An individualized system medicine platform to guide treatment decisions for therapy-resistant Acute Myeloid Leukemia

ITQB Seminar

Title: An individualized system medicine platform to guide treatment decisions for therapy-resistant Acute Myeloid Leukemia

Speaker: Muntasir Mamun Majumder

Affiliation: FIMM, Institute for Molecular Medicine Finland

Host: Catarina Brito, Animal Cell Technology Unit

Abstract:

The Institute for Molecular Medicine Finland FIMM is an international, multi-disciplinary research institute focusing on building a bridge from discovery to medical applications. Research at FIMM involves the combination of high-quality science with unique patient materials and state-of-the-art technologies that range from high throughput screening, next generation sequencing, proteomics, metabolomics, imaging to bioinformatics. One of the major focuses at the institute is individualized system medicine (ISM) to treat acute myeloid leukemia (AML). The aim is to utilize cutting-edge technologies for AML patient sample analyses including next-gen genomic and transcriptomic sequencing, proteomics and high-throughput drug screening. Integrative processing of datasets generated from these analyses is used to identify patient specific biomarkers and to determine novel therapeutic options.

As an example, we applied this platform to samples from a 54-year old cytogenetically normal AML-M5 patient who was initially refractory to three consecutive high-dose induction treatments and had limited therapy options. Earlier routine diagnostic testing showed a FLT3-ITD mutation, which was initially used as a minimal residual disease (MRD) biomarker, but was lost after the first round of induction therapy. To identify alternate MRD biomarkers and new treatment options,

AML blasts from the patient were profiled by exome sequencing, RNA sequencing, phosphoproteomic analyses and combined with drug sensitivity and resistance testing (DSRT) data generated ex vivo for 240 approved and investigational drugs. Transcriptomic sequencing revealed the rare fusion transcript NUP98-NSD1 while exome sequencing revealed a number of different mutant clones. In addition, phospho-protein analysis showed increased insulin receptor, glycogen synthase kinase-3 and STAT transcription factor phosphorylation. Initial DSRT screening showed that the patient’s cells were sensitive to a set of tyrosine kinase inhibitors (TKIs) and mTOR pathway inhibitors. Based on these findings, treatment options were recommended, which included the targeted drugs dasatinib, sunitinib and temsirolimus.  Clinical translation of the customized treatment regime resulted in a remarkable response and the patient went into complete remission. However, the patient relapsed after 4 weeks with DSRT analysis showing a decrease in response to the previous treatment, while the molecular data implied evolution of a new resistant clone.

Taken together, we have demonstrated, how molecular profiling and functional ex vivo drug sensitivity and resistance data can be used to individually optimize patient treatment. Remission was achieved in a patient with advanced, treatment-refractory AML. Serial sampling from human AML patients coupled with molecular profiling and drug sensitivity testing may shed light on clonal progression of disease, and the molecular events underlying drug response.
 
Speaker´s short biography:

Muntasir Mamun Majumder is a Pharmacy graduate from Bangladesh. He did his Masters in Toxicology in Stockholm University, Sweden. He worked with Professor Thomas Helleday on DNA damage response and signalling pathways in Cancer. After Graduation He joined Institute for molecular medicine Finland as a FIMM/EMBL PhD student. He is working in Personalized Medicine group headed by FiDiPro Jonathan Knowles. His research interest focuses on driver cell signalling pathways and integration of genomic and proteomic data to identify biomarkers to individualize therapy in leukaemia.