Nucleoside analogue drugs depend on nucleoside transporters to enter the cells where they exert
their effect (Fig. 1). Cytarabine and gemcitabine are two anticancer drugs that
depend on human Equilibrative Nucleoside Transporter 1 (hENT1) for their effect.
This has important practical consequences
as a considerable proportion of cancer cells have low expression of hENT1 (Fig. 2). Low clinical effect of treatment has been
correlated with reduced or no presence of hENT1 in the cancer cells. This has been confirmed in clinical trials 1,2,3.
Clavis Pharma's LVT drugs, elacytarabine and CP-4126, are derivatives of cytarabine and gemcitabine
respectively. In contrast to the established nucleoside drugs, the LVT compounds are able to enter the cells (Fig.3) and therefore
retain their effect independent of the hENT1 expression level4,5. The uptake in hENT1 deficient cells have been
confirmed also in vitro with confirmed high formation of the active triphosphate metabolite of elacytarabine and CP-4126 in deficient cancer
cells6.
Once inside the cell the lipid tail of the LVT drug is cleaved off and the parent drug is released.
With the lack of hENT1 transporter the drug is trapped inside the cell (Fig.3)
and high concentrations of active metabolites have been measured
.
The above mentioned observations indicate that elacytarabine and CP-4126 may be active
in tumours that are resistant to cytarabine and gemcitabine due to the lack of hENT1. This could be important for patients
with a poor response to treatment in both AML patients and pancreatic cancer patients.
Clavis Pharma is in the process of implementing hENT1 level measurements in tumours from patients
in its clinical development programme. The data will both give information on the prevalence of hENT1 expression in the relevant
tumours, and also open for the selection of patients for treatment, based on the hENT1 expression level, thus selecting the
patients with the extra chance of clinical benefit.
The methods will be validated in accordance with required standards.
From a patient perspective, this approach is in line with current trends toward more personalised treatment.
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