Periodic Reporting for period 2 - INTEGRATA (Integrating chemical and biological approaches to target NAD production and signaling in cancer)
Periodo di rendicontazione: 2020-11-01 al 2023-04-30
Biological targets in focus. INTEGRATA aimed at exploiting the therapeutic potential of nicotinamide phosphoribosyltransferase (NAMPT) as a target to inhibit, but also of additional enzymes from the NAD-biosynthetic and NAD/nucleotide signaling apparatus, for which mounting evidence indicates a role in cancer. These included nicotinic acid phosphoribosyltransferase (NAPRT), SIRT6, CD73, transient receptor potential cation channel, subfamily M, member 2 (TRPM2), and the ADP sugar-pyrophosphatase NUDT5.
On these grounds, INTEGRATA pursued the following scientific and technological objectives:
• To develop new agents for interfering with NAD biosynthesis in cancer cells [NAMPT, NAPRT, inhibitors and Ab drug conjugates (ADCs) to target NAMPT inhibitors to multiple myeloma (MM), B-cell lymphoma and AML cells], neutralizing monoclonal antibodies (mAb) against eNAMPT and eNAPRT and inhibitors of SIRT6, NUDT5, CD73, and TRPM2.
• To perform an extensive testing of the newly generated NAD biosynthesis and NAD/nucleotide-signaling inhibitors in cultured cells and in in vivo cancer models, including models for assessing angiogenesis and cancer cells’ metastatic spread.
• To conduct pre-formulation/fingerprinting, formulation and pharmacokinetics (PK) studies with the newly produced NAD biosynthesis and NAD/nucleotide-signaling inhibitors.
• To define anticancer activity and potential toxicities of the newly generated agents, as well as of a dietary approach based on a NA-free diet w/ or w/o antibiotics (to reduce NAPRT activity) in relevant in vivo cancer models.
• The ESRs from the INTEGRATA consortium successfully produced new inhibitors with the ability to reduce intracellular NAD+ stores, such as NAMPT and NAPRT inhibitors, as well as Ab drug conjugates (ADCs) to target NAMPT inhibitors to multiple myeloma cells. Neutralizing monoclonal antibodies (mAb) against eNAMPT as well as NAD/nucleotide signaling inhibitors, such as NUDT22 and TRPM2 inhibitors have also been developed and tested.
• The newly generated NAD biosynthesis and NAD/nucleotide-signaling inhibitors were extensively tested in cultured cells and in in vivo cancer models. Pre-formulation/fingerprinting, formulation and pharmacokinetics studies were performed with SIRT6 inhibitors and with selected NAMPT inhibitors.
• Finally, anticancer activity and potential toxicities of a dietary approach based on a NA-free diet w/ or w/o antibiotics (to reduce NAPRT activity) in relevant in vivo cancer models have also been determined.
Overall, the project achieved its goals and had a major scientific impact as shown by the numerous scientific articles that have been published so far or that are in preparation or in press. The INTEGRATA ESRs performed numerous dissemination activities [such as taking part in international scientific meetings or in public events such as the “Notte dei Ricercatori” (“Researchers’ night”)] and attended courses on topics such as “Scientific communication and presentation of scientific data”, “Business and financial analysis in drug discovery, patenting, entrepreneurship, regulatory affairs”, etc. The latter activities helped building their scientific background and increasing their opportunities for a future, successful career in science. Therefore, the project has achieved significant scientific advances and has successfully trained fourteen young scientist in the field of NAD+ biology and cancer metabolism through a truly interdisciplinary approach.