Berberine is an isoquinoline alkaloid exhibiting a myriad of therapeutic activities. Isolated from medicinal herbs, exhibits antiproliferative activity in vitro and induced apoptosis/necrosis in several cancer cell lines. Although the precise molecular basis of the biological activities is still debated, emerging new information continues to build up data that is exploitable for clinical applications.
The anticancer activity of berberine appears to derive from its ability to form strong complexes with nucleic acids, induce DNA damage, and exert related effects such as telomerase inhibition, topoisomerase poisoning, and inhibition of gene transcription. Berberine has emerged as an attractive lead compound for the development of functional DNA and RNA binding drugs. (However, it has poor bioavailability, which seriously limits its application and development. The chemical transformation of the natural product is an effective method to improve pharmacological activities. Research carried out in collaboration with Naxospharma under EuroTransBio BERTA project, an international funding initiative supported by European program, led to the modification of berberine structure obtaining newer analogues with better pharmacological properties (refer to Dr. Lombardi publications).
NAX035 is the first lead selected to advance into clinics. It has shown robust preclinical proof of concept in several in vitro and animal models, with activity in mesothelioma.
Towards a clinically validated target
Thymidylate Synthase is a well-known, validated
and clinically relevant target in cancer.Despite being one of the earliest
approaches to treat cancer, the inhibition of thymidylate biosynthesis and
disruption of tumour DNA replication continues to stand the test of time as a
widely employed and successful strategy in cancer treatment for the last 60
years. Not only, the agents targeting these processes remain integral
components in some of the most important therapeutic regimens presently used in
the treatment of various cancers, but such agents have also received additional
approvals for new indications, profoundly altering the clinical landscape in
some of the most difficult-to-treat cancers within the past 5–10 years.
In mesothelioma, the standard of care drug Pemetrexed,
targets and binds this enzyme inhibiting its function. Levels of Thymidylate
Synthase has been clinically validated as an independent biomarker: high
protein levels confer resistance to pemetrexed-based therapy not only in
mesothelioma but also in non-small cell lung cancer (NSCLC)patients.
The predictive and prognostic value of the target Thymidylate Synthase has been demonstrated and thus, approaching this target with a newer drug capable of diminishing/silencing its levels, will overcome existing limitations of the current standard of care and it will represent a real alternative for refractory malignant mesothelioma patients.
Highly innovative strategy
NAX035 is a selective and first-in-class drug
targeting Thymidylate Synthase. An RNA-targeted small molecule that acts
disrupting this pivotal clinical target by blocking its translation into
protein from RNA. It has successfully
completed preclinical stage with excellent results. BERMES project will allow
to advance on its evaluation as candidate for
future clinical studies to treat malignant mesothelioma.
 Chamizo C et al
Synthase expression as a predictive biomarker of pemetrexed in advanced
non-small cell lung cancer. BMC Pulm Med 15:32-39