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Last Updated: 06/26/15

Individualizing Colon Cancer Therapy Using Hybrid RNA and DNA Molecular Signatures

Timothy J. Yeatman, MD
Gibbs Cancer Center, Spartunburg, SC

Dr. Yeatman’s team has recently developed gene expression signatures, RAS and PI3K signatures, to measure the activation of two of the most important pathways in colon cancer for which there is an increasing availability of pathway targeted therapeutics. Due to the complex nature of these pathways, simple analysis of single gene mutations only identifies a proportion of the patients who may respond to these targeted agents. In their SPECS II project, this team will combine RNA gene expression signatures with gene mutation assessments to identify responders and non-responders to cetuximab therapy.

Collaborators:

  • The project team includes investigators from the H. Lee Moffitt Cancer Center and Research Institute, Merck Research Laboratories, Covance Genomics Laboratory, and High Throughput Genomics, Inc.
  • Specimens will be acquired from the H. Lee Moffitt Cancer Center’s biorepository.
  • Statistical support will be provided by the Biostatistics Core for the H. Lee Moffitt Cancer Center.

Projects:

  • Technically validate the existing RAS and PI3K signatures and refine their performance through novel mutational assessments.
  • Clinically validate the improved multi-analyte signatures in a CLIA environment with a cohort of colorectal cancer patients treated with cetuximab therapy.

Publications:

Co-evolution of somatic variation in primary and metastatic colorectal cancer may expand biopsy indications in the molecular era

Authors: Kim, R., Schell, M. J., Teer, J. K., Greenawalt, D. M., Yang, M., Yeatman, T. J.

Source: PLoS One 10(5): e0126670 Epub date 2015/05/15 PMCID 4431733

Abstract: Metastasis is thought to be a clonal event whereby a single cell initiates the development of a new tumor at a distant site. However the degree to which primary and metastatic tumors differ on a molecular level remains unclear. To further evaluate these concepts, we used next generation sequencing (NGS) to assess the molecular composition of paired primary and metastatic colorectal cancer tissue specimens. METHODS: 468 colorectal tumor samples from a large personalized medicine initiative were assessed by targeted gene sequencing of 1,321 individual genes. Eighteen patients produced genomic profiles for 17 paired primary:metastatic (and 2 metastatic:metastatic) specimens. RESULTS: An average of 33.3 mutations/tumor were concordant (shared) between matched samples, including common well-known genes (APC, KRAS, TP53). An average of 2.3 mutations/tumor were discordant (unshared) among paired sites. KRAS mutational status was always concordant. The overall concordance rate for mutations was 93.5%; however, nearly all (18/19 (94.7%)) paired tumors showed at least one mutational discordance. Mutations were seen in: TTN, the largest gene (5 discordant pairs), ADAMTS20, APC, MACF1, RASA1, TP53, and WNT2 (2 discordant pairs), SMAD2, SMAD3, SMAD4, FBXW7, and 66 others (1 discordant pair). CONCLUSIONS: Whereas primary and metastatic tumors displayed little variance overall, co-evolution produced incremental mutations in both. These results suggest that while biopsy of the primary tumor alone is likely sufficient in the chemotherapy-naive patient, additional biopsies of primary or metastatic disease may be necessary to precisely tailor therapy following chemotherapy resistance or insensitivity in order to adequately account for tumor evolution.

MicroRNA-147 induces a mesenchymal-to-epithelial transition (MET) and reverses EGFR inhibitor resistance

Authors: Lee, C. G., McCarthy, S., Gruidl, M., Timme, C., Yeatman, T. J.

Source: PLoS One 9(1): e84597 Epub date 2014/01/24 PMCID 3893127

Abstract: order to adequately account for tumor evolution. MicroRNA-147 induces a mesenchymal-to-epithelial transition (MET) and reverses EGFR inhibitor resistance Authors: Lee, C. G., McCarthy, S., Gruidl, M., Timme, C., Yeatman, T. J. Source: PLoS One 9(1): e84597 Epub date 2014/01/24 PMCID 3893127 Abstract: The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer progression and may promote resistance to therapy. An analysis of patients (n = 71) profiled with both gene expression and a global microRNA assessment ( approximately 415 miRs) identified miR-147 as highly anti-correlated with an EMT gene expression signature score and postulated to reverse EMT (MET). METHODS AND FINDINGS: miR-147 was transfected into colon cancer cells (HCT116, SW480) as well as lung cancer cells (A-549). The cells were assessed for morphological changes, and evaluated for effects on invasion, motility, and the expression of key EMT markers. Resistance to chemotherapy was evaluated by treating cells with gefitinib, an EGFR inhibitor. The downstream genes regulated by miR-147 were assayed using the Affymetrix GeneChip U133 Plus2.0 platform. miR-147 was identified to: 1. cause MET primarily by increasing the expression of CDH1 and decreasing that of ZEB1; 2. inhibit the invasion and motility of cells; 3. cause G1 arrest by up-regulating p27 and down-regulating cyclin D1. miR-147 also dramatically reversed the native drug resistance of the colon cancer cell line HCT116 to gefitinib. miR-147 significantly repressed Akt phosphorylation, and knockdown of Akt with siRNA induced MET. The morphologic effects of miR-147 on cells appear to be attenuated by TGF-B1, promoting a plastic and reversible transition between MET and EMT. CONCLUSION: miR-147 induced cancer cells to undergo MET and induced cell cycle arrest, suggesting a potential tumor suppressor role. miR-147 strikingly increased the sensitivity to EGFR inhibitor, gefitinib in cell with native resistance. We conclude that miR-147 might have therapeutic potential given its ability to inhibit proliferation, induce MET, as well as reverse drug sensitivity.