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Crit Rev Oncol Hematol. 2015 Jul;95(1):114-24. doi: 10.1016/j.critrevonc.2015.01.003. Epub 2015 Jan 12.

Tumor phosphatidylinositol 3-kinase signaling in therapy resistance and metastatic dissemination of rectal cancer: opportunities for signaling-adapted therapies.

Author information

1
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.
2
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.
3
Department of Tumor Biology, Oslo University Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway. Electronic address: mariegs@gmail.com.
4
Department of Tumor Biology, Oslo University Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway. Electronic address: sigurd.folkvord@gmail.com.
5
Department of Oncology, Oslo University Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway. Electronic address: svedue@ous-hf.no.
6
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.
7
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.

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.

KEYWORDS:

Angiogenesis; Biomarkers; Metastasis; PI3K; Radiation; Rectal cancer; Tumor hypoxia; Tyrosine kinase array

[Indexed for MEDLINE]

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