Precision medicine and phosphoproteomics for the identification of novel targeted therapeutic avenues in sarcomas

Fordham, Ashleigh M.; Ekert, Paul G.; Fleuren, Emmy D.G.

doi:10.1016/j.bbcan.2021.188613

Cited by 13 publications

(14 citation statements)

References 60 publications

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“…Kinase overexpression and/or activation signatures are becoming increasingly recognized as potentially actionable driver targets in OS and ES tumors. In various pediatric and AYA sarcoma models, including OS and ES, drug target/ligand overexpression and activation signatures could be linked to kinase inhibitor sensitivity, including examples of potential correlations for anti-angiogenic multi-RTK inhibitors ( 9 , 61 – 66 ). In preclinical OS models, sorafenib treatment for example stabilized growth in an OS patient-derived xenograft (PDX) model with high VEGFR2 and VEGFA expression, whereas a non-VEGFA-amplified OS model did not respond ( 64 ).…”

Section: Novel Predictive Biomarker Avenues: Target Overexpression An...mentioning

confidence: 99%

“…As it is well known that activation of the drug targets and associated pathways is required to mediate sensitivity to targeted drugs, another approach could be to directly investigate drug target activation levels ( 9 ). In OS cell lines and patient-derived models for example, PDGFR and FGFR1/2 (pazopanib, sorafenib, regorafenib, anlotinib and lenvatinib targets), and AXL, MET and RET (cabozantinib targets) were among the proteins found to be recurrently activated.…”

Section: Novel Predictive Biomarker Avenues: Target Overexpression An...mentioning

confidence: 99%

“…In OS cell lines and patient-derived models for example, PDGFR and FGFR1/2 (pazopanib, sorafenib, regorafenib, anlotinib and lenvatinib targets), and AXL, MET and RET (cabozantinib targets) were among the proteins found to be recurrently activated. RET was found to be recurrently affected in ES ( 9 ). In individual cases, higher levels of for example pPDGFR were also demonstrated in ES, and also within the group of OS there were differences in drug target activation levels ( 61 , 63 ).…”

Section: Novel Predictive Biomarker Avenues: Target Overexpression An...mentioning

confidence: 99%

“…In individual cases, higher levels of for example pPDGFR were also demonstrated in ES, and also within the group of OS there were differences in drug target activation levels ( 61 , 63 ). One of the main advantages of phosphoproteomics investigations over gene overexpression signatures, is that pathway activity can in many instances act as a more specific predictive or response biomarker compared to target expression levels ( 9 ). A particular challenge in the clinical setting however, is maintaining specimen integrity to allow the generation of high-quality phosphoproteomics data.…”

Section: Novel Predictive Biomarker Avenues: Target Overexpression An...mentioning

confidence: 99%

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Recent advances on anti-angiogenic multi-receptor tyrosine kinase inhibitors in osteosarcoma and Ewing sarcoma

2023

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Osteosarcoma (OS) and Ewing sarcoma (ES) are the two most common types of primary bone cancer that predominantly affect the young. Despite aggressive multimodal treatment, survival has not improved significantly over the past four decades. Clinical efficacy has historically been observed for some mono-Receptor Tyrosine Kinase (RTK) inhibitors, albeit in small subsets of OS and ES patients. Clinical efficacy in larger groups of OS or ES patients was reported recently with several newer generation multi-RTK inhibitors. All these inhibitors combine a strong anti-angiogenic (VEGFRs) component with simultaneous inhibition of other key RTKs implicated in OS and ES progression (PDGFR, FGFR, KIT and/or MET). However, despite interesting clinical data, none of these agents have obtained a registration for these indications and are thus difficult to implement in routine OS and ES patient care. It is at present also unclear which of these drugs, with largely overlapping molecular inhibition profiles, would work best for which patient or subtype, and treatment resistance almost uniformly occurs. Here, we provide a critical assessment and systemic comparison on the clinical outcomes to the six most tested drugs in this field in OS and ES to date, including pazopanib, sorafenib, regorafenib, anlotinib, lenvatinib and cabozantinib. We pay special attention to clinical response evaluations in bone sarcomas and provide drug comparisons, including drug-related toxicity, to put these drugs into context for OS and ES patients, and describe how future trials utilizing anti-angiogenic multi-RTK targeted drugs could be designed to ultimately improve response rates and decrease toxicity.

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Section: Novel Predictive Biomarker Avenues: Target Overexpression An...mentioning

confidence: 99%

Section: Novel Predictive Biomarker Avenues: Target Overexpression An...mentioning

confidence: 99%

Section: Novel Predictive Biomarker Avenues: Target Overexpression An...mentioning

confidence: 99%

Section: Novel Predictive Biomarker Avenues: Target Overexpression An...mentioning

confidence: 99%

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Recent advances on anti-angiogenic multi-receptor tyrosine kinase inhibitors in osteosarcoma and Ewing sarcoma

2023

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“…In most normal cells, including immune cells, RTKs are normally expressed at low levels. Overexpression and activation of RTKs is a feature of many cancer types, including paediatric and AYA sarcomas, even in the absence of activating mutations or structural variants [ 34 , 35 , 36 ]. Consequently, several RTK inhibitors have been tested in the preclinical and clinical setting in these tumours, to inhibit potentially oncogenic RTK signalling within the tumour cells [ 36 , 37 ].…”

Section: Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Enhancing the Potential of Immunotherapy in Paediatric Sarcomas: Breaking the Immunosuppressive Barrier with Receptor Tyrosine Kinase Inhibitors

et al. 2021

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Despite aggressive surgery, chemotherapy, and radiotherapy, survival of children and adolescents and young adults (AYAs) with sarcoma has not improved significantly in the past four decades. Immune checkpoint inhibitors (ICIs) are an exciting type of immunotherapy that offer new opportunities for the treatment of paediatric and AYA sarcomas. However, to date, most children do not derive a benefit from this type of treatment as a monotherapy. The immunosuppressive tumour microenvironment is a major barrier limiting their efficacy. Combinations of ICIs, such as anti-PD-1 therapy, with targeted molecular therapies that have immunomodulatory properties may be the key to breaking through immunosuppressive barriers and improving patient outcomes. Preclinical studies have indicated that several receptor tyrosine kinase inhibitors (RTKi) can alter the tumour microenvironment and boost the efficacy of anti-PD-1 therapy. A number of these combinations have entered phase-1/2 clinical trials, mostly in adults, and in most instances have shown efficacy with manageable side-effects. In this review, we discuss the status of ICI therapy in paediatric and AYA sarcomas and the rationale for co-treatment with RTKis. We highlight new opportunities for the integration of ICI therapy with RTK inhibitors, to improve outcomes for children with sarcoma.

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Incremental Modification in the Existing Approaches for Affinity Chromatographic Enrichment of Phosphoproteins Improves Their Profile in Liquid Chromatography‐Tandem Mass Spectrometry Analysis

Agrawal,

Govekar

2024

Analytical Science Advances

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Cell signalling is a vital process in cell physiology, which is driven by protein phosphorylation. Global phosphoproteome analysis by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) has thus gained importance in cell signalling research. However, phosphoprotein identification by LC‐MS/MS in whole cell lysates, which are complex protein mixtures, is hindered by their poor ionization coupled with suppression of peaks due to low abundance. Enrichment by immobilized metal ion‐ and metal oxide‐affinity chromatography (IMAC and MOAC), which preferentially enrich multi‐ and mono‐phosphorylated proteins, respectively, have improved their detection by MS. However, preferential enrichment limits phosphoproteome coverage in global analyses of cell lysates which contain mono‐ and multi‐phosphorylated proteins. Improvement in their coverage by sequential elution approach that exploits the complementary chemistries of these matrices has been reported. In this study, we observed that the number of phosphoproteins detected using the sequential elution approach was lower (∼250–400) as compared to the theoretically predicted number (>500) based on their reported 30% abundance in the cell proteome (1700–2200 proteins detected by MS in our cell lines). Acknowledging the merit of using multiple matrices, we used IMAC and MOAC individually and pooled the data. We observed a remarkable increase (>30%) in phosphoproteome coverage. Further, though 98% of phosphoproteins were enriched by IMAC, among the remaining 2%, those detected exclusively by MOAC were biologically important. This justified the use of multiple matrices. Thus, an incremental modification of using multiple matrices individually rather than sequentially and pooling the data markedly improved the phosphoproteome coverage, which can positively impact cell signalling research.

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Precision medicine and phosphoproteomics for the identification of novel targeted therapeutic avenues in sarcomas

Cited by 13 publications

References 60 publications

Recent advances on anti-angiogenic multi-receptor tyrosine kinase inhibitors in osteosarcoma and Ewing sarcoma

Recent advances on anti-angiogenic multi-receptor tyrosine kinase inhibitors in osteosarcoma and Ewing sarcoma

Enhancing the Potential of Immunotherapy in Paediatric Sarcomas: Breaking the Immunosuppressive Barrier with Receptor Tyrosine Kinase Inhibitors

Incremental Modification in the Existing Approaches for Affinity Chromatographic Enrichment of Phosphoproteins Improves Their Profile in Liquid Chromatography‐Tandem Mass Spectrometry Analysis

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