1,721,003 research outputs found
Innovative strategies for tailoring therapy in cancer patient pharmacogenetics and therapy personalization in metastatic colorectal cancer patients treated with irinotecan
Full text linkPharmacogenetics focuses on inter-subject variation in drug therapeutic effects and toxicity depending on genetic polymorphisms. Irinotecan and fluoropyrimidine, currently used in cancer chemotherapy, are characterized by a sometimes unpredictably severe toxicity. Pharmacogenomics was largely applied in the last years to the irinotecan-based colorectal cancer (CRC) treatment personalization with limited data regarding validated marker of severe toxicity.
In the first part of my thesis, I have been focusing on the investigation of innovative pharmacogenetic markers of neutropenia or gastrointestinal toxicity irinotecan-related using the “tagging polymorphisms (SNPs)” (TagSNPs) approach. Since therapeutic implications of cancer-related inflammation have gained great attention in recent years, innovative prospects for the optimization of tailored therapy arose. Two hundred and fifty metastatic CRC patients, homogeneously treated with an irinotecan-including regimen (FOLFIRI), have been collected retrospectively for this study. Clinical parameters of toxicity (by NCI-CTC scale) and response to the therapy (by WHO criteria) were monitored all along the study. They were genotyped for 246 htSNPs characterizing 22 transcriptional regulators and cytokines inflammation-related genes; positive findings were replicated in a cohort of 167 metastatic CRC patients receiving FOLFIRI-based therapy. One polymorphism (rs1053004) in STAT-3 gene resulted predictive of severe GI toxicity in both discovery and replication cohort with a protective effect toward the risk of developing grade 3-4 events (OR=0.51 CI=0.27-0.99 p=0.045; OR=0.38 CI=0.15-0.95 p=0.038, respectively). Additional variants in NRs genes, especially HNF4α and VDR, although not validated, were suggested to contribute to determining the risk of developing neutropenia and GI toxicity. Preliminary pharmacokinetic data supported the observed genotype/phenotype clinical associations. A validated contribution of STAT-3 rs1053004 in determining GI toxicity risk after FOLFIRI therapy was pointed out. Further potential predictive markers of irinotecan-related toxicity were suggested. These findings could represent a further step towards personalized FOLFIRI therapy.
UGT1A1*28 polymorphism has been demonstrated in the last years to have an impact on irinotecan pharmacokinetics and toxicity to the treatment. Although, the adoption of a pre-emptive UGT1A1*28 genotyping to increase irinotecan safety and to better characterize patient “Diagnosis Related Groups”, for therapy reimbursement purposes in clinical practice, is still limited. The second part of my thesis aimed to estimate the effect of UGT1A1*28 on the costs associated with irinotecan-related toxicity. A retrospective analysis of the costs of toxicity management was conducted on a subset of the aforementioned population of 250 mCRC patients. 243 mCRC patients treated with FOLFIRI have been genotyped for UGT1A1*28. The mean predicted cost per patient was higher for *1/*28 (1,119€) and *28/*28 (4,886€), as compared to *1/*1 (812€) (P<0.001). This is consistent with a different grade 4 toxicity profile among the three groups of patients, and a higher frequency of costly interventions like hospitalization among patients with the *28 allele.
The aim of the third part of my thesis consisted of evaluating the implementation of the routine application of prospective DPYD risk variants and UGT1A1*28 screening at the National Cancer Center CRO of Aviano. A Pharmacogenetic implementation infrastructure has been set-up starting from January 2014 for the prevention of irinotecan (UGT1A1*28 rs8175347) and/or fluoropyrimidine (DPYD rs3918290, rs55886062, rs67376798)-associated toxicity in the clinical routine of the National Cancer Center CRO of Aviano. Genotyping was performed by PCR-based methods, such as pyrosequencing, Sanger sequencing, and fragment analysis. A digital Pharmacogenomic report including the dose-adjustment recommended according to the published pharmacogenetics guidelines will finally be embedded in patients’ clinical record and ultimately made available to the medical personnel. From September 2011 to September 2016, a total of 393 patients were genotyped for such variants at CRO-Aviano. Three hundred and eighty-six out of 393 patients were screened for at least one DPYD variants and 40 for UGT1A1*28. Of these patients, 9 patients (2.58%) were found to carry at least one DPYD variants, and two patients (5.00%) were found to carry two *28 risk alleles for UGT1A1. Moreover, twenty-three patients out of 393 (5.85%) were referred for toxicity from the CRO-Aviano oncologists.
In conclusion, in this work of thesis, interesting molecular markers with a predictive value on pharmacokinetics and pharmacodynamics of irinotecan were described. A possible application of these parameters in the clinical practice will be useful to design a tailored irinotecan dosing based on peculiar characteristics of each patient. In addition to the prevention of severe toxicity, pre-treatment UGT1A1*28 genotyping should be considered to save economic resources related to the management of irinotecan-related toxicities and for innovative reimbursement strategies. Plus, the implementation of pre-emptive pharmacogenetics tests is now part of a European Project (U-PGx) with the aim of providing the final proof of pharmacogenetics efficacy in increasing drug safety when fully integrated into the clinical practice
Pregnane X receptor, constitutive androstane receptor and hepatocyte nuclear factors as emerging players in cancer precision medicine
No full textGreat research effort has been focused on elucidating the contribution of host genetic variability on pharmacological outcomes in cancer. Nuclear receptors have emerged as mediators between environmental stimuli and drug pharmacokinetics and pharmacodynamics. The pregnane X receptor, constitutive androstane receptor and hepatocyte nuclear factors have been reported to regulate transcription of genes that encode drug metabolizing enzymes and transporters. Altered nuclear receptor expression has been shown to affect the metabolism and pharmacological profile of traditional chemotherapeutics and targeted agents. Accordingly, polymorphic variants in these genes have been studied as pharmacogenetic markers of outcome variability. This review summarizes the state of knowledge about the roles played by pregnane X receptor, constitutive androstane receptor and hepatocyte nuclear factor expression and genetics as predictive markers of anticancer drug toxicity and efficacy, which can improve cancer precision medicine
Body mass index impacts adverse events and drug plasma concentration: should dose intensity be included in the palbociclib equation?
No full textImproving decision making on DPYD and <i>UGT1A1*28</i> patients’ profiling with an innovative reimbursement strategy
No full textUbiquitous Pharmacogenomics (U-PGx): The Time for Implementation is Now. An Horizon2020 Program to Drive Pharmacogenomics into Clinical Practice
No full textPersonalised Therapeutic
The use of pharmacogenetics to increase the safety of colorectal cancer patients treated with fluoropyrimidines
Full text linkFluoropyrimidines (FP) are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast, head and neck and gastric cancer. FP present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening toxicity. With the high number of patients receiving FP-based therapies, and the significant effects of toxicities on their quality of life, the prevention of FP-related adverse events is of major clinical interest. Host genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase (DPYD) gene are related to the occurrence of extremely severe, early onset toxicity in FP treated patients. The pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic guidelines. Several prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical practice. Multiple pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways, TYMS and MTHFR, but no additional clinically validated genetic markers of toxicity are available to date. The development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic markers. Moreover, the investigation of the genetic variation in the patients immunological system, a pivotal target in cancer treatment, could bring notable advances in the field. This review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients
Lipid rafts as viral entry routes and immune platforms: A double-edged sword in SARS-CoV-2 infection?
No full textLipid rafts are nanoscopic compartments of cell membranes that serve a variety of biological functions. They play a crucial role in viral infections, as enveloped viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can exploit rafts to enter or quit target cells. On the other hand, lipid rafts contribute to the formation of immune synapses and their proper functioning is a prerequisite for adequate immune response and viral clearance. In this narrative review we dissect the panorama focusing on this singular aspect of cell biology in the context of SARS-CoV-2 infection and therapy. A lipid raft-mediated mechanism can be hypothesized for many drugs recommended or considered for the treatment of SARS-CoV-2 infection, such as glucocorticoids, antimalarials, immunosuppressants and antiviral agents. Furthermore, the additional use of lipid-lowering agents, like statins, may affect the lipid composition of membrane rafts and thus influence the processes occurring in these compartments. The combination of drugs acting on lipid rafts may be successful in the treatment of more severe forms of the disease and should be reserved for further investigation
Germline and Somatic Pharmacogenomics to Refine Rectal Cancer Patients Selection for Neo-Adjuvant Chemoradiotherapy
Full text linkNeoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the standard of care for patients with Locally Advanced Rectal Cancer (LARC). Current selection for nCRT is based on clinical criteria regardless of any molecular marker. Pharmacogenomics may be a useful strategy to personalize and optimize nCRT in LARC. This review aims to summarize the most recent and relevant findings about the role of germline and somatic pharmacogenomics in the prediction of nCRT outcome in patients with LARC, discussing the state of the art of their application in the clinical practice. A systematic literature search of the PubMed database was completed to identify relevant English-language papers published up to January 2020. The chemotherapeutic backbone of nCRT is represented by fluoropyrimidines, mainly metabolized by DPD (Dihydro-Pyrimidine Dehydrogenase,DPYD). The clinical impact of testingDPYD*2A, DPYD*13,c.2846A > Tandc.1236G > A-HapB3before a fluoropyrimidines administration to increase treatment safety is widely acknowledged. Other relevant target genes areTYMS(Thymidylate Synthase) andMTHFR(Methylene-Tetrahydro-Folate Reductase), whose polymorphisms were mainly studied as potential markers of treatment efficacy in LARC. A pivotal role of aTYMSpolymorphism in the gene promoter region (rs34743033) was reported and was pioneeringly used to guide nCRT treatment in a phase II study. The pharmacogenomic analysis of other pathways mostly involved in the cellular response to radiation damage, as the DNA repair and the activation of the inflammatory cascade, provided less consistent results. A high rate of somatic mutation in genes belonging to PI3K (Phosphatidyl-Inositol 3-Kinase) and MAPK (Mitogen-Activated Protein Kinase) pathways, asBRAF (V-raf murine sarcoma viral oncogene homolog B1), KRAS(Kirsten Rat Sarcoma viral oncogene homolog), NRAS(Neuroblastoma RAS viral (v-ras) oncogene homolog),PIK3CA(Phosphatidyl-Inositol-4,5-bisphosphate 3-Kinase, Catalytic Subunit Alpha), as well asTP53(Tumor Protein 53) was reported in LARC. Their pharmacogenomic role, already defined in colorectal cancer, is under investigation in LARC with promising results concerning specific somatic mutations inKRASandTP53, as predictors of tumor response and prognosis. The availability of circulating tumor DNA in plasma may also represent an opportunity to monitor somatic mutations in course of therapy
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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