Melanoma Tumor Mutational Burden and Indoor Tanning Exposure.

Importance: UV-induced mutagenesis leads to a higher tumor mutational burden (TMB) in cutaneous melanoma relative to other cancer types. TMB is an important prognostic marker in advanced melanoma; higher TMB is associated with greater clinical response to immune checkpoint inhibition and improved survival.

Objective: To evaluate the association between cutaneous melanoma TMB and indoor tanning exposure, as well as other demographic, dermatologic, and tumor characteristics.

Preexisting Skin-Resident CD8 and γδ T-cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ∼50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA sequencing (RNA-seq) with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In nonresponders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL1.

Pharmacological agents targeting drug-tolerant persister cells in cancer.

Current cancer therapy can be effective, but the development of drug resistant disease is the usual outcome. These drugs can eliminate most of the tumor burden but often fail to eliminate the rare, "Drug Tolerant Persister" (DTP) cell subpopulations in residual tumors, which can be referred to as "Persister" cells. Therefore, novel therapeutic agents specifically targeting or preventing the development of drug-resistant tumors mediated by the remaining persister cells subpopulations are needed.

Molecular and immune targets in cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and often confers a good prognosis. Though surgery is the gold standard of treatment, unresectable or metastatic disease can necessitate systemic therapy. Of systemic agents, there is increasing interest in the use of immunotherapies and targeted therapy.

Drug-Tolerant Persister Cells in Cancer Therapy Resistance.

One of the current stumbling blocks in our fight against cancer is the development of acquired resistance to therapy, which is attributable to approximately 90% of cancer-related deaths. Undercutting this process during treatment could significantly improve cancer management. In many cases, drug resistance is mediated by a drug-tolerant persister (DTP) cell subpopulation present in tumors, often referred to as persister cells.

The Merkel Cell Carcinoma Patient Registry: From Promise to Prototype to Patient.

The Merkel Cell Carcinoma (MCC) Patient Registry is a national multi-institutional collaborative effort that will prospectively follow and record outcomes and events in MCC patients. MCC is the prototypical rare tumor, and this Registry will trail blaze new methodologies that will enable multiple investigators to examine real world outcome data in real time. Deliverables from the Registry include precise patient stratification into risk categories, identification of best practices, real-world data for drug development programs, revelations about optimal sequence and combinations therapies, uncovering low incidence toxicities, and the generation of novel testable hypotheses.

A MAPK/miR-29 Axis Suppresses Melanoma by Targeting MAFG and MYBL2.

The miR-29 family of microRNAs is encoded by two clusters, miR-29b1~a and miR-29b2~c, and is regulated by several oncogenic and tumor suppressive stimuli. While in vitro evidence suggests a tumor suppressor role for miR-29 in melanoma, the mechanisms underlying its deregulation and contribution to melanomagenesis have remained elusive. Using various in vitro systems, we show that oncogenic MAPK signaling paradoxically stimulates transcription of pri-miR-29b1~a and pri-miR-29b2~c, the latter in a p53-dependent manner.

Activating Sphingosine-1-phospahte signaling in endothelial cells increases myosin light chain phosphorylation to decrease endothelial permeability thereby inhibiting cancer metastasis.

Targeting the metastatic process to prevent disease dissemination in cancer remains challenging. One step in the metastatic cascade involves cancer cells transiting through the vascular endothelium after inflammation has increased the permeability of this cellular layer. Reducing inflammation-mediated gaps in the vascular endothelium could potentially be used to retard metastasis.

Five-year survival in patients with nodular and superficial spreading melanomas in the US population.

Background: Although superficial spreading melanomas (SSM) are diagnosed as thinner lesions, nodular melanomas (NM) have a more rapid growth rate and are biologically more aggressive compared with other histologic subtypes.

Objective: To determine the difference in 5-year relative survival in patients with NM and SSM at the same Breslow depth and TNM stage.

Methods: A population-based cross-sectional analysis compared the 5-year relative survival of patients with NM and SSM using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)∗Stat software (version 8.

Integrative transcriptomic analysis for linking acute stress responses to squamous cell carcinoma development.

Cutaneous squamous cell carcinoma (cuSCC) is the second most common skin cancer and commonly arises in chronically UV-exposed skin or chronic wounds. Since UV exposure and chronic wounds are the two most prominent environmental factors that lead to cuSCC initiation, we undertook this study to test whether more acute molecular responses to UV and wounding overlapped with molecular signatures of cuSCC. We reasoned that transcriptional signatures in common between acutely UV-exposed skin, wounded skin, and cuSCC tumors, might enable us to identify important pathways contributing to cuSCC.

Salubrinal in Combination With 4E1RCat Synergistically Impairs Melanoma Development by Disrupting the Protein Synthetic Machinery.

Increased protein synthesis is a key process in melanoma, which is regulated by the ALDH18A1 gene encoding pyrroline-5-carboxylate synthase (P5CS). P5CS is involved in proline biosynthesis and targeting ALDH18A1 has previously been shown to inhibit melanoma development by decreasing intracellular proline levels to increase the phosphorylation of eIF2α mediated by GCN2, which then impairs mRNA translation. Since there are no current inhibitors of P5CS, decreased eIF2α phosphorylation in melanoma was targeted using salubrinal (a specific inhibitor of eIF2α phosphatase enzymes).

The role of exosomes in metastasis and progression of melanoma.

The mechanisms of melanoma metastasis have been the subject of extensive research for decades. Improved diagnostic and therapeutic strategies are of increasing importance for the treatment of melanoma due to its high burden of mortality in the advanced stages of the disease. Intercellular communication is a critical event for the progression of cancer.

Design, synthesis characterization and biological evaluation of novel multi-isoform ALDH inhibitors as potential anticancer agents.

The aldehyde dehydrogenases (ALDHs) are a family of detoxifying enzymes that are overexpressed in various cancers. Increased expression of ALDH is associated with poor prognosis, stemness, and drug resistance. Because of the critical role of ALDH in cancer stem cells, several ALDH inhibitors have been developed.

Referral practices to dermatologists for the treatment of radiation dermatitis in the USA: a call for a multidisciplinary approach.

Purpose: Acute radiation dermatitis (RD) is a disfiguring and painful rash that occurs in up to 95% of patients receiving radiation therapy (RT) for cancer. Treatment for RD varies among practitioners with no evidence-based gold standard for management. While a multi-disciplinary approach has been utilized to manage other cancer-related toxicities, RD is most often managed by the treating radiation oncologist.

Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent.

The aldehyde dehydrogenases (ALDH) are a major family of detoxifying enzymes that contribute to cancer progression and therapy resistance. ALDH overexpression is associated with a poor prognosis in many cancer types. The use of multi-ALDH isoform or isoform-specific ALDH inhibitors as anticancer agents is currently hindered by the lack of viable candidates.

Aldehyde Dehydrogenase Inhibitors for Cancer Therapeutics.

Aldehyde dehydrogenases (ALDHs) are highly expressed in the chemotherapy- and radiotherapy-resistant cell subpopulations of many different cancer types. Accordingly, the development of ALDH inhibitors may be the most direct approach to target these cell populations. However, inhibiting multiple ALDH family members can be toxic and isoform-specific inhibition is often ineffective.

Advanced cutaneous squamous cell carcinoma: how is it defined and what new therapeutic approaches are available?

Purpose Of Review: Despite the overall excellent survival rates in patients with cutaneous squamous cell carcinoma (cSCC), advanced cutaneous SCCs are associated with high patient morbidity and mortality. Therefore, important unmet clinical needs persist: identifying high risk patients and choosing optimal treatment approaches.

Recent Findings: In recent years, a better understanding of the biology of cSCC and its clinical progression have led to improved staging systems and new promising treatments for advanced disease.

Molecular and immune targets for Merkel cell carcinoma therapy and prevention.

Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin, for which the exact mechanisms of carcinogenesis remain unknown. Therapeutic options for this highly aggressive malignancy have historically been limited in both their initial response and response durability. Recent improvements in our understanding of MCC tumor biology have expanded therapeutic options for these patients, namely through the use of immunotherapies such as immune checkpoint inhibitors.

Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity.

Metastatic melanoma is a significant clinical problem with a 5-year survival rate of only 15-20%. Recent approval of new immunotherapies and targeted inhibitors have provided much needed options for these patients, in some cases promoting dramatic disease regressions. In particular, antibody-based therapies that block the PD-1/PD-L1 checkpoint inhibitory pathway have achieved an increased overall response rate in metastatic melanoma, yet durable response rates are reported only around 15%.

Aldehyde dehydrogenase in regulatory T-cell development, immunity and cancer.

The role of aldehyde dehydrogenase (ALDH) in carcinogenesis and resistance to cancer therapies is well known. Mounting evidence also suggests a potentially important role for ALDH in the induction and function of regulatory T (Treg) cells. Treg cells are important cells of the immune system involved in promoting immune tolerance and preventing aberrant immune responses to beneficial or non-harmful antigens.

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease.