personalized lung cancer treatment: targeting stem cell pathways david m. jablons, m.d. professor...
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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
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STEM CELL FATE: TO SELF-RENEW OR TO DIFFERENTIATE?
A
B
C+/-
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Signaling Pathways
Stem cell self-renewal Tumorigenesis
NSC NSCCSC
CSC
CSC
CSCNSC NSC NSC NPC
Solid tumorsMature cells
CC
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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
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Conventional therapies may shrink tumors by killing mainly cells with limited proliferative potential
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Cancer stem cell properties and therapeutic resistance
Oncotarget 2010; 1: 563 - 566
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Signalling Pathways Regulating Self-renewal During Normal Stem Cell Development and Transformation
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Key signaling pathways for targeted therapies in lung cancer
Ray, Jablons & He. Expert Rev. R esp. Med. 4 (5), (2010)
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Canonical Wnt Signaling in Cancer
Oncotarget 2010; 1: 563 - 566
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Barker N & Clevers H. Nature Reviews; 2006
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Cancer Therapeutics Targeting Components of the Canonical Wnt Pathway
Klaus A & Birchmeier W. Nature Review Cancer, 2008
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Summary of Current Status of Targeting Wnt Signaling Pathway for Cancer Therapy
Oncotarget 2010; 1: 563 - 566
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CBP/beta-catenin antagonism eliminates imatinib-resistant leukemic stem cells
Clin Cancer Res; 16(12) June 15, 2010
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Deregulated pathways leading stem cells to cancer
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Hedgehog and Wnt Signaling Pathways
, Wnt
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Effect of Hit Compound on Expression of Wnt Gene Family in NSCLC Cells
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Wild corn lily
1960’s: Lynn James and Richard Keeler1996: Philip Beachy (Stanford University)
Blueprint for new cancer drugs
SHH PATHWAYTHE LAMB & THE FLOWER
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Hedgehog Pathway and Cancer
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Scales S. & de Sauvage F. Trends in Pharmacological Sciences, 2009
Cancer Therapeutics Targeting Components of the Hh Pathway
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25
Models of Hh pathway activation in cancer
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Ligand dependent: Autocrine signaling
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Ligand dependent: Paracrine signaling
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Ligand independent: Genetic mutations in Ptch or Smo
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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
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Low and de Sauvage. J Clin Oncol 28, 2010.
Novel Hh pathway inhibitors in clinical testing
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N ENGL J MEDVOLUME 361(12):1164-1172
SEPTEMBER 17, 2009
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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.
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Treatment of Medulloblastomawith Hedgehog Pathway Inhibitor GDC-0449
Rudin CM, et al.. Engl J Med. 2009 Sep 17;361(12):1173-8.
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TUMOR-SPECIFIC HEDGEHOG PATHWAY ACTIVATION
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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.
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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
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Hot Show = Hot TargetHot Show = Hot Target
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Targeting Gli Transcription Activation Domain
(Gli: glioma-associated oncogene homology)
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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
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Hit Compound Inhibits Gli/TAF Dependent Wnt2 Transcription Screen in NSCLC Cells
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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
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Acknowledgement
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Acknowledgement