Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline

In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes

HyBryte™ use in early-stage cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma of the skin, where at later stages skin-homing malignant T-cells affect lymph nodes, blood, and visceral organs. Even though early CTCL does not affect survival, it can progress to more advanced stages of disease and have a significant effect on the quality of life of patients. Although expectant management is a treatment consideration in early disease stages, most patients cycle through different skin-directed therapies throughout their lifetime. It can become a challenge to manage the serious and accumulating risk of side effects of these therapies, including various skin cancers and skin damage. Adverse effects from topical therapies limit their long-term utility. Thus, there is an unmet need for well-characterized therapies that have a rapid onset of action and minimal long-term/cumulative side effect profile. Most recently, the results of a Phase 3 study of topical HyBryte™ as a potential treatment for CTCL demonstrated its efficacy and safety profile. This article summarizes what is known about HyBryte™, focuses on its mechanism of action, and highlights its effectiveness, safety, and tolerability in the context of other current FDA-approved topical therapies for CTCL

Evaluation of the Relationship between Alopecia Areata and Viral Antigen Exposure

BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by non-scarring alopecia with T-cell infiltration at the affected hair follicle. OBJECTIVE: Our aim was to study the potential link between hepatitis B virus (HBV) antigen exposure and AA. METHODS: Two pediatric patients with AA following hepatitis B vaccination were identified in a general dermatology clinic. A bioinformatics analysis and an electronic medical record (EMR) database query were performed at the University of Rochester Medical Center to identify patients with AA, coexisting viral infections, vaccinations, or interferon (IFN) therapy in order to determine if the presence of AA and these conditions was higher than in AA patients without these associated conditions or therapy. RESULTS: An increased frequency of AA among those who received the HBV surface protein antigen [odds ratio (OR) 2.7, p \u3c 0.0001] was identified, and an independent analysis revealed an increased frequency of AA in those receiving IFN-β treatment (OR 8.1, p \u3c 0.05). One potential antigenic target identified was SLC45A2, a melanosomal transport protein important in skin and hair pigmentation. The longest potential vaccine peptide fragment match (8-mer) was to a segment of natural killer (NK) cell inhibitory receptors, KIR3DL2 and KIR3DL1. Predictive modeling of major histocompatibility complex (MHC)-peptide binding demonstrated potential binding of this peptide to MHC relevant to AA. LIMITATIONS: The results will need to be verified in additional patient databases allowing analysis of temporal relationships, and with molecular experiments of the identified antigens. CONCLUSIONS: Our data confirm associations between viral infection and IFN treatment with AA. It establishes that the hepatitis B surface protein antigen has shared epitopes with human killer immunoglobulin-like receptors

A role for NF-κB activity in skin hyperplasia and the development of keratoacanthomata in mice.

Previous studies have implicated NF-κB signaling in both cutaneous development and oncogenesis. However, these studies have been limited in part by the lethality that results from extreme over- or under-expression of NF-κB in available mouse models. Even cre-driven tissue specific expression of transgenes, or targeted deletion of NF-κB can cause cell death. Therefore, the present study was undertaken to evaluate a novel mouse model of enhanced NF-κB activity in the skin.A knock-in homologous recombination technique was utilized to develop a mouse model (referred to as PD mice) with increased NF-κB activity.The data show that increased NF-κB activity leads to hyperproliferation and dysplasia of the mouse epidermis. Chemical carcinogenesis in the context of enhanced NF-κB activity promotes the development of keratoacanthomata.Our findings support an important role for NF-κB in keratinocyte dysplasia. We have found that enhanced NF-κB activity renders keratinocytes susceptible to hyperproliferation and keratoacanthoma (KA) development but is not sufficient for transformation and SCC development. We therefore propose that NF-κB activation in the absence of additional oncogenic events can promote TNF-dependent, actinic keratosis-like dysplasia and TNF-independent, KAs upon chemical carcinogensis. These studies suggest that resolution of KA cannot occur when NF-κB activation is constitutively enforced

Randomized Mechlorethamine/Chlormethine Induced Dermatitis Assessment Study (MIDAS) Establishes Benefit of Topical Triamcinolone 0.1% Ointment Cotreatment in Mycosis Fungoides

INTRODUCTION: Treatment of early-stage mycosis fungoides (MF) requires safe, skin-directed therapies. Medication side effects can lead to underutilization of effective therapies. The objective of this study was to assess the use of topical triamcinolone 0.1% ointment as a means of reducing contact dermatitis associated with topical mechlorethamine/chlormethine gel for the treatment of MF. METHODS: This prospective, randomized, open-label study evaluated 28 adults with mycosis fungoides who were eligible for treatment with topical mechlorethamine/chlormethine gel from December 17, 2017 to December 23, 2020. Patients were treated for 4 months with clinical follow-up through 12 months. Patients had half of their lesions also treated with topical triamcinolone 0.1% ointment (while the other half were treated with mechlorethamine/chlormethine alone). The study was self-controlled with separate lesions in the same patient receiving each treatment arm. Treatment arms were determined by the flip of a coin. RESULTS: Twenty-eight patients enrolled (17 men (61%) and 11 women (39%)). Demographics included 25 White, 2 African Americans, and 1 Asian patient. Twenty-five completed the 12-month follow-up. Triamcinolone 0.1% ointment led to increased tolerability of mechlorethamine/chlormethine gel but did not change the efficacy of mechlorethamine/chlormethine. There was a statistically significant 50% decrease in dermatitis (SCORD score) at month 2 in the triamcinolone-treated arm. CONCLUSIONS: Topical triamcinolone ointment is a helpful adjuvant therapy when treating patients with topical mechlorethamine/chlormethine gel. It diminishes inflammation and does not reduce efficacy. The peak incidence of dermatitis in the study occurred in the second and third months. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03380026