title: PI3Kδ inhibitors in cancer: rationale and serendipity merge in the clinic.
abstract: Several phosphoinositide 3-kinase (PI3K) inhibitors are in the clinic and many more are in preclinical development. CAL-101, a selective inhibitor of the PI3Kδ isoform, has shown remarkable success in certain hematologic malignancies. Although PI3Kδ signaling plays a central role in lymphocyte biology, the degree of single-agent therapeutic activity of CAL-101 during early-phase development has been somewhat unexpected. CAL-101 works in part by blocking signals from the microenvironment that normally sustain leukemia and lymphoma cells in a protective niche. As PI3Ks enter the arena of molecular-targeted therapies, CAL-101 provides proof of principle that isoform-selective compounds can be effective in selected cancer types and patient populations.
  
  
  CONCLUSIONS
  A key question is whether compounds targeting a single PI3K catalytic isoform can provide meaningful single agent efficacy in cancer cells that express multiple isoforms. Clinical studies of the drug CAL-101 have provided a significant advance by showing that selective targeting of PI3Kδ achieves efficacy in chronic lymphocytic leukemia, in part through targeting the tumor microenvironment.
authors.affiliation: Department of Molecular Biology and Biochemistry and Institute for Immunology, University of California, Irvine, Irvine, California 92697-3900, USA. dfruman@uci.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Fruman
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D052999:Quinazolinones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; C552946:idelalisib