1524P - AG-120, a novel IDH1 targeted molecule, inhibits invasion and migration of chondrosarcoma cells in vitro.

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Basic Science
Sarcoma
Presenter VICTORIA HEREDIA
Citation Annals of Oncology (2017) 28 (suppl_5): v521-v538. 10.1093/annonc/mdx387
Authors V. HEREDIA1, M. Mendiola2, E. Ortiz3, D. Bernabéu4, J.J. Pozo-Kreilinger5, M. Miguel1, R. Crespo6, A. Berjón5, V. Martínez-Marín7, A. Redondo7
  • 1Molecular Pathology And Therapeutic Targets Laboratory, IdIPAZ – Hospital Universitario La Paz, 28046 - Madrid/ES
  • 2Molecular Pathology And Therapeutic Targets Laboratory, IdIPAZ – Hospital Universitario La Paz, Madrid/ES
  • 3Orthopedic Traumatology Surgery Department, Hospital Universitario La Paz, 28046 - Madrid/ES
  • 4Radiology Department, Hospital Universitario La Paz, 28046 - Madrid/ES
  • 5Pathology Department, Hospital Universitario La Paz, 28046 - Madrid/ES
  • 6Translational Oncology, IdIPAZ – Hospital Universitario La Paz, Madrid/ES
  • 7Medical Oncology Department, Hospital Universitario La Paz, 28046 - Madrid/ES

Abstract

Background

Chondrosarcoma (CS) is the second most frequent primary malignant bone tumor in adults. Surgery is the best treatment option for these patients since most subtypes are resistant to chemotherapy and radiotherapy, thus novel systemic therapies are needed for patients with unresectable tumors. The majority of cases correspond to the conventional central CS histology, were recurrent mutations in isocitrate dehydrogenases (IDH1/2) coding genes are found. Therefore, IDH1 has been reported as a potential therapeutic target and several selective inhibitor molecules, such as AGI-5198 and, more recently, AG-120, have been developed and are currently being evaluated in clinical trials. In this work, we have explored the in vitro effects of AG-120 on a central CS cell line, JJ012, which carries a mutation in IDH1.

Methods

JJ012 cells were cultured both in monolayer and three-dimensional (3D) spheroids and treated with increasing concentrations of AG-120. IDH1 mutation in arginine residue R132G was verified by PCR sequencing. Proliferation and cytotoxic screening were done with Sulforhodamine B (SRB) assay. Monolayer invasion and migration assays were performed with FluoroBlok and wound healing assays respectively and 3D experiments were developed using a Matrigel matrix.

Results

R132G mutation of IDH1 was confirmed by PCR sequencing. Previous reports with AGI-5198 inhibitor show contradictory results regarding their effect on CS cells. In this work, we show how novel molecule AG-120 inhibits both invasion and migration of CS IDH1 mutated JJ012 cell line in monolayer and 3D cell culture, although it does not affect their proliferation. Minor effects on viability were only detected at high dose (100 µM).

Conclusions

These results support AG-120 as a new possible therapeutic agent for patients with metastatic CS, and further research is needed to understand its action mechanisms in this pathology.

Clinical trial identification

Legal entity responsible for the study

Fundación para la Investigación Biomédica del Hospital Universitario La Paz (FIBHULP)

Funding

Fundación para la Investigación Biomédica del Hospital Universitario La Paz (FIBHULP)

Disclosure

All authors have declared no conflicts of interest.