Despite the efficacy of BCR-ABL tyrosine kinase inhibitors (TKIs) in chronic phase-chronic myeloid leukemia, the management of blast phase-chronic myeloid leukemia (BP-CML) remains a challenge. Therefore, there is an urgent need to identify alternative agents that act synergistically with BCR-ABL TKIs in BP-CML. Our results show that the anti-malarial agent, mefloquine augments the efficacy of TKIs in CML cell lines and primary CML cells in vitro, including those with the T315I mutation. This effect is selective as mefloquine is more effective in inducing apoptosis, inhibiting colony formation and self-renewal capacity of CD34+ cells derived from TKI-resistant BP-CML patients than normal cord blood (CB) CD34+ stem/progenitor cells. Notably, the combination of mefloquine and TKIs at sublethal concentrations leads to synergistic effects in CML CD34+ cells, while sparing normal CB CD34+ cells. We further demonstrate that the initial action of mefloquine in CML cells is to increase lysosomal biogenesis and activation, followed by oxidative stress, lysosomal lipid damage and functional impairment. Taken together, our work elucidates that mefloquine selectively augments the effects of TKIs in CML stem/progenitor cells by inducing lysosomal dysfunction.

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by extensive heterogeneity in genetics, response to therapy and long-term outcomes, making it a prototype example of development for personalized medicine. Given the accessibility to hematologic malignancy patient samples and recent advances in high-throughput technologies, large amounts of biological data that are clinically relevant for diagnosis, risk stratification and targeted drug development have been generated. Recent studies highlight the potential of implementing genomic-based and phenotypic-based screens in clinics to improve survival in patients with refractory AML. In this review, we will discuss successful applications as well as challenges of most up-to-date high-throughput technologies, including artificial intelligence (AI) approaches, in the development of personalized medicine for AML, and recent clinical studies for evaluating the utility of integrating genomics-guided and drug sensitivity testing-guided treatment approaches for AML patients.

(2018). BIM deletion polymorphism profiling complements prognostic values of risk scores in imatinib-treated Asian chronic myeloid leukemia patients. Leukemia & Lymphoma. Ahead of Print.

The resistance of chronic myeloid leukaemia (CML) to tyrosine kinase inhibitors (TKIs) remains a significant clinical problem. Targeting alternative pathways, such as protein prenylation, is known to be effective in overcoming resistance. Simvastatin inhibits 3-hydroxy-3-methylglutaryl-CoA reductase (a key enzyme in isoprenoid-regulation), thereby inhibiting prenylation. We demonstrate that simvastatin alone effectively inhibits proliferation in a panel of TKI-resistant CML cell lines, regardless of mechanism of resistance. We further show that the combination of nilotinib and simvastatin synergistically kills CML cells via an increase in apoptosis and decrease in prosurvival proteins and cellular proliferation. Mechanistically, simvastatin inhibits protein prenylation as shown by increased levels of unprenylated Ras and rescue experiments with mevalonate resulted in abrogation of synergism. The combination also leads to an increase in the intracellular uptake and retention of radio-labelled nilotinib, which further enhances the inhibition of Bcr-Abl kinase activity. In primary CML samples, this combination inhibits clonogenicity in both imatinib-naive and resistant cells. Such combinatorial effects provide the basis for utilising these Food and Drug Administration-approved drugs as a potential clinical approach in overcoming resistance and improving CML treatment.

Cardiovascular disease is the worldwide leading cause of mortality among survivors of cancer due in part to the cardiotoxicity of anticancer therapies. This paper explores the progress in precision cardio-oncology, particularly in genetic testing and therapeutics, and its impact on cardiovascular diseases in clinical and laboratory settings. These advancements enable clinicians to better assess risk, diagnose conditions, and deliver personalised, cost-effective therapeutics. Through case studies of cancer-therapy-related cardiac dysfunction, clonal haematopoiesis of indeterminate potential, and polygenic risk scoring, we demonstrate the benefits of incorporating precision genomics in individualised care in cardio-oncology. Furthermore, leveraging real-world genomic data in clinical settings can advance our understanding of long noncoding RNAs and microRNAs, which play important regulatory roles in cardio-oncology. Additionally, employing human-induced pluripotent stem cells to stratify risk and guide prevention strategies represents a promising avenue for modelling precision cardio-oncology. While these advancements showcase the significant progress in genetic approaches, they also raise substantial ethical, legal, and societal concerns. Regulatory oversight of genetic and genomic technologies should therefore evolve suitably to keep up with rapid advancements in technology and analysis. Provider education is crucial for the appropriate use of new genetic and genomic applications, including on the existing protection available for patients regarding genetic information. This can provide confidence for diverse study groups to advance genetic studies looking to develop a comprehensive understanding and effective clinical applications for heterogeneous populations. In clinical settings, the implementation of genetic and genomic applications within electronic medical records can offer point-of-care clinical decision support, thus providing timely information to guide clinical management decisions.