title: Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy.
abstract: The PI3K pathway is hyperactivated in most cancers, yet the capacity of PI3K inhibitors to induce tumor cell death is limited. The efficacy of PI3K inhibition can also derive from interference with the cancer cells' ability to respond to stromal signals, as illustrated by the approved PI3Kδ inhibitor idelalisib in B-cell malignancies. Inhibition of the leukocyte-enriched PI3Kδ or PI3Kγ may unleash antitumor T-cell responses by inhibiting regulatory T cells and immune-suppressive myeloid cells. Moreover, tumor angiogenesis may be targeted by PI3K inhibitors to enhance cancer therapy. Future work should therefore also explore the effects of PI3K inhibitors on the tumor stroma, in addition to their cancer cell-intrinsic impact.
  
  
  
  The PI3K pathway extends beyond the direct regulation of cancer cell proliferation and survival. In B-cell malignancies, targeting PI3K purges the tumor cells from their protective microenvironment. Moreover, we propose that PI3K isoform-selective inhibitors may be exploited in the context of cancer immunotherapy and by targeting angiogenesis to improve drug and immune cell delivery. Cancer Discov; 6(10); 1090-105. ©2016 AACR.
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom. bart.vanh@ucl.ac.uk klaus.okkenhaug@babraham.ac.uk mgraupera@idibell.cat.
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.affiliation: Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. bart.vanh@ucl.ac.uk klaus.okkenhaug@babraham.ac.uk mgraupera@idibell.cat.
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom. bart.vanh@ucl.ac.uk klaus.okkenhaug@babraham.ac.uk mgraupera@idibell.cat.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D006801:Humans; D007167:Immunotherapy; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D052999:Quinazolinones / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; C552946:idelalisib