Imatinib treatment of poor prognosis mesenchymal-type primary colon cancer: a proof-of-concept study in the preoperative window period (ImPACCT).

Autor: Ubink I; Department of Surgical Oncology, Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands., Bloemendal HJ; Department of Medical Oncology, Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.; Department of Medical Oncology, Meander Medical Center, Maatweg 3, 3813TZ, Amersfoort, the Netherlands., Elias SG; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584CG, Utrecht, The Netherlands., Brink MA; Department of Gastroenterology, Meander Medical Center, Maatweg 3, 3813TZ, Amersfoort, the Netherlands., Schwartz MP; Department of Gastroenterology, Meander Medical Center, Maatweg 3, 3813TZ, Amersfoort, the Netherlands., Holierhoek YCW; Department of Gastroenterology, Meander Medical Center, Maatweg 3, 3813TZ, Amersfoort, the Netherlands., Verheijen PM; Department of Surgery, Meander Medical Center, Maatweg 3, 3813TZ, Amersfoort, the Netherlands., Boerman AW; Department of Medical Oncology, Meander Medical Center, Maatweg 3, 3813TZ, Amersfoort, the Netherlands., Mathijssen RHJ; Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands., de Leng WWJ; Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands., de Weger RA; Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands., van Grevenstein WMU; Department of Surgical Oncology, Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands., Koopman M; Department of Medical Oncology, Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands., Lolkema MP; Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands., Kranenburg O; Department of Surgical Oncology, Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands. o.kranenburg@umcutrecht.nl., Borel Rinkes IHM; Department of Surgical Oncology, Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands. i.h.m.borelrinkes@umcutrecht.nl.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2017 Apr 19; Vol. 17 (1), pp. 282. Date of Electronic Publication: 2017 Apr 19.
DOI: 10.1186/s12885-017-3264-y
Abstrakt: Background: The identification of four Consensus Molecular Subtypes (CMS1-4) of colorectal cancer forms a new paradigm for the design and evaluation of subtype-directed therapeutic strategies. The most aggressive subtype - CMS4 - has the highest chance of disease recurrence. Novel adjuvant therapies for patients with CMS4 tumours are therefore urgently needed. CMS4 tumours are characterized by expression of mesenchymal and stem-like genes. Previous pre-clinical work has shown that targeting Platelet-Derived Growth Factor Receptors (PDGFRs) and the related KIT receptor with imatinib is potentially effective against mesenchymal-type colon cancer. In the present study we aim to provide proof for the concept that imatinib can reduce the aggressive phenotype of primary CMS4 colon cancer.
Methods: Tumour biopsies from patients with newly diagnosed stage I-III colon cancer will be analysed with a novel RT-qPCR test to pre-select patients with CMS4 tumours. Selected patients (n = 27) will receive treatment with imatinib (400 mg per day) starting two weeks prior to planned tumour resection. To assess treatment-induced changes in the aggressive CMS4 phenotype, RNA sequencing will be performed on pre- and post-treatment tissue samples.
Discussion: The development of effective adjuvant therapy for primary colon cancer is hindered by multiple factors. First, new drugs that may have value in the prevention of (early) distant recurrence are almost always first tested in patients with heavily pre-treated metastatic disease. Second, measuring on-target drug effects and biological consequences in tumour tissue is not commonly a part of the study design. Third, due to the lack of patient selection tools, clinical trials in the adjuvant setting require large patient populations. Finally, the evaluation of recurrence-prevention requires a long-term follow-up. In the ImPACCT trial these issues are addressed by including newly diagnosed pre-selected patients with CMS4 tumours prior to primary tumour resection, rather than non-selected patients with late-stage disease. By making use of the pre-operative window period, the biological effect of imatinib treatment on CMS4 tumours can be rapidly assessed. Delivering proof-of-concept for drug action in early stage disease should form the basis for the design of future trials with subtype-targeted therapies in colon cancer patients.
Trial Registration: ClinicalTrials.gov: NCT02685046 . Registration date: February 9, 2016.
Databáze: MEDLINE
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