Novel Biomarkers and Druggable Targets in Advanced Melanoma

Abstract

Immunotherapy with Ipilimumab or antibodies against programmed death (ligand) 1 (anti-PD1/PDL1), targeted therapies with BRAF-inhibitors (anti-BRAF) and their combinations significantly changed melanoma treatment options in both primary, adjuvant and metastatic setting, allowing for a cure, or at least long-term survival, in most patients. However, up to 50% of those with advance or metastatic disease still have no significant benefit from such innovative therapies, and clinicians are not able to discriminate in advance neither who is going to respond and for how long nor who is going to develop collateral effects and which ones. However, druggable targets, as well as affordable and reliable biomarkers are needed to personalize resources at a single-patient level. In this manuscript, different molecules, genes, cells, pathways and even combinatorial algorithms or scores are included in four biomarker chapters (molecular, immunological, peripheral and gut microbiota) and reviewed in order to evaluate their role in indicating a patient’s possible response to treatment or development of toxicities.

Visualizing Galectin-3 Binding Protein Expression with ImmunoPET

“…All three exhibited Gal-3BP staining on par with the A375-MA1 cells, a finding that aligns with literature reports regarding the expression of Gal-3BP in melanoma (Figures 2 and S5). 25,31 In light of these in vitro data, we moved to interrogate the behavior of [ 89 Zr]Zr-DFO-1959 in athymic nude mice bearing subcutaneous PDXs. As shown in Figure 3 and Table S3, the radioimmunoconjugate clearly visualized JW-217a, JW-218a, and JW-159a xenografts with high tumor-to-background contrast.…”

“…All three exhibited Gal-3BP staining on par with the A375-MA1 cells, a finding that aligns with literature reports regarding the expression of Gal-3BP in melanoma (Figures and S5). , …”

“…Over the last two decades, ADCs have emerged as a highly promising class of therapeutics, with several gaining Food and Drug Administration (FDA) approval and many more in the clinical pipeline. , Yet the biochemical complexity of human tumors means that the accurate selection of patients likely to respond to ADC therapy is critical. PET imaging  and particularly immunoPET using mAbs labeled with zirconium-89 ( 89 Zr; t 1/2 ≈ 3.3 d)  has shown great promise in the preclinical development and clinical deployment of ADCs. , The ZEPHIR trial, for example, clearly demonstrated that theranostic immunoPET with 89 Zr-trastuzumab can help delineate patients likely to respond to therapy with trastuzumab emtansine: investigators found that patients in the “positive” immunoPET group exhibited a median time-to-treatment failure (TTF) of 11.2 months compared to 3.5 months for those in the “negative” immunoPET group …”

“…PET imaging � and particularly immunoPET using mAbs labeled with zirconium-89 ( 89 Zr; t 1/2 ≈ 3.3 d) � has shown great promise in the preclinical development and clinical deployment of ADCs. 24,25 The ZEPHIR trial, for example, clearly demonstrated that theranostic immunoPET with 89 Zr-trastuzumab can help delineate patients likely to respond to therapy with trastuzumab emtansine: investigators found that patients in the "positive" immunoPET group exhibited a median time-totreatment failure (TTF) of 11.2 months compared to 3.5 months for those in the "negative" immunoPET group. 26 Herein, we report the synthesis, characterization, and in vivo evaluation of two Gal-3BP-targeting radioimmunoconjugates: [ 89 Zr]Zr-DFO-1959 and [ 89 Zr]Zr-DFO-1959-sss/DM4 (DFO = desferrioxamine).…”

Chemokines as possible therapeutic targets in metastatic melanoma

“…Melanoma tumour cells exist in a tumour microenvironment, 15 comprised of the extracellular matrix (ECM), connective tissue, and a variety of accessory cells such as stromal fibroblasts, endothelial cells, and immune cells 16 . The tumour microenvironment provides structure and promotes tumour angiogenesis, proliferation, and survival 16,17 .…”