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Background And Purpose: Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF-mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF-melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin-peptide from the Octopus kaurna, Octpep-1 in melanoma.
Experimental Approach: We evaluated the cytotoxicity of Octpep-1 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep-1 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR/Cas9 technology, high-throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish).
Key Results: Octpep-1 selectively reduced the proliferative capacity of human melanoma BRAF -mutated cells with minimal effects on fibroblasts. In melanoma-treated cells, Octpep-1 increased ROS with unaltered mitochondrial membrane potential and promoted non-mitochondrial and mitochondrial respiration with inefficient ATP coupling. Molecular modelling revealed that the cytotoxicity of Octpep-1 depends upon the α-helix and polyproline conformation in the C-terminal region of the peptide. A truncated form of the C-terminal end of Octpep-1 displayed enhanced potency and efficacy against melanoma. Octpep-1 reduced the progression of tumours in xenograft melanoma mice and zebrafish.
Conclusion And Implications: We unravel the intrinsic anti-tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF-mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma.
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http://dx.doi.org/10.1111/bph.15923 | DOI Listing |
Case Rep Oncol Med
December 2024
Oncology Unit Fondazione, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
This case series highlights the complexity of sarcoidosis-like reactions (SLRs) during cancer treatment, specifically in patients receiving immunotherapy or targeted therapies for melanoma. SLRs can either mimic disease progression or present as part of the clinical manifestation, making diagnosis and treatment challenging. Our study reviewed the medical records of 31 patients who were candidates for postoperative treatment between June 2022 and June 2024.
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November 2024
University of Perugia, Unit of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.
A unique collaboration of multi-disciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with one to two-centimeter safety margins. For a correct stage classification and treatment decision, a sentinel lymph node biopsy shall be offered in patients with tumor thickness ≥ 1.
View Article and Find Full Text PDFEur J Cancer
November 2024
University of Perugia, Unit of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.
This guideline was developed in close collaboration with multidisciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF) and the European Organization for Research and Treatment of Cancer (EORTC). Recommendations for the diagnosis and treatment of melanoma were developed on the basis of systematic literature research and consensus conferences. Cutaneous melanoma (CM) is the most dangerous form of skin tumor and accounts for 90 % of skin cancer mortality.
View Article and Find Full Text PDFCancer Res
December 2024
The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States.
Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. A better understanding of the temporal dynamics and specific pathways leading into and out of the persister state is needed to identify strategies to prevent treatment failure. Using spatial transcriptomics in patient-derived xenograft models, we captured clonal lineage evolution during treatment.
View Article and Find Full Text PDFCell Death Dis
December 2024
Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.
The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses Braf melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i.
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