University of Southampton Faculty of Medicine, Southampton, United Kingdom of Great Britain and Northern IrelandPriority Research Centre for Healthy Lungs and School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia, Newcastle, AustraliaThe University of Newcastle, Centre for Asthma & Respiratory Disease, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Vaccines, Infection, Viruses &...
Centre for Inflammation, Sydney, New South Wales, AustraliaGhent University Hospital, Respiratory Diseases, Ghent, BelgiumUniversity of Southampton Faculty of Medicine, Southampton, United Kingdom of Great Britain and Northern IrelandHunter Medical Research Institute, Vaccines, Immunity, Viruses and Asthma Group, Newcastle, New South Wales, AustraliaUniversity of Southampton Faculty of Medicine, Clinical & Experimental Sciences, Southampton, United Kingdom of Great Britain and Northern...
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Molecularly defined subsets of Ewing Sarcoma tumors differ in their responses to IGF1R and WEE1 inhibitionAbstract. Purpose: Targeted cancer therapeutics have not significantly benefited Ewing sarcoma patients with metastatic or relapsed disease. Understanding the molecular underpinnings of drug-resistance can lead to biomarker-driven treatment selection. Experimental Design: Receptor tyrosine kinase (RTK) pathway activation was analyzed in tumor cells derived from a panel of Ewing sarcoma tumors, including primary and metastatic tumors from the same patient. Phospho-RTK arrays, Western blots and immunohistochemistry were used. Protein localization and the levels of key markers were determined using immunofluorescence. DNA damage tolerance was measured through PCNA ubiquitination levels and the DNA fiber assay. Effects of pharmacological inhibition were assessed in-vitro and key results validated in-vivo using patient-derived xenografts. Results: Ewing sarcoma tumors fell into two groups. In one IGF1R was predominantly nuclear (nIGF1R), DNA damage tolerance pathway was upregulated, cells had low replication stress and RRM2B levels, and high levels of WEE1 and RAD21. These tumors were relatively insensitive to IGF1R inhibition. The second group had high replication stress and RRM2B, low levels of WEE1 and RAD21, membrane-associated IGF1R (mIGF1R) signaling, and sensitivity to IGF1R or WEE1-targeted inhibitors. Moreover, the matched primary and metastatic tumors differed in IGF1R localization, levels of replication stress, and inhibitor sensitivity. In all instances combined IGF1R and WEE1 inhibition led to tumor regression. Conclusions: IGF1R signaling mechanisms and replication stress levels can vary among Ewing sarcoma tumors (including in the same patient) influencing the effects of IGF1R and WEE1-treatment. These findings make the case for using biopsy-derived predictive biomarkers at multiple stages of Ewing sarcoma disease-management.
Source: medical_xpress - 🏆 101. / 51 Read more »
Evaluating differences in viral and symptom rebounds between Paxlovid-treated and untreated COVID-19 patientsEvaluating differences in viral and symptom rebounds between Paxlovid-treated and untreated COVID-19 patients medrxivpreprint scrippsresearch Paxlovid COVID19 SARSCoV2
Source: NewsMedical - 🏆 19. / 71 Read more »