Precision Medicine in Diseases Caused by Alterations in Lipid Metabolism

Choline kinase α (ChoKα) is a critical enzymes involved in the regulation of phsophatidylcholine metabolism, the major phospholipid in all eukaryotic membranes. Overexpression of ChoKa is oncogenic and modulates the expression of genes directly involved in the regulation of cell proliferation and apoptosis, promoting the progression of tumours. ChoKα affects signalling pathways including ERK, AKT, PI3K, c-Src and EGFR. Inhibition of ChoKa induces endoplasmic reticulum stress (ERS) and Unfold Protein Response (UPR), and leads to a drastic reduction in the levels of the G1->S phase checkpoint mediators pRB and E2F1α. These effects results in a potent antitumor activity, promoting a variety of effects as increased ceramides production and the subsequent activation of cell death, with an exquisite specificity towards cancer cells and a reversible, non-toxic effect on normal, non-tumorigenic cells.

A better knowledge of the mechanisms by which ChoKα contributes to cancer onset and progression and those involved in sensitivity and resistance to drugs targeting enzymes involved in lipid metabolism may facilitate the design of more specific and effective therapies. Indeed, due to their unique mechanism of action, ChoKα inhibitors (ChoKαIs) could be used in many combinatorial regimes against a broad spectrum of human cancers. ChoKαIs show potent antitumor activity, and one of our drugs, RSM-932A, has completed the first Phase I clinical trial in humans. However, and as expected for any chemotherapeutic approach, resistance to ChoKαIs has also been found. This makes imperative the search for tools that discriminate sensitive from resistant tumours to ChoKαIs.

Precision oncology requires the development of adequate tools and protocols for the selection of patients suffering from each specific type of cancer to optimize their clinical management. Especially relevant is the case of PDAC and NSCLC tumours, with dreadful prognosis that can benefit from a targeted personalised treatment. These protocols would result from the combination of studies using appropriate biological reagents such as Patient-Derived Xenografts (PDX) and the use of omic analysis. We are using this strategy to identify genomic, proteomic and lipidomic alterations induced by modulation of ChoKα activity to identify specific biomarkers in both sensitive and resistant tumours to inhibitors of ChoKα. These results will allow the selection of candidates that may benefit from targeted, personalized, precision therapeutic approaches. Our group is focused in the study of PDAC and NSCLC models to identify RPS for each pathology in response to ChoKα inhibitors (ChoKαIs).

ChoKα has been involved in other human diseases. We provided strong evidence that inhibition of ChoKα has the potential to be used as therapeutic approaches in malaria, an illness caused by Plasmodium falciparum, and others have reported similar studies for Leishmania infantum, the causative agent of Leishmaniasis. Also we demonstrated the successful use of ChoKαIs against Gram-positive S. pneumoniae and Gram-negative H. influenzae.

In animal models of, ChoKαIs are also very successful, suggesting that these drugs have the potential to be used as potent therapeutics in inflammatory diseases. This includes rheumatoid arthritis (RA), LPS-induced septic shock model, Muckle–Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID). These last three syndromes are a consequence of mutations in the NLRP3 gene that cause chronic activation of the inflammasome.

Therefore, ChoKα inhibition may play an important role in the treatment of a diversity of human diseases. Further research on the clinical application of our ChoKαIs in this plethora of human illnesses will disclose and clarify whether its tremendous potential as broad-spectrum therapeutics can be a reality. We are working to resolve this challenging enterprise.


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