Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205)

Shitara, Kohei; Doi, Toshihiko; Nagano, Osamu; Imamura, Chiyo K.; Ozeki, Takeshi; Ishii, Yuya; Tsuchihashi, Kazufumi; Takahashi, Shunji; Nakajima, Takako Eguchi; Hironaka, Shuichi; Fukutani, Miki; Hasegawa, Hiromi; Nomura, Shosaku; Sato, Akihiro; Einaga, Yasuaki; Kuwata, Takeshi; Saya, Hideyuki; Ohtsu, Atsushi

doi:10.1007/s10120-016-0610-8

Cited by 86 publications

(79 citation statements)

References 19 publications

(38 reference statements)

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“…Moreover, we demonstrate that SLC7A11 expression is a reliable predictive biomarker for tumour response to these therapies. This, and the fact that APR-246 and system x C − inhibitors have been safely trialled in humans3637, should facilitate rapid translation of our findings to improve treatment outcomes for patients with mut-p53 cancers.…”

Section: Discussionmentioning

confidence: 87%

Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation

et al. 2017

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TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system xC−, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System xC− inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that SLC7A11 expression is a novel and robust predictive biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system xC− antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant-p53 protein by inhibiting the SLC7A11–glutathione axis.

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Section: Discussionmentioning

confidence: 87%

Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation

et al. 2017

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“…Recent studies have reported the association of the cystine transporter xCT with cisplatin resistance in bladder cancer [13], and its potential prognostic role in hepatocellular carcinoma [52]. Drug repurposing of sulfasalazine, a xCT inhibitor, is currently in clinical testing [53]. Taken together, our findings suggest a role for xCT in the resistant phenotype and provide not only an additional potential predictive marker to be incorporated in a composite molecular signature for cisplatin resistance, but also a rational target for therapeutic interventions in patients with bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts

et al. 2016

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PurposeEffective systemic therapeutic options are limited for bladder cancer. In this preclinical study we tested whether bladder cancer gene alterations may be predictive of treatment response.Experimental designWe performed genomic profiling of two bladder cancer patient derived tumor xenografts (PDX). We optimized the exome sequence analysis method to overcome the mouse genome interference.ResultsWe identified a number of somatic mutations, mostly shared by the primary tumors and PDX. In particular, BLCAb001, which is less responsive to cisplatin than BLCAb002, carried non-sense mutations in several genes associated with cisplatin resistance, including MLH1, BRCA2, and CASP8. Furthermore, RNA-Seq analysis revealed the overexpression of cisplatin resistance associated genes such as SLC7A11, TLE4, and IL1A in BLCAb001. Two different PIK3CA mutations, E542K and E545K, were identified in BLCAb001 and BLCAb002, respectively. Thus, we tested whether the genomic profiling was predictive of response to a dual PI3K/mTOR targeting agent, LY3023414. Despite harboring similar PIK3CA mutations, BLCAb001 and BLCAb002 exhibited differential response, both in vitro and in vivo. Sustained target modulation was observed in the sensitive model BLCAb002 but not in BLCAb001, as well as decreased autophagy. Interestingly, computational modelling of mutant structures and affinity binding to PI3K revealed that E542K mutation was associated with weaker drug binding than E545K.ConclusionsOur results suggest that the presence of activating PIK3CA mutations may not necessarily predict in vivo treatment response to PI3K targeted therapies, while specific gene alterations may be predictive for cisplatin response in bladder cancer models and, potentially, in patients as well.

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“…Accordingly, a dose-escalation clinical study for targeting CD44v + CSCs by the oral administration of sulfasalazine (SSZ, an inhibitor of xCT) in patients with AGC was conducted. The results showed that SSZ was safe and efficacious in patients, some of whom exhibited decreased levels of CD44v + cells and glutathione in their biopsy samples (Shitara et al , 2016). Moreover, several types of mAbs, such as bivatuzumab mertansine (BIMI1) and RO5429083, have been designed to fight CD44 + cells.…”

Section: Clinical Targeted Therapymentioning

confidence: 99%

A unified model of the hierarchical and stochastic theories of gastric cancer

et al. 2017

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Gastric cancer (GC) is a life-threatening disease worldwide. Despite remarkable advances in treatments for GC, it is still fatal to many patients due to cancer progression, recurrence and metastasis. Regarding the development of novel therapeutic techniques, many studies have focused on the biological mechanisms that initiate tumours and cause treatment resistance. Tumours have traditionally been considered to result from somatic mutations, either via clonal evolution or through a stochastic model. However, emerging evidence has characterised tumours using a hierarchical organisational structure, with cancer stem cells (CSCs) at the apex. Both stochastic and hierarchical models are reasonable systems that have been hypothesised to describe tumour heterogeneity. Although each model alone inadequately explains tumour diversity, the two models can be integrated to provide a more comprehensive explanation. In this review, we discuss existing evidence supporting a unified model of gastric CSCs, including the regulatory mechanisms of this unified model in addition to the current status of stemness-related targeted therapy in GC patients.

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Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205)

Abstract: This is the first study of SSZ as an xCT inhibitor for targeting CSCs. Reduction of the levels of CD44v-positive cells and GSH was observed in some patients, consistent with the mode of action of SSZ in CSCs.

Cited by 86 publications

References 19 publications

Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation

Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation

Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts

A unified model of the hierarchical and stochastic theories of gastric cancer

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