Personalized Lung Cancer Treatment: Targeting Stem Cell Pathways

David M. Jablons, M.D.Professor and Chief Thoracic Surgery

Ada Distinguished Professor of Thoracic OncologyUniversity 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 NSCCSC

CSC

CSC

CSCNSC NSC NSC NPC

Solid tumorsMature cells

CC

Niche for epithelial stem cellsNSC

NPC

NPC

Genetic mutationsEpigenetic 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: 563 - 566

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: 563 - 566

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: 563 - 566

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 Keeler1996: Philip Beachy (Stanford University)

Blueprint for new cancer drugs

SHH PATHWAYTHE 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, 3829-3845.)

Cancer Therapeutics Targeting Components of the Hh Pathway

Low and de Sauvage. J Clin Oncol 28, 2010.

Novel Hh pathway inhibitors in clinical testing

N ENGL J MEDVOLUME 361(12):1164-1172

SEPTEMBER 17, 2009

GDC-0449 Activity in Patients with Locally Advanced Basal-Cell Carcinoma

Von Hoff DD, et al. N Engl J Med. 2009 Sep 17;361(12):1164-72.

Treatment of Medulloblastomawith Hedgehog Pathway Inhibitor GDC-0449

Rudin CM, et al.. Engl J Med. 2009 Sep 17;361(12):1173-8.

TUMOR-SPECIFIC HEDGEHOG PATHWAY ACTIVATION

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 InhibitionTherapeutic Significance of Gli InhibitionTherapeutic Significance of Gli InhibitionTherapeutic Significance of Gli Inhibition

Gli inhibitorsHh/SMO

AKT

RAS

TGFß

Tumor

development

Alternativepathways

Gli

Hot Show = Hot TargetHot Show = Hot Target

Targeting Gli Transcription Activation Domain

(Gli: glioma-associated oncogene homology)

0%

25%

50%

75%

100%

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95 97

Compounds

8x

Gli

-BS

Lu

c a

cti

vit

y (

%)

Compound Screening: Transcription Activity Assay Compound Screening: Transcription Activity Assay

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

ConclusionsConclusions

• Personalized therapy for cancer esp. NSCLC Personalized therapy for cancer esp. NSCLC have evolved but new targets and strategies have evolved but new targets and strategies neededneeded

• Therapeutic resistance to therapy targeted and Therapeutic resistance to therapy targeted and chemotherapy remains problematicchemotherapy remains problematic

• Stem cell pathways including Wnt, Hedgehog Stem cell pathways including Wnt, Hedgehog may regulate EMT and resistance mechanismsmay regulate EMT and resistance mechanisms

• Novel therapeutics to stem cell pathways are Novel therapeutics to stem cell pathways are emerging and entering clinical testingemerging and entering clinical testing

Acknowledgement

Acknowledgement