Combination is key – new treatments for lung and colon cancer?

Researchers from the Experimental Pharmacology and Oncology (EPO) in Berlin-Buch in cooperation with academic partners identified new experimental approaches to treat therapy resistant cancer. Patients with advanced colon cancer have limited treatment options as tumors frequently metastasizes to the peritoneum or the liver. Together with the Charite, Alacris, the Max-Plack-Institute for Molecular Genetics in Berlin and the University of Graz, scientists have identified genetic instability and mutations in the mitogen-activated protein kinase pathway (MAPK) as common markers for therapy resistance in experimental colon cancer models. Evaluation of new therapy combinations, targeting specific pathways revealed strong tumor growth inhibition in those otherwise resistant colon cancers. The study was recently published by Marlen Keil and colleagues (1) in Cancers and is demonstrating, that molecular profiling allows identification of colon cancer subgroups for personalized combination treatments. Genetically stable colon cancers with mutations in the MAPK pathway (KRAS and BRAF) have shown responses to the combination of drugs inhibiting EGFR (cetuximab), MEK (trametinib), and BRAF (regorafenib), providing a strong hypothesis for further clinical evaluation. In addition we have seen that PI3K, mTOR and RET inhibition by everolimus or regorafenib seems to be additive with EGFR inhibition (cetuximab) in selected colon cancers with those activated pathways. A second study is addressing lung cancer without targetable oncogenic mutations, still a major challenge for oncologists. Lung tumors can be conceived as an organ constituted of different cell types with distinct biologic functions, building a Cellular Tumorigenic Network. Next to the neoplastic cells, originating from critical genetic alterations, non-neoplastic cells such as cancer associated fibroblasts, endothelial cells and immune cells comprise a heterogenic tumor microenvironment. The simultaneous inhibition of signaling within the Cellular Tumorigenic Network and suppression of cellular interdependency by targeting critical paracrine signaling axes is intended to inhibit tumor cell proliferation and thus to overcome drug resistances. Bioinformatics analysis of gene expression profiles provides evidence of a relationship between the expression of the paracrine signaling 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. All 16 PDX tumors were completely growth suppressed by this drug 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)
(2) Guergen et al. Breaking the crosstalk of the Cellular Tumorigenic Network by low-dose combination therapy in lung cancer patient-derived xenografts. Commun Biol 5, 59 (2022)