title: Tumor phosphatidylinositol 3-kinase signaling in therapy resistance and metastatic dissemination of rectal cancer: opportunities for signaling-adapted therapies.
abstract: Locally advanced rectal cancer (LARC) comprises heterogeneous tumors with predominant hypoxic components, a hallmark of the tumor microenvironment and determinant of resistance to cytotoxic therapies, local recurrence, and metastatic progression. A rational integration of molecularly targeted agents in established combined-modality treatment regimens may improve local and systemic disease control, but will require a clear definition of functional biomarkers for patient stratification. In a prospective study of LARC patients given neoadjuvant chemotherapy and radiation, we applied a kinase substrate array technology to analyze the patients' tumor biopsies sampled at the time of diagnosis, and observed that receptor tyrosine kinase activities integrated by high phosphatidylinositol 3-kinase signaling were correlated both with poor tumor response to the neoadjuvant treatment and adverse progression-free survival. Conceptually, the specific tumor signature of phosphatidylinositol 3-kinase signaling activity may point to actionable therapy targets in LARC patients with unfavorable disease features. Clinical trial registration number NCT00278694.
authors.affiliation: Department of Oncology, Akershus University Hospital, P.O. Box 1000, 1478 Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway. Electronic address: a.h.ree@medisin.uio.no.
authors.forename: Anne Hansen
authors.initials: AH
authors.lastname: Ree
authors.affiliation: Department of Tumor Biology, Oslo University Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway; Department of Gastroenterological Surgery, Oslo University Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway. Electronic address: kjersti.flatmark@rr-research.no.
authors.forename: Kjersti
authors.initials: K
authors.lastname: Flatmark
authors.affiliation: Department of Tumor Biology, Oslo University Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway. Electronic address: mariegs@gmail.com.
authors.forename: Marie Grøn
authors.initials: MG
authors.lastname: Saelen
authors.affiliation: Department of Tumor Biology, Oslo University Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway. Electronic address: sigurd.folkvord@gmail.com.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Folkvord
authors.affiliation: Department of Oncology, Oslo University Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway. Electronic address: svedue@ous-hf.no.
authors.forename: Svein
authors.initials: S
authors.lastname: Dueland
authors.affiliation: Department of Oncology, Akershus University Hospital, P.O. Box 1000, 1478 Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway. Electronic address: juergen.geisler@medisin.uio.no.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Geisler
authors.affiliation: Department of Oncology, Akershus University Hospital, P.O. Box 1000, 1478 Lørenskog, Norway; Department of Clinical Molecular Biology, Akershus University Hospital, P.O. Box 1000, 1478 Lørenskog, Norway. Electronic address: kathrine.roe@medisin.uio.no.
authors.forename: Kathrine Røe
authors.initials: KR
authors.lastname: Redalen
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009362:Neoplasm Metastasis / Q000473:pathology / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012004:Rectal Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000532:radiotherapy / Q000628:therapy*; D012007:Rectum / Q000201:enzymology / Q000473:pathology* / Q000528:radiation effects; D015398:Signal Transduction; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D019869:Phosphatidylinositol 3-Kinases
keywords: Angiogenesis; Biomarkers; Metastasis; PI3K; Radiation; Rectal cancer; Tumor hypoxia; Tyrosine kinase array