INTEGRATA — Integrating chemical and biological approaches to target NAD production and signaling in cancer

Results in brief

Integrating chemical and biological approaches to target NAD production and signaling in cancer

INTEGRATA aimed at providing a group of early stage researchers (ESRs) with a highly interdisciplinary and intersectoral training in drug discovery, focusing specifically on NAD production and on NAD/nucleotide signaling as targets for the development of new cancer therapeutics1. This given that interrupting NAD production, or specifically targeting enzymes from the NAD/nucleotide signaling apparatus, is considered a very appealing and novel approach in oncology and one of the most promising areas of investigation for the development of new drugs2. 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.

Data: CORDIS, © European Union

Project objective

Deregulated nicotinamide adenine dinucleotide (NAD) biosynthesis and signaling underlies many aspects of carcinogenesis. NAD biosynthetic enzymes, such as nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT), are commonly upregulated in cancer cells, where they fuel increased metabolic demands and downstream enzymes involved in DNA repair and in the promotion of cell growth, cell motility, de-differentiation and immune escape. In addition, NAD-producing enzymes, such as NAMPT, moonlight in the extracellular space, exerting strongly pro-oncogenic, autocrine and paracrine effects. Many of these roles of NAD-producing and NAD-utilizing enzymes appear to be shared between solid and haematological cancers. Thus, agents targeting NAD production or signaling are expected to have broad applicability. INTEGRATA will: 1. develop new NAD biosynthesis and NAD/nucleotide signaling inhibitors; 2. assess pharmacology and toxicity of the new therapeutics in preclinical models; 3. achieve the proof-of-concept of activity of the newly generated agents in relevant in vivo cancer models. INTEGRATA will train 14 PhD students in an overarching, interdisciplinary training programme that will include training-by-research, joint courses of technical, scientific, and transferrable skills, active participation to public scientific events, and an intense intersectoral networking exchange plan. The INTEGRATA Consortium encompasses academic institutions, research centres, and SMEs/biotech pharma, all with proven experience in higher education and training, and geared with state-of-the-art scientific and technical expertise and infrastructures.

Original text from CORDIS.

Participants

UNIVERSITA DEGLI STUDI DI GENOVA · GENOVACoordinatorItaly
CENTRE HOSPITALIER UNIVERSITAIRE VAUDOIS · LausanneSwitzerland
HEIDELBERG PHARMA RESEARCH GMBH · LADENBURGGermany
INNOVAMOL SRL · ModenaItaly
INNOVATION ACTA SRL · SIENAItaly
NOVIMMUNE SA · Plan Les Ouates GeneveSwitzerland
THE UNIVERSITY OF SHEFFIELD · SHEFFIELDUnited Kingdom
UNIVERSIDAD DE SEVILLA · SevillaSpain
UNIVERSITA DEGLI STUDI DI TORINO · TorinoItaly
UNIVERSITA DEGLI STUDI DI TRENTO · TrentoItaly
UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF · HamburgGermany
UNIVERSITATSKLINIKUM BONN · BonnGermany
UNIVERSITE DE GENEVE · GeneveSwitzerland
UNIVERSITE DE LAUSANNE · LAUSANNESwitzerland
UNIVERSITE DE MONTPELLIER · MontpellierFrance

INTEGRATA · Integrating chemical and biological approaches to target NAD production and signaling in cancer

Results in brief

Integrating chemical and biological approaches to target NAD production and signaling in cancer

Project objective

Participants

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