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

EMBO Mol Med. 2022 Apr 7;14(4):e14608. doi: 10.15252/emmm.202114608.

Loretta M S Lau ¹ ² ³, Chelsea Mayoh ¹ ², Jinhan Xie ¹, Paulette Barahona ¹, Karen L MacKenzie ¹, Marie Wong ¹ ², Alvin Kamili ¹ ², Maria Tsoli ¹, Tim W Failes ¹ ⁴, Amit Kumar ¹ ⁵, Emily V A Mould ¹, Andrew Gifford ¹ ², Shu-Oi Chow ¹ ⁴, Mark Pinese ¹ ², Jamie I Fletcher ¹ ², Greg M Arndt ¹ ⁴, Dong-Anh Khuong-Quang ⁵ ⁶, Carol Wadham ¹, Daniel Batey ¹, Georgina Eden ¹, Peter Trebilcock ¹, Swapna Joshi ¹, Stephanie Alfred ¹, Anjana Gopalakrishnan ¹, Aaminah Khan ¹, Dylan Grebert Wade ¹, Patrick A Strong ¹, Elodie Manouvrier ¹, Lisa T Morgan ¹, Miriam Span ¹, Jin Yi Lim ¹, Roxanne Cadiz ¹, Caitlin Ung ¹, David M Thomas ⁷ ⁸, Katherine M Tucker ⁹ ¹⁰, Meera Warby ⁹, Geoffrey B McCowage ¹¹, Luciano Dalla-Pozza ¹¹, Jennifer A Byrne ¹² ¹³, Federica Saletta ¹, Andrew Fellowes ¹⁴, Stephen B Fox ¹⁴ ¹⁵, Murray D Norris ¹ ² ¹⁶, Vanessa Tyrrell ¹, Toby N Trahair ¹ ² ³, Richard B Lock ¹ ², Mark J Cowley ¹ ² ¹⁷, Paul G Ekert ¹ ² ¹⁴, Michelle Haber ¹ ², David S Ziegler ^# ¹ ² ³, Glenn M Marshall ^# ¹ ² ³

Affiliations

1 Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia.
2 School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia.
3 Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
4 ACRF Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
5 Children's Cancer Centre, Royal Children's Hospital, Parkville, Vic., Australia.
6 Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.
7 Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
8 Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Kensington, NSW, Australia.
9 Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia.
10 Prince of Wales Hospital Clinical School, UNSW Sydney, Randwick, NSW, Australia.
11 Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, NSW, Australia.
12 Children's Cancer Research Unit, Kids Research, Westmead, NSW, Australia.
13 Faculty of Medicine and Health, The University of Sydney, NSW, Australia.
14 Peter MacCallum Cancer Centre, Melbourne, Vic., Australia.
15 Department of Medical Oncology, University of Melbourne, Melbourne, Vic., Australia.
16 University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, Vic., Australia.
17 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
# Contributed equally.

PMID: 34927798 DOI: 10.15252/emmm.202114608

Abstract

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.

Keywords

drug screen; patient-derived xenograft; pediatric cancer; precision medicine.

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