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Looking into a Better Future: Novel Therapies for Metastatic Melanoma.

ABSTRACT: Even though melanoma represents a small percentage of all cutaneous cancers, it is responsible for most deaths from skin neoplasms. In early stages it can be successfully treated with surgery, but as the disease expands the survival rate drops significantly. For many years the mainstay of treatment for metastatic melanoma was chemotherapeutic agents, even though they failed to prove survival prolongation. After the advent of ipilimumab, a survival benefit and better overall response rate could be offered to the patients. Other new therapies, such as immunotherapies, targeted therapies, vaccines, and small molecules, are currently being studied. Also, combination regimens have demonstrated superiority to some monotherapies. Nowadays, ipilimumab should no longer be considered the first-line therapy given its severe toxicity and lower efficacy, while nivolumab remains efficacious and has a good safety profile. T-VEC as monotherapy has been shown to be an elegant alternative even for the elderly or cases of head and neck melanomas. If the BRAF mutation status is positive, the combination of dabrafenib and trametinib could be an option to consider. Despite the success of the novel treatments, their effectiveness is still limited. New studies have opened up new avenues for future research in melanoma treatment, which is expected to lead to better therapeutic outcomes for our patients. The objective of this review is to discuss the novel therapies for metastatic melanoma that have been tested in humans during the last 3 years to obtain a sharper perspective of the available treatment options for specific patient characteristics.

SUBMITTER: Villani A

PROVIDER: S-EPMC8163929 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Looking into the future: Gene and cell therapies for glaucoma.

Project description:Glaucoma is a complex group of optic neuropathies that affects both humans and animals. Intraocular pressure (IOP) elevation is a major risk factor that results in the loss of retinal ganglion cells (RGCs) and their axons. Currently, lowering IOP by medical and surgical methods is the only approved treatment for primary glaucoma, but there is no cure, and vision loss often progresses despite therapy. Recent technologic advances provide us with a better understanding of disease mechanisms and risk factors; this will permit earlier diagnosis of glaucoma and initiation of therapy sooner and more effectively. Gene and cell therapies are well suited to target these mechanisms specifically with the potential to achieve a lasting therapeutic effect. Much progress has been made in laboratory settings to develop these novel therapies for the eye. Gene and cell therapies have already been translated into clinical application for some inherited retinal dystrophies and age-related macular degeneration (AMD). Except for the intravitreal application of ciliary neurotrophic factor (CNTF) by encapsulated cell technology for RGC neuroprotection, there has been no other clinical translation of gene and cell therapies for glaucoma so far. Possible application of gene and cell therapies consists of long-term IOP control via increased aqueous humor drainage, including inhibition of fibrosis following filtration surgery, RGC neuroprotection and neuroregeneration, modification of ocular biomechanics for improved IOP tolerance, and inhibition of inflammation and neovascularization to prevent the development of some forms of secondary glaucoma.

| S-EPMC7979454 | biostudies-literature

Novel Drugs and Combination Therapies for the Treatment of Metastatic Melanoma.

Project description:Metastatic melanoma (MM) still remains as one of the most worrisome cancer known to mankind. In last two decades, treatment of melanoma took a dramatic turn with the discovery of targeted therapy which targets the mutations in mitogen-activated protein kinase (MAPK) pathway and immune checkpoint inhibitors. These new findings have led to emergence of many novel drugs that have been approved by FDA. Targeted therapy drugs such as vemurafenib, trametinib and dabrafenib target the MAPK pathway whereas immunotherapies such as ipilimumab, nivolumab and pembrolizumab block immune checkpoint receptors on T lymphocytes. All these drugs have shown to improve the overall survival in MM. Despite these recent discoveries, treatment of MM remains challenging because of rapid development of resistance to targeted therapy. This review will discuss recently approved drugs and their adverse effects and also shed light on combination therapy in treatment of melanoma.

| S-EPMC4701060 | biostudies-literature

Multiplying therapies and reducing toxicity in metastatic melanoma.

Project description:Prior to 2011, only 2 systemic treatments were approved for the treatment of melanoma and these had limited efficacy. In the past 4 years, 6 novel agents have received FDA approval. Herein, we will focus on 4 recently published NEJM papers reporting the results of clinical trials, comprising 4 agents targeting the MAPK pathway: the BRAF inhibitors vemurafenib and dabrafenib, and the MEK inhibitors trametinib and cobimetenib. These have been developed in parallel with a class of immunologic mediators often referred to as "immune checkpoint inhibitors." These recent studies represent a marked acceleration of progress in the treatment of metastatic melanoma. While it was hoped that combining BRAF and MEK inhibitors would significantly mitigate drug resistance, such combinations have yielded only modestly better results than monotherapy. However, these combinations were successful in reducing the development of cutaneous squamous cell carcinomas and keratocanthomas. Therefore, combination therapies are clearly warranted. Thus far there are only limited data addressing the value of combinations of immunotherapeutic agents: a phase 1 trial of concurrent nivolumab plus ipilimumab suggested enhanced activity that may not depend on BRAF mutation status. Despite the attention and publicity given to the progress achieved in the therapy of melanoma, the majority of patients with metastatic disease still have a poor prognosis. Even novel combination regiments of BRAF and MEK inhibitors achieve complete response in only 13% of patients and a median PFS of 11.4 months in all patients. Better therapies remain desperately needed, especially for the 30-40% of patients with wild-type BRAF, for whom BRAF/MAPK inhibition offers no benefit. In the latter benefit is expected from emerging immunotherapies either singly or in combinations. The extent to which immunotherapies will add to regimens targeting BRAF remains to be determined.

| S-EPMC4623483 | biostudies-literature

Advanced Acral Melanoma Therapies: Current Status and Future Directions.

Project description:Opinion statementMelanoma is one of the deadliest malignancies. Its incidence has been significantly increasing in most countries in recent decades. Acral melanoma (AM), a peculiar subgroup of melanoma occurring on the palms, soles, and nails, is the main subtype of melanoma in people of color and is extremely rare in Caucasians. Although great progress has been made in melanoma treatment in recent years, patients with AM have shown limited benefit from current therapies and thus consequently have worse overall survival rates. Achieving durable therapeutic responses in this high-risk melanoma subtype represents one of the greatest challenges in the field. The frequency of BRAF mutations in AM is much lower than that in cutaneous melanoma, which prevents most AM patients from receiving treatment with BRAF inhibitors. However, AM has more frequent mutations such as KIT and CDK4/6, so targeted therapy may still improve the survival of some AM patients in the future. AM may be less susceptible to immune checkpoint inhibitors because of the poor immunogenicity. Therefore, how to enhance the immune response to the tumor cells may be the key to the application of immune checkpoint inhibitors in advanced AM. Anti-angiogenic drugs, albumin paclitaxel, or interferons are thought to enhance the effectiveness of immune checkpoint inhibitors. Combination therapies based on the backbone of PD-1 are more likely to provide greater clinical benefits. Understanding the molecular landscapes and immune microenvironment of AM will help optimize our combinatory strategies.

| S-EPMC9526689 | biostudies-literature

Latest approved therapies for metastatic melanoma: what comes next?

Project description:Nowadays, oncogene-directed therapy and immunotherapy represent the two most promising avenues for patients with metastatic melanoma. The recent oncogene-directed therapeutic, vemurafenib, usually produces high level of tumor shrinkage and survival benefits in many patients with B-RAF (V600E) mutant melanomas, although the fast and high degrees of responses are likely short-lived. Conversely, the newly-approved immunotherapeutic, ipilimumab, produces durable responses in patients presenting CTLA-4 T-cell surface protein. Nevertheless, the possible synergy in combining these two therapeutic strategies primarily rely on the rational design of medical protocols (e.g., sequence and timing of agent administration; drug selectivity; compatibility of combined therapies i.e., adoptive T cell or agents, i.e., MEK inhibitor trametinib, PD-1 and PDL-1 blockers). Improved therapeutic protocols shall overcome therapeutic limitations such as the (i) tolerability and safety (i.e., minimal toxic side-effects); (ii) progression free survival (e.g., reduced relapse disease frequency); (iii) duration response (i.e., decreased drug resistance). Eventually, multidisciplinary approaches are still requested (e.g., genomics for personalized medicine, nanomedicine to overcome low free-drug bioavailability and targeting, systematic search of "melanoma stem cells" to enhance the prognosis and develop more valuable theranostics). In this paper, I will mainly present and discuss the latest and promising treatments for advanced cutaneous melanomas.

| S-EPMC3595667 | biostudies-literature

Metastatic melanoma - a review of current and future drugs.

Project description:BackgroundMelanoma is one of the most aggressive cancers, and it is estimated that 76,250 men and women will be diagnosed with melanoma of the skin in the USA in 2012. Over the last few decades many drugs have been developed but only in 2011 have new drugs demonstrated an impact on survival in metastatic melanoma.MethodsA systematic search of literature was conducted, and studies providing data on the effectiveness of current and/or future drugs used in the treatment of metastatic melanoma were selected for review. This review discusses the advantages and limitations of these agents, evaluating past, current and future clinical trials designed to overcome such limitations.ResultsTo date, there are four drugs approved by the Food and Drug Administration for melanoma (dacarbazine, interleukin-2, ipilimumab and vemurafenib). Despite efforts to develop new drugs, few of them have demonstrated any clinical benefits. Approved in 1975, dacarbazine remains the gold standard in chemotherapy, although ipilimumab and vemurafenib have raised many hopes in the last few years. Combining dacarbazine or other chemotherapy agents with new pharmacological agents may be a new way to achieve better clinical responses in patients with metastatic melanoma.DiscussionAdvances in the molecular knowledge of melanoma have led to major improvements in the treatment of patients with metastatic melanoma, providing new targets and insights. However, heterogeneity amongst study populations, different approaches to treatment and the different melanoma types and localisations included in the trials makes their comparison difficult. New studies focusing on drugs developed in recent decades are warranted.

| S-EPMC3885142 | biostudies-literature

Immunoproteasome expression is associated with better prognosis and response to checkpoint therapies in melanoma

Project description:Predicting the outcome of immunotherapy treatment in melanoma patients is challenging. Alterations in genes involved in antigen presentation and the interferon gamma (IFN) pathway play an important role in the immune response to tumors. We describe here that the overexpression of PSMB8 and PSMB9, two components of the immunoproteasome, is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients. We study the mechanism that underlies this connection by analyzing the antigenic peptide repertoire of cells that overexpress these subunits using HLA peptidomics. We find a higher response of patient-matched tumor infiltrating lymphocytes against antigens deferentially presented after immunoproteasome overexpression. which may explain the higher immune infiltration observed in patients with high immunoproteasome expression levels. Importantly, we find that PSMB8 and PSMB9 expression levels are much stronger predictors of melanoma patients immune response to checkpoint inhibitors than the tumors mutational burden. Taken together, these results suggest that their expression levels can serve as important biomarkers for stratifying melanoma patients for immune-checkpoint treatment.

2020-02-18 | PXD015957 | Pride

Metastatic disease from uveal melanoma: treatment options and future prospects.

Project description:Uveal melanoma represents ?85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis. There is currently little published evidence for the optimal management and treatment of metastatic uveal melanoma and the lack of effective therapies in this setting has led to the widespread use of systemic treatments for patients with cutaneous melanoma. Uveal and cutaneous melanomas are intrinsically different diseases and so dedicated management strategies and therapies for uveal melanoma are much needed. This review explores the biology of uveal melanoma and how this relates to ongoing trials of targeted therapies in the metastatic disease setting. In addition, we consider the options to optimise patient management and care.

| S-EPMC5256122 | biostudies-literature

Targeted therapies in metastatic gastric cancer: Current knowledge and future perspectives.

Project description:Gastric cancer (GC) represents a leading cause of cancer related morbidity and mortality worldwide accounting for more than 1 million of newly diagnosed cases and thousands of deaths every year. In the last decade, the development of targeted therapies and the optimization of already available chemotherapeutic drugs has expanded the available treatment options for advanced GC and granted better survival expectations to the patients. At the same time, global efforts have been undertaken to investigate in detail the genomic and epigenomic heterogeneity of this disease, resulting in the identification of new specific and sensitive predictive and prognostic biomarkers and in innovative molecular classifications based on gene expression profiling. Nonetheless, several randomized studies aimed at exploring new innovative agents, such as immune checkpoint inhibitors, failed to demonstrate clinically meaningful survival advantages. Therefore, it is essential to further improve the molecular characterization of GC subgroups in order to provide researchers and medical oncologists with new tools for patients' selection and stratification in future clinical development programs and subsequent trials. The aim of the present manuscript is to provide a global overview of the recent molecular classifications from The Cancer Genome Atlas and the Asian Cancer Research Group and to present key promising developments in the field of immunotherapy and targeted therapies in metastatic GC.

| S-EPMC6801189 | biostudies-literature

Anti-angiogenic therapies for metastatic colorectal cancer: current and future perspectives.

Project description:Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the second leading cause of cancer death in both men and women in the United States, with about 142820 new cases and 50830 deaths expected in 2013. Metastatic disease (mCRC) remains a challenge for oncologists worldwide due to its potential comorbidities. Recently, chemotherapy regimens containing 5-fluorouracil, leucovorin, oxaliplatin and irinotecan combinations are a standard of care in the metastatic disease. Currently, biological therapies involving vascular endothelial growth factor and epidermal growth factor receptor pathways, such as bevacizumab and cetuximab, have emerged as good option for improving mCRC patient survival. Now, aflibercept plus standard chemotherapy has also been approved in second line regimen for mCRC patients. Our review will discuss novel biological drugs and their indications for mCRC patients and will bring future perspectives in this regard.

| S-EPMC3848143 | biostudies-literature

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