Recurrent Respiratory Papillomatosis RRP: Celebrex and COX2 Inhibition

1
Recurrent Respiratory Papillomatosis
(RRP)Celebrex and COX-2 Inhibition

• Mark J. Shikowitz, MD
• Long Island Jewish Medical Center
• Institute for Medical Research
• North Shore LIJ Health System
• The University Hospital and Long Island Campus
  for the
• Albert Einstein College of Medicine

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Demographics of RRP

• International Data
• incidence 3.8 - 7.0 / million population/ year
• prevalence 1/100,000
• two peaks - juvenile onset 2-5 years of age
• adult onset 20-40 years of age
• juvenile 11 male/female, adult 21
• LIJ Data
• total patients treated 254
• adult onset 138 juvenile onset 116
• 175 males, 79 females

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Appearance of Mild and Severe Larynx Papillomas
4
What Causes Mass of Tissue ?External Signals
Control Cell Functions
5
EGF Receptor Is Overexpressed in Papillomas
Normal
Papilloma
6
EGF-R Activates Many Signaling Pathways,Including
COX-2
Jak/STAT
PI-3-K
IKK
ras
PIP2
PTEN
STAT3-P
PKC
raf
PTEN
PI-3,4,5-P
NF?B- I?B?
STAT3
MEK 1,2
NF?B
AKT 1,2,3 (PKB-P)
MAPK-P
COX-2 Expression
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Cyclooxygenase-2 (COX-2)

• Enzyme elevated in inflammation
• Also elevated in many premalignant and malignant
  tumors
• Colorectal polyps
• Respiratory papillomas
• Head and neck cancer
• Breast cancer
• Lung cancer
• Cervical cancer
• Prostate cancer

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COX-2 Induces Prostaglandins
Arachidonic Acid
COX-2
PGG2
COX-2
PGH2
PGD2
PGE2
PGF2a
PGI2
TXA2
angiogenesis, cell death, immune
surveillance
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COX-2, A Key Signaling Protein in Cancers
Reduce immune surveillance
EGF R
COX-2
PGE2
Stimulate EGF receptor
Stimulate tumor growth
Stimulate tumor blood vessels
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Overexpression of COX-2 in Papillomas
COX-2
Relative COX-2 levels
Neg control
Papilloma
Normal
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PGE2 Is Also Overexpressed in Papillomas
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Effect of PGE2 On Growth of Papilloma Cells
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Celebrex (Celecoxib)

• A selective COX-2 inhibitor
• Blocks enzyme activity
• Approved for treatment of familial colon polyps
• Clinical trials in progress to treat breast,
  lung, bladder and prostate cancers

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Celebrex Reduces Both PGE2 and COX-2 LevelsIn
Papilloma Cells
15
Celebrex also Increases Apoptosis (Cell Death)
of Papilloma Cells
16
EGF Receptor and COX-2 - A Positive Feed-Back
Loop Disrupted by Celebrex
Celebrex
PGE2
HPV
EGFR
COX-2
Inhibit cell- mediated immunity
Enhance Tumor mass
Celebrex
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Goals of Clinical Trial of Celebrex

• Determine whether Celebrex is a good adjunct to
  surgery for RRP
• Determine how it works
• Determine which patients will benefit from
  Celebrex

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Celebrex NIH Grant Proposal

• Project 1. Papilloma cells in tissue culture
  (Steinberg)
• Mechanism effects on cell growth, EGF receptor
  signaling
• Project 2. Celebrex trial in patients (Abramson,
  Shikowitz)
• Prevent or reduce recurrence compared to
  surgery alone
• If variable response, why
• Can we find markers to predict who will respond
• Project 3. Effects on host immune response to HPV
  proteins (Bonagura)

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Participants In New Celebrex Study

• Multi-centered study
• Richard Smith, Nancy Bauman, Jose Manaligod
• Univ. Iowa
• Glenn Peters
• Univ. Alabama, Birmingham
• Clark Rosen
• Univ. Pittsburgh
• John Sinacori
• Eastern Virginia Medical School
• Craig Derkay Consultant
• Eastern Virginia Medical School

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Celebrex Study Design

• Patients Age 18 or older, with 3 or more
  surgeries in past year, or tracheal/bronchial
  involvement
• Randomized - two start times (6 and 12 months)
  after enrollment - late group is control
  group, all receive celebrex
• Celebrex dose 400 mg BID max FDA approved
  dose
• Score disease at endoscopy every 3 months for
  total of 2 years
• Blood and biopsy studies celebrex levels,
  COX-2, PGE2, etc.
• Important that patients be treated by celebrex
  through study

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The Challenge of Clinical Trials
The next time you experiment with a new recipe,
Lorettta, Id like to be in the control group
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Acknowledgements
Rong Wu, MD, PhD.
Bettie Steinberg, Ph.D.
Allan Abramson, MD
May Nouri, MS
Supported by grant P50 DC00203 from the National
Institute on Deafness and Other Communication
Disorders, National Institutes of Health