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 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 New drug developments in metastatic gastric cancer

2018 ◽  
Vol 11 ◽  
pp. 175628481880807 ◽  
Author(s):  
Aaron C. Tan ◽  
David L. Chan ◽  
Wasek Faisal ◽  
Nick Pavlakis
Keyword(s):  
Gastric Cancer ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Metastatic Gastric Cancer ◽  
New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

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.

Emerging Strategies in Systemic Therapy for the Treatment of Melanoma

2018 ◽  
pp. 751-758 ◽  
Author(s):  
Paolo A. Ascierto ◽  
Keith Flaherty ◽  
Stephanie Goff
Keyword(s):  
Targeted Therapy ◽  
Targeted Therapies ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
Adoptive Cell Transfer ◽  
Mek Inhibition

Recent years have seen major improvements in survival of patients with advanced melanoma with the advent of various novel systemic immunotherapies and targeted therapies. As our understanding of these agents and their various mechanisms of action improves, even more impressive outcomes are being achieved through use of various combination strategies, including the combining of different immunotherapies with one another as well as with other modalities. However, despite the improved outcomes that have been achieved in advanced melanoma, responses to treatment are heterogeneous and may not always be durable. Additional advances in therapy are required, and several emerging strategies are a focus of interest. These include the investigation of several new immunotherapy and/or targeted therapy combinations, such as checkpoint inhibitors (anti–PD-1/anti–CTLA-4) with other immunotherapies (e.g., indoleamine 2,3 dioxygenase [IDO] inhibitors, antilymphocyte activation 3 [anti–LAG-3], histone deacetylase [HDAC] inhibitors, Toll-like receptor 9 [TLR-9] agonists, antiglucocorticoid-induced tumor necrosis factor receptor [anti-GITR], pegylated interleukin-2 [IL-2]), combined targeted therapies (e.g., MEK and CDK4/6 coinhibition), and combined immunotherapy and targeted therapy (e.g., the triplet combination of BRAF/MEK inhibition with anti–PD-1s). The identification of novel therapeutic targets in the MAP kinase pathway also offers opportunities to improve outcomes by overcoming de novo and acquired resistance to BRAF/MEK inhibition (e.g., the development of ERK inhibitors). In addition, adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, may have a potential role in patients whose disease has progressed after immunotherapy. Taken together, these new approaches offer further potential to increase systemic treatment options and improve long-term outcomes for patients with advanced melanoma.

Genomic testing and treatment landscape in patients with advanced non-small cell lung cancer (aNSCLC) using real-world data from community oncology practices.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1585-1585 ◽  
Author(s):  
Hinco Jasper Gierman ◽  
Seth Goldfarb ◽  
Monica Labrador ◽  
Caroline M. Weipert ◽  
Bill Getty ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
P Value ◽  
Genomic Testing ◽  
Tumor Type ◽  
Real World Data ◽  
Nccn Guidelines ◽  
Community Oncology

1585 Background: While aNSCLC is a leading cause of US cancer deaths, targeted therapies and immune checkpoint inhibitors (ICPi) have emerged as important new treatment options for these pts NCCN guidelines recommend testing of eight genes in aNSCLC patients at diagnosis. Targetable alterations (TA) in four genes, EGFR, ALK, ROS1, and BRAF, are associated with FDA-approved therapies. The labels for ICPis indicate that pts with TAs in EGFR and ALK are not candidates for first line treatment with ICPi. Methods: The Integra Connect database, which includes electronic medical record (EMR) and claims data on approximately 600,000 cancer patients, was queried across five community oncology practices (289 oncologists) to identify aNSCLC patients (stage 3B or 4) treated since January 2017. Manual review of charts was done to abstract tumor type/stage, drug regimens, and evidence of somatic genetic testing. A Wilcoxon rank sum test was used to test difference in time to results (TTR) for blood- vs tissue-based tests. Results: A total of 1,203 aNSCLC patients were identified. Testing rates varied from 54% for EGFR to 22% for all 4 genes (table). 163 patients had a TA in EGFR, ALK, ROS1 or BRAF, and 55% of these pts did not receive targeted therapy. 84 pts with TA’s in EGFR or ALK had no evidence of progression on targeted therapy, yet 31 (37%) received an ICPi; 24% had the TA test result prior to ICPi use and 13% received the TA result after starting ICPi. Median TTR for blood-based somatic tests was shorter than tissue-based tests (4 vs 14 days, p-value= 3.5-e07). Conclusions: Our analysis in the community oncology setting for aNSCLC pts finds evidence of underutilization of genomic testing, underutilization of targeted therapies, and ICPi use outside of label. Further research is needed to identify strategies to increase testing in aNSCLC pts to provide physicians with the information needed to make optimal treatment decisions. [Table: see text]

scholarly journals Landscape of Current Targeted Therapies for Advanced Colorectal Cancer

2021 ◽  
Author(s):  
Ana João Pissarra ◽  
Catarina Abreu ◽  
André Mansinho ◽  
Ana Lúcia Costa ◽  
Sara Dâmaso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Disease ◽  
Targeted Therapies ◽  
High Throughput Sequencing ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Her2 Overexpression ◽  
Braf Mutations ◽  
Therapeutic Landscape ◽  
Cancer Types

Colorectal cancer (CRC) is one of the most frequent and lethal cancer types worldwide. While surgery with chemotherapy and radiotherapy remains the only curative approach for localized CRC, for metastatic disease the therapeutic landscape has significantly evolved over the last years. Development and approval of novel targeted therapies, such as monoclonal antibodies against EGFR and VEGF, have significantly increased the median survival of patients with metastatic disease, with some trials reporting a benefit over 40 months. Increasing accessibility of high throughput sequencing has unraveled several new therapeutic targets. Actionable alterations, such as HER2 overexpression, BRAF mutations, and NTRK fusions, are currently available in metastatic disease, providing significant therapeutic opportunities for these patients, while new emerging agents, as immune checkpoint inhibitors, promise better treatment options in the near future. In this chapter, an overview of established and future CRC targeted therapies in the clinical setting is provided, as well as their mechanism of action, limitations, and future applicability.

Immunotherapy and potential predictive biomarkers in the treatment of neuroendocrine neoplasia

2020 ◽  
Author(s):  
Guanghui Xu ◽  
Yuhao Wang ◽  
Hushan Zhang ◽  
Xueke She ◽  
Jianjun Yang
Keyword(s):  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
The Body ◽  
Low Grade ◽  
Ablative Therapies ◽  
Cancer Types ◽  
New Treatment ◽  
Well Differentiated

Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.

scholarly journals Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3708
Author(s):  
Bhaba K. Das ◽  
Aarthi Kannan ◽  
Quy Nguyen ◽  
Jyoti Gogoi ◽  
Haibo Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Aurora Kinase ◽  
Selective Inhibition ◽  
Potential Candidate ◽  
Cycle Arrest

Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.

scholarly journals Update on the role of pembrolizumab in patients with unresectable or metastatic colorectal cancer

2021 ◽  
Vol 14 ◽  
pp. 175628482110244
Author(s):  
Vanessa Wookey ◽  
Axel Grothey
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Cancer Type ◽  
Cancer Therapies ◽  
Multiple Cancer ◽  
Multiple Treatment

Colorectal cancer (CRC) is the third most common cancer type in both men and women in the USA. Most patients with CRC are diagnosed as local or regional disease. However, the survival rate for those diagnosed with metastatic disease remains disappointing, despite multiple treatment options. Cancer therapies for patients with unresectable or metastatic CRC are increasingly being driven by particular biomarkers. The development of various immune checkpoint inhibitors has revolutionized cancer therapy over the last decade by harnessing the immune system in the treatment of cancer, and the role of immunotherapy continues to expand and evolve. Pembrolizumab is an anti-programmed cell death protein 1 immune checkpoint inhibitor and has become an essential part of the standard of care in the treatment regimens for multiple cancer types. This paper reviews the increasing evidence supporting and defining the role of pembrolizumab in the treatment of patients with unresectable or metastatic CRC.

scholarly journals Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 561
Author(s):  
Anca Bobircă ◽  
Florin Bobircă ◽  
Ioan Ancuta ◽  
Alesandra Florescu ◽  
Vlad Pădureanu ◽  
...  
Keyword(s):  
Immune System ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Multidisciplinary Approach ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Cancer Cell Growth ◽  
Inhibitory Mechanisms ◽  
Checkpoint Inhibitor Therapy

The advent of immunotherapy has changed the management and therapeutic methods for a variety of malignant tumors in the last decade. Unlike traditional cytotoxic chemotherapy, which works by interfering with cancer cell growth via various pathways and stages of the cell cycle, cancer immunotherapy uses the immune system to reduce malignant cells’ ability to escape the immune system and combat cell proliferation. The widespread use of immune checkpoint inhibitors (ICIs) over the past 10 years has presented valuable information on the profiles of toxic adverse effects. The attenuation of T-lymphocyte inhibitory mechanisms by ICIs results in immune system hyperactivation, which, as expected, is associated with various adverse events defined by inflammation. These adverse events, known as immune-related adverse events (ir-AEs), may affect any type of tissue throughout the human body, which includes the digestive tract, endocrine glands, liver and skin, with reports of cardiovascular, pulmonary and rheumatic ir-AEs as well. The adverse events that arise from ICI therapy are both novel and unique compared to those of the conventional treatment options. Thus, they require a multidisciplinary approach and continuous updates on the diagnostic approach and management.

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