Personalized platform that includes a complex fly genetic model used to identify a treatment strategy for a specific patient

A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer.

Erdem Bangi1,*, Celina Ang2,3, Peter Smibert1,†, Andrew V. Uzilov4,5, Alexander G. Teague1, Yevgeniy Antipin4,5, Rong Chen4,5, Chana Hecht1, Nelson Gruszczynski1,‡, Wesley J. Yon1, Denis Malyshev1, Denise Laspina1, Isaiah Selkridge2, Hope Rainey2, Aye S. Moe4,5, Chun Yee Lau4,5, Patricia Taik4,5, Eric Wilck6, Aarti Bhardwaj2, Max Sung2,3, Sara Kim7, Kendra Yum7, Robert Sebra4,5, Michael Donovan3,8, Krzysztof Misiukiewicz2,3, Eric E. Schadt4,5,3, Marshall R. Posner2,3 and Ross L. Cagan1,3,§

1Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5SEMA4, a Mount Sinai Venture, 333 Ludlow Street, South Tower, 3rd floor, Stamford, CT 06902, USA.
6Department of Radiology, The Mount Sinai Hospital, New York, NY 10029, USA.
7Department of Pharmacy, The Mount Sinai Hospital, New York, NY 10029, USA.
8Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Abstract: "Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor’s genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease’s genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer."

 

Read the article at Science Advances.

See also, coverage of the story in The Scientist.