Cancer is the second most common source of mortality in this country and solid tumors account for 90% of all cancers. They are a primary target for drug therapeutics but success has been limited in bringing long-term cure or remission. To achieve this elusive goal, further work is needed to understand the complexity of cancer, which is a multigenic disease with the ability to 'adapt'to treatment. 90% of cancer deaths are due to metastasis and this is becoming an increasing focus of cancer research. A fundamental difficulty of cancer is its complexity: it is typically a multigenic disease with extensive in situ crosstalk. Successful drug screens will need to account for these whole animal aspects of efficacy. To date, however, most whole animal compound screens are too expensive to achieve at a reasonable throughput. This proposal describes a whole animal approach to cancer progression utilizing the fruit fly Drosophila. It focuses on single and multigenic models generated through activation of Src either directly or through reduced activity of its major negative regulator Csk. Data is presented supporting a novel model of metastasis in which local signals from neighboring epithelial cells provoke release and metastasis of transformed cells from the outer border of tumors. Evidence is presented for similar molecular events occurring in human squamous cell carcinomas. This proposal explores the nature of these signals by examining how high Src activity acts in synergy with RTK/Ras signaling. In addition, this Proposal seeks to establish a novel model of tumorigenesis by generating discrete adult 'tumors'. This latter model is designed to identify genes that direct mature tumors and drugs that reverse rather than prevent them. Finally, this proposal proposes to expand our efforts in candidate drug discovery. We will expand our initial efforts eight-fold by screening a large private compound library with an emphasis on 'druggable'compounds. Hits will be further assessed by multiple secondary assays and further studies such as initial structure/activity relationship analysis will be pursued. The goal is to define useful chemical space as well as complement our genetic efforts towards identifying mechanisms and therapeutic targets that address overgrowth and metastasis.

Public Health Relevance

Cancer is the second leading cause of death in the United States, with most deaths deriving from solid tumor metastasis. In this proposal, we use the fruit fly Drosophila as a whole animal model to identify mechanisms that direct cancer growth and spread. In addition, we screen for compounds that define useful 'chemical space'for therapeutics.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Yassin, Rihab R,
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
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Sonoshita, Masahiro; Scopton, Alex P; Ung, Peter M U et al. (2018) A whole-animal platform to advance a clinical kinase inhibitor into new disease space. Nat Chem Biol 14:291-298
Das, Tirtha K; Cagan, Ross L (2018) Non-mammalian models of multiple endocrine neoplasia type 2. Endocr Relat Cancer 25:T91-T104
Das, Tirtha Kamal; Cagan, Ross Leigh (2017) KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub. Cell Rep 20:2368-2383
Bangi, Erdem; Murgia, Claudio; Teague, Alexander G S et al. (2016) Functional exploration of colorectal cancer genomes using Drosophila. Nat Commun 7:13615
Levine, Benjamin D; Cagan, Ross L (2016) Drosophila Lung Cancer Models Identify Trametinib plus Statin as Candidate Therapeutic. Cell Rep 14:1477-1487
Levinson, Sarah; Cagan, Ross L (2016) Drosophila Cancer Models Identify Functional Differences between Ret Fusions. Cell Rep 16:3052-3061
Hirabayashi, Susumu; Cagan, Ross L (2015) Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila. Elife 4:e08501
Rudrapatna, V A; Bangi, E; Cagan, R L (2014) A Jnk-Rho-Actin remodeling positive feedback network directs Src-driven invasion. Oncogene 33:2801-6
Das, Tirtha K; Cagan, Ross L (2013) A Drosophila approach to thyroid cancer therapeutics. Drug Discov Today Technol 10:e65-71
Das, T K; Sangodkar, J; Negre, N et al. (2013) Sin3a acts through a multi-gene module to regulate invasion in Drosophila and human tumors. Oncogene 32:3184-97

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