Optimizing Narrowband UVB Phototherapy: Is It More Challenging for Your Older Patients?

Narrowband UVB (NB-UVB) phototherapy remains versatile, safe, and efficacious for multiple dermatologic conditions even with recent pharmacologic treatment advances. Polypharmacy contributes to prescribers pursuing phototherapy as a nonpharmacologic treatment, but some wonder if it is as effective and safe for older patients. This study aimed to determine if NB-UVB is equally effective in both older and younger adults treated with the same protocol and to examine the association between photosensitizing medications, clearance, and erythema rates in older vs younger adults.

Phototherapy: Safe and Effective for Challenging Skin Conditions in Older Adults.

Identifying safe, effective, and affordable evidence-based dermatologic treatments for older adults can be challenging because of age-related changes. Few studies have examined the effectiveness of phototherapy in older adults. Our retrospective study of patients 65 years and older who were treated with narrowband UVB(NB-UVB) phototherapy aimed to (1) identify the most common dermatologic conditions treated with phototherapy in older adults, (2) examine the effectiveness and safety of phototherapy in older adults, and (3) compare the outcomes to 2 similar studies in the United Kingdom and Turkey.

Association between Lithium Use and Melanoma Risk and Mortality: A Population-Based Study.

Laboratory studies show that lithium, an activator of the Wnt/ß-catenin signaling pathway, slows melanoma progression, but to our knowledge no published epidemiologic studies have explored this association. We conducted a retrospective cohort study of adult white Kaiser Permanente Northern California members (n = 2,213,848) from 1997-2012 to examine the association between lithium use and melanoma risk. Lithium exposure (n = 11,317) was assessed from pharmacy databases, serum lithium levels were obtained from electronic laboratory databases, and incident cutaneous melanomas (n = 14,056) were identified from an established cancer registry.

Control of the interface between heterotypic cell populations reveals the mechanism of intercellular transfer of signaling proteins.

Direct intercellular transfer of cellular components is a recently described general mechanism of cell–cell communication. It is a more non-specific mode of intercellular communication that is not actively controlled by the participating cells. Though membrane bound proteins and small non-protein cytosolic components have been shown to be transferred between cells, the possibility of transfer of cytosolic proteins has not been clearly established, and its mechanism remains unexplained.

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors.

About half of all melanomas harbor a mutation that results in a constitutively active BRAF kinase mutant (BRAF(V600E/K)) that can be selectively inhibited by targeted BRAF inhibitors (BRAFis). While patients treated with BRAFis initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. Here, we observed marked elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy.

Targeted BRAF inhibition impacts survival in melanoma patients with high levels of Wnt/β-catenin signaling.

Unprecedented clinical responses have been reported in advanced stage metastatic melanoma patients treated with targeted inhibitors of constitutively activated mutant BRAF, which is present in approximately half of all melanomas. We and others have previously observed an association of elevated nuclear β-catenin with improved survival in molecularly-unselected melanoma patients. This study sought to determine whether levels of Wnt/β-catenin signaling in melanoma tumors prior to treatment might predict patient responses to BRAF inhibitors (BRAFi).

FAM129B is a novel regulator of Wnt/β-catenin signal transduction in melanoma cells.

The inability of targeted BRAF inhibitors to produce long-lasting improvement in the clinical outcome of melanoma highlights a need to identify additional approaches to inhibit melanoma growth. Recent studies have shown that activation of the Wnt/β-catenin pathway decreases tumor growth and cooperates with ERK/MAPK pathway inhibitors to promote apoptosis in melanoma. Therefore, the identification of Wnt/β-catenin regulators may advance the development of new approaches to treat this disease.

Protein kinase PKN1 represses Wnt/β-catenin signaling in human melanoma cells.

Advances in phosphoproteomics have made it possible to monitor changes in protein phosphorylation that occur at different steps in signal transduction and have aided the identification of new pathway components. In the present study, we applied this technology to advance our understanding of the responses of melanoma cells to signaling initiated by the secreted ligand WNT3A. We started by comparing the phosphopeptide patterns of cells treated with WNT3A for different periods of time.

Activation of Wnt/β-catenin signaling increases apoptosis in melanoma cells treated with trail.

While the TRAIL pathway represents a promising therapeutic target in melanoma, resistance to TRAIL-mediated apoptosis remains a barrier to its successful adoption. Since the Wnt/β-catenin pathway has been implicated in facilitating melanoma cell apoptosis, we investigated the effect of Wnt/β-catenin signaling on regulating the responses of melanoma cells to TRAIL. Co-treatment of melanoma cell lines with WNT3A-conditioned media and recombinant TRAIL significantly enhanced apoptosis compared to treatment with TRAIL alone.

WLS inhibits melanoma cell proliferation through the β-catenin signalling pathway and induces spontaneous metastasis.

Elevated levels of nuclear β-catenin are associated with higher rates of survival in patients with melanoma, raising questions as to how ß-catenin is regulated in this context. In the present study, we investigated the formal possibility that the secretion of WNT ligands that stabilize ß-catenin may be regulated in melanoma and thus contributes to differences in ß-catenin levels. We find that WLS, a conserved transmembrane protein necessary for WNT secretion, is decreased in both melanoma cell lines and in patient tumours relative to skin and to benign nevi.

Targeting Wnt pathways in disease.

Wnt-mediated signal transduction pathways have long been recognized for their roles in regulating embryonic development, and have more recently been linked to cancer, neurologic diseases, inflammatory diseases, and disorders of endocrine function and bone metabolism in adults. Although therapies targeting Wnt signaling are attractive in theory, in practice it has been difficult to obtain specific therapeutics because many components of Wnt signaling pathways are also involved in other cellular processes, thereby reducing the specificity of candidate therapeutics. New technologies, and advances in understanding the mechanisms of Wnt signaling, have improved our understanding of the nuances of Wnt signaling and are leading to promising new strategies to target Wnt signaling pathways.

Regulating the response to targeted MEK inhibition in melanoma: enhancing apoptosis in NRAS- and BRAF-mutant melanoma cells with Wnt/β-catenin activation.

The limitations of revolutionary new mutation-specific inhibitors of BRAF(V600E) include the universal recurrence seen in melanoma patients treated with this novel class of drugs. Recently, our lab showed that simultaneous activation of the Wnt/β-catenin signaling pathway and targeted inhibition of BRAF(V600E) by PLX4720 synergistically induces apoptosis across a spectrum of BRAF(V600E) melanoma cell lines. As a follow-up to that study, treatment of BRAF-mutant and NRAS-mutant melanoma lines with WNT3A and the MEK inhibitor AZD6244 also induces apoptosis.

Wnt/β-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma.

Because the Wnt/β-catenin signaling pathway is linked to melanoma pathogenesis and to patient survival, we conducted a kinome small interfering RNA (siRNA) screen in melanoma cells to expand our understanding of the kinases that regulate this pathway. We found that BRAF signaling, which is constitutively activated in many melanomas by the BRAF(V600E) mutation, inhibits Wnt/β-catenin signaling in human melanoma cells. Because inhibitors of BRAF(V600E) show promise in ongoing clinical trials, we investigated whether altering Wnt/β-catenin signaling might enhance the efficacy of the BRAF(V600E) inhibitor PLX4720.

Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers.

Aberrant Wnt/β-catenin signaling is widely implicated in numerous malignancies, including cancers of the gastrointestinal tract. Dysregulation of signaling is traditionally attributed to mutations in Axin, adenomatous polyposis coli, and β-catenin that lead to constitutive hyperactivation of the pathway. However, Wnt/β-catenin signaling is also modulated through various other mechanisms in cancer, including cross talk with other altered signaling pathways.

Chemical-genetic screen identifies riluzole as an enhancer of Wnt/β-catenin signaling in melanoma.

To identify new protein and pharmacological regulators of Wnt/β-catenin signaling, we used a cell-based reporter assay to screen a collection of 1857 human-experienced compounds for their ability to enhance activation of the β-catenin reporter by a low concentration of WNT3A. This identified 44 unique compounds, including the FDA-approved drug riluzole, which is presently in clinical trials for treating melanoma. We found that treating melanoma cells with riluzole in vitro enhances the ability of WNT3A to regulate gene expression, to promote pigmentation, and to decrease cell proliferation.

A re-evaluation of the "oncogenic" nature of Wnt/beta-catenin signaling in melanoma and other cancers.

In cancer, Wnt/beta-catenin signaling is ubiquitously referred to as an "oncogenic" pathway that promotes tumor progression. This review examines how the regulation and downstream effects of Wnt/beta-catenin signaling in cancer varies depending on cellular context, with a focus on malignant melanoma. We emphasize that the cellular homeostasis of Wnt/beta-catenin signaling may represent a more appropriate concept than the simplified view of the Wnt/beta-catenin pathway as either oncogenic or tumor-suppressing.

Wnt and related signaling pathways in melanomagenesis.

Given the pivotal roles of morphogen pathways including Wnt, Notch, Hedgehog, and BMP pathways in the development of the neural crest lineage, it is not surprising that these signaling networks have also been implicated in the biology of malignant melanoma. Understanding the mechanisms by which these pathways can alter cell fate and other biological properties in tumor cells will be essential for determining whether the therapeutic targeting of these pathways has a potential role in melanoma treatment. This review highlights some of the recent findings with regards to how morphogen signaling may regulate melanoma cell biology.

Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis.

Wnt/beta-catenin regulates cellular functions related to tumor initiation and progression, cell proliferation, differentiation, survival, and adhesion. Beta-catenin-independent Wnt pathways have been proposed to regulate cell polarity and migration, including metastasis. In this review, we discuss the possible roles of both beta-catenin-dependent and -independent signaling pathways in tumor progression, with an emphasis on their regulation of Rho-family GTPases, cytoskeletal remodeling, and relationships with cell-cell adhesion and cilia/ciliogenesis.

A Wnt survival guide: from flies to human disease.

It has been two decades since investigators discovered the link between the Drosophila wingless (Wg) gene and the vertebrate oncogene int-1, thus establishing the family of signaling proteins known as Wnts. Since the inception of the Wnt signaling field, there have been 19 Wnt isoforms identified in humans. These secreted glycoproteins can activate at least two distinct signaling pathways in vertebrate cells, leading to cellular changes that regulate a vast array of biological processes, including embryonic development, cell fate, cell proliferation, cell migration, stem cell maintenance, tumor suppression, and oncogenesis.

Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model.

This study demonstrates that in malignant melanoma, elevated levels of nuclear beta-catenin in both primary tumors and metastases correlate with reduced expression of a marker of proliferation and with improved survival, in contrast to colorectal cancer. The reduction in proliferation observed in vivo is recapitulated in B16 murine melanoma cells and in human melanoma cell lines cultured in vitro with either WNT3A or small-molecule activators of beta-catenin signaling. Consistent with these results, B16 melanoma cells expressing WNT3A also exhibit decreased tumor size and decreased metastasis when implanted into mice.

Subungual Bowen disease in a patient with epidermodysplasia verruciformis presenting clinically as longitudinal melanonychia.

Epidermodysplasia verruciformis (EV) is a rare autosomal-recessive condition associated with a predisposition to infection with specific types of human papillomaviruses. A spectrum of wart-like lesions on the face, dorsa of the hands, and legs are characteristic clinical findings. Lesions usually develop in early childhood, persist, and may eventuate in cutaneous squamous cell carcinoma, usually in sun-exposed areas.