Tales from... Dr Dorothea Lesche

There are almost 8 billion people living on planet Earth and everyone is unique, a “limited edition” combining genes and personal history. What if our healthcare could be tailored to each individual necessities and responding with the best possible treatment, at the optimal dose, at the right time?

I was always startled by the the fact that it is not only the dose that makes the poison but that people react very differently to medication while apparently treating the same disease, even when adjusting the dose of a certain medication. At most times the only way to find the right drug and its optimal dose is bland trial and error. This might be acceptable with over the counter pain medication you use while having a cold but can be life threatening in cancer therapy and in many other circumstances.

I started an undergraduate degree in human biology focussing on pharmacology and human genetics. I loved both disciplines but was always wondering how to bring them together. My fellow students and professors often asked me what I am going to do with this subject combination and told me that I should have chosen other subjects that fit better together. Being a quite stubborn person, I stuck to what I had started and kept on the lookout for new developments in pharmaceutical research. In one of the last classes before summer break, I was melting in the small lecture hall of the pharmacological institute listening to a young lecturer giving a talk about his current research on chemotherapies and how patients reacted very differently to classic cytotoxic drugs. That was the first time I heard about the term pharmacogenetics! Spellbound I listened to his work about how one’s personal genetic make-up could influence the response to medication and might even lead to severe life-threatening toxicity. What a fascinating thought being able to choose the right drug for someone based on a genetic test!

In the following years, I dedicated my studies to the broad field of pharmacogenomics and personalised medicine in both discovery research and clinical implementation. Firstly, I studied inherited genetic factors that influence the response to immunosuppressive therapies after heart transplantation. I moved from Europe to Australia after finishing my PhD and started to study the genetic variation that affects the response to anti-psychotic medication. Before I joined Peter Mac in 2018, I had only looked into inherited factors that may change one’s individual drug response. As a researcher in the ‘Cancer Genomics Program’ I investigated how gene mutations arising from the cancer itself can assist the diagnosis of cancer and determine the right treatment for different cancer types. The role of genomics in cancer diagnosis and treatment has evolved at a staggering speed in the last decade and is still doing so. Personalised medicine has helped moving cancer treatment from a one-size-fits-all approach to treatments tailored to the individual genetic background of the patient’s cancer. Cancer chemotherapy has seen an evolution away from non-specific cytotoxic drugs to more specific agents and immunotherapy approaches. With faster and less expensive gene sequencing now available, personalised medicine is used more frequently to diagnose and treat patients – also here at Peter Mac.

Earlier this year, I joined the Pathology Department at Peter Mac. The Molecular Haematology team is using molecular diagnostics to help clinicians establish the most accurate cancer diagnosis and identify the right therapy for their patients. Besides conventional molecular methods, my team is using high-throughput next-generation sequencing (NGS) methods to assess the genetic profile of a wide spectrum of haematological malignancies such as myeloproliferative neoplasms, myelodysplastic syndromes, leukaemias and lymphomas. We are processing around 400 requests per months from all over Australia and New Zealand. My role encompasses the detection of genetic variants and the comprehensive curation and interpretation of them in the given disease context. We are not just providing clinicians with a list of detected mutations but instead offer a comprehensive evaluation of mutational patterns and the importance for the patient’s prognosis and potentially available targeted therapies. For example, specific mutations in the IDH2 gene make patients with acute myeloid leukaemia eligible for treatment with enasidenib while the presence of specific mutations in the FLT3 gene offers the opportunity of treatment with midostaurin. These drugs interact specifically with the cell pathways disrupted by these mutations and will only work in presence of the mutation. Genetic profiles can also influence a patient’s cancer prognosis, such as TP53 mutations in chronic lymphocytic leukaemia are associated with an unfavourable prognosis. Similarly, ASXL1 mutations in primary myelofibrosis are associated with higher risk of leukaemic transformation. Both findings can prompt an earlier and maybe more aggressive treatment to prevent further disease progression.

Besides the routine clinical work, I assist researchers with their clinical research projects and perform genetic testing for clinical trials. While my focus remains on the implementation of current scientific knowledge into diagnostic practice, I am also further improving the comprehensive genetic profiling we provide every day. Personalised medicine has come a long way since that day back in a lecture hall in a small university town in Germany. Although many biological processes remain to be understood, I am amazed every day by the work we are already doing to help our patients at Peter Mac and beyond to bring their cancer journey to a positive end.

Figure legend: ​Workflow of a comprehensive mutational profiling for patients with haematological malignancy (created with BioRender)

Dr Dorothea Lesche is a curation scientist in the Molecular Haematology Laboratory lead by Dr Piers Blombery and Michelle McBean providing the basis for genomic personalised care to patients with haematological malignancies. Her expertise includes large-scale genomic data analysis, gene variant curation in somatic and germline contexts as well as pharmacogenomics research and clinical application. In 2017, she received the J.N. Peters Bequest Postdoctoral Fellowship from the University of Melbourne for her project studying the pharmacogenetics of the anti-psychotic drug clozapine.

Twitter: @doro_lesche

Linked-In: www.linkedin.com/in/dorothea-lesche

Email: [email protected]