Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data.

Marlen Keil,Ulrich Keilholz,Johannes Haybaeck,Theresia Conrad,Michael Becker,Hans Lehrach,Marie-Laure Yaspo,Moritz Schütte,Jens Hoffmann

doi:10.3390/cancers13236018

Abstract

Simple SummaryThis experimental preclinical study developed a strategy to identify signatures for the personalized treatment of colon cancer focusing on target-specific drug combinations. Tumor growth inhibition was analyzed in a preclinical phase II study using 25 patient-derived xenograft models (PDX) treated with drug combinations blocking alternatively activated oncogenic pathways. Results reveal an improved response by combinatorial treatment in some defined molecular subgroups and potential alternative treatment options in KRAS- and BRAF-mutated colon cancer.The current standard therapies for advanced, recurrent or metastatic colon cancer are the 5-fluorouracil and oxaliplatin or irinotecan schedules (FOxFI) +/− targeted drugs cetuximab or bevacizumab. Treatment with the FOxFI cytotoxic chemotherapy regimens causes significant toxicity and might induce secondary cancers. The overall low efficacy of the targeted drugs seen in colon cancer patients still is hindering the substitution of the chemotherapy. The ONCOTRACK project developed a strategy to identify predictive biomarkers based on a systems biology approach, using omics technologies to identify signatures for personalized treatment based on single drug response data. Here, we describe a follow-up project focusing on target-specific drug combinations. Background for this experimental preclinical study was that, by analyzing the tumor growth inhibition in the PDX models by cetuximab treatment, a broad heterogenic response from complete regression to tumor growth stimulation was observed. To provide confirmation of the hypothesis that drug combinations blocking alternatively activated oncogenic pathways may improve therapy outcomes, 25 models out of the well-characterized ONCOTRACK PDX panel were subjected to treatment with a drug combination scheme using four approved, targeted cancer drugs.

Highlights

KRAS and BRAF mutations have been established as biomarkers for cetuximab resistance in colorectal cancer (CRC), the predictive value is not satisfying
35% of the KRAS wild-type population does not respond to cetuximab, while there is growing evidence that some mutant tumors might respond to the treatment
The selected panel of 25 colon cancer PDX models with heterogeneous sensitivity towards cetuximab was tested for response to the single drugs and the drug combinations with cetuximab and trametinib, cetuximab and regorafenib, and cetuximab with everolimus

Summary

Introduction

KRAS and BRAF mutations have been established as biomarkers for cetuximab resistance in colorectal cancer (CRC), the predictive value is not satisfying. KRAS and BRAF mutations have been established as biomarkers for cetux-2 of 13 imab resistance in colorectal cancer (CRC), the predictive value is not satisfying. As. As cetuximab is usually combined with FOxFI, it is difficult to define the contribution to cetuximab is usually combined with FOxFI, it is difficult to define the contribution to the the overall response [1]. In some colon cancer PDX models treated with single overall response [1]. In some colon cancer PDX models treated with single cecetuximab, almost complete regressions were observed [2], raising questions as to whether tuximab, almost complete regressions were observed [2], raising questions as to whether the combination with FOxFI is mandatory for all patients

Methods

Results

Conclusion