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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

MetAction: Actionable Targets in Cancer Metastasis - from Bed to Bench to Byte to Bedside

Awarded: NOK 22.8 mill.

Project Number:

218325

Application Type:

Project Period:

2012 - 2018

Location:

The aim of MetAction was to translate recent progress in molecular and cellular biology into clinical benefit. Towards this end we planned three activities: 1) Design and conduct a clinical study where treatment decisions should be based on Next Generation Sequencing (NGS) data from progressing metastatic lesions; 2) Perform an explorative study to identify novel actionable targets in metastatic melanoma, breast or colorectal carcinoma; 3) Develop bioinformatics tools to efficiently deliver activities 1 and 2. Activity I: Actionable target identification for palliative systemic therapy Mutational status in single genes forms the basis for treatment in some types of cancer. NGS-data, reporting on gene aberrations in several genes simultaneously, have previously never been used in treatment decisions in clinical trials in Norway. The top priority for MetAction was therefore to initiate and conduct a clinical trial where such data, together with clinical information, was used for treatment decisions in advanced cancer. The MetAction clinical trial has been conducted at two study centers, AHUS and OUS. Patients eligible for the study had metastatic cancer from any solid tumor and had experienced progression on at least one standard treatment. Initially, and after approval of the study protocol by the Medical Agency of Norway, the project established a diagnostic pipeline with the required workflow efficiency within the context of late-stage patient management. This consisted of imaging-guided biopsy sampling, targeted DNA sequencing, data interpretation in multidisciplinary Molecular Tumor Board (MTB) before integration with clinical information and treatment decisions in Clinical Tumor Board (CTB). Between May 2014 and August 2015, 24 patients were enrolled onto the study. A single case of a procedure-specific adverse event was recorded, so the diagnostic pipeline was deemed safe. No case was identified with an actionable target. Modelling of costs for three month of follow-up, comparing personnel salaries and expenses for analyses, equipment, medication, and admission from adverse events, indicated that the MetAction approach was 2.5-fold more expensive than best supportive care (Ree et al, ESMO Open 2017). The study was temporarily closed between September 2015 and March 2016 when we obtained approval for three principal protocol amendments: 1. Change of the diagnostic gene mutation panel from a ?hotspot?-based to a comprehensive panel; 2. Extended liberty for the MTB to interpret the mutation data; 3. The opportunity for the CTB to conclude on combination regimens (with established safety data). The remaining 26 patients were included in the study until March 2017. We identified actionable targets in 13, and commenced treatment in 10, patients. Six of the patients reached the primary endpoint (progression-free survival 1.3xlonger than previous line of treatment). Four patients (4/26=15%) experience long lasting responses and reversal of their end-stage cancer disease. Activity II: Novel target identification in metastatic cancer Tissue samples have been processed and DNA and RNA isolated from patients with malignant melanoma (MM, n=54 lymph node met), colon cancer (CRC, n=51 liver met) or breast cancer (BC, n=50 lymph node met) to study tumor heterogeneity and identification of possible "actionable targets." Genomic analyses included identification of the mutation status of known cancer associated genes (Ion Torrent PGM, Cancer HotSpot panel), copy number variation and microarray gene expression. We have reported on the importance of immune-related mechanisms in CRC liver metastasis (Østrup et al, 2017). To further explore immune profiles in CRC liver metastases, immune cell populations are related to molecular and clinical data (Dagenborg et al, in prep), and a gene expression signature with capacity of directing immune cell polarization has been identified (Nygaard et al, in prep). Extraction of immune profiles has also been performed from the MM samples and will be associated with clinical parameters (Wernhof et al, in prep). Furthermore, we have compared molecular data from metastases across the three tumor types and found that the basic molecular architecture of the primary tumors is maintained during the metastatic processes (Salwal-Pandit et al, in prep). We have also performed molecular analyses (targeted DNA and RNAseq) of 57 brain metastatic specimens, aiming to identify molecular profiles that are of biological and clinical relevance. The role of targeted therapy is currently undefined for brain metastases. Hence the identification of actionable targets at this metastatic site is of particular interest. Activity III: Integrative computational analyses The IonTorrent technology was selected as NGS-platform in the clinical study. Before patient enrollment, bioinformatics pipeline and procedures for base calling, quality control and sequence interpretations were established.

The MetAction vision is to move from bed ? to bench ? to byte ? to bedside. By facilitating multidirectional flow of ideas and knowledge between clinical and basic research groups we aim to translate recent progress in cancer biology into clinical benefit . The great majority of cancer related deaths is caused by metastatic disease, and for personally-adapted treatment it is essential to molecularly characterize the metastases and choose therapy based on rate limiting and actionable targets present. By a dapting therapy to the individual cancer patient the expectation is to improve treatment efficacy, reduce toxicity and minimize cost in cancer care. To achieve this goal we have to increase our knowledge on molecular changes driving tumor progression - th ereby defining the rate limiting and actionable targets. In addition, biomarkers must be identified allowing reliable identification of patients likely to respond and to demonstrate response upon molecularly-driven therapy. Finally, for clinical utilizati on the molecular portrait of the tumor has to be interpreted in the context of patient parameters to decide on optimal therapy. This puts new demands on the clinical team in charge of patient management and an important goal for the MetAction project is t o sophisticate multi-disciplinary teams and infrastructure to create a solid basis for personalized cancer medicine. By molecular profiling of metastatic tumors in a palliative setting MetAction will gain knowledge that relatively quickly can be translat ed into clinical benefit. The multilevel molecular characterization and integrative computational analyses will further enhance the understanding of cancer progression and novel actionable targets and biomarkers will be identified.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering