Cancer stem cells (CSCs) are the root of all solid tumors, and are considered the main cellular drivers of tumorigenesis, chemoresistance and cancer relapse. Therefore, from a clinical perspective, targeting the CSC population represents a very appealing strategy to treat cancer, as it would ensure tumor elimination and prevent CSC-mediated relapse. In this ERC PoC project, we have explored the preclinical potential of tailored metallocomplexes as a new type of anticancer agents that works by targeting CSCs. Most of the efforts have been focused on ruthenium complexes exhibiting different types of polypyridine ligands, and one labile coordination position, which is key for biological activity. As proposed in the project, we have optimized chemical synthesis protocols to obtain this type of compounds in a rapid and versatile manner. We have also scaled up the synthesis of the parent lead ruthenium complex, working under GLP-like conditions. We are now in position to export the protocols to an external CRO for large-scale preparation. Our collaborative work with the Biology group of Dr. Bruno Sainz has revealed important mechanistic information, confirming that these compounds work by targeting mitochondrial respiration (OXPHOS). RNAseq and other specific experiments (for instance, PCR amplification with isolated mtDNA), strongly supporting a direct action at the level of mitochondrial DNA that results in a decrease in the expression of key genes regulating CSC mitochondrial respiration.
We have also completed many pre-clinical in vivo experiments (laboratory of Dr. Sainz), which confirmed that our parent complex is capable of halting and even reducing tumor growth in cancer patient-derived xenografts of different tumor entities, both alone or in combination with other standard of car (SOC) therapies. We have mainly investigated pancreatic ductal adenocarcinoma (PDAC), but we do also have strong preliminary data suggesting that the parent compound is very effective for other cancers like colorectal tumors and osteosarcomas. Overall, we have successfully progressed to an advanced preclinical stage, and are currently working with external CROs to further confirm efficacy, safety and dosing. We are also working together with external consultants to complete a business plan than can facilitate the access of our compounds to the market.
