Journal Article

In vitro and in vivo drug screens of tumor cells identify novel therapies for high‐risk child cancer

Span, Miriam, Batey, Daniel, Lim, Jin Yi, Cowley, Mark J, Mould, Emily V A, Norris, Murray D, Barahona, Paulette, Marshall, Glenn M, Khuong‐Quang, Dong‐Anh, Lock, Richard B, Thomas, David M, Chow, Shu‐Oi, Tucker, Katherine M, Alfred, Stephanie, Pinese, Mark, Gopalakrishnan, Anjana, Wadham, Carol, Tsoli, Maria, MacKenzie, Karen L, Arndt, Greg M, Joshi, Swapna, Strong, Patrick A, McCowage, Geoffrey B, Eden, Georgina, Wong, Marie, Trebilcock, Peter, Ung, Caitlin, Fletcher, Jamie I, Khan, Aaminah, Fox, Stephen B, Cadiz, Roxanne, Trahair, Toby N, Fellowes, Andrew, Haber, Michelle, Xie, Jinhan, Grebert Wade, Dylan, Warby, Meera, Failes, Tim W, Dalla‐Pozza, Luciano, Mayoh, Chelsea, Manouvrier, Elodie, Ekert, Paul G, Gifford, Andrew, Tyrrell, Vanessa, Kamili, Alvin, Saletta, Federica, Ziegler, David S, Lau, Loretta M S, Kumar, Amit, Morgan, Lisa T, Byrne, Jennifer A

2022

Overview

Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high‐throughput drug screening (HTS) and patient‐derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high‐risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high‐risk pediatric cancer patients. Synopsis A precision diagnostic platform integrating genomics and transcriptomics with drug testing of patient's primary tumor cells in high throughput drug screening (HTS) and patient‐derived xenograft (PDX) was established to improve identification of therapies in high‐risk pediatric cancer patients. Treatment options could be identified for 70% of patients across the four‐part platform. HTS provided orthogonal proof of drug efficacy suggested by molecular analyses and identified many new drug responses without prior molecular hallmarks. Effective treatments were observed in more than half of PDX models. There was a strong correlation between HTS and PDX results, and the clinical responses in patients. Graphical Abstract A precision diagnostic platform integrating genomics and transcriptomics with drug testing of patient's primary tumor cells in high throughput drug screening (HTS) and patient‐derived xenograft (PDX) was established to improve identification of therapies in high‐risk pediatric cancer patients.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Antineoplastic drugs / Antitumor agents / Cancer / Cancer therapies / Child / Disease Models, Animal / Drug dosages / Drug efficacy / drug screen / Drug screening / Drug testing / EMBO03 / EMBO08 / EMBO09 / Genomics / Genomics - methods / Humans / Leukemia / Neoplasms - pathology / Patients / patient‐derived xenograft / pediatric cancer / Pediatrics / Precision medicine / Precision Medicine - methods / Transcriptomics / Tumor cells / Tumors / Xenograft Model Antitumor Assays / Xenografts