Blood cancers, particularly acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), affect over 470,000 patients annually worldwide. Outcomes remain poor, above all for so-called high-risk (HR) patients, who account for approximately 40% of all AML/MDS cases. This group consists predominantly of elderly individuals with multiple co-morbidities, who face one-year survival rates below 10% for AML and approximately 35% for MDS. Intensive chemotherapy and modern immunotherapies are frequently unsuitable for these patients due to excessive toxicity, leaving hypomethylating agents (HMAs) such as decitabine (DEC) and azacitidine (AZA) as the primary and often only treatment option.
HMAs aim to change the genetic expression pattern of cancerous cells, in order to allows activation of previously silenced tumour suppressor genes, rather than killing the cell by toxic interference.
The clinical utility of current HMAs is, however, fundamentally constrained by their intrinsic chemical and enzymatic instability. This limits achievable therapeutic concentrations, necessitates frequent dosing, and results in modest response rates of only 20–30% with median response durations of 8–12 months. Treatment consequently remains largely palliative rather than curative, and there is a clear, unmet medical need for a more effective and better tolerated alternative.
The leuCAB project addresses this need by advancing Carbacitabine (CAB), a novel carbocyclic HMA developed at LMU Munich. CAB is structurally derived from DEC through a single targeted molecular modification: the replacement of the deoxyribose ring oxygen with a methylene group (CH2). This carbocyclic modification confers markedly enhanced resistance to both hydrolytic degradation and enzymatic inactivation, while fully preserving the established mechanism of action — inhibition of DNA methyltransferases (DNMTs) and reactivation of silenced tumor suppressor genes. In preclinical studies, CAB demonstrated up to 100-fold reduced hematotoxicity compared to DEC, alongside superior anti-leukemic efficacy in patient-derived xenograft (PDX) mouse models, including the capacity to overcome resistance mechanisms that render current HMAs ineffective. leuCAB was designed to consolidate this preclinical promise into a validated, commercially viable drug candidate by optimizing the lead structure, advancing synthesis scalability, establishing a regulatory roadmap, and securing the intellectual property and business development foundations required for clinical advancement.
