The main INTEGRTA objective is to train ESRs 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.
The INTEGRATA ESRs will be trained in the following scientific and technological goals:
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- 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 NAD/nucleotide signaling inhibitors (SIRT6, NUDT5, CD73, and TRPM2 inhibitors).
- To perform an extensive testing of the newly generated NAD biosynthesis and NAD/nucleotide-signaling inhibitors (and of inhibitors that have been recently developed by partners from the Consortium) 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.