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AT-0174, a novel dual IDO1/TDO2 enzyme inhibitor, synergises with temozolomide to improve survival in an orthotopic mouse model of glioblastoma.
Bickerdike, Michael J; Nafia, Imane; Bessede, Alban; Chen, Cheng-Bang; Wangpaichitr, Medhi.
Afiliación
  • Bickerdike MJ; Antido Therapeutics (Australia) Pty Ltd, Level 7, 616 St Kilda Road, Melbourne, VIC, 3004, Australia. mike@biotarget.co.nz.
  • Nafia I; BioTarget Consulting Ltd, Auckland, New Zealand. mike@biotarget.co.nz.
  • Bessede A; Explicyte Immuno-Oncology, Bordeaux, France.
  • Chen CB; Explicyte Immuno-Oncology, Bordeaux, France.
  • Wangpaichitr M; College of Engineering, University of Miami, Miami, FL, USA.
BMC Cancer ; 24(1): 889, 2024 Jul 24.
Article en En | MEDLINE | ID: mdl-39048947
ABSTRACT

BACKGROUND:

Glioblastoma is an aggressive brain cancer, usually of unknown etiology, and with a very poor prognosis. Survival from diagnosis averages only 3 months if left untreated and this only increases to 12-15 months upon treatment. Treatment options are currently limited and typically comprise radiotherapy plus a course of the DNA-alkylating chemotherapeutic temozolomide. Unfortunately, the disease invariably relapses after several months of treatment with temozolomide, due to the development of resistance to the drug. Increased local tryptophan metabolism is a feature of many solid malignant tumours through increased expression of tryptophan metabolising enzymes. Glioblastomas are notable for featuring increased expression of the tryptophan catabolizing enzymes indole-2,3-dioxygenase-1 (IDO1), and especially tryptophan-2,3-dioxygenase-2 (TDO2). Increased IDO1 and TDO2 activity is known to suppress the cytotoxic T cell response to tumour cells, and this has led to the proposal that the IDO1 and TDO2 enzymes represent promising immuno-oncology targets. In addition to immune modulation, however, recent studies have also identified the activity of these enzymes is important in the development of resistance to chemotherapeutic agents.

METHODS:

In the current study, the efficacy of a novel dual inhibitor of IDO1 and TDO2, AT-0174, was assessed in an orthotopic mouse model of glioblastoma. C57BL/6J mice were stereotaxically implanted with GL261(luc2) cells into the striatum and then administered either vehicle control, temozolomide (8 mg/kg IP; five 8-day cycles of treatment every 2 days), AT-0174 (120 mg/kg/day PO) or both temozolomide + AT-0174, all given from day 7 after implantation.

RESULTS:

Temozolomide decreased tumour growth and improved median survival but increased the infiltration of CD4+ Tregs. AT-0174 had no significant effect on tumour growth or survival when given alone, but provided clear synergy in combination with temozolomide, further decreasing tumour growth and significantly improving survival, as well as elevating CD8+ T cell expression and decreasing CD4+ Treg infiltration.

CONCLUSION:

AT-0174 exhibited an ideal profile for adjunct treatment of glioblastomas with the first-line chemotherapeutic drug temozolomide to prevent development of CD4+ Treg-mediated chemoresistance.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triptófano Oxigenasa / Glioblastoma / Sinergismo Farmacológico / Indolamina-Pirrol 2,3,-Dioxigenasa / Temozolomida Límite: Animals / Humans Idioma: En Revista: BMC Cancer Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Australia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triptófano Oxigenasa / Glioblastoma / Sinergismo Farmacológico / Indolamina-Pirrol 2,3,-Dioxigenasa / Temozolomida Límite: Animals / Humans Idioma: En Revista: BMC Cancer Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Australia