Cancer’s Achilles Heel

The nucleotide cytidine 5′ triphosphate (CTP) is a precursor required for the synthesis of DNA, RNA and phospholipids. CTP originates from two sources: the nucleotide salvage pathway and the de novo nucleotide synthesis pathway. De novo synthesis of CTP is required for DNA replication. The rate limiting step is conversion of UTP to CTP which can be catalyzed by CTP Synthase 1 (CTPS1) or CTPS2.

In 2014 Prof. Alain Fischer and his collaborators at the Imagine Institute identified loss-of-function homozygous CTPS1 mutations in eight children which caused a novel immunodeficiency characterised by impaired capacity of activated lymphocytes to proliferate, without affecting cells outside the blood system (Martin et al., Nature. 2014 Jun 12;510(7504):288-92).

These findings demonstrated that CTPS1 has an essential and non-redundant role in lymphocyte proliferation while CTPS2 allows normal non-blood cells to proliferate independently from CTPS1.

Whilst CTPS2 activity is sufficient for the proliferation of normal cells outside the blood system, our work suggests that all cancer cells have become addicted to CTPS1.

Based upon this ground-breaking research, Step Pharma was founded to convert this human genetic observation into a potential therapy for blood cancers and solid tumours.

The human genetic studies demonstrated that CTPS1 is essential for lymphocyte proliferation and thus inhibition of CTPS1 would be a therapeutic option for malignancies such as leukaemia and lymphoma. Further genetic studies have shown that many solid tumours have deleted CTPS2 also making them exclusively dependent on CTPS1 for pyrimidine synthesis.