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Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy
- Source :
- Oncotarget
- Publication Year :
- 2017
- Publisher :
- Impact Journals, LLC, 2017.
-
Abstract
- Tumor cells are particularly dependent on NAD+ due to higher rates of metabolism, DNA synthesis and repair. Nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) inhibit NAD+ biosynthesis and represent promising new anti-cancer agents. However, clinical efficacy has been limited by toxicities demonstrating the need for drug combinations to broaden the therapeutic index. One potential combination involves niacin/NAMPTi co-administration. Niacin can rescue NAD+ biosynthesis through a parallel pathway that depends on nicotinic acid phosphoribosyltransferase (NAPRT) expression. Most normal tissues express NAPRT while a significant proportion of malignant cells do not, providing a possible selection marker for patients to achieve NAMPTi efficacy while minimizing toxicities. Here we identify and validate a novel highly NAPRT-specific monoclonal antibody (3C6D2) that detects functional NAPRT in paraffin embedded tissue sections by immunohistochemistry (IHC). NAPRT detection by 3C6D2 coincides with the ability of niacin to rescue cells from NAMPTi induced cytotoxicity in cell lines and animal xenograft models. 3C6D2 binds to an epitope that is unique to NAPRT among phosphoribosyltransferases. In a series of primary tumor samples from lung and brain cancer patients, we demonstrate that >70 % of human small cell lung carcinomas, glioblastomas and oligodendrogliomas lack NAPRT identifying them as potentially suitable indications for the NAMPT/niacin combination.
- Subjects :
- 0301 basic medicine
medicine.drug_class
Cell
Nicotinamide phosphoribosyltransferase
Pharmacology
Biology
Monoclonal antibody
NAMPT
NAPRT
Epitope
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
NAD+ biosynthesis
medicine
Cytotoxicity
NAMPT inhibitor
medicine.disease
Primary tumor
3. Good health
030104 developmental biology
medicine.anatomical_structure
Oncology
chemistry
030220 oncology & carcinogenesis
biomarker
NAD+ kinase
Niacin
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....3cc4d0aa6d82b2aefdf53cf22fa9f32e
- Full Text :
- https://doi.org/10.18632/oncotarget.20840