Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design

Abstract

SUMMARY Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)—many of which are refractory to current standard-of-care treatments—from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.

Development and characterization of the novel human osteosarcoma cell line COS-33 with sustained activation of the mTOR pathway

“…The COS-33 cell line was subcultured for more than 50 passages without obvious changes in morphology or proliferative potential after cryopreservation and resuscitation. The cytological features of COS-33 cells in the grafted tumor are similar to those in the parental PDX tumor (Figure 8), and previous studies demonstrated that the PDX tumors accurately reflect the genetic and biologic characteristics of the tumor of origin [4,16]. Thus, COS-33 cells may constitute an excellent in vitro and in vivo model representative of the original tumor.…”

“…mTOR is an intracellular serine/threonine kinase involved in the PI3K/AKT pathway, that indirectly regulates ribosomal translation of mRNA into proteins necessary for cell growth, cell cycle progression, and cell metabolism, making it an excellent target for cancer cells to hijack. Because of its demonstrable response to mTOR-targeted rapamycin monotherapy, the PDX OS-33 model has been frequently used in many studies to test new mTOR inhibitors (e. g. temsirolimus), and the activity of combinations of rapamycin with other anticancer agents such as cisplatin, bevacizumab, eribulin (against the tubulin binding agent), and R1507 (a fully human monoclonal antibody targeting IGF-1R) [4,[20][21][22][23][24]. In addition, it was used to test new drugs inhibiting other signaling pathways such as STAT3 [17,22].…”

“…Current multimodal therapy consisting of surgery combined with drug treatment using chemotherapy agents (cisplatin, doxorubicin, ifosfamide, and high-dose methotrexate) achieves a five-year survival rate of approximately 60-70% for localized OS, while the rate for patients with metastases is less than 30% [2]. Recent genomic studies with patient tumor samples and models of human OS have improved our understanding of the disease etiology and have also provided a road map for drug development [3][4][5][6]. However, the clinical and survival outcomes for patients with OS have not improved over the last four decades.…”

“…Among them, Saos-2 contains homozygous deletion mutations of TP53, whereas the others express the wild-type gene [15]. Nonetheless, it is still unknown how TP53 mutation status affects therapeutic strategies and overall patient survival [4,5]. Due to the rarity of the disease, establishing novel OS cancer cell lines representative of the extensive heterogeneity of these tumors will likely provide additional insights and serve as valuable platforms for developing effective therapies.…”

“…Over the past 30 years, numerous groups have used models of PDXs for basic and preclinical studies, including the Pediatric Preclinical Testing Consortium (PPTC), previously known as the Pediatric Preclinical Testing Program [9,[16][17][18][19]. One of the lines was named OS-33 (or HxOS-33), but it has seldom been grown and studied in culture [4,[20][21][22][23][24]. In this study, we report the successful establishment of a novel human OS cell line derived from OS-33, herein designated COS- 33, and demonstrate retention of the biological features and drug sensitivity of the original PDX tumors.…”