Moving molecular targeted drug therapy towards personalized medicine: issues related to clinical trial design.
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ABSTRACT:
SUBMITTER: Verweij J
PROVIDER: S-EPMC5528372 | biostudies-other | 2012 Apr
REPOSITORIES: biostudies-other
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Project description:BackgroundDrug resistance is a major obstacle to effective cancer therapy. In order to detect the change in tumor genomic states under drug selection pressure, we use next-generation sequencing technology to investigate the underlying potential mechanisms of drug resistance.MethodsIn our study, we presented a bladder cancer patient who had been a bona fide responder to first-line gemcitabine plus cisplatin regimen and second-line pazopanib (tyrosine kinase inhibitor (TKI) for FGFR3-TACC3 fusion) but finally had disease progression as an ideal case for showing genomic alteration during drug resistance. We applied whole-exome sequencing and ultra-deep target sequencing to the patient pre- and post- pazopanib resistance. Protein-protein interaction (PPI) network and Gene Ontology (GO) analyses were used to analysis protein interactions and genomic alterations. Patient-derived xenograft (PDX) model was built to test drug sensitivity.ResultsTwelve mutations scattered in 12 genes were identified by WES pre- pazopanib resistance, while 63 mutations in 50 genes arose post- pazopanib resistance. PPI network showed proteins from multiple epigenetic regulator families were involved post- pazopanib resistance, including subunits of chromatin remodeler SWI/SNF complex ARID1A/1B and SMARCA4, histone acetylation writers CREBBP, histone methylation writer NSD1 and erasers KDM6A/5A. GO enrichment analysis showed pazopanib resistance genes were prominently tagged for chromatin modification, transcription, as well as gland development, leaving genes with the best adaptive FGFR TKI-coping mechanisms. In addition, significantly elevated tumor mutational burden suggested possible utility of immunotherapy. Intriguingly, PDX model suggested that, sensitivity to original chemotherapy regimen (cisplatin) was restored in patient tumor post-pazopanib.ConclusionsEpigenetic regulation may play a role in acquired TKI resistance. Our study traced the complete tumor genomic variation course from chemo-resistant but TKI-sensitive to TKI-resistant but chemo-(re) sensitive, revealing the potential complex dynamic drug-driven mechanisms of resistance.
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Project description:Personalized medicine refers to the application of an individual's biological fingerprint - the comprehensive dataset of unique biological information - to optimize medical care. While the principle itself is straightforward, its implementation remains challenging. Advances in pharmacogenomics as well as functional assays of vascular biology now permit improved characterization of an individual's response to medical therapy for vascular disease. This review describes novel strategies designed to permit tailoring of four major pharmacotherapeutic drug classes within vascular medicine: antiplatelet therapy, antihypertensive therapy, lipid-lowering therapy, and antithrombotic therapy. Translation to routine clinical practice awaits the results of ongoing randomized clinical trials comparing personalized approaches with standard of care management.
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Project description:Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Since the discovery that the KIT and PDGFRA receptor tyrosine kinases are the primary oncogenic drivers in the vast majority of GISTs, targeted therapy with tyrosine kinase inhibitors has been the mainstay of treatment for this disease. Using molecular profiling of tumor specimens, researchers also discovered that KIT and PDGFRA mutations are non-random and occur in specific regions of the receptors, and furthermore, that particular genotypes predicted response or resistance to targeted therapy. Imatinib, the first tyrosine kinase inhibitor used to treat GIST, remains the first-line therapy in advanced GIST and the only therapy confirmed through clinical trials in the adjuvant or neoadjuvant setting for resectable disease. Resistance to imatinib is well described and is either primary or secondary. Primary resistance is associated with specific tumor genotypes, so genotyping of individual patient tumors helps guide decision-making into whether to offer imatinib and at what dose. Secondary resistance occurs due to the acquisition of secondary mutations during therapy. Currently, the main strategy to combat imatinib resistance is to switch to another tyrosine kinase inhibitor, because imatinib-resistant GIST is usually still oncogenically addicted to KIT/PDGFRA signaling. Surgery can also be used to combat resistant disease in select settings. Unfortunately, progression-free and overall survival remains dismal for patients who develop imatinib-resistant disease, and further research into alternative strategies is still needed.
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