for treating hereditary tyrosinemia type 1, elevates plasma tyrosine levels, and increases eye and hair pigmentation

Radiation therapy (RT) represents an important adjuvant treatment modality for high-risk squamous cell carcinomas (SCCs). Despite the frequency of aggressive cutaneous and extracutaneous malignancies, there have been relatively few reports of RT in individuals with xeroderma pigmentosum (XP). We describe 2 adolescent boys with XP and high-risk SCCs of the skin that were treated with standard RT regimens without acute or chronic complications. After follow-up periods of 2 and 7 years, both of these patients had developed fewer skin cancers on the treated side of the face. A review of reported cases revealed that XP patients generally have normal cellular and clinical responses to ionizing radiation, which reflects the specificity of their nucleotide excision repair defect for ultraviolet radiation-induced DNA damage

ABSTRACT: BACKGROUND: Brain metastases afflict approximately half of patients with metastatic melanoma (MM) and small cell lung cancer (SCLC) and represent the direct cause of death in 60 to 70% of those affected. Standard of care remains ineffective in both types of cancer with the challenge of overcoming the blood brain barrier (BBB) exacerbating the clinical problem. Our purpose is to determine and characterize the potential of albendazole (ABZ) as a cytotoxic and radiosensitizing agent against MM and SCLC cells. METHODS: Here, ABZ's mechanism of action as a DNA damaging and microtubule disrupting agent is assessed through analysis of histone H2AX phosphorylation and cell cyle progression. The cytotoxicity of ABZ alone and in combination with radiation therapy is determined though clonogenic cell survival assays in a panel of MM and SCLC cell lines. We further establish ABZ's ability to act synergistically as a radio-sensitizer through combination index calculations and apoptotic measurements of poly (ADP-ribose) polymerase (PARP) cleavage. RESULTS: ABZ induces DNA damage as measured by increased H2AX phosphorylation. ABZ inhibits the growth of MM and SCLC at clinically achievable plasma concentrations. At these concentrations, ABZ arrests MM and SCLC cells in the G2/M phase of the cell cycle after 12 hours of treatment. Exploiting the notion that cells in the G2/M phase are the most sensitive to radiation therapy, we show that treatment of MM and SCLC cells treated with ABZ renders them more sensitive to radiation in a synergistic fashion. Additionally, MM and SCLC cells co-treated with ABZ and radiation exhibit increased apoptosis at 72 hours. CONCLUSIONS: Our study suggests that the orally available antihelminthic ABZ acts as a potent radiosensitizer in MM and SCLC cell lines. Further evaluation of ABZ in combination with radiation as a potential treatment for MM and SCLC brain metastases is warranted

Background: Accumulation of immature proteins in the Endoplasmic Reticulum (ER) causes organelle stress that is counteracted by the unfolded protein stress response (UPR). Three pathways compose the UPR and are initiated when Ire1, Perk and Atf6 respectively, are released from heterodimers formed with the ER chaperone BiP. The UPR signals down-regulation of global translation and increased ER-chaperone expression. Ire1 is phosphorylated, activating its nuclease activity, which leads to splicing of the X-box binding protein 1 (Xbp1). The spliced RNA encodes a transcription factor that regulates expression of a subset of genes that comprise one arm of the UPR. Apoptosis is initiated if homeostasis is not re-established following UPR activation. The Ire1 pathway has recently been shown to play arole in the development of vitiligo, while the UPR has been implicated in keratinocyte response to UVB and in drug resistance in melanoma. We therefore investigated the melanocyte response to ER stress induced by chemical ER disruptors and by oxidative stress (the mechanism by which we propose UV exposure perturbs the melanocyte ER). Method: Wild-type mouse melanocytes were treated with thapsigargin, which disrupts the calcium balance in the ER causing UPR induction, and cells harvested at 6, 12 and 24 h. Western blot and microarray analyses were performed and data evaluated to identify pathways activated by thapsigargin treatment. In addition, melanocytes were dosed with compounds that induce oxidative stress. RNA was harvested and evaluated for activation of the UPR by Xbp-1 splicing. Results: IRE1 expression was upregulated within 6 h of treatment with thapsigargin, which promoted splicing of XBP1 mRNA and activation of its transcription factor activity. PERK and its downstream target CHOP were phosphorylated and HA-tagged ATF6 was cleaved within 6-12 h of treatment. Up-regulation of BiP and ER chaperones such as Ero1 and down-regulation of tyrosinase were also observed. In addition, several p53-related pathways were modulated in response to thapsigargin. Induction of oxidative stress was found to induce Xbp1 splicing. Conclusions: The UPR may play an important role in melanocyte response to stress, including response to oxidative stress induced by UV exposure. Dysfunction of this response may contribute to initiation and progression of vitiligo and drug resistance in melanoma

An 11-year-old girl with a history of diabetes mellitus type I and celiac disease presented with multiple, depressed patches of purple-brown skin on the right lower extremity and central back, with histopathologic features of early morphea. Though morphea may coexist with other autoimmune diseases, its presentation with both diabetes mellitus type I and celiac disease has not yet been described