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Poster display session

4562 - Identification of an RNF43 mutated gastric cancer patient population with potential sensitivity to porcupine inhibitor RXC004 and development of a complimentary ctDNA liquid biopsy assay for patient screening.

Date

09 Sep 2017

Session

Poster display session

Topics

Translational Research;  Gastric Cancer

Presenters

Matilda Bingham

Citation

Annals of Oncology (2017) 28 (suppl_5): v209-v268. 10.1093/annonc/mdx369

Authors

M. Bingham1, I. Bhamra1, R. Armer1, B. Thompson1, S. Woodcock1, A. Thomason1, C. Phillips1, H. McKeever1, J. Bradford2, B. Chaffey3, L. Little3, G. Clack4

Author affiliations

  • 1 Oncology And Immunology, Redx Pharma Plc, SK10 4TG - Manchester/GB
  • 2 Department Of Oncology And Metabolism, University of Sheffield, S10 - Sheffield/GB
  • 3 Bioscience Building, NewGene Ltd, NE1 4EP - Newcastle-Upon-Tyne/GB
  • 4 Faculty Of Medicine, University of Sheffield, S10 2TN - Sheffield/GB
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Resources

Abstract 4562

Background

RXC004 is a small molecule PORCN inhibitor, entering first-in-human trials in 2017. PORCN inhibition has been shown to have potential for the treatment of molecularly selected pancreatic and colorectal cancers, as well as the ability to synergise with anti-PD1 checkpoint inhibition. The aim of this study was to identify additional patient segments predicted to benefit from treatment with a PORCN inhibitor.

Methods

Mutation incidence for the WNT pathway gene RNF43 was analysed in 674 gastric cancer samples. RXC004 was profiled in gastric, pancreatic and biliary PDX models carrying the RNF43 mutations and growth inhibition was correlated with WNT pathway inhibition. To support the clinical trial a patient selection strategy, based on detection of RNF43 mutations from a liquid biopsy, using MassArray mass spectrometry technology is described.

Results

Bioinformatics data-mining of TCGA identified that the prevalence of RNF43 mutation in gastric cancer is 14-16%. A specific hot spot mutation (G659Vfs*41) has been identified, which accounts for ∼70% of the RNF43 mutations. Profiling of RXC004 in RNF43 mouse models of gastric and pancreatic cancer shows the potential for monotherapy efficacy. In order to translate our findings to the clinic, we developed an assay suitable for detection of RNF43 mutations in circulating tumour DNA (ctDNA) from patient plasma. Multiplexed assays for RNF43 mutations, including the G659Vfs*41 hotspot, have been developed using MassArray technology. By converting to UltraSeek MassArray methodology we are targetting a sensitivity of 0.1% allelic frequency and specificity >99% in patient ctDNA.

Conclusions

RXC004 is entering first-in-human trials in 2017 with a modular phase I/IIa clinical protocol design which allows for phase IIa expansion arms in molecularly selected patient segments including gastric cancer. We demonstrate that there is an RNF43 mutated patient segment which may benefit from therapy with RXC004, and that these patients have the potential to be identified by a ctDNA screening approach.

Clinical trial identification

EudraCT Number 2017-000720-98

Legal entity responsible for the study

Redx Pharma Plc

Funding

Redx Pharma Plc

Disclosure

M. Bingham, I. Bhamra, R. Armer, S. Woodcock, A. Thomason, C. Phillips, H. McKeever: Employee of Redx Pharma Plc. B. Thompson: Employee of Redx Pharma Plc at the time of this work. B. Chaffey, L. Little: Employee of NewGene Ltd. G. Clack: Consultant for Redx Pharma Plc. All other authors have declared no conflicts of interest.

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