The fourteen ESRs will work in Individual Research Projects within five, well-integrated and highly interconnected research Work-packages.

WP1 - Development and in vitro testing of new NAD-lowering agents:

New compounds and Ab-drug conjugates (ADCs) with NAD-lowering effects will be generated and extensively tested by the ESRs in biochemical assays, in cultured tumor cells and in non-cancer cells (e.g. fibroblasts cell lines, HaCat keratinocytes, rat cardiomyocytes, MCF10A and HMLE mammary epithelial cells, HPND and HPDE ductal pancreatic epithelial cells and PBMCs) to preliminarily define potential toxicities. ESRs 3,5,8,9,11,12,14.

WP2 - Development and in vitro testing of neutralizing anti-eNAMPT and anti-eNAPRT Abs:

WP2 aims at developing neutralizing anti-eNAMPT Ab and anti-eNAPRT Abs which shall interfere with their pro-tumorigenic moonlighting and at testing in vitro their anticancer properties as well as potential toxic effects (testing in cultured non-cancer cells). ESRs 1,13.

WP3 - Development and in vitro testing of new NAD/nucleotide signaling inhibitors:

WP3 aims at developing inhibitors of the sirtuin, SIRT6 (for uses in actinic keratosis and skin cancer), of the ADPR-activated cation channel, TRPM2, and of the nucleotide-metabolizing enzymes, CD73 and NUDT22, by CADD and at testing them in cultured cancer cells and vs. non-cancer cells (to preliminarily define potential toxicities). ESRs 2,4,7,10.

WP4 - Preclinical pharmacology and biodistribution studies of new NAD production and NAD/nucleotide signaling inhibitors:

WP4 aims at performing studies of fingerprinting/ pre-formulation, formulation and PK with the newly generated compounds (NAD-lowering compounds and inhibitors of NAD/nucleotide signaling) to be done at HDP. ESRs 2,3,4,5,6,7,8,9,10,11,12.

WP5 - PoC studies of new agents targeting NAD production or signaling and of a NA-deficient diet w/ or w/o antibiotics:

WP5 aims at defining the anticancer effects of the NAD-lowering drugs/ADCs and of the NAD/nucleotide signaling inhibitors that shall be the focus of the different ESR programs in appropriate in vivo cancer models. In addition, it will also define the effects of a NA-deficient diet w/ or w/o antibiotics as a means to sensitize ovarian cancer xenografts to NAMPT inhibitors and chemotherapeutics. ESRs 1,2,3,4,5,6,7,9,10,13,14.

The research WPs are completed by additional WPs aimed at ensuring the successful recruitment of students (WP6), training (WP7) and management (WP8) of the project by establishing effective communication among partners and management of intellectual property rights and patent applications. Finally, WP9 comprises outreach and includes activities to disseminate the scientific and training results of INTEGRATA to the scientific community and to the general public.

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