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.

The holo'ome. Fly and mouse model of colon-microbial interplay in the context of colon cancer

Panagi M, Georgila K, Eliopoulos AG, Apidianakis Y. Constructing personalized longitudinal holo'omes of colon cancer-prone humans and their modeling in flies and mice. Oncotarget. 2015 Dec 4. PMID: 26643871.

From the abstract: "Specific host genes and intestinal microbes, dysbiosis, aberrant immune responses and lifestyle may contribute to intestinal inflammation and cancer, but each of these parameters does not suffice to explain why sporadic colon cancer develops at an old age and only in some of the people with the same profile. ... longitudinal multi-omic and personalized studies will help to pinpoint combinations of ... factors ... The intestinal holo'ome - defined as the combination of host and microbiota genomes, transcriptomes, proteomes, and metabolomes - may be imbalanced and shift to disease when the wrong host gene expression profile meets the wrong microbiota composition. ... Detrimental combinations of factors could therefore be pinpointed computationally and validated using animal models, such as mice and flies. ... treatment strategies that break these harmful combinations could be tested in clinical trials. ... we provide an overview of the literature and a roadmap to this end."

Fly study points to mechanisms for the Netrin and Deleted in Colorectal Carcinoma (DCC) proteins

Manhire-Heath R, Golenkina S, Saint R, Murray MJ. Netrin-dependent downregulation of Frazzled/DCC is required for the dissociation of the peripodial epithelium in Drosophila. Nat Commun. 2013;4:2790. PMID: 24225841.

From the abstract: "Netrins are secreted chemoattractants with roles in axon guidance, cell migration and epithelial plasticity. Netrin-1 also promotes the survival of metastasized cells by inhibiting the pro-apoptotic effects of its receptor Deleted in Colorectal Carcinoma (DCC). Here we report that Netrins can also regulate epithelial dissociation during Drosophila wing eversion. ... we provide evidence that Frazzled acts through the ERM-family protein Moesin to inhibit eversion. This mechanism may also help explain the role of Netrin and DCC in cancer metastasis."

Recent fly studies and reviews related to cancer

Sechi S, Colotti G, Belloni G, Mattei V, Frappaolo A, Raffa GD, Fuller MT, Giansanti MG. GOLPH3 Is Essential for Contractile Ring Formation and Rab11 Localization to the Cleavage Site during Cytokinesis in Drosophila melanogaster. PLoS Genet. 2014 May 1;10(5):e1004305. PMID: 24786584; PubMed Central PMCID: PMC4006750.

Huo G, Lu J, Qu Z, Lin Z, Zhang D, Yang Y, Li B. [The applications and advantages of Drosophila melanogaster in cancer research]. Yi Chuan. 2014 Jan;36(1):30-40. Chinese. PubMed PMID: 24846916.

Reddy BA, van der Knaap JA, Bot AG, Mohd-Sarip A, Dekkers DH, Timmermans MA, Martens JW, Demmers JA, Verrijzer CP. Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization. Mol Cell. 2014 Feb 6;53(3):458-70. PMID: 24462112.  From the abstract: "... Here, we show that guanosine 5'-monophosphate synthase (GMPS) is required for USP7-mediated stabilization of p53. ... Intriguingly, cytoplasmic sequestration of GMPS requires ubiquitylation by TRIM21, a ubiquitin ligase associated with autoimmune disease. These results implicate a classic nucleotide biosynthetic enzyme and a ubiquitin ligase, better known for its role in autoimmune disease, in p53 control."

Markstein M. Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies. Drug Discov Today Technol. 2013 Spring;10(1):e73-81. PMID: 24050233. From the abstract: "This review discusses recent shifts in the understanding of colorectal cancer ... recent advances in the culturing of colorectal stem cells using mammalian organoids, zebrafish, and Drosophila offer promising avenues for anti-CSC drug discovery."

Das TK, Cagan RL. A Drosophila approach to thyroid cancer therapeutics. Drug Discov Today Technol. 2013 Spring;10(1):e65-71. doi: 10.1016/j.ddtec.2012.09.004. PMID: 24050232; PubMed Central PMCID: PMC3779345. From the abstract: "Thyroid neoplasias represent among the fastest growing cancers. ... recent Drosophila models have proven useful both for understanding disease mechanism as well as helping identify new generation therapeutics"

Lourenço FC, Munro J, Brown J, Cordero J, Stefanatos R, Strathdee K, Orange C, Feller SM, Sansom OJ, Vidal M, Murray GI, Olson MF. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut. 2014 Mar;63(3):480-93. PMID: 23585469; PubMed Central PMCID: PMC3932979.

Drosophila studies & cancer -- three new reports

Two reviews:

Markstein M. Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies. Drug Discov Today Technol. 2013  Spring;10(1):e73-81. PMID: 24050233.  
From the abstract: "This review discusses recent shifts in the understanding of colorectal cancer as a stem cell based disease ... recent advances in the culturing of colorectal stem cells using mammalian organoids, zebrafish, and Drosophila offer promising avenues for anti-CSC drug discovery."

Das TK, Cagan RL. A Drosophila approach to thyroid cancer therapeutics. Drug Discov Today Technol. 2013 Spring;10(1):e65-71. PMID: 24050232; PMCID: PMC3779345.  
From the abstract: "... In this review, we examine the contributions of work in the fruit fly Drosophila toward multiple endocrine neoplasia type 2 (MEN2), a Ret-based disease to which recent Drosophila models have proven useful both for understanding disease mechanism as well as helping identify new generation therapeutics."

And a research resport:

Lourenço FC, Munro J, Brown J, Cordero J, Stefanatos R, Strathdee K, Orange C, Feller SM, Sansom OJ, Vidal M, Murray GI, Olson MF. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut.2014 Mar;63(3):480-93. PMID: 23585469; PMCID: PMC3932979.

From the abstract: "... Genetic analysis in Drosophila midgut and intestinal epithelial cells isolated from genetically modified mice revealed a conserved role for LIMK2 in constraining gastrointestinal stem cell proliferation. ..."

Review--flies and study of colorectal cancer

Bell GP, Thompson BJ. Colorectal cancer progression: Lessons from Drosophila? Semin Cell Dev Biol. 2014 Feb 27. pii: S1084-9521(14)00019-6. PMID: 24583474.