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

Anne Hansen Ree; Kjersti Flatmark; Marie Grøn Saelen; Sigurd Folkvord; Svein Dueland; Jürgen Geisler; Kathrine Røe Redalen

doi:10.1016/j.critrevonc.2015.01.003

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

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

Authors

Anne Hansen Ree¹, Kjersti Flatmark², Marie Grøn Saelen³, Sigurd Folkvord⁴, Svein Dueland⁵, Jürgen Geisler⁶, Kathrine Røe Redalen⁷

Affiliations

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.

PMID: 25624177
DOI: 10.1016/j.critrevonc.2015.01.003

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.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Female
Humans
Male
Middle Aged
Neoadjuvant Therapy* / methods
Neoplasm Metastasis / pathology
Neoplasm Metastasis / therapy
Phosphatidylinositol 3-Kinases / metabolism*
Rectal Neoplasms / enzymology
Rectal Neoplasms / pathology*
Rectal Neoplasms / radiotherapy
Rectal Neoplasms / therapy*
Rectum / enzymology
Rectum / pathology*
Rectum / radiation effects
Signal Transduction*
Survival Analysis
Treatment Outcome

Substances

Phosphatidylinositol 3-Kinases

Associated data

ClinicalTrials.gov/NCT00278694