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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - LeukaemiaTargeted (Selecting genetic lesions with essential function for patients\' leukaemia in vivo as targets for precision medicine)

Teaser

Summary

In Europe, around two million individuals die from cancer each year. Cancer is a genetic disease and each patient\'s tumour contains several genetic lesions which are identified by next generation sequencing (NGS) and influence patient\'s outcome. A global current challenge lies in translating NGS data into benefit of cancer patients.
As attractive novel therapeutic concept, precision medicine addresses genetic lesions using targeted therapies. A large number of targeted drugs and compounds exist and are currently developed such as kinase inhibitors; unfortunately, numerous clinical trials on targeted therapies failed.
In order to better exploit NGS data, it is important to discriminate between genetic lesions that are required and maintain patients\' tumours in vivo and others that do not â€“ an impossible mission so far. My proposal aims at solving this key question.
Using acute leukaemia as model tumour disease, we propagate primary tumour cells from patients in immuno-deficient mice. We recently pioneered a worldwide unique technique which allows the distinct genetic manipulation of individual patients\' tumour cells while they grow in vivo.
We will molecularly target tumour-specific genetic lesions one by one; if tumour load is reduced, the lesion fulfils an essential function; essential lesions represent attractive therapeutic targets. Using our cutting edge technology, we will identify genetic lesions with essential,
tumour-relevant function
(i) in established tumour disease and
(ii) in the clinically challenging situations of minimal residual disease and relapse.
Our approach implements a new paradigm for target selection in oncology. Our work introduces molecular target validation as important step into the value chain of precision medicine which will tailor drug development by industry and academia. Our approach will improve patient care and the success rate of clinical trials for the benefit of patients suffering acute leukaemia and putatively other cancers.

Work performed

In the first 30 months of funding, we have established primary tumor cells from numerous patients with acute leukaemias (AL) on immune-incompetent mice to generate patient-derived xenograft (PDX) models. In parallel, we have described all genetic lesions of each AL sample using next generation sequencing. We have used genetic engineering using lentiviruses and have molecularly modified established PDX cells. We have described two novel, yet unknown vulnerabilities of PDX AL models, namely the anti-apoptotic protein XIAP as well as the transcription factor KLF4 (manuscripts in preparation). Our data suggest using Smac mimetics targeting XIAP in patients with overexpressed XIAP as well as Azacytidin in acute lymphoblastic leukemia with downregulated KLF4.

Final results

Our technical approach is worldwide unique and by itself beyond state of the art. We can work with patients tumor cells on a molecular level and in the in vivo situation having the animal as xenograft host. We use lentiviruses for molecular modifications and recombinant markers as readouts.

In the upcoming months, we will use our in vivo systems to validate further targets. As a final result, we will have molecularly validated targets for decisive PDX AL samples as well as a pipeline allowing for molecular target validation in the future.