Personalised medicine and its application in patients with complex disorders

Abstract

Personalised medicine aims to achieve the best treatment outcome with the highest safety margin tailored for each individual patient. It is essential to develop biomarkers of disease characteristics, prognosis and response to treatment for the implementation of personalised medicine. Widely used in postmenopausal women with estrogen receptor positive breast cancer, third-generation aromatase inhibitors (AIs) have nevertheless marked interindividual variability in efficacy and safety. Personalised treatment with AIs is required to achieve the best therapeutic response with highest safety margin. In the first specific aim, the current implementation of different approaches for personalised medicine of AIs in patients with breast cancer was reviewed, and future prospects were proposed. In the second specific aim, I reviewed details of the current research progress of personalised medicine with aromatase inhibitors specifically from a pharmacogenetic perspective. Schizophrenia is a genetically complex disorder. Even though it has been extensively studied, our understanding of the molecular etiology of schizophrenia remains incomplete, and current pharmaceutical treatments are not a complete solution. In the third specific aim, I conducted a genome-wide association study (GWAS) of schizophrenia in an Australian population. Post-GWAS analyses were subsequently conducted by leveraging GWAS summary statistics. The strongest finding (P=2.01×10-6, odds ratio (OR) =1.82, 95% confidence interval (CI) =1.42-2.33) in GWAS was with rs10252923 at 7q21.13, downstream of FZD1 (Frizzled Class Receptor 1). While this did not stand alone after statistical correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance (P=2.78×10-6). The identification of FZD1, an independent association signal at the gene level, provided new insights regarding susceptibility for schizophrenia, as well as potential targets for developing new treatments. Very early- and early-onset schizophrenia (VEOS and EOS) are more severe forms of the disorder and have worse prognosis than adult-onset counterparts. There is evidence supporting schizophrenia onset at an early age to be associated with a greater genetic predisposition. In the fourth specific aim, a genome-wide association study for VEOS and EOS was carried out. Further functional follow-up analyses were performed using GWAS summary statistics. rs3825884 in NTRK3 (Neurotrophic Receptor Tyrosine Kinase 3), located at 15q25.3 showed the strongest genome-wide significant association (P=3.09×10-8, OR=2.63, 95% CI=1.87-3.71). Furthermore, immune alterations were implicated in VEOS and EOS through pathway enrichment analysis (T-cell and B-cell receptors signaling pathways, false discovery rate of 1.00×10−4 and 0.015, respectively). Our findings of genetic markers and pathways may aid in elucidating molecular mechanisms underlying VEOS and EOS, and offer insights into developing novel, tailored pharmacologic interventions. The combination of dabrafenib and trametinib is a standard of care for the management of BRAF mutant metastatic melanoma. Clinical trials of dabrafenib-trametinib combination therapy exclude patients with end-stage kidney disease (ESKD) and, as such, no data are available regarding the safety, efficacy and pharmacokinetics of these drugs in such patients. In the fifth specific aim, pharmacokinetic profiling of trametinib, dabrafenib and its metabolites were similar pre- and post- dialysis and comparable to those in patients with normal renal function. In the era of personalised medicine, this study provided evidence for the feasibility of administering dabrafenib and trametinib to patients with ESKD undergoing haemodialysis.