An open-label phase I dose-finding study of APR-246 in hematological malignancies

Deneberg, Stefan; Cherif, Honar; Lazarevic, Vladimir; Andersson, Per; Euler, Mikael von; Juliusson, Gunnar; Lehmann, Sören

doi:10.1038/bcj.2016.60

Cited by 77 publications

(56 citation statements)

References 5 publications

(6 reference statements)

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“…On the basis of these findings, we propose that other system x C − inhibitors such as erastin analogs33 and sorafenib34, should also effectively synergize with APR-246. Indeed, in a recently completed Phase I trial of APR-246 in patients with haematological malignancies, it was noted that the addition of APR-246 to a patient receiving concurrent sorafenib resulted in complete remission of their acute myeloid leukaemia35. This provides proof-of-concept that combining system x C − inhibitors with APR-246 is clinically translatable and may potentially have significant therapeutic efficacy against mut-p53 malignancies.…”

Section: Discussionmentioning

confidence: 96%

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: 96%

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

et al. 2017

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“…A number of in vitro , ex vivo and in silico approaches have been applied to identify small molecules that reactivate mutant p53 by restoring wild-type p53 conformation 10, 30 . The mutant p53-targeting compound APR-246 has been tested in a phase I/IIa clinical trial in patients with hematological malignancies or prostate cancer 18, 31 , and is currently being tested in a phase II clinical trial in patients with high-grade serous (HGS) ovarian cancer (see clincaltrials.gov). Both PRIMA-1 and APR-246 are converted to methylene quinuclidinone (MQ) 19 .…”

Section: Discussionmentioning

confidence: 99%

APR-246 reactivates mutant p53 by targeting cysteines 124 and 277

Zhang

Bykov

Wiman

et al. 2017

Preprint

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“…Although the thermodynamic requirements for achieving this seem daunting, structural studies and in silico predictions have propelled multiple strategies that supply proof-of-principle for this approach, including peptides and small molecules that stabilize unstructured mutants (Boeckler et al, 2008; Friedler et al, 2002; Yu et al, 2012). One drug, APR-246, which is purported to reactivate mutant p53 but also has off target effects, is currently in clinical trials (NCT03072043, NCT02999893)(Deneberg et al, 2016). Other agents that directly stabilize the p53 DNA binding domain show promise in preclinical studies (Cheok and Lane, 2017).…”

Section: Harnessing the P53 Networkmentioning

confidence: 99%

Putting p53 in Context

Kastenhuber

Lowe

2017

Cell

1,511

1,366

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TP53 is the most frequently mutated gene in human cancer. Functionally, p53 is activated by a host of stress stimuli and, in turn, governs an exquisitely complex anti-proliferative transcriptional program that touches upon a bewildering array of biological responses. Despite the many unveiled facets of the p53 network, a clear appreciation of how and in what contexts p53 exerts its diverse effects remains unclear. How can we interpret p53’s disparate activities and the consequences of its dysfunction to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes, and how might we restore its tumor suppressive activities in cancer?

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An open-label phase I dose-finding study of APR-246 in hematological malignancies

Cited by 77 publications

References 5 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

APR-246 reactivates mutant p53 by targeting cysteines 124 and 277

Putting p53 in Context

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