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- Costa Svedman, Fernanda
(author)
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Molecular markers for prediction of response and progression free survival to novel therapies in cutaneous malignant melanoma
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Drugs inhibiting the MAPK-pathway (MAPKi) and immune checkpoint inhibitors (ICI) have changed the clinical outcome of metastatic cutaneous malignant melanoma (CMM) in a significant way. Nonetheless, many patients have primary resistance or develop acquired resistance to these therapies within a relatively short period of time. This thesis was performed to explore mechanisms of resistance and possible predictive biomarkers to further improve treatment outcome and to help individualize treatment in this patient population. In Paper I, we compared mRNA and protein expression in MAPKi resistant and sensitive melanoma cell lines. By applying gene expression and proteome profiling we identified two previously described (MET and EPHA2) and two novel (FLI1 and CD13/ANPEP) candidate biomarkers that, when overexpressed, were associated with treatment resistance to MAPKi. The overexpression of MET and EPHA2 was confirmed in melanoma samples from patients with metastatic CMM when comparing samples taken before and after treatment with MAPKi. In cell lines, we demonstrated that an inhibitor of EPHA2 (the multikinase inhibitor dasatinib), re-sensitized cells to MAPKi treatment. In Paper II, we analyzed plasma samples from 28 patients with metastatic CMM before and during treatment with MAPKi. Micro-RNA (miRNA) was extracted from plasmatic extra cellular microvesicles (EVs) and miRNA profiling was performed by microarray, using a panel with 372 human miRNAs. We assessed the association of the miRNA levels with response to treatment and progression free survival (PFS) and found that an increased level of let-7g-5p during treatment, compared to before treatment, was correlated with better response. A high level of miRNA 497-5p during treatment was associated with longer PFS. In Paper III, we investigated if plasmatic proteins were related to response and PFS to MAPKi or ICI in 109 patients with metastatic CMM. Proteomic profiling of plasma samples collected before and during treatment was performed by mass spectroscopy and the abundance of proteins was then correlated with treatment response and PFS. We identified that the plasma levels of 43 proteins, either before or during treatment, were prognostic/predictive of treatment outcome. An inverse correlation between acute-phase inflammatory proteins and apolipoproteins was observed. Patients with high levels of acute-phase inflammatory proteins and low levels of apolipoproteins had worse outcome to therapy. In Paper IV, we analyzed mRNA expression by targeted RNA sequencing of pre-treatment tumor samples from 28 patients with metastatic CMM who underwent treatment with MAPKi or ICI. Transcriptomic data was correlated with treatment response and PFS in gene set enrichment analysis (GSEA). Enrichment of genes in IFN-gamma and inflammatory response was associated with longer PFS to MAPKi therapy, and decreased expression of proliferative genes and increased expression of immune genes correlated with longer PFS to ICI. Finally, lower expression of proliferation genes and immune evasion genes was associated with increased response to ICI. In summary, we have identified possible mechanisms of resistance and potential predictive biomarkers to novel therapies in patients with metastatic CMM. Our studies were performed in small cohorts of patients and further studies to validate our findings are warranted.
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| 2. |
- Karlsson, Max J., et al.
(author)
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Inflammation and Apolipoproteins Are Potential Biomarkers for Stratification of Cutaneous Melanoma Patients for Immunotherapy and Targeted Therapy
- 2021
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In: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:9, s. 2545-2555
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Journal article (peer-reviewed)abstract
- Malignant cutaneous melanoma is one of the most common cancers in young adults. During the last decade, targeted and immunotherapies have significantly increased the overall survival of patients with malignant cutaneous melanoma. Nevertheless, disease progression is common, and a lack of predictive biomarkers of patient response to therapy hinders individualized treatment strategies. To address this issue, we performed a longitudinal study using an unbiased proteomics approach to identify and quantify proteins in plasma both before and during treatment from 109 patients treated with either targeted or immunotherapy. Linear modeling and machine learning approaches identified 43 potential prognostic and predictive biomarkers. A reverse correlation between apolipoproteins and proteins related to inflammation was observed. In the immunotherapy group, patients with low pretreatment expression of apolipoproteins and high expression of inflammation markers had shorter progression-free survival. Similarly, increased expression of LDHB during treatment elicited a significant impact on response to immunotherapy. Overall, we identified potential common and treatment-specific biomarkers in malignant cutaneous melanoma, paving the way for clinical use of these biomarkers following validation on a larger cohort. Significance: This study identifies a potential biomarker panel that could improve the selection of therapy for patients with cutaneous melanoma.
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| 3. |
- Villabona Lisa Villabona, Lisa, et al.
(author)
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Immunrelaterade biverkningari tarm, lever, lungor och njurar : BIVERKNINGAR I SAMBAND MED IMMUNTERAPI MOT CANCER, DEL 1 [Overview of immune-related side effects from immune checkpoint inhibitors. Part 1: Gastrointestinal, lung and kidney toxicity]
- 2021
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In: Läkartidningen. - : Sveriges Läkarförbund. - 0023-7205 .- 1652-7518. ; 118
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Research review (peer-reviewed)abstract
- In the past decade, immunotherapy with checkpoint inhibitors has revolutionized the field of oncology. Checkpoint inhibitors have been approved for several types of cancer and thousands of patients in Sweden now receive oncological immunotherapy annually. Immune-related side effects are common and can occur in almost any organ. These side effects are different from those that occur with traditional oncological treatments. The side effects are usually mild, but can be serious and even lethal. In a short time, health care providers have had to readjust to be able to handle these side effects. Early and correct diagnosis of immune-related side effects, proper management and a multidisciplinary approach is crucial. Here, we give an overview of the presentation, diagnosis and treatment of immune-related side effects, with emphasis of those occurring in gastrointestinal organs, lungs and kidneys.
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