Description
The project presents a new collaborative research initiative within the field of cancer therapy, main objective is to perform preclinical evaluation of a novel therapeutic strategy against cancer cells based on a combination of chemotherapeutic drugs with viral gene therapy vectors. The aim of this study is to develop an efficient strategy for cancer treatment based on an application of image-guided targeted chemotherapeutics in combination with gene therapy vectors. Special attention will be paid to training of young researchers in cutting-edge imaging techniques, advanced immunological methods and mass spectrometry approaches. The research credibility is justified by the broad and complementary expertise of participating groups from three institutions. The involvement of Proteomics Research Group at OUH will bring the necessary expertise for a quantitative comparative proteomic analysis of cancer cells susceptible and unsusceptible to alphavirus infections with the aim to identify the molecular mechanisms underlying alphaviral tumor tropism. The group has a long time experience in mass spectrometry Outcomes: Strengthened research capacity and increased application of research results: 2 internationally refereed scientific publications, 2 scientific publications co-authored by one or more reserchers from Norway and Latvia and 1 scientific publications.
Summary of project results
The project contributes to development of new anti-cancer therapies based on alphaviral vectors expressing immunomodulating cytokines and 1,4-dihydropiridine-based chemotherapeutics with fluorescent properties. The main idea of the project was to design viral vectors for activation of tumorocidal functions of tumor assotiated macrophages, which will be applied in combination with chemical drugs possessing antiproliferative as well as infrared-spectrum emission characteristics. In a frame of development of novel chemotherapeutics, three potential anti-cancer drugs were selected for combined treatment with alphaviral vectors. The compounds demonstrated inhibition of Lewis lung carcinoma growth through induction of necrosis of tumor nodules, as was confirmed by histochemical analysis of tumors. Fluorescent properties of the compounds were evaluated using microscopy and in vivo imaging system. More than ten compounds and linkers were designed and synthesized in order to improve their tumor targeting properties and fluorescence characteristics. The next step will include the attachment of tumor homing ligands to the most promising compounds. Furthermore, a mouse model based on patient derived tumor xenografts was developed and comprehensively characterised in terms of immune cell composition and growth dynamics. The model allows evaluation of therapeutic effects in presence of human immune cells, which are transplanted within the xenograft pieces. In summary, although the obtained results were fruitful, the implemented project represents a beginning of collaborative research initiative between Latvia and Norway in the field of cancer therapy. The involved groups with complementary expertize have a clear vision of sustainable collaboration. Practically, next steps will include further development of anti-cancer drugs, evaluation of 1,4-dihydropiridine-based drugs in PDX models, activation of human macrophages with alphaviral vectors and optimization of vector delivery mode in mouse allograft and human xenograft models. The project resulted in 6 articles in international peer-reviewed journals (4 published, 1 accepted and one submitted for publication), 2 of them are joint publications with the OUH.
Summary of bilateral results
The participating research groups have complementary scientific backgrounds within virology, immunology and chemistry. The obtained results represent a basis for sustainable collaboration focused on development of novel therapeutics: (i) the gene candidates, identified by proteome analysis, which are up/down regulated in susceptible cells, can be respectively overexpressed/silenced in different cancer cells to enhance tumor tropism of alphaviral vectors; (ii) the advanced formulations of drugs (LIOS) can be further assessed and optimized in the context of combined treatment using xenograft models; (iii) other TAM reprogramming gene candidates designed at LBMC will be tested in vitro in macrophage activation assay (OUH); (iv) labelling of drugs with tumor homing ligands will be performed (LIOS, LBMC); (v) combination with check-point inhibitors could represent another strategy; (vi) identification of the immune-cell landscape and molecular characteristics of tumors upon alphavirus infections.