Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data
Open accessAbstract
Purpose Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials.Methods A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy.Results Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials.Conclusions Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In clinical trials, NAMPT inhibitors used as single agents have not caused tumor remission.
“In clinical trials, use of these inhibitors as single agents has not caused tumor remission (von Heideman et al., 2010), but additional studies may uncover how best to safely use these drugs for patient benefit.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as von Heideman et al., 2010
Cites
Tumor cell metabolism: cancer's Achilles' heel
Kroemer, G., & Pouyssegur, J. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.05.005 · Cited by 2,337 · see citing works
Chemotherapy and the war on cancer
Chabner, B. A., & Roberts, T. G. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1529 · Cited by 2,152 · see citing works
Hypoxia, HIF1 and glucose metabolism in the solid tumour
Denko, N. C. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2468 · Cited by 1,707 · see citing works
Hasmann, M., & Schemainda, I. (2003) · PubMed · Cited by 618 · see citing works
Holen, K. D., Saltz, L. B., Hollywood, E. M., Burk, K., & Hanauske, A.-R. (2007) · Investigational New Drugs · doi:10.1007/s10637-007-9083-2 · Cited by 303 · see citing works
Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents
Khan, J., Tao, X., & Tong, L. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1105 · Cited by 274 · see citing works
The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies
Nahimana, A., Attinger, A., Aubry, D., Greaney, P., Ireson, C., Thougaard, A. V., Tjørnelund, J., Dawson, K. M., Dupuis, M., & Duchosal, M. A. (2009) · Blood · doi:10.1182/blood-2008-08-173369 · Cited by 190 · see citing works
Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery
Khan, J., Forouhar, F., Tao, X., & Tong, L. (2007) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.11.5.695 · Cited by 174 · see citing works
Anticancer agent CHS-828 inhibits cellular synthesis of NAD
Olesen, U. H., Christensen, M. K., Björkling, F., Jäättelä, M., Jensen, P. B., Sehested, M., & Nielsen, S. J. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.01.019 · Cited by 122 · see citing works
A Phase I study of CHS 828 in patients with solid tumor malignancy.
Hovstadius, P., Larsson, R. L., Jonsson, E., Skov, T., Kissmeyer, A., Krasilnikoff, K., Bergh, J. C. S., Karlsson, M. O., Lönnebo, A., & Ahlgren, J. (2002) · PubMed · Cited by 119 · see citing works
Self-citationRavaud, A., Cerny, T., Terret, C., Wanders, J., Bui, B., Hess, D., Droz, J., Fumoleau, P., & Twelves, C. J. (2005) · European Journal of Cancer · doi:10.1016/j.ejca.2004.12.023 · Cited by 105 · see citing works
Overview of the clinical efficacy of investigational anticancer drugs
Nygren, P., & Larsson, R. L. (2003) · Journal of Internal Medicine · doi:10.1046/j.1365-2796.2003.01098.x · Cited by 79 · see citing works
Self-citationPogrebniak, A., Schemainda, I., Azzam, K., Pelka‐Fleischer, R., Nuessler, V., & Hasmann, M. (2006) · PubMed · Cited by 61 · see citing works
A close look at NAD biosynthesis
Mattevi, A. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb0706-563 · Cited by 29 · see citing works
Activity of CHS 828 in primary cultures of human hematological and solid tumors in vitro
Åleskog, A., Hassan, S. B., Hovstadius, P., Kristensen, J., Höglund, M., Tholander, B., Binderup, L., Larsson, R. L., & Jonsson, E. (2001) · Anti-Cancer Drugs · doi:10.1097/00001813-200111000-00005 · Cited by 23 · see citing works
Self-citationIn vivo activity of CHS 828 on hollow-fibre cultures of primary human tumour cells from patients
Jonsson, E., Friberg, L. E., Karlsson, M. O., et al. (2001) · Cancer Letters · doi:10.1016/s0304-3835(00)00661-3 · Cited by 22 · see citing works
Pishvaian, M. J., Marshall, J. L., Hwang, J. J., Malik, S., He, A. R., Deeken, J. F., Kelso, C. B., Cotarla, I., & Berger, M. S. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.15_suppl.3581 · Cited by 21 · see citing works
A phase 1 trial of GMX1777: An inhibitor of nicotinamide phosphoribosyl transferase (NAMPRT)
Pishvaian, M. J., Marshall, J. L., Hwang, J., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.26.15_suppl.14568 · Cited by 13 · see citing works
In vitro activity of the novel cytotoxic agent CHS 828 in childhood acute leukemia
Frost, B., Lönnerholm, G., Nygren, P., Larsson, R. L., & Lindhagen, E. (2002) · Anti-Cancer Drugs · doi:10.1097/00001813-200208000-00008 · Cited by 12 · see citing works
Self-citationEkelund, S., Persson, I. A. ‐., Larsson, R. L., et al. (2002) · Chemotherapy · doi:10.1159/000063874 · Cited by 4 · see citing works
Self-citationMetabolic effects of the cytotoxic guanidino-containing drug CHS 828 in human U-937 lymphoma cells.
Ekelund, S., Larsson, R. L., & Nygren, P. (2002) · PubMed · Cited by 3 · see citing works
Self-citationRoulston, A., Watson, M. H., Bernier, C., Chan, H. H. L., Gratton, M., Jang, A., Koch, E. M., Lavoie, M., Paquette, D., Mitchell, M. W., et al. (2007) · Molecular Cancer Therapeutics · Cited by 3 · see citing works
Watson, M., Roulston, A., Chan, H. H. L., et al. (2008) · European Journal of Cancer Supplements · doi:10.1016/s1359-6349(08)72404-2 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971 · see citing works
Physiological and pathophysiological roles of NAMPT and NAD metabolism.
Garten, A., Schuster, S., Penke, M., Gorski, T., de Giorgis, T., & Kiess, W. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.117 · Cited by 708 · see citing works
Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer
Sampath, D., Zabka, T. S., Misner, D. L., O’Brien, T., & Dragovich, P. S. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.02.004 · Cited by 258 · see citing works
Grozio, A., Sociali, G., Sturla, L., Caffa, I., Soncini, D., Salis, A., Raffaelli, N., De Flora, A., Nencioni, A., & Bruzzone, S. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.470435 · Cited by 158 · see citing works
Piacente, F., Caffa, I., Ravera, S., Sociali, G., Passalacqua, M., Vellone, V. G., Becherini, P., Reverberi, D., Monacelli, F., Ballestrero, A., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-3079 · Cited by 113 · see citing works
- Authors
- von Heideman, A., Berglund, Å., Larsson, R., & Nygren, P.
- Affiliations
- Uppsala University (SE)
- Corresponding author
- Nygren, Peter
- Venue
- Cancer Chemotherapy and Pharmacology
- Published
- 2009-09-30
- Volume
- 65
- Issue
- 6
- Pages
- 1165-1172
- ISSN
- 0344-5704 (ISSN-L)
- 1432-0843
- OpenAlex
- W2026814500
- Cited by
- 201
- References
- 23
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 17 · 2023: 18 · 2022: 14 · 2021: 13 · 2020: 15 · 2019: 10 · 2018: 13 · 2017: 24 · 2016: 5 · 2015: 15 · 2014: 7 · 2013: 8 · 2012: 7
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- green
- hal.science
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Cancer Chemotherapy and Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- NAD+ depletion, FK866, gastrointestinal toxicity, thrombocytopenia, hyperuricemia, hypokalemia, advanced solid tumors, antitumor efficacy
- MeSH terms
- Acrylamides, Aged, Cyanides, Dose-Response Relationship, Drug, Drug Administration Schedule, Fatigue, Female, Guanidines, Humans, Male, Middle Aged, NAD, Nausea, Neoplasms, Piperidines, Thrombocytopenia, Vomiting, Meta-Analysis as Topic, Treatment Outcome, Clinical Trials, Phase I as Topic, Nicotinamide Phosphoribosyltransferase
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
