BackgroundColorectal cancer (CRC) is a heterogeneous and biologically poorly understood disease. To tailor CRC treatment, it is essential to first model this heterogeneity by defining subtypes of patients with homogeneous biological and clinical characteristics and second match these subtypes to cell lines for which extensive pharmacological data is available, thus linking targeted therapies to patients most likely to respond to treatment.MethodsWe applied a new unsupervised, iterative approach to stratify CRC tumor samples into subtypes based on genome-wide mRNA expression data. By applying this stratification to several CRC cell line panels and integrating pharmacological response data, we generated hypotheses regarding the targeted treatment of different subtypes.ResultsIn agreement with earlier studies, the two dominant CRC subtypes are highly correlated with a gene expression signature of epithelial-mesenchymal-transition (EMT). Notably, further dividing these two subtypes using iNMF (iterative Non-negative Matrix Factorization) revealed five subtypes that exhibit activation of specific signaling pathways, and show significant differences in clinical and molecular characteristics. Importantly, we were able to validate the stratification on independent, published datasets comprising over 1600 samples. Application of this stratification to four CRC cell line panels comprising 74 different cell lines, showed that the tumor subtypes are well represented in available CRC cell line panels. Pharmacological response data for targeted inhibitors of SRC, WNT, GSK3b, aurora kinase, PI3 kinase, and mTOR, showed significant differences in sensitivity across cell lines assigned to different subtypes. Importantly, some of these differences in sensitivity were in concordance with high expression of the targets or activation of the corresponding pathways in primary tumor samples of the same subtype.ConclusionsThe stratification presented here is robust, captures important features of CRC, and offers valuable insight into functional differences between CRC subtypes. By matching the identified subtypes to cell line panels that have been pharmacologically characterized, it opens up new possibilities for the development and application of targeted therapies for defined CRC patient sub-populations.

Purpose: To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo.Experimental Design: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors.Results: In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC 50 , 4 nmol/L), erbB2 (IC 50 , 3 nmol/L), and erbB3 (IC 50 , 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.Conclusions: AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2. Clin Cancer Res; 16(4); 1159-69. ©2010 AACR.The erbB receptor family is composed of four related receptor tyrosine kinases [epidermal growth factor receptor (EGFR, erbB1), erbB2 (human epidermal growth factor receptor 2, HER2), erbB3 (HER3), and erbB4 (HER4)]. ErbB2 lacks ligand-binding capacity and erbB3 is intrinsically inactive as a kinase. There are two main ligand classes: the first bind specifically to EGFR whereas the second includes the neu differentiation factors, or heregulins, which bind erbB3 and erbB4 (1). In cancer, activation of erbB2 may arise by (a) receptor overexpression inducing homodimerization and (b) receptor heterodimerization with another family member, of which erbB3 is considered to be the preferred and most oncogenic partner (2).Homodimerization and/or heterodimerization of erbB receptors results in the phosphorylation of key tyrosine residues in the intracellular domain and leads to the stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival (3, 4). The deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival and has been described in many human cancers, in...

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Low-grade endometrial endometrioid adenocarcinomas (LGEECa) can recur in the vagina (VRec), pelvic and abdominal region (PARec), or distant sites (DMet). Tumor size, histopathologic features, and lymph node involvement at presentation have been linked to the development of these recurrences. However, the amount of information on risk factors to predict site of recurrence is limited. Methods: In this multi-institutional study, we analyzed data from 589 patients with FIGO grades 1 and 2 LGEECa and found 116 patients with VRec, PARec, or DMet. They were compared with 187 age-matched controls with negative lymph nodes, no adjuvant treatment, and no recurrences; mean follow-up times were 44 and 59 months, respectively. Cox proportional hazards analysis was used to identify univariable and multivariable risk factors for each type of recurrence (P b .05).Results: Forty-one patients had VRec, 33 had PARec (pelvic soft tissue, 14; abdominal tissue, 9; liver capsule, 5; retroperitoneum, 3; colorectal wall, 2), and 42 had DMet (lung, 19; lymph nodes, 17; bone and soft tissue, 5; brain, 1) as the initial site of recurrence. Univariate and multivariate analysis of histopathologic features are summarized in Table 1. In addition, features associated with vaginaonly recurrence included superficial myometrial invasion (P = .002); low nuclear grade (P = .03); lymphovascular invasion (LVI) adjacent to tumor, but not deeper than invasive tumor front (P b .001); less than 5% microcystic elongated and fragmented pattern (MELF) at invasive tumor front (P = .014); and no pelvic lymph node metastasis at presentation (P = .019). These features were not significantly different from controls. Conclusions: (1) Features of LGEECa that predicted VRec included superficialy invasive, low nuclear grade tumors with minimal MELF, minimal or no LVI, and no lymph node metastasis. These features were more closely related with tumors that did not recur than with recurrent tumors. (2) LGEECa with PARec differed from those with VRec, because the tumors were larger and deeply invasive and MELF at invasive tumor front, suggesting a different dissemination route than tumors with VRec. (3) Significant predictor features of LGEECa with DMet included intraglandular tumor necrosis, cell clusters at the invasive front and adjacent to areas of LVI, and cervical stromal involvement. The latter feature might be indicative of venous rather of lymphatic invasion.

HighlightsThe case presented is that of a primary debulking surgery for presumed ovarian cancer.Final pathology revealed diffusely metastatic endocervical adenocarcinoma.After primary chemotherapy, the patient has remained disease-free 30 months after surgery.

A broad range of targeted agents are in early development for treatment of solid tumours. It is important that patients receive treatments which are tailored to work optimally based on their individual tumour biology. Retrospective analysis of clinical data for the EGFR tyrosine kinase inhibitor, Iressa, in lung cancer demonstrated cell line panels can provide a platform to direct targeted therapies towards specific patient subpopulations. In order to evaluate targeted agents in colorectal cancer we have characterized a panel of 49 colorectal tumour cell lines derived from Dukes stage A-D of CRC for commonly occurring mutations (KRas, BRAF, PI3Ka, PTEN), microsatellite instability, gene copy number alterations (Agilent 244K ArrayCGH), mRNA expression (Affymetrics HG_U133_plus_2) and miRNA expression (TLDA – 177 miRNAs). These data have been used to characterize the differentiation status of the cell lines and to link to compound activity. We have probed the anti-proliferative activity of compounds from several growth factor pathways, EGFR, RAS/MEK and PI3K to evaluate pathway dependence and linkage to molecular data. The greatest activity of the EGFR TKI inhibitor was in Ras, Raf, PTEN, PI3K wild type (quadruple negative (QN)) CRC lines, in agreement with clinical data for EGFR antibodies. However, of the 9 QN lines profiled, only 4 were hypersensitive (GI50 <0.5uM), the hypersensitive lines had an epithelial phenotype (E-cadherin mRNA, miR200c & B-Cat protein positive; vimentin mRNA negative). In contrast the QN lines that did not respond to EGFR inhibition had either a mesenchymal (E-cadherin mRNA, miR200c, B-Catenin protein negative, vimentin positive) or an intermediate phenotype (E-cadherin mRNA, miR200c & B-Cat protein low; vimentin negative). KRAS and BRAF mutant cell lines were relatively resistant to EGFRi compared to QN cell lines (p = 0.009 and 0.06 respectively), with the exception of two lines with G13D KRAS mutations which had GI50s of 0.3 and 1.8uM. Interestingly, the epithelial QN lines were co-sensitive to EGFR, MEK and PI3K inhibitors. In contrast the mesenchymal QN lines were relatively insensitive to the kinase inhibitors used. The QN lines with an intermediate phenotype did not respond to EGFR or MEKi but did respond to PI3K inhibition. In conclusion, the data suggests that both mutation status and cellular differentiation status contribute to the response to targeted agents. Through profiling the anti-proliferative activity of inhibitors from across a range of pathways co-dependencies of kinase targets were revealed as well as anti-correlations which indicate potential combination strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5365. doi:10.1158/1538-7445.AM2011-5365