Translational Research in Cutaneous Melanoma: New Therapeutic Perspectives

2018 ◽  
Vol 18 (2) ◽  
pp. 166-181 ◽  
Author(s):  
Antonio Marra ◽  
Cristina R. Ferrone ◽  
Celeste Fusciello ◽  
Giosue Scognamiglio ◽  
Soldano Ferrone ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Poor Prognosis ◽  
Immune Escape ◽  
Checkpoint Inhibitor ◽  
Predictive Biomarkers ◽  
Driver Mutations ◽  
Targeted Agents ◽  
Therapeutic Approaches ◽  
Aggressive Form ◽  
Immune Escape Mechanisms

Melanoma is an aggressive form of skin cancer characterized by poor prognosis and high mortality. The development of targeted agents based on the discovery of driver mutations as well as the implementation of checkpoint inhibitor-based immunotherapy represents a major breakthrough in the treatment of metastatic melanoma. However, in both cases the development of drug resistance and immune escape mechanisms as well as the lack of predictive biomarkers limits their extraordinary clinical efficacy. In this article, we summarize the available therapeutic options for patients with metastatic melanoma, outline the mechanisms implicated in the resistance to both targeted agents and immunotherapy, discuss potential predictive biomarkers and outline future therapeutic approaches under investigation.

scholarly journals The Effect of the Combinations of 5-Fluorouracil, Leptin and Leptin Antagonist in Glioblastoma

Proceedings ◽  
2019 ◽  
Vol 40 (1) ◽  
pp. 19
Author(s):  
Taşpinar ◽  
Denizler ◽  
Taşpinar
Keyword(s):  
Brain Tumor ◽  
Cell Lines ◽  
Poor Prognosis ◽  
Leptin Receptor ◽  
Cell Type ◽  
Therapeutic Approaches ◽  
Cytotoxic Effects ◽  
New Therapeutic Approaches ◽  
Aggressive Form ◽  
The Relationship

Glioblastoma (GB) is the most aggressive form of brain tumor and resistant to chemotherapy. New therapeutic approaches are needed to improve the efficacy of chemotherapy. It was reported that there may be a relationship between obesity and poor prognosis in GB treatment. However, there is no study investigating the relationship between leptin, leptin receptor and chemotherapy in GB. The aim of this study was to investigate the cytotoxic effects of 5-Fluorouracil (5-FU) in the treatment of GB in the presence of leptin and leptin receptor antagonist SHLA. LN-405, T98G and U373-MG GB cell lines were used for this purpose. The cytotoxic effects of these molecules in both single and combination were determined by MTT. The sensitivities of GB cell lines to 5-FU were found to be different and leptin and SHLA had no cytotoxic effects in GB cells. It was determined that leptin increased 5-FU toxicity by 8–57% depending on 5-FU dose and cell type in all three cell lines in combination groups. A similar effect was detected in combinations of SHLA with 5-FU (6–58%). This is the first study to show that combinations of 5-FU with leptin and SHLA increase the cytotoxicity of 5-fluorouracil in cancer.

scholarly journals The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 742 ◽  
Author(s):  
Rita Cabrita ◽  
Shamik Mitra ◽  
Adriana Sanna ◽  
Henrik Ekedahl ◽  
Kristina Lövgren ◽  
...  
Keyword(s):  
T Cell ◽  
Metastatic Melanoma ◽  
Immune Evasion ◽  
Immune Escape ◽  
Therapy Response ◽  
Predictive Biomarkers ◽  
Cell Infiltration ◽  
Pten Gene ◽  
T Cell Infiltration

Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The PTEN gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor (MITF) gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of MITF expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.

scholarly journals HLA dependent immune escape mechanisms in B-cell lymphomas: Implications for immune checkpoint inhibitor therapy?

2017 ◽  
Vol 6 (4) ◽  
pp. e1295202 ◽  
Author(s):  
Marcel Nijland ◽  
Rianne N. Veenstra ◽  
Lydia Visser ◽  
Chuanhui Xu ◽  
Kushi Kushekhar ◽  
...  
Keyword(s):  
B Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Escape ◽  
Checkpoint Inhibitor ◽  
Inhibitor Therapy ◽  
B Cell Lymphomas ◽  
Checkpoint Inhibitor Therapy ◽  
Immune Escape Mechanisms

scholarly journals The evolving immunotherapeutic landscape in advanced oesophagogastric cancer

2018 ◽  
Vol 10 ◽  
pp. 175883591878622 ◽  
Author(s):  
Michael Flynn ◽  
Kate Young ◽  
David Cunningham ◽  
Naureen Starling
Keyword(s):  
Median Overall Survival ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Predictive Biomarkers ◽  
Resistance Mechanisms ◽  
Therapeutic Approaches ◽  
Mutational Burden ◽  
Directed Research ◽  
Relative Scarcity ◽  
Oesophagogastric Cancer

Improvements in median overall survival in the advanced oesophagogastric (OG) setting have plateaued, underlining the need for improved therapeutic approaches in this patient population. Immunotherapeutics are inducing unexpected durable responses in an expanding list of advanced disease indications. Although OG cancers have traditionally been considered to be more challenging to treat with immunotherapy than some other malignancies because of their variable tumour mutational burden and relative scarcity of infiltrating T cells, immune checkpoint inhibitor (ICPI) trials conducted over the last few years suggest there is an important role for these treatments. ICPI efficacy may be demonstrated in specific molecular subtypes of OG cancer. This review outlines the improvements in defining predictive biomarkers of responsiveness to ICPIs. Increasingly, identification of an expanding list of ICPI resistance mechanisms will drive biomarker-directed research. In addition, the specific rationale to combine ICPIs with chemotherapies, radiotherapies, targeted therapies and other novel immunotherapeutic drugs will be discussed.

Therapeutic Approaches for the Treatment of Epidermal Growth Factor Receptor Mutated Lung Cancer

2018 ◽  
Vol 18 (8) ◽  
pp. 773-791
Author(s):  
Dhaval Sanchala ◽  
Lokesh K. Bhatt ◽  
Kedar S. Prabhavalkar
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Driver Mutations ◽  
Therapeutic Approaches ◽  
Epidermal Growth ◽  
Egfr Mutant

Lung cancer surfaces to be the predominant determinant of mortality worldwide constituting 13% and 19% of all new cancer cases and deaths related to cancer respectively. Molecular profiling has now become a regular trend in lung cancer to identify the driver mutations. Epidermal Growth Factor Receptor (EGFR) is the most regular driver mutation encountered in Non-Small Cell Lung Cancer (NSCLC). Targeted therapies are now available for the treatment of EGFR mutant NSCLC. EGFR mutation is more frequently expressed in adenocarcinoma than squamous cell carcinoma. This article presents a detailed molecular insight of the therapeutic approaches for the treatment of EGFR mutant lung cancer. The article delineates molecular mechanism of the drugs that are approved, the drugs that are in clinical trial and the drugs that have not entered a clinical trial but shows promising future in the treatment of EGFR mutant lung cancer. Furthermore, this article provides concise information on relevant combinational or monotherapy clinical trials that have been completed for various approaches.

scholarly journals No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 475
Author(s):  
Michele Guida ◽  
Nicola Bartolomeo ◽  
Pietro Quaglino ◽  
Gabriele Madonna ◽  
Jacopo Pigozzo ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitor ◽  
Progression Free Survival ◽  
Nras Mutation ◽  
Disease Free Interval ◽  
Free Survival ◽  
Mutational Status ◽  
Metastatic Sites ◽  
Disease Free ◽  
Mutant Braf

Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7–18) versus 9 months (95% CI, 6–16) and 32 (95% CI, 23–49) versus 27 months (95% CI, 16–35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM.

scholarly journals How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

2021 ◽  
Vol 10 (7) ◽  
pp. 1412
Author(s):  
Michele Ghidini ◽  
Angelica Petrillo ◽  
Andrea Botticelli ◽  
Dario Trapani ◽  
Alessandro Parisi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Clinical Implementation ◽  
T Cell Therapy ◽  
Dismal Prognosis

Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.

scholarly journals Systematic Review of Recurrent Osteosarcoma Systemic Therapy

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1757
Author(s):  
Ioanna Gazouli ◽  
Anastasios Kyriazoglou ◽  
Ioannis Kotsantis ◽  
Maria Anastasiou ◽  
Anastasios Pantazopoulos ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
Treatment Effectiveness ◽  
Treatment Strategies ◽  
Bone Cancer ◽  
Predictive Biomarkers ◽  
Mtor Inhibitors ◽  
Cytotoxic Chemotherapy ◽  
Driver Mutations ◽  
Preclinical Research ◽  
Primary Bone

Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review of the available clinical evidence, regarding treatment of recurrent and/or refractory osteosarcoma over the last two decades. Among the 72 eligible studies, there were 56 prospective clinical trials, primarily multicentric, single arm, phase I or II and non-randomized. Evaluated treatment strategies included cytotoxic chemotherapy, tyrosine kinase and mTOR inhibitors and other targeted agents, as well as immunotherapy and combinatorial approaches. Unfortunately, most treatments have failed to induce objective responses, albeit some of them may sustain disease control. No driver mutations have been recognized, to serve as effective treatment targets, and predictive biomarkers of potential treatment effectiveness are lacking. Hopefully, ongoing and future clinical and preclinical research will unlock the underlying biologic mechanisms of recurrent and refractory osteosarcoma, expanding the therapeutic choices available to pre-treated osteosarcoma patients.

scholarly journals Identification of an Immature Subset of PMN-MDSC Correlated to Response to Checkpoint Inhibitor Therapy in Patients with Metastatic Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1362
Author(s):  
Françoise Gondois-Rey ◽  
Magali Paul ◽  
Florence Alcaraz ◽  
Sarah Bourass ◽  
Jilliana Monnier ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitor ◽  
T Cell Proliferation ◽  
Low Density ◽  
Direct Cytotoxicity ◽  
Radiological Response ◽  
Checkpoint Inhibitor Therapy ◽  
Pre Treatment ◽  
Immature Cells

PMN-MDSCs support tumor progression and resistance to ICI therapy through their suppressive functions but their heterogeneity limits their use as biomarkers in cancer. Our aim was to investigate the phenotypic and functional subsets of PMN-MDSCs to identify biomarkers of response to ICI therapy. We isolated low-density CD15+ PMNs from patients with metastatic melanoma and assessed their immune-suppressive capacities. Expression of CD10 and CD16 was used to identify mature and immature subsets and correlate them to inhibition of T cell proliferation or direct cytotoxicity. Frequencies of the PMN-MDSCs subsets were next correlated to the radiological response of 36 patients receiving ICI therapy. Mature activated cells constituted the major population of PMN-MDSCs. They were found in a higher proportion in the pre-treatment blood of patients non responders to ICI. A subset of immature cells characterized by intermediate levels of CD10 and CD16, the absence of expression of SIRPα and a strong direct cytotoxicity to T cells was increased in patients responding to ICI. The paradoxical expansion of such cells during ICI therapy suggests a role of PMNs in the inflammatory events associated to efficient ICI therapy and the usefulness of their monitoring in patients care.

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