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

Abstract

BackgroundThe 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.MethodsTumour 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.DiscussionThe 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 registrationClinicalTrials.gov: NCT02685046. Registration date: February 9, 2016.

The tumour–stroma ratio in colon cancer: the biological role and its prognostic impact

“…Another activated signalling pathway is the PDGFR pathway which can be targeted by the imatinib anticancer drug. The ongoing ImPACCT clinical trial investigates the efficacy of the drug in patients with colon cancer characterised as CMS4, described in Ubink et al …”

“…49 For an extensive summary of TGF-b targeting drugs, see the review by Colak et al 50 Another activated signalling pathway is the PDGFR pathway which can be targeted by the imatinib anticancer drug. The ongoing ImPACCT clinical trial investigates the efficacy of the drug in patients with colon cancer characterised as CMS4, described in Ubink et al 51 Therapeutically targeting CAFs can also promote anti-tumour response, and it could be used in combination with standard therapy in order to target both CAFs and cancer cells. For instance, sibrotuzumab is an antibody that inactivates the CAF marker FAP.…”

Prognostic value of low CDX2 expression in colorectal cancers with a high stromal content – a short report

“…Therefore, studies are underway to identify targeted therapeutic options beneficial for the CMS4 subtype (rectal adenocarcinoma NCT02688712, phase II and tyrosine kinase inhibitor Fig. 2 Survival of patients with CRC (N = 201) stratified by tumourstroma ratio (a) and by CDX2 status in the stroma-low subgroup (b; N = 105) and the stroma-high subgroup (c; N = 96) (log-rank test, pairwise comparisons controlling for false discovery rate using the Benjamini-Hochberg procedure and unadjusted p value for interaction between tumour-stroma ratio and CDX2 status in disease-free survival and overall survival) [18]). Once a beneficial treatment for this subgroup will be available, an easy to use stratification method will be necessary.…”

Dysregulated PDGFR alpha expression and novel somatic mutations in colorectal cancer: association to RAS wild type status and tumor size

“…Platelet derived growth factor (PDGF) signaling pathway promotes processes of cancer aggressiveness as epithelial mesenchymal transition (EMT), tumor proliferation, growth and progression, angiogenesis, inhibition of apoptosis, recurrence and metastatic dissemination via the activation of various signaling pathway as PI3K/AKT and RAS/MAPK signaling pathways [3][4][5]. Platelet-derived growth factor receptors (PDGFR) and their ligands were reported as highly expressed in consensus molecular subtypes 4 (CMS4) colon tumors and identified as potential therapeutic targets for this subtype [6]. Dysregulation of PDGFR alpha (PDGFRα), one of receptors tyrosine kinase (RTK), has been reported in a broad range of cancer including glioblastoma, breast cancer, hepatocellular carcinomas, pancreatic cancer, and ovarian cancer [4,[7][8][9], either by protein overexpression or by the effect of mutations and chromosomal rearrangements.…”

“…Moreover, this receptor has been approved by the Food and Drug Administration as therapeutic target for the treatment of patients with gastrointestinal stromal tumors (GISTs) (https ://www.brimr .org/PKI/ PKIs.htm). It was shown that Imatinib (PDGFRα inhibitor) can reduce the aggressive phenotype of CMS4 class colorectal tumors [6,10].…”