Establishment and Comprehensive Characterization of a Novel Preclinical Platform of Metastatic Retinoblastoma for Therapeutic Developments

SANTIAGO ZUGBI; ASCHERO ROSARIO; DAIANA GANIEWICH; MARÍA B CANCELA; WINTER, URSULA; OTTAVIANI DANIELA; SAMPOR CLAUDIA; MILAGROS DINARDI; ANA V TORBIDONI; MARCELA MENA; LEIRE BALAGUER-LLUNA; GABRIELA LAMAS; MARIANA SGROI; EDUARDO LAGOMARSINO; LUBIENIECKI FABIANA; FANDIÑO, ADRIANA; FRANÇOIS RADVANYI; DAVID H. ABRAMSON; OSVALDO PODHAJCER; ANDREA LLERA; EDUARDO G. CAFFERATA; CHANTADA GUILLERMO; ANGEL M. CARCABOSO; SCHAIQUEVICH PAULA

Investigative Ophthalmology and Visual Science

Association for Research in Vision and Ophthalmology Inc.

Lugar: St. Louis, Mosby; Año: 2023 vol. 64

PurposeAlthough there have been improvements in the management of metastatic retinoblastoma, most patients do not survive, and all patients suffer from multiple short- and long-term treatment toxicities. Reliable and informative models to assist clinicians are needed. Thus we developed and comprehensively characterized a novel preclinical platform of primary cell cultures and xenograft models of metastatic retinoblastoma to provide insights into the molecular biology underlying metastases and to perform drug screening for the identification of hit candidates with the highest potential for clinical translation.MethodsOrbital tumor, bone marrow, cerebrospinal fluid, and lymph node tumor infiltration specimens were obtained from seven patients with metastatic retinoblastoma at diagnosis, disease progression, or relapse. Tumor specimens were engrafted in immunodeficient animals, and primary cell lines were established. Genomic, immunohistochemical/immunocytochemical, and pharmacological analysis were performed.ResultsWe successfully established five primary cell lines: two derived from leptomeningeal, two from orbital, and one from lymph node tumor dissemination. After the intravitreal or intraventricular inoculation of these cells, we established cell-derived xenograft models. Both primary cell lines and xenografts accurately retained the histological and genomic features of the tumors from which they were derived and faithfully recapitulated the dissemination patterns and pharmacological sensitivity observed in the matched patients.ConclusionsOurs is an innovative and thoroughly characterized preclinical platform of metastatic retinoblastoma developed for the understanding of tumor biology of this highly aggressive tumor and has the potential to identify drug candidates to treat patients who currently lack effective treatment options.