Combination Drug Scheduling Defines a “Window of Opportunity” for Chemopotentiation of Gemcitabine by an Orally Bioavailable, Selective ChK1 Inhibitor, GNE-900

Blackwood, Elizabeth M.; Epler, Jennifer; Yen, Ivana; Flagella, Michael; O’Brien, Tom; Evangelista, Marie; Schmidt, Stephen D.; Xiao, Yang; Choi, Jonathan; Kowanetz, Kaska; Ramiscal, Judi; Wong, Kenton; Jakubiak, Diana; Yee, Sharon; Cain, Gary; Gazzard, Lewis; Williams, Karen; Halladay, Jason; Jackson, Peter K.; Malek, Shiva

doi:10.1158/1535-7163.mct-12-1218

Cited by 33 publications

(32 citation statements)

References 46 publications

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“…Combination therapy with BPTES-NPs and gemcitabine, which is the current standard adjuvant chemotherapy after surgery for PDAC, using a previously reported dosing regimen for gemcitabine (25,26), did not result in significant tumor reduction compared with treatment with gemcitabine (P = 0.058) or BPTESNPs (P = 0.46) alone (Fig. S7A).…”

Section: Pdac Cells That Survive Bptes-np Treatment Are Reliant On Glmentioning

confidence: 87%

“…Tumors were excised from the pancreas, weighed, and measured using digital calipers, and tumor volume (V) was calculated by the formula V = (largest tumor dimension) × (smallest tumor dimension) 2 × 0.52 (39,(49)(50)(51). Once a tumor volume of 50 mm 3 was reached (4 wk postimplantation), mice were treated with 12.5 mg/kg BPTES by intraperitoneal injection, 200 mg/kg CB-839 twice per d by oral gavage, 54 mg/kg BPTES-NPs (1.2 mg BPTES in 100 μL nanoparticles per mouse) by intravenous injection, blank-NPs (100 μL per mouse) by intravenous injection, 25 mg/kg gemcitabine intraperitoneally (25,26), 250 mg/kg metformin intraperitoneally daily (32,33), or a combination of BPTES-NPs with gemcitabine or metformin. BPTES-NPs were injected once every 3 d for a total of six injections over 16 d.…”

Section: Methodsmentioning

confidence: 99%

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Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Elgogary

Poore

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

192

159

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Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.pancreatic ductal adenocarcinoma | glutaminolysis | glucose metabolism | KRAS mutation | intratumoral hypoxia P atients with pancreatic ductal adenocarcinoma (PDAC) have among the highest fatality rates of all cancers (1). Pancreatic cancer is predicted to become the second-leading cause of cancer death in the United States by the year 2030 (2). Over 90% of PDACs display mutations in oncogenic KRAS (Kirsten rat sarcoma viral oncogene homolog) (3, 4), a known regulator of glutamine metabolism that can render cancer cells dependent on glutamine for survival and proliferation (5, 6)-a state known as "glutamine addiction" (7, 8)-suggesting that dependency on glutamine could be exploited to develop new therapies for KRAS-mutated PDAC. The first step of glutamine metabolism is the conversion of glutamine to glutamate and ammonia, which is catalyzed by glutaminase (GLS). Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), which is an allosteric, time-dependent (9), and specific inhibitor of GLS1, exhibits unique binding at the oligomerization interface of the glutaminase tetramer (10, 11). Although BPTES is more selective than other prototype glutaminase inhibitors, such as 6-diazo-5-oxo-L-norleucine (12) or ebselen (9), and can effectively inhibit GLS1 (13) and tumor growth (13-15), poor solubility (0.144 μg/mL) (16) has limited its clinical development. Recently, CB-839 (17) was tested in a phase I clinical trial. Abnormal liver and kidney function tests, lymphop...

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Section: Pdac Cells That Survive Bptes-np Treatment Are Reliant On Glmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Elgogary

Poore

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

192

159

View full text Add to dashboard Cite

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“…Recently the interest in the use of CHK1 inhibitors in cancer therapy has grown dramatically (Bennett et al, 2012;Blackwood et al, 2013;Carrassa and Damia, 2011;Cole et al, 2011). CHK1 kinase has been reported not only to regulate cell cycle progression from S to M phase following disruption of DNA replication or some types of DNA lesion but also play a role in S phase procession even in undisturbed cells (Petermann and Helleday, 2010; Chapter 3 The Response of Normal Urothelial Cells to CHK1 Inhibitors 75 Petermann et al, 2006).…”

Section: Qpcrmentioning

confidence: 99%

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

2014

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“…S2A), which has a similar in vitro profile but has improved pharmacokinetic properties and supports efficient chemopotentiation in vivo (29). GNE-900 can be effectively combined with gemcitabine or SN38 in HT29 cells and with temozolomide in A2058 cells (Supplementary Fig.…”

Section: Robust Chemopotentiation In Vitro Translates Into Enhanced Ementioning

confidence: 99%

Identification of Preferred Chemotherapeutics for Combining with a CHK1 Inhibitor

Xiao¹,

Ramiscal²,

Kowanetz³

et al. 2013

Molecular Cancer Therapeutics

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Here we report that GNE-783, a novel checkpoint kinase-1 (CHK1) inhibitor, enhances the activity of gemcitabine by disabling the S-and G 2 cell-cycle checkpoints following DNA damage. Using a focused library of 51 DNA-damaging agents, we undertook a systematic screen using three different cell lines to determine which chemotherapeutics have their activity enhanced when combined with GNE-783. We found that GNE-783 was most effective at enhancing activity of antimetabolite-based DNA-damaging agents; however, there was a surprisingly wide range of activity within each class of agents. We, next, selected six different therapeutic agents and screened these in combination with GNE-783 across a panel of cell lines. This revealed a preference for enhanced chemopotentiation of select agents within tumor types, as, for instance, GNE-783 preferentially enhanced the activity of temozolomide only in melanoma cell lines. Additionally, although p53 mutant status was important for the overall response to combinations with some agents; our data indicate that this alone was insufficient to predict synergy. We finally compared the ability of a structurally related CHK1 inhibitor, GNE-900, to enhance the in vivo activity of gemcitabine, CPT-11, and temozolomide in xenograft models. GNE-900 significantly enhanced activity of only gemcitabine in vivo, suggesting that strong chemopotentiation in vitro can translate into chemopotentiation in vivo. In conclusion, our results show that selection of an appropriate agent to combine with a CHK1 inhibitor needs to be carefully evaluated in the context of the genetic background and tumor type in which it will be used. Mol Cancer Ther; 12(11); 2285-95. Ó2013 AACR.

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Combination Drug Scheduling Defines a “Window of Opportunity” for Chemopotentiation of Gemcitabine by an Orally Bioavailable, Selective ChK1 Inhibitor, GNE-900

Cited by 33 publications

References 46 publications

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

Identification of Preferred Chemotherapeutics for Combining with a CHK1 Inhibitor

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