Retinoid Therapy Research Articles

PRAME Expression in Endometrioid and Serous Endometrial Carcinoma: A Potential Immunotherapeutic Target and Possible Diagnostic Pitfall.

Preferentially expressed antigen in melanoma (PRAME) is a cancer testes antigen initially employed as a diagnostic marker for melanoma. Although negative in most normal tissues, its expression has been reported in benign endometrial glands. Additionally, PRAME expression has been identified in a growing list of solid and hematologic malignancies and is of interest as a predictive biomarker, as cancer vaccination strategies and adoptive T-cell transfer targeting this molecule are under clinical investigation; additionally, PRAME may identify candidates for retinoid therapy. However, expression of PRAME has not been well-studied in endometrial cancers. We herein evaluate PRAME expression in endometrial carcinomas to better characterize its limitations as a diagnostic melanoma marker as well as its potential as a predictive biomarker in endometrial carcinomas. PRAME expression was evaluated in 256 endometrioid (n=235) and serous (n=21) endometrial carcinomas via tissue microarray. In all, 89% (227/256) demonstrated some degree of nuclear PRAME expression, including 88% (207/235) of endometrioid carcinomas and 95% (20/21) of serous carcinomas. Diffuse (>50%) expression was observed in 70% (179/256) of all cases, including 69% (163/235) of endometrioid carcinomas and 76% (16/21) of serous carcinomas. There was no association between degree of expression and grade, mismatch repair protein status, or stage. The widespread expression of PRAME in endometrial carcinomas suggests this marker should not be interpreted as specific for melanoma in this context. However PRAME may have utility as a predictive biomarker in endometrial cancer, and expansion of testing of PRAME-based therapies to endometrioid and serous endometrial carcinomas may lead to new therapeutic options for these endometrial cancer subtypes.

Use of retinoids in dermatology

Background: Retinoid, whose existence was first known in the 20th century, was initially referred to as a naturally occurring substance with vitamin A action. However, now it has become a generic term for all substances exhibiting an active action through the retinoid receptor located in the nucleus of the cells. Retinoids are biologically important substances involved in many functions, including reproduction, embryonic morphogenesis, regulation of epithelial proliferation and differentiation, reduction of sebaceous gland, immune and anti-inflammatory effects, tumor prevention, and effects on extracellular matrix components.Current Concepts: Topical retinoids are used to treat several conditions, including acne, photoaging, and psoriasis. Their side effects are dose-related skin irritations, while teratogenicity risk is rare to non-existent. Systemic retinoids are a treatment of choice for acne and keratinization disorders. They are also useful for the treatment of psoriasis, pityriasis rubra pilaris, cutaneous T-cell lymphoma, and chronic hand eczema. Systemic retinoid therapy requires the careful patient selection and monitoring due to associated teratogenicity. Other important side effects are hypertriglyceridemia, dryness of lips, blepharoconjunctivitis, bone pain, increased muscle tone, myopathy, hypothyroidism, and neutropenia.Discussion and Conclusion: Awareness of the side effects and proper use of retinoids are important for successful treatment outcomes of the above-mentioned dermatological conditions.

Diffuse plate-like sheets of desquamation

Diffuse plate-like sheets of desquamation

Multiple, Eruptive and Generalised Lobular Capillary HaemangiomasA Rare Morphological Variant

Lobular Capillary Haemangioma or Pyogenic Granuloma (PG) is a common benign, vascular proliferative lesion, usually occurring at sites of preceding trauma. It is known to occur more commonly in children and young females. The most common presentation is a solitary lesion. Multiple, eruptive PG have been reported after antecedent burns, trauma and following retinoid therapy and as satellite lesions after treatment of a primary lesion. A 14-year-old female, without any co-morbidities presented with spontaneous onset of multiple, eruptive and generalised skin coloured papules and nodules over face, neck, upper chest and upper back. The lesions were eruptive in nature, involved the back, face and upper trunk over duration of 4 months. There was intermittent bleeding from the lesions after trivial trauma. Clinical diagnosis of lobular capillary haemangioma was confirmed by histopathology which showed lobules of variably dilated network of blood filled capillaries in the papillary dermis surrounded by typical epithelial collarette. The lesions were removed by Radiofrequency (RF) in subsequent sittings. This case report features an interesting and unusual morphological presentation of generalised eruptive lobular capillary haemangioma, which occurred de novo in a young female without any associated skin or systemic disease.

A New Prospect in Retinoid Therapy: Trifarotene

A New Prospect in Retinoid Therapy: Trifarotene

The unfolding role of ceramide in coordinating retinoid-based cancer therapy.

Sphingolipid-mediated regulation in cancer development and treatment is largely ceramide-centered with the complex sphingolipid metabolic pathways unfolding as attractive targets for anticancer drug discovery. The dynamic interconversion of sphingolipids is tightly controlled at the level of enzymes and cellular compartments in response to endogenous or exogenous stimuli, such as anticancer drugs, including retinoids. Over the past two decades, evidence emerged that retinoids owe part of their potency in cancer therapy to modulation of sphingolipid metabolism and ceramide generation. Ceramide has been proposed as a 'tumor-suppressor lipid' that orchestrates cell growth, cell cycle arrest, cell death, senescence, autophagy, and metastasis. There is accumulating evidence that cancer development is promoted by the dysregulation of tumor-promoting sphingolipids whereas cancer treatments can kill tumor cells by inducing the accumulation of endogenous ceramide levels. Resistance to cancer therapy may develop due to a disrupted equilibrium between the opposing roles of tumor-suppressor and tumor-promoter sphingolipids. Despite the undulating effect and complexity of sphingolipid pathways, there are emerging opportunities for a plethora of enzyme-targeted therapeutic interventions that overcome resistance resulting from perturbed sphingolipid pathways. Here, we have revisited the interconnectivity of sphingolipid metabolism and the instrumental role of ceramide-biosynthetic and degradative enzymes, including bioactive sphingolipid products, how they closely relate to cancer treatment and pathogenesis, and the interplay with retinoid signaling in cancer. We focused on retinoid targeting, alone or in combination, of sphingolipid metabolism nodes in cancer to enhance ceramide-based therapeutics. Retinoid and ceramide-based cancer therapy using novel strategies such as combination treatments, synthetic retinoids, ceramide modulators, and delivery formulations hold promise in the battle against cancer.

The significant health threat from sunbed use as a self treatment in patients with acne.

Patients with acne are increasingly using sunbeds as a self treatment despite the harmful effects. Little is known about sunbed use in adult patients with acne under dermatology care. This questionnaire study explored prevalence and behaviours surrounding sunbed use in patients with acne at a UK dermatology centre. Over a quarter (26%) of respondents used sunbeds and of these, 72% used them at least weekly. Respondents using sunbeds were more likely to be older, to be female, to have a longer duration of acne diagnosis and to have previously been offered blue-light therapy by their doctor (P < 0.05 for all) Reasons for use included recommendations from external sources (including the Internet), the perceived greater efficacy compared with physician-prescribed treatments and that light therapy was not offered by their doctor. Nearly half (49%) of respondents were taking isotretinoin at the time of sunbed use, which carries an increased risk for photosensitivity and sunburn in this cohort. Dermatologists have a responsibility to address this gap in public awareness by directly counselling patients at risk of sunbed use, particularly for those concomitantly prescribed oral retinoid therapy.

Ichthyosiform Erythroderma, a Multifaceted Syndromic Entity.

Ichthyosiform Erythroderma, a Multifaceted Syndromic Entity.

Abstract 3045: Investigating the influence of glycosylation using cellular models of neuroblastoma

Abstract Background: Neuroblastoma is a common childhood malignancy with approximately 800 new cases diagnosed each year in the United States. Treatment of neuroblastoma directly depends on patient risk categories and includes combinations of surgery, radiation therapy, chemotherapy, stem cell therapy, immunotherapy, and retinoid therapy. Various characteristics of cancer in general and some specific to neuroblastoma cell lines contribute to a difficulty in delivering clinically relevant concentrations of therapeutic agents to neuroblastoma masses. Amplification of the MYCN gene in certain neuroblastoma cell lines correlates with increased cellular surface glycosylation levels as well as a worse prognosis for patients. Overexpression of the MUC1 gene is also associated with increased glycosylation, specifically type-O, in various cancers, but the role of MUC1 in neuroblastoma has not been thoroughly defined. The objective of this study was to evaluate the influence of type-O glycosylation on therapeutic uptake in different neuroblastoma cell lines. Methods: The neuroblastoma cell line SK-N-DZ, a MYCN-amplified line, was compared to SK-N-SH, a non-MYCN-amplified line (negative control) and BT-20, a highly glycosylated breast cancer cell line (positive control). Benzyl-α-GalNAc, an O-glycosylation inhibitor, was introduced to each cell line. To determine glycosylation levels in the respective cell lines, fluorescence assays were performed using CD227 (anti-MUC1) antibody. In vitro cytotoxicity assays were performed to determine maximum non-toxic concentrations of the glycosylation inhibitor (benzyl-α-GalNAc) and antibody (CD227) and to subsequently evaluate the functional role of glycosylation using cellular models of neuroblastoma. Results: The maximum non-toxic concentrations per 10,000 cells for each neuroblastoma cell line was 0.05 mg/ml of benzyl-α-GalNAc, and 6 µl of CD227 stock preparation. Preliminary results from fluorescence detection studies showed an increase in CD227-FITC antibody uptake by the MYCN-amplified neuroblastoma cells (SK-N-DZ) following exposure to the O-glycosylation inhibitor (benzyl-α-GalNAc). Cellular uptake of CD227-FITC by non-MYCN-amplified cell line (SK-N-SH) was less by comparison. Conclusion: Preliminary findings suggest that O-glycosylation is a barrier capable of limiting cellular uptake of agents in MYCN-amplified neuroblastoma cell lines. Ongoing studies are focused on investigating the influence of glycosylation inhibition on cytotoxicity of FDA-approved therapeutic agents. Citation Format: Meghan Cook, Alma Garcia, Katie Konieczny, Meghan Ferguson, Robert Campbell. Investigating the influence of glycosylation using cellular models of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3045.

BG13: A review of oral retinoid therapy for patients with inherited disorders of keratinization attending tertiary referral genodermatosis services

BG13: A review of oral retinoid therapy for patients with inherited disorders of keratinization attending tertiary referral genodermatosis services

Ophthalmic Assessment in Patients With Darier Disease

To assess the prevalence of ophthalmic findings in patients with Darier disease, an autosomal dominant genetic skin disorder, in an effort to evaluate the need for eye examinations in the management of the disease. Prospective observational case series. Thirty-six individuals with Darier disease were evaluated by both ocular assessment questionnaire and a comprehensive ophthalmic examination (visual acuity, refraction, external examination, and slit-lamp examination) with emphasis on the eyelids, conjunctiva, and cornea. In addition, questionnaire-based medical interview and skin examination were conducted. According to the medical questionnaire, 39% of patients reported eye problems, 36% dry eye, and 42% eye fatigue after prolonged reading. Ocular examination revealed Darier disease lesions on the eyelids in 55% of the patients, blepharitis in 44%, conjunctival hyperemia in 28%, and short tear film break-up time in 83%. There was no significant relationship between any of these ophthalmic findings and systemic retinoid therapy, sex, or age. The high prevalence of blepharitis and dry eye highlights the importance of ophthalmologic evaluation of patients with Darier disease.

The Dermatology Provider's Role in the Antibiotic Resistance Crisis

ABSTRACT Dermatology healthcare providers commonly treat acne vulgaris with oral and topical antibiotics. In the face of the current antibiotic resistance crisis, alternative therapies should be considered prior to the use of antibiotics and antibiotics should be used sparingly. Alternative therapies include retinoid therapies, retinoid combination therapies, hormonal therapies, and light-based therapies, as well as various combinations of these therapies. Patients would benefit from the initial exclusion of an underlying endocrine pathology prior to initiating vitamin A-derived therapies, light-based therapies, or more subtle hormonal therapies.

Endogenous and combination retinoids are active in myelomonocytic leukemias

Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL) but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting of RXR ligands (e.g., bexarotene) and RARA ligands (e.g., all-trans retinoic acid), which induced either leukemic maturation or apoptosis depending on cell culture conditions. Co-repressor release from the RARA:RXRA heterodimer occurred with RARA activation, but not RXRA activation, providing an explanation for the combination synergy. Combination synergy could be replicated in additional, but not all, AML cell lines and primary samples, and was associated with improved survival in vivo, although tolerability of bexarotene administration in mice remained an issue. These data provide insight into the basal presence of natural retinoids in leukemias in vivo and a potential strategy for clinical retinoid combination regimens in leukemias beyond APL.

Genetic Predictors of Severe Skin Toxicity in Patients with Stage III Colon Cancer Treated with Cetuximab: NCCTG N0147 (Alliance).

Cetuximab, an EGFR inhibitor used to treat multiple cancer types, including colon cancer, causes severe skin toxicity in 5%-20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity. Our study included 1,209 patients with stage III colon cancer randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating approximately 10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade ≥ 3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as P < 5 × 10-8. Participants were predominantly middle-aged white men; 20% (n = 243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity [OR, 3.93; 95% confidence interval (CI), 2.47-6.25; P < 7.8 × 10-9]. Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions. Identified variants could represent a potential target for risk stratification of patients with colon cancer receiving cetuximab. Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.

Correlation of Serum Retinol and Atherogenic Indices in Type 2 Diabetes Mellitus: A Case-Control Study.

Dyslipidemia is an important risk factor for atherosclerosis and coronary heart disease, leading to mortality and morbidity in subjects with T2DM. This risk is higher in subjects with diabetes who are on retinoid therapy for some other indication, where hypercholesterolemia, hypertriglyceridemia, and low serum high-density lipoprotein cholesterol (HDL-C), and sudden cardiovascular deaths have been reported. Our study aimed to find the correlation of serum retinol and atherogenic index (AI) in subjects with T2DM and compare them with healthy controls. We found there was a significant difference in systolic and diastolic blood pressure, body mass index, waist circumference, waist hip ratio, total cholesterol (TC), Triglycerides (TG), non-high density lipoprotein cholesterol (non-HDL-C), the atherogenic ratio of cholesterol (ARC), atherogenic index of plasma (AIP) and AI between the two groups. There was a significant positive correlation of serum retinol with TC, TG, LDL-C, Non-HDL-C, ARC, AIP, and AI. In our study we found an association of serum retinol with atherogenic index and dyslipidemia in subjects with T2DM. Serum retinol can be a novel predictor of cardiovascular risk in subjects with T2DM.

What you need to know about treatment of acne?

In clinical practice, many drugs are used to treat acne, which can have both positive and negative effects. The frequency of adverse reactions can be reduced through the rational and controlled use of drugs, which is impossible without proper training of medical staff and provision of sufficient information to them. Today, the safety of medicines is given much attention in many countries around the world, where various methods of monitoring congenital anomalies and adverse reactions in fetuses and newborns are developed and successfully applied in practice. Systemic isotretinoin occupies one of the leading positions in prescriptions to patients with acne and recurrent acne. Drugs that have long been used in medical practice (Roaccutane) are well studied and their effects are predictable. There are many myths about retinoids. It is known that no drug is 100% safe, so it should be prescribed only when the expected benefits outweigh the risks of its use. It is necessary to prescribe the combined oral contraceptive Belara (in the absence of contraindications specified in the instructions) during treatment with Roaccutane. This is justified and mandatory in accordance with the current guidelines of the European Medicines Agency (EMA, 2018). The combined oral contraceptive must be prescribed 5 weeks before the start of systemic isotretinoin therapy and continued for 5 weeks after the end of retinoid therapy, if no maintenance treatment is required.

Vulval acne: a case series describing clinical features and management.

Intermittent inflammation of the vulval pilosebaceous units is common and usually self-limiting, but some patients experience recurrent and more troublesome symptoms. There is a scarcity of information on this problem. We describe the clinical and histological features in these patients and the response to treatment. A retrospective, observational study of 16 patients with this phenomenon of recurrent, protracted folliculocentric inflammation of the vulval pilosebaceous unit was performed. Details on the clinical features, histology and response to treatment were collected. Mean age at presentation was 32years (range 21-45). All patients reported recurrent painful papules and pustules on the labia majora and labia minora. Nine patients reported a cyclical pattern to the development of lesions, with premenstrual exacerbation being most common. Histological examination of these lesions showed a folliculocentric microabscess formation surrounded by an acute and chronic inflammatory cell infiltrate, with a focal foreign-body granulomatous reaction. All our patients responded well to tetracycline, antiandrogenic or retinoid therapy. We propose the term 'vulval acne' for this condition and propose a stepwise approach to its management. We hope to highlight this as a common but underreported entity.

Protein Kinase C Alpha (PKCα) overexpression leads to a better response to retinoid acid therapy through Retinoic Acid Receptor Beta (RARβ) activation in mammary cancer cells.

Retinoids have proved to be effective for hematologic malignancies treatment but till nowadays, their use as single agent for the solid tumor's management is still controversial. All-trans retinoic acid (ATRA), the main active metabolite of vitamin A, exerts non-genomic interactions with different members of the protein kinase C (PKC) family, recognized modulators of different tumor progression pathways. To determine whether a group of patients could become benefited employing a retinoid therapy, in this study we have evaluated whether PKCα expression (a poor prognosis marker in breast cancer) could sensitizes mammary cells to ATRA treatment. PKCα overexpression was achieved by stable transfection and confirmed by western blot. Transfected PKC functionality was determined by nuclear translocation-induction and confocal microscopy. In vitro proliferation was evaluated by cell counting and cell cycle distribution was analyzed by flow cytometry. In vivo studies were performed to evaluate orthotopic tumor growth and experimental lung colonization. Retinoic acid response elements (RARE) and AP1 sites-dependent activity was studied by gene reporter assays and retinoic acid receptors (RARs) were measured by RT-qPCR. Our findings suggest that high PKCα levels improve the differentiation response to ATRA in a RAR signaling-dependent manner. Moreover, RARβ expression appears to be critical to induce ATRA sensitization, throughout AP1 trans-repression. Here we propose that retinoids could lead a highly personalized anticancer treatment, bringing benefits to patients with aggressive breast tumors resulting from high PKCα expression but, an adequate expression of the RARβ receptor is required to ensure the effect on this process.

Retinoic acid induces differentiation in neuroblastoma via ROR1 by modulating retinoic acid response elements.

Neuroblastoma is the most common inheritable, solid neoplasm in children found under the age of 7 and accounts for approximately 7% of childhood cancers. A common treatment that has been prescribed for over a decade is retinoid therapy [using all-trans retinoic acid (RA)]. Treatment with this differentiating agent has been revealed to progress the cells from their stem-cell state to a mature neuronal state gaining classical neuronal characteristics, including the suppression of proliferation. However, the molecular mechanism underlying the action of RA treatment remains to be elucidated. In the present study, a novel mechanism of RA-induced differentiation via regulation of receptor tyrosine kinase-like orphan receptor 1 (ROR1) is reported. ROR1 is overexpressed in neuroblastoma but significantly downregulated in mature differentiated neurons. Hence, it was hypothesized that RA may modulate ROR1 leading to differentiation and termination of cancerous properties. Immunoblotting revealed that following RA treatment, ROR1 levels initially increased then sharply decreased by 96 h. This was paired with synaptophysin, a mature neuron marker, sharply increasing concurrently, providing evidence of differentiation by 96 h. Investigation of the ROR1 pathway confirmed ROR1-dependent downstream activation of the PI3K/AKT signaling axis, a growth pathway previously demonstrated to promote differentiation. Chromatin immunoprecipitation revealed an increase in RAR binding to the promoters of ROR1 and its endogenous ligand, Wnt5a. This research provided compelling evidence that RA is able to modulate the expression of ROR1 and Wnt5a to promote differentiation through the expression of synaptophysin. This data combined with the overarching data from the scientific community regarding proliferation and other proliferative factors in early-stage neurons provides a more in-depth model of the process of differentiation in neurons.

Characterization of CYP26B1-Selective Inhibitor, DX314, as a Potential Therapeutic for Keratinization Disorders

Inhibition of CYP450-mediated retinoic acid (RA) metabolism by RA metabolism blocking agents increases endogenous retinoids and is an alternative to retinoid therapy. Currently available RA metabolism blocking agents (i.e., liarozole and talarozole) tend to have fewer adverse effects than traditional retinoids but lack target specificity. Substrate-based inhibitor DX314 has enhanced selectivity for RA-metabolizing enzyme CYP26B1 and may offer an improved treatment option for keratinization disorders such as congenital ichthyosis and Darier disease. In this study, we used RT-qPCR, RNA sequencing, pathway, upstream regulator, and histological analyses to demonstrate that DX314 can potentiate the effects of all-trans-RA in healthy and diseased reconstructed human epidermis. We unexpectedly discovered that DX314, but not all-trans-RA or previous RA metabolism blocking agents, appears to protect epidermal barrier integrity. In addition, DX314-induced keratinization and epidermal proliferation effects are observed in a rhino mice model. Altogether, the results indicate that DX314 inhibits all-trans-RA metabolism with minimal off-target activity and shows therapeutic similarity to topical retinoids invitro and invivo. Findings of a barrier-protecting effect require further mechanistic study but may lead to a unique strategy in barrier-reinforcing therapies. DX314 is a promising candidate compound for further study and development in the context of keratinization disorders.