Personalized Lung Cancer Treatment: Targeting Stem Cell Pathways David M. Jablons, M.D. Professor and Chief Thoracic Surgery Ada Distinguished Professor of Thoracic Oncology University of California at San Francisco

STEM CELL FATE: TO SELF-RENEW OR TO DIFFERENTIATE? A B C +/-

Signaling Pathways Stem cell self-renewal Tumorigenesis NSC CSC NSC NPC Solid tumorsMature cells CC

Niche for epithelial stem cells NSC NPC Genetic mutations Epigenetic changes Alterations in pathways, such as Wnt, Hedgehog CSC Mutated NPC Redifferentiation to stem-like cell CC Solid tumor formation Cancer

Conventional therapies may shrink tumors by killing mainly cells with limited proliferative potential

Cancer stem cell properties and therapeutic resistance Oncotarget 2010; 1:

Signalling Pathways Regulating Self-renewal During Normal Stem Cell Development and Transformation

Key signaling pathways for targeted therapies in lung cancer Ray, Jablons & He. Expert Rev. R esp. Med. 4 (5), (2010)

Canonical Wnt Signaling in Cancer Oncotarget 2010; 1:

Barker N & Clevers H. Nature Reviews; 2006

Cancer Therapeutics Targeting Components of the Canonical Wnt Pathway Klaus A & Birchmeier W. Nature Review Cancer, 2008

Summary of Current Status of Targeting Wnt Signaling Pathway for Cancer Therapy Oncotarget 2010; 1:

CBP/beta-catenin antagonism eliminates imatinib-resistant leukemic stem cells Clin Cancer Res; 16(12) June 15, 2010

Deregulated pathways leading stem cells to cancer

“What’s the Connection?”

Hedgehog and Wnt Signaling Pathways, Wnt

Effect of Hit Compound on Expression of Wnt Gene Family in NSCLC Cells

Wild corn lily 1960’s: Lynn James and Richard Keeler 1996: Philip Beachy (Stanford University) Blueprint for new cancer drugs SHH PATHWAY THE LAMB & THE FLOWER

Hedgehog Pathway and Cancer

Scales S. & de Sauvage F. Trends in Pharmacological Sciences, 2009 Cancer Therapeutics Targeting Components of the Hh Pathway

25 Models of Hh pathway activation in cancer

Ligand dependent: Autocrine signaling

Ligand dependent: Paracrine signaling

Ligand independent: Genetic mutations in Ptch or Smo

Hedgehog pathway activators and inhibitors. The Hh receptor Ptch is a transmembrane protein that inhibits the activity of Smo in the absence of Hh. Binding of Hh results in activation of Smo, which then modulates Gli transcription factors to initiate transcription of Hh target genes. Proteins involved in modulating signal relay between Smo and Gli are as indicated. Pathway suppressors are indicated in red and activators in green. The molecules in this pathway that are targets for chemical inhibitors include Smo and Gli. (J. Med. Chem. 2009, 52, ) Cancer Therapeutics Targeting Components of the Hh Pathway

Low and de Sauvage. J Clin Oncol 28, Novel Hh pathway inhibitors in clinical testing

N ENGL J MED VOLUME 361(12): SEPTEMBER 17, 2009

GDC-0449 Activity in Patients with Locally Advanced Basal-Cell Carcinoma Von Hoff DD, et al. N Engl J Med Sep 17;361(12):

Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449 Rudin CM, et al.. Engl J Med Sep 17;361(12):

T UMOR -S PECIFIC H EDGEHOG P ATHWAY A CTIVATION

Identification of a SMO mutation in tumor samples from a medulloblastoma patient who relapsed after an initial response to GDC-0449 Yauch RL, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 2009;326:572.

Therapeutic Significance of Gli Inhibition Gli inhibitors Hh/SMO AKT RAS TGFß Tumor development Alternative pathways Gli

Hot Show = Hot Target

Targeting Gli Transcription Activation Domain (Gli: glioma-associated oncogene homology)

Compound Screening: Transcription Activity Assay

Hit Compound Inhibits Gli/TAF Dependent Wnt2 Transcription Screen in NSCLC Cells

Conclusions Personalized therapy for cancer esp. NSCLC have evolved but new targets and strategies neededPersonalized therapy for cancer esp. NSCLC have evolved but new targets and strategies needed Therapeutic resistance to therapy targeted and chemotherapy remains problematicTherapeutic resistance to therapy targeted and chemotherapy remains problematic Stem cell pathways including Wnt, Hedgehog may regulate EMT and resistance mechanismsStem cell pathways including Wnt, Hedgehog may regulate EMT and resistance mechanisms Novel therapeutics to stem cell pathways are emerging and entering clinical testingNovel therapeutics to stem cell pathways are emerging and entering clinical testing

Acknowledgement