Abstract B29: High tumor PI3K signaling in resistance to chemoradiotherapy and metastatic dissemination of locally advanced rectal cancer
Authors: Ree Anne Hansen , Flatmark Kjersti , Saelen Marie Gron , Folkvord Sigurd , Dueland Svein , Geisler Jurgen , Roe Kathrine 
Published: October 2015

Hypoxia is an important hallmark of the tumor microenvironment and a main mechanism in tumor resistance to cytotoxic therapy, local recurrence, and metastatic progression. Locally advanced rectal cancer (LARC) comprises heterogeneous tumors with predominant hypoxic components, growing with locally advanced disease manifestations within the pelvic cavity. Despite the introduction of multimodal therapy, primarily the combination of surgery and radiation that frequently results in local control, a substantial number of patients will experience metastatic dissemination. A rational integration of molecularly targeted therapies in combined-modality regimens might cause both improvement of local control in remaining poor-responding patients and reduction in metastasis risk. This strategy, however, will require a clear definition of functional biomarkers for risk assessment and treatment stratification, and technologies comprising the resultant condition of interacting tumor signaling effects may be particularly advantageous. Within this frame of reference, kinase substrate array technologies are tools for global profiling of kinase activities in tissue samples without prior knowledge of which signaling pathways are activated, theoretically portraying the state of composite information flow through signaling cascades. The present work summarizes our experiences from a prospective study of LARC patients given neoadjuvant chemotherapy and radiation followed by surgery and no further treatment (NCT00278694). Using kinase substrate arrays to analyze study patients' tumor biopsies sampled at the time of diagnosis, we hypothesized that the approach might enable identification of potentially actionable therapy targets implicated in hypoxic tumor signaling. At first, tumor phosphorylation of array substrates was correlated to histologic tumor response to the neoadjuvant treatment. Essentially, patients with poor response had significantly elevated tumor kinase activity, representing signaling mediated by VEGFR, EGFR, and PI3K, compared to good-responding patients. Next, it appeared that phosphorylation of array substrates representing PDGFR was strongly inhibited by the addition of the anti-angiogenic agent sunitinib to tumor samples from patients without detectable tumor cells in the bone marrow at the time of diagnosis. The recognition that PDGFR-mediated signaling is central for maturation of pericytes during angiogenesis makes it tempting to speculate that intact pericytic signaling of the tumor vasculature is associated with low likelihood of early systemic tumor dissemination in LARC. Finally, unsupervised clustering analysis of the array phosphosubstrate data separated the tumor samples into two phenotypic populations. The smaller of the patient groups, displaying high tumor activities within the PI3K signaling network, showed a particularly aggressive disease course as almost a half of cases had developed metastatic disease by less than one year of follow-up, suggesting a functional biomarker for rapid failure of metastatic disease control following radical treatment of the pelvic cavity. Given our findings that PI3K may be a key signaling orchestrator both of poor local tumor response to neoadjuvant treatment and importantly, of metastatic development, therapeutic targeting of components of the PI3K complex might be rational to integrate into combined-modality treatment regimens in LARC with hypoxic tumor features.

Citation Format: Anne Hansen Ree, Kjersti Flatmark, Marie Gron Saelen, Sigurd Folkvord, Svein Dueland, Jurgen Geisler, Kathrine Roe. High tumor PI3K signaling in resistance to chemoradiotherapy and metastatic dissemination of locally advanced rectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B29.