scholarly journals Canine Oral Melanoma Genomic and Transcriptomic Study Defines Two Molecular Subgroups with Different Therapeutical Targets

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 276
Author(s):  
Anais Prouteau ◽  
Stephanie Mottier ◽  
Aline Primot ◽  
Edouard Cadieu ◽  
Laura Bachelot ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Chromosomal Rearrangements ◽  
Mucosal Melanoma ◽  
T Cell Response ◽  
Lower Content ◽  
Molecular Subgroups ◽  
Oral Melanoma ◽  
Complex Chromosomal Rearrangements ◽  
Canine Chromosome

Mucosal melanoma (MM) is a rare, aggressive clinical cancer. Despite recent advances in genetics and treatment, the prognosis of MM remains poor. Canine MM offers a relevant spontaneous and immunocompetent model to decipher the genetic bases and explore treatments for MM. We performed an integrative genomic and transcriptomic analysis of 32 canine MM samples, which identified two molecular subgroups with a different microenvironment and structural variant (SV) content. The overexpression of genes related to the microenvironment and T-cell response was associated with tumors harboring a lower content of SVs, whereas the overexpression of pigmentation-related pathways and oncogenes, such as TERT, was associated with a high SV burden. Using whole-genome sequencing, we showed that focal amplifications characterized complex chromosomal rearrangements targeting oncogenes, such as MDM2 or CDK4, and a recurrently amplified region on canine chromosome 30. We also demonstrated that the genes TRPM7, GABPB1, and SPPL2A, located in this CFA30 region, play a role in cell proliferation, and thus, may be considered as new candidate oncogenes for human MM. Our findings suggest the existence of two MM molecular subgroups that may benefit from dedicated therapies, such as immune checkpoint inhibitors or targeted therapies, for both human and veterinary medicine.

scholarly journals Canine oral melanoma genomic and transcriptomic study defines two molecular subgroups with different therapeutical targets

2021 ◽  
Author(s):  
Anais Prouteau ◽  
Stephanie Mottier ◽  
Aline Primot ◽  
Edouard Cadieu ◽  
Laura Bachelot ◽  
...  
Keyword(s):  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Chromosomal Rearrangements ◽  
T Cell Response ◽  
Molecular Subgroups ◽  
Oral Melanoma ◽  
Copy Numbers ◽  
Genetic Features ◽  
Genetic Mechanisms

Mucosal melanoma (MM) is a rare and aggressive clinical cancer that occurs mostly in the head, neck, and anogenital regions. Despite recent advances in genetics and the development of revolutionary treatments, such as immunotherapy, the prognosis for MM remains poor. Canine MM shares several clinical, histological, and genetic features with its human counterpart, offering a relevant spontaneous and immunocompetent model to decipher the genetic bases and explore treatment options for human MM. We performed an integrative genomic and transcriptomic analysis of 32 canine MM samples, which allowed us to identify two molecular subgroups differing in microenvironment and structural variant (SV) content. The overexpression of genes related to the microenvironment and T-cell response was associated with tumors harboring a lower content of structural variants, whereas the overexpression of pigmentation-related pathways and oncogenes such as TERT were associated with a high SV burden. To detail the SVs, especially those with focal amplifications, whole-genome sequencing was performed on four canine MM cell lines. We showed that focal amplifications characterized complex chromosomal rearrangements targeting oncogenes such as MDM2 or CDK4 and a recurrently amplified region on canine chromosome 30, comprising the genes TRPM7, GABPB1, USP8, and SPPL2A, were candidate oncogenes for MM. We showed that the copy numbers of these genes were significantly correlated with their expression levels. Finally, we demonstrated that the genes TRPM7, GABPB1, and SPPL2A play a role in cell proliferation; thus, these may be considered new candidate oncogenes for human MM. Our findings suggest the existence of two MM molecular subgroups that may benefit from dedicated therapies, such as immune checkpoint inhibitors or targeted therapies. These results illustrate the relevance of dog models for deciphering genetic mechanisms in spontaneous MM, along with the potential to screen for efficient targeted therapies for rare and aggressive cancers in humans.

scholarly journals Immune-related adverse events of immune checkpoint inhibitors: a brief review

2018 ◽  
Vol 25 (5) ◽  
Author(s):  
G. Myers
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Health Care Professionals ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Hematologic Malignancies ◽  
T Cell Response ◽  
Proactive Management ◽  
Organ Systems

Immune checkpoint inhibitors (icis) such as inhibitors of ctla-4, PD-1, and PD-L1, given as monotherapy or combination therapy have emerged as effective treatment options for immune-sensitive solid tumours and hematologic malignancies. The benefits of icis can be offset by immune-related adverse events (iraes) that leave all organ systems vulnerable and subsequently increase the risk for morbidity and mortality.Because of fluctuating onset and prolonged duration, the toxicities associated with iraes represent a shift from the understanding of conventional anticancer toxicities. The ctla-4 and PD-1/PD-L1 inhibitors modulate T-cell response differently, resulting in distinct toxicity patterns, toxicity kinetics, and dose–toxicity relationships. Using individualized patient education, screening, and assessment for the early identification of iraes is key to proactive management and is therefore key to improving outcomes and prolonging therapy.Management of iraes is guided by appropriate grading, which sets the stage for the treatment setting (outpatient vs. inpatient), ici treatment course (delay vs. discontinuation), supportive care, corticosteroid use, organ specialist consultation, and additional immunosuppression. Health care professionals in oncology must work collaboratively with emergency and community colleagues to facilitate an understanding of iraes in an effort to optimize seamless care.

scholarly journals Successful Treatment of a Patient with anti-PD1 Antibody-Resistant Advanced Mucosal Melanoma with Nivolumab, Ipilimumab plus Denosumab Combination Therapy

2020 ◽  
Vol 13 (1) ◽  
pp. 271-275 ◽  
Author(s):  
Taku Fujimura ◽  
Yumi Kambayashi ◽  
Kentaro Ohuchi ◽  
Ryo Amagai ◽  
Yota Sato ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Combination Therapy ◽  
Nasal Cavity ◽  
Immune Checkpoint ◽  
Cutaneous Melanoma ◽  
Japanese Population ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mucosal Melanoma ◽  
Mutation Burden

Since the incidence of mucosal melanoma is higher in the Japanese population compared to Caucasians, and since mucosal melanoma possesses a lower mutation burden compared to cutaneous melanoma, the efficacy of anti-PD1 antibody (Ab) monotherapy for mucosal melanoma is limited. Therefore, other targeting molecules that enhance the anti-tumor effects of immune checkpoint inhibitors are needed. In this report, we present a case with anti-PD1 Ab-resistant recurrent malignant melanoma of the nasal cavity successfully treated with nivolu­mab, ipilimumab plus denosumab combination therapy.

scholarly journals Immune checkpoint inhibitors in advanced or metastatic mucosal melanoma: a systematic review

2020 ◽  
Vol 12 ◽  
pp. 175883592092202 ◽  
Author(s):  
Jiarui Li ◽  
Haoxuan Kan ◽  
Lin Zhao ◽  
Zhao Sun ◽  
Chunmei Bai
Keyword(s):  
Systematic Review ◽  
Monoclonal Antibodies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Single Agent ◽  
Progression Free Survival ◽  
Mucosal Melanoma ◽  
One Year

Background: Conventional cytotoxic chemotherapy offers minor benefit to patients with mucosal melanoma (MM). Although immune checkpoint inhibitors (ICIs) have become the preferred approach in patients with advanced or metastatic cutaneous melanoma, the evidence of their clinical use for MM is still limited. This systematic review aims to summarize the efficacy and safety of ICIs in advanced or metastatic MM. Methods: We searched electronic databases, conference abstracts, clinical trial registers and reference lists for relevant studies. The primary outcomes included the overall response rate (ORR), median progression-free survival (PFS), median overall survival (OS), one-year PFS rate, and one-year OS rate. Results: This review identified 13 studies assessing anti-CTLA-4 monotherapy, 22 studies assessing anti-PD-1 monotherapy, two studies assessing anti-CTLA-4 and anti-PD-1 combination therapy, one study assessing anti-PD-1 antibodies combined with axitinib, and three studies assessing anti-PD-1 antibodies combined with radiotherapy. For most patients who received ipilimumab monotherapy, the ORR ranged from 0% to 17%, the median PFS was less than 5 months, and the median OS was less than 10 months. For patients who received nivolumab or pembrolizumab monotherapy, most studies showed an ORR of more than 15% and a median OS of more than 11 months. The combined administration of anti-CTLA-4 and anti-PD-1 agents showed benefits over single-agent therapy with an ORR of more than 33.3%. In a phase Ib trial of toripalimab in combination with axitinib, approximately half of patients had complete or partial responses. Three retrospective studies that investigated anti-PD-1 antibodies combined with radiotherapy showed an ORR of more than 50%, which was higher than each single modality treatment. Conclusions: Immune checkpoint inhibitors, especially anti-PD-1 monoclonal antibodies alone and in combination with anti-CTLA-4 monoclonal antibodies or other modalities, are promising treatment options for advanced or metastatic MM. However, high-level evidence is still needed to support the clinical application.

Response of metastatic mucosal melanoma to immunotherapy: It can get worse before it gets better

2016 ◽  
Vol 23 (3) ◽  
pp. 215-219 ◽  
Author(s):  
Shebli Atrash ◽  
Issam Makhoul ◽  
Jason S Mizell ◽  
Laura Hutchins ◽  
Fade Mahmoud
Keyword(s):  
Computed Tomography ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Mucosal Melanoma ◽  
Response To Treatment ◽  
Computed Tomography Scans ◽  
New Onset

Immune therapy with checkpoint inhibitors has revolutionized the management of metastatic melanoma. Ipilimumab, nivolumab, and pembrolizumab are all FDA-approved immune checkpoint inhibitors to treat metastatic melanoma. Responses to immune checkpoint inhibitors are usually delayed. An interim progression on restaging computed tomography scans “pseudo-progression” may be observed before response to treatment occur. In this case, we report a significant interim progression of metastatic mucosal melanoma before meaningful responses to immunotherapy occurred. The patient developed significant immune therapy-related colitis and new onset vitiligo. Further restaging computed tomography scans showed sustained tumor response despite stopping the immune therapy.

scholarly journals Oncolytic Adenoviruses for Cancer Therapy

2021 ◽  
Vol 22 (5) ◽  
pp. 2517
Author(s):  
Lorella Tripodi ◽  
Maria Vitale ◽  
Vincenzo Cerullo ◽  
Lucio Pastore
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Strategies ◽  
T Cell Response ◽  
Oncolytic Adenoviruses ◽  
Tumor Selectivity ◽  
Transgene Delivery ◽  
Fight Against Cancer

Many immuno-therapeutic strategies are currently being developed to fight cancer. In this scenario, oncolytic adenoviruses (Onc.Ads) have an interesting role for their peculiar tumor selectivity, safety, and transgene-delivery capability. The major strength of the Onc.Ads is the extraordinary immunogenicity that leads to a strong T-cell response, which, together with the possibility of the delivery of a therapeutic transgene, could be more effective than current strategies. In this review, we travel in the adenovirus (Ads) and Onc.Ads world, focusing on a variety of strategies that can enhance Onc.Ads antitumoral efficacy, passing through tumor microenvironment modulation. Onc.Ads-based therapeutic strategies constitute additional weapons in the fight against cancer and appear to potentiate conventional and immune checkpoint inhibitors (ICIs)-based therapies leading to a promising scenario.

Abstract #827: Panhypopituitarism Due to Immune Checkpoint Inhibitors

2017 ◽  
Vol 23 ◽  
pp. 176-177
Author(s):  
Kaitlyn Steffensmeier ◽  
Bahar Cheema ◽  
Ankur Gupta
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors
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