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University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

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  1. 1. ET Retreat 2009 T Meiller DDS, PhD
  2. 2. Head and Neck Squamous Cell Carcinoma <ul><li>The most common type of cancer to affect the oral cavity (90%) </li></ul><ul><li>30,000 new cases in the United States-2005 (6 th ) and 500,000 worldwide (3 rd ) </li></ul><ul><li>Approximately 200,000 deaths occur worldwide due to oral and pharyngeal cancer annually </li></ul><ul><li>Despite advances in surgery, radiotherapy and chemotherapy, the improvement in survival rates has been minimal </li></ul>
  3. 3. Premalignant Lesions <ul><li>1/3 become cancer within 10y </li></ul><ul><li>36-80% OSCC pre-exist as dysplasia/ 16-62% leukoplakia </li></ul><ul><li>Severe-CIS 43% -> OSCC </li></ul><ul><li>Dx early 80% chance cure & functional, decreased morbidity/mortality </li></ul><ul><li>Non-invasive </li></ul><ul><li>Multiple signaling pathways: loss cell control </li></ul><ul><li>JAK, Stat3, MAPK, </li></ul><ul><li>mTOR, Survivin </li></ul>
  4. 4. Premalignant Development <ul><li>Early genetic abnormalities (3p, 9p, 17p) </li></ul><ul><li>Inactivation tumor suppressors (mut/del/meth) p53, CDKN2A </li></ul><ul><li>Activation oncogenes (mut/amp) </li></ul><ul><li>Allelic loss: 3p FHIT, telomerase repressor; 8q LRP12, Myc; 7p EGFR; 9p; 11q cyclin D1; 17q survivin </li></ul><ul><li>Telomerase activation-> loss of senescence & immortality </li></ul>
  5. 5. Mixed Results Historically Some Efficacy but Unacceptable Toxicities <ul><li>Previous studies using this model have shown efficacy but unacceptable toxicity of 13 cis-retinoic acid (Acutane) (Papadimitrakopoulou & Hong, Proc Soc Exp Biol Med 1997;216:283). A recently completed trial of the selective COX-2 inhibitor celecoxib (Celebrex) did not show efficacy (Boyle et al, AACR Meeting Abstracts 2006:B149). A negative trial of topical ketorolac was recently reported but delivery of the agent to the lesion was not proven (Mulshine et al, Clin Cancer Res 2004;10:1565; Boyle, Clin Cancer Res 2004;10:1557). </li></ul>
  6. 6. Prevention of Oral Squamous Cell Carcinoma <ul><li>Erlotinib Prevention of Oral Cancer (EPOC) </li></ul><ul><li>Phase IIB Randomized, Placebo Controlled Trial of Pioglitazone for Oral Premalignant Lesions </li></ul>
  7. 7. Pre-malignant and malignant epithelial lesions Oral Pathology Acquisitions DS SCC CIS Severe Dysplasia Moderate Dysplasia Mild Dysplasia Hyperkeratosis Hyperortho-keratosis Hyperpara-keratosis Acanthosis Years 41 2 9 13 23 15 103 80 109 1997 52 10 15 10 18 6 90 80 95 1998 69 4 9 12 17 7 85 74 103 1999 64 3 7 8 12 3 80 78 75 2000 97 6 8 10 19 12 90 89 129 2001 91 6 12 11 20 10 107 112 178 2002 87 8 9 25 16 4 98 88 138 2003 56 7 12 8 9 3 94 95 133 2004 71 12 13 12 26 5 78 117 132 2005 65 2 11 18 16 2 97 84 139 2006 69 4 14 19 26 7 105 118 170 2007 83 6 10 14 32 0 102 120 130 2008 36 1 8 7 19 3 51 78 86 2009*
  8. 8. Patient Accrual Assumptions <ul><li>intraepithelial neoplasia using the 169 (3 year total) </li></ul><ul><li>assuming a recall rate of 50%, that will give us approximately 84 patients </li></ul><ul><li>assuming approximately 50% of these will have the deletions that are necessary to be included, would give us a base of approximately 42 patients. It has been our experience that in studies such as this, our initial enrollment should be at a very minimum of 50%, giving us approximately 21 patients eligible for the EPOC trial almost immediately. </li></ul><ul><li>If you examine the curatively treated sample of 207, the numbers will be slightly higher, however, many of these patients may not be eligible, but an additional 10-15 would likely be available. </li></ul><ul><li>In addition to the recruitment using our current records of date, we have an active stream of new patients entering the system for biopsy and diagnosis and using the last two months as a gauge, we would have had an addition 20 eligible patients. Again using the estimates as above of 50%, etc. and recruitment successes of 60% would give us an addition four to five patients potentially entering the project. </li></ul><ul><li>pioglitazone (Actos®) treatment of oral premalignant lesions (OPL), namely dysplastic oral leukoplakia, hyperplastic leukoplakia in high risk locations (dorsal, lateral or ventral tongue or floor of the mouth) or erythroplakia of any histology. </li></ul>
  9. 9. Erlotinib Prevention of Oral Cancer (EPOC) NCI P01 CA106451 IEN alone Proportion of cases not developing SOM (%) IEN plus cancer history
  10. 10. Microdissection DNA extraction PCR Patient eligibility determined within 7 business days Data entered in Web-based database for automatic calculations Determining Protocol Eligibility by LOH DNA fragment separation and quantification
  11. 11. Erlotinib as an EGFR inhibitor <ul><li>The strong rationale for EGFR inhibition in this setting is based on the following: </li></ul><ul><li>1) EGFR is overexpressed in virtually all oral IEN; </li></ul><ul><li>2) levels of EGFR ligands are increased in oral IEN and in the oral mucosa of smokers; </li></ul><ul><li>3) suppression of EGFR signaling leads to reduced levels of cyclooxygenase-2 (COX-2) and decreased synthesis of prostaglandin E2 (PGE 2 ) in a model of oral IEN; PGE 2 -mediated </li></ul><ul><li>activation of EGFR signaling is dampened by an EGFR TKI; </li></ul><ul><li>4) EGFR TKIs suppress growth in oral cancer xenografts and IEN cells; </li></ul><ul><li>5) suppression of EGFR signaling is active in preclinical and clinical head and neck and lung prevention models. </li></ul>
  12. 12. <ul><li>PPAR gamma agonist pioglitazone (Actos®) may have activity against tobacco-related intraepithelial neoplasia (IEN) in humans, and this activity may be suggested by clinical or histologic response to pioglitazone (Actos®) treatment of oral premalignant lesions (OPL), namely dysplastic oral leukoplakia, hyperplastic leukoplakia in high risk locations (dorsal, lateral or ventral tongue or floor of the mouth) or erythroplakia of any histology. </li></ul>
  13. 13. Primary objective To determine the clinical and histologic response of oral premalignant lesions to 24 weeks of therapy with pioglitazone, 45 mg qd, defined as 50% or greater reduction in the measured product of perpendicular dimensions of the target lesion. <ul><li>Secondary Objectives </li></ul><ul><li>PPAR gamma, </li></ul><ul><li>cyclin D1 and p21 as indirect measures of pharmacological effect </li></ul><ul><li>TUNEL for apoptosis and Ki-67 for proliferation </li></ul><ul><li>transglutaminase and involucrin as markers of squamous differentiation </li></ul><ul><li>To determine the degree of change of C-reactive protein (CRP) in serum </li></ul><ul><li>To assess tobacco and alcohol use among trial participants and to examine the relationship of </li></ul><ul><li>tobacco and alcohol use to treatment response. </li></ul><ul><li>To assess the safety of this agent in this population. </li></ul>