RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: Phase I trial to study the effectiveness of CHS 828 in treating patients who have solid tumors.

Start Date01 Apr 1999

Sponsor / Collaborator

Eortc

100 Clinical Results associated with CHS-828

100 Translational Medicine associated with CHS-828

100 Patents (Medical) associated with CHS-828

Literatures (Medical) associated with CHS-828

01 Oct 2024·Biochemistry (Moscow)

Glioblastoma Sensitization to Therapeutic Effects by Glutamine Deprivation Depends on Cellular Phenotype and Metabolism

Article

Author: Antipova, Nadezhda V ; Gasparian, Marine E. ; Isakova, Alina A ; Antipova, Nadezhda V. ; Mozherov, Artem M ; Krasnov, Kirill S. ; Fadeev, Roman S. ; Gasparian, Marine E ; Yagolovich, Anne V. ; Krasnov, Kirill S ; Mazur, Diana V ; Mozherov, Artem M. ; Druzhkova, Irina N. ; Yagolovich, Anne V ; Fadeev, Roman S ; Druzhkova, Irina N ; Isakova, Alina A. ; Mazur, Diana V.

Glutamine plays an important role in tumor metabolism. It is known that the core region of solid tumors is deprived of glutamine, which affects tumor growth and spread. Here we investigated the effect of glutamine deprivation on cellular metabolism and sensitivity of human glioblastoma cells U87MG and T98G to drugs of various origin: alkylating cytostatic agent temozolomide; cytokine TRAIL DR5-B - agonist of the DR5 receptor; and GMX1778 - a targeted inhibitor of the enzyme nicotinamide phosphoribosyltransferase (NAMPT), limiting NAD biosynthesis. Bioinformatics analysis of the cell transcriptomes showed that U87MG cells have a more differentiated phenotype than T98G, and also differ in the expression profile of the genes associated with glutamine metabolism. Upon glutamine deprivation, growth rate of the U87MG and T98G cells decreased. Analysis of cellular metabolism by FLIM microscopy of NADH as well as assessment of lactate content in the medium showed that glutamine deprivation shifted metabolic status of the U87MG cells towards glycolysis. This was accompanied by the increase in expression of the stemness marker CD133, which collectively could indicate de-differentiation of these cells. At the same time, we observed increase in both expression of the DR5 receptor and sensitivity of the U87MG cells to DR5-B. On the contrary, glutamine deprivation of T98G cells induced metabolic shift towards oxidative phosphorylation, decrease in the DR5 expression and resistance to DR5-B. The effects of NAMPT inhibition also differed between the two cell lines and were opposite to the effects of DR5-B: upon glutamine deprivation, U87MG cells acquired resistance, while T98G cells were sensitized to GMX1778. Thus, phenotypic and metabolic differences between the two human glioblastoma cell lines caused divergent metabolic changes and contrasting responses to different targeted drugs during glutamine deprivation. These data should be considered when developing treatment strategies for glioblastoma via drug-mediated deprivation of amino acids, as well as when exploring novel therapeutic targets.

01 Aug 2024·Molecular Cancer Therapeutics

Exploiting Metabolic Defects in Glioma with Nanoparticle-Encapsulated NAMPT Inhibitors

Article

Author: Noronha, Katelyn J. ; Saltzman, W.M. ; Bindra, Ranjit S. ; Suh, Hee-Won ; Sundaram, Ranjini K. ; Murray, Matthew A. ; Wang, Yazhe ; Friedman, Anna P. ; Paradkar, Sateja ; Brenner, Charles

AbstractThe treatment of primary central nervous system tumors is challenging due to the blood–brain barrier and complex mutational profiles, which is associated with low survival rates. However, recent studies have identified common mutations in gliomas [isocitrate dehydrogenase (IDH)-wild-type and mutant, WHO grades II–IV; with grade IV tumors referred to as glioblastomas (GBM)]. These mutations drive epigenetic changes, leading to promoter methylation at the nicotinic acid phosphoribosyl transferase (NAPRT) gene locus, which encodes an enzyme involved in generating NAD+. Importantly, NAPRT silencing introduces a therapeutic vulnerability to inhibitors targeting another NAD+ biogenesis enzyme, nicotinamide phosphoribosyl transferase (NAMPT), rationalizing a treatment for these malignancies. Multiple systemically administered NAMPT inhibitors (NAMPTi) have been developed and tested in clinical trials, but dose-limiting toxicities—including bone marrow suppression and retinal toxicity—have limited their efficacy. Here, we report a novel approach for the treatment of NAPRT-silenced GBMs using nanoparticle (NP)-encapsulated NAMPTis administered by convection-enhanced delivery (CED). We demonstrate that GMX1778 (a NAMPTi) can be formulated in degradable polymer NPs with retention of potency for NAMPT inhibition and anticancer activity in vitro, plus sustained drug release in vitro and in vivo. Direct injection of these drugs via CED into the brain is associated with reduced retinal toxicity compared with systemic administration. Finally, we show that CED of NP-encapsulated GMX1778 to NAPRT-silenced intracranial GBM xenografts in mice exhibit significant tumor growth delay and extends survival. These data support an approach to treat gliomas harboring defects in NAD+ metabolism using CED of NP-encapsulated NAMPTis to greatly improve the therapeutic index and treatment efficacy for this class of drugs.

04 Oct 2023·Cancer research communications

Combined Targeting of NAD Biosynthesis and the NAD-dependent Transcription Factor C-terminal Binding Protein as a Promising Novel Therapy for Pancreatic Cancer.

Article

Author: Ellis, Keith C ; Dcona, M Michael ; Singh, Sahib J ; Grossman, Steven R ; West, Jacqueline L ; Chougoni, Kranthi Kumar ; Dcona, Diana T

Cancer therapies targeting metabolic derangements unique to cancer cells are emerging as a key strategy to address refractory solid tumors such as pancreatic ductal adenocarcinomas (PDAC) that exhibit resistance to extreme nutrient deprivation in the tumor microenvironment. Nicotinamide adenine dinucleotide (NAD) participates in multiple metabolic pathways and nicotinamide phosphoribosyl transferase (NAMPT) is one of the key intracellular enzymes that facilitate the synthesis of NAD. C-terminal binding proteins 1 and 2 (CtBP) are paralogous NAD-dependent oncogenic transcription factors and dehydrogenases that nucleate an epigenetic complex regulating a cohort of genes responsible for cancer proliferation and metastasis. As adequate intracellular NAD is required for CtBP to oligomerize and execute its oncogenic transcriptional coregulatory activities, we hypothesized that NAD depletion would synergize with CtBP inhibition, improving cell inhibitory efficacy. Indeed, depletion of cellular NAD via the NAMPT inhibitor GMX1778 enhanced growth inhibition induced by either RNAi-mediated CtBP1/2 knockdown or the CtBP dehydrogenase inhibitor 4-chlorophenyl-2-hydroxyimino propanoic acid as much as 10-fold in PDAC cells, while untransformed pancreatic ductal cells were unaffected. The growth inhibitory effects of the NAMPT/CtBP inhibitor combination correlated pharmacodynamically with on-target disruption of CtBP1/2 dimerization, CtBP2 interaction with the CoREST epigenetic regulator, and transcriptional activation of the oncogenic target gene TIAM1. Moreover, this same therapeutic combination strongly attenuated growth of PDAC cell line xenografts in immunodeficient mice, with no observable toxicity. Collectively, our data demonstrate that targeting CtBP in combination with NAD depletion represents a promising therapeutic strategy for PDAC.SIGNIFICANCEEffective precision therapies are lacking in PDAC. We demonstrate that simultaneous inhibition of NAD metabolism and the oncoprotein CtBP is potently effective at blocking growth of both PDAC cells in culture and human PDAC-derived tumors in mice and should be explored further as a potential therapy for patients with PDAC.

100 Deals associated with CHS-828

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 2	AT	Eortc	01 Apr 1999
Solid tumor	Phase 2	CH	Eortc	01 Apr 1999
Solid tumor	Phase 2	NL	Eortc	01 Apr 1999
Solid tumor	Phase 2	FR	Eortc	01 Apr 1999
Solid tumor	Phase 2	NO	Eortc	01 Apr 1999
Solid tumor	Phase 2	GB	Eortc	01 Apr 1999
Solid tumor	Phase 2	BE	Eortc	01 Apr 1999
Lymphoma	Phase 2	-	Teva Pharmaceutical Industries Ltd.	-
Lymphoma	Phase 2	-	Leo Pharma, Inc.	-
Neoplasms	Phase 2	-	LEO Pharma A/S	-

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