Patients with advanced colon cancer have limited treatment options as tumors frequently metastasize to the peritoneum or to the liver. Together with the Charité, Alacris, the Max-Plack-Institute for Molecular Genetics in Berlin and the University of Graz, EPO scientists have developed a strategy to identify signatures for the personalized treatment of colon cancer by focusing on target-specific drug combinations.
The study was recently published by Marlen Keil and colleagues (1) in Cancers and is demonstrating, that molecular profiling allows the identification of colon cancer subgroups for personalized combination therapies. Genetically stable colon cancers with mutations in KRAS or BRAF have shown response to the combination of drugs inhibiting EGFR (cetuximab), MEK (trametinib), and BRAF (regorafenib), providing a strong hypothesis for further clinical evaluation. In addition, inhibition of PI3K, mTOR (everolimus), and RET (regorafenib) was synergizing with EGFR (cetuximab) inhibition for selected colon cancers models in which these pathways were found to be activated.
A second study is addressing lung cancer without targetable mutated oncogenes that still is a major challenge for oncologists.
Lung tumors can be perceived as organs constituted of different cell types with distinct biologic functions, building a cellular tumorigenic network. In addition to the neoplastic cells, originating from critical genetic alterations, non-neoplastic cells such as cancer associated fibroblasts, endothelial cells and immune cells form a heterogeneous tumor microenvironment. The concomitant inhibition of signaling within the cellular tumorigenic network and suppression of the cellular interdependency by targeting critical paracrine signaling axes is intended to inhibit tumor cell proliferation and to overcome drug resistance. Bioinformatics analysis of gene expression profiles provides evidence for a connection between the expression of the paracrine signalling pathway members and common drug resistances.
Based on this hypothesis, Stefan Langhammer (2) together with scientists from the University of Kiel and EPO compiled a low-dose targeted drug regimen combining drugs inhibiting tumor, endothelial and immune cell as well as cancer associated fibroblasts function by blocking VEGFR and HGFR (cabozantinib), SDF1α and CXCR4 (plerixafor), the EGFR pathway (afatinib), and COX2 (etoricoxib). For experimental validation of this hypothesis, highly resistant patient derived lung cancer xenograft (PDX) models have been subjected to treatment with the proposed drug combination regimen. The growth of all tested sixteen PDX tumors was completely suppressed by this treatment regimen, leading to an objective response rate of 81% and a clinical benefit rate of 100% with an excellent safety profile.
These results strongly encourage the further validation of this cabozantinib, afatinib, plerixafor and etoricoxib combination therapy in preclinical and clinical studies for advanced stage lung cancer patients without current therapeutic options.
(1) Keil et al. Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data. Cancers 2021 (PMID: 34885128)
(2) Gürgen et al. Breaking the crosstalk of the Cellular Tumorigenic Network by low-dose combination therapy in lung cancer patient-derived xenografts Comm Bio 2022 (PMID: 34885128)