chemo prevention

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Introduction

Oral cancer is a major global threat to publichealth with 300,000 new cases diagnosedworldwide on an annual basis.

Notably, the great morbidity and mortality ratesof this devastating disease have not improved indecades.

Oral cancer development is a tobacco-relatedmultistep and multifocal process involving fieldcarcinogenesis and intraepithelial clonal spread.


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Biomarkers of genomic instability, such asaneuploidy and allelic imbalance, can accurately

measure the cancer risk of oral premalignantlesions or intraepithelial neoplasia (IEN). Clinical management of oral IEN varies from

watchful waiting to complete resection, althoughcomplete resection does not prevent oral cancerin high-risk patients.

New approaches, such as interventions withmolecular-targeted agents and agentcombinations in molecularly defined high-risk

oral IEN patients, are being developed to reducethe devastating worldwide consequences of oralcancer.


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Oral leukoplakia is the most common oralintraepithelial neoplasia (IEN) and is a

precursor of oral squamous cell carcinoma(OSCC).

Oral IEN is far more prevalent than OSCC,

however, and preventing OSCC fromdeveloping in oral IEN patients will dependon accurately measuring these patientsrisk of oral cancer.

It is now possible to measure this riskthrough molecular assessments.


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Tobacco and alcohol are widely recognizedrisk factors for head and neck squamouscell carcinoma (HNSCC).

Some patients will achieve long-termsurvival, particularly those diagnosed with

early-stage disease.

However, patients with recurrent diseaseor distant metastases have a median

survival of only 68 months.


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Field cancerization and the multistepprocess of carcinogenesis are the twoconcepts which help in understanding thepathogenesis of head and neck cancer andother epithelial cancers.

Field cancerization was proposed bySlaughterin the 1950s, when it wasobserved that tissue adjacent to oral

carcinomas revealed dysplasia, carcinomain situ, and other histologic changes.


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This concept explained the increased risks forSPTs and local recurrences.

More recently, the discovery of geneticalterations supports this theory.

These events comprise the multistep process,

which includes inherited genetic alterations,damage from carcinogens such as tobacco andalcohol, and viral infections .

There has been great interest in developing

ways to interrupt these processes.


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CHEMOPREVENTION

Chemoprevention has been studied in severalmalignancies; however, its success is greatest in breastcancer, where tamoxifen has been shown to decreasethe incidence of invasive breast cancer in women at high

risk . Epidemiologic studies have suggested that nonsteroidal

anti-inflammatory drugs decreased the risk of coloncancer.

The cyclooxygenase-2 (COX-2) inhibitor celecoxib hasbeen shown to decrease the number of colonic polyps by28% in familial adenomatous polyposis, a condition thatconfers a markedly increased risk of colorectal cancer.


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Oral leukoplakia is a mucosal lesion that confersan increased risk for the development of

squamous cell carcinoma. Histologically, oral leukoplakia includes

hyperplasia, hyperkeratosis, dysplasia, andcarcinoma in situ.

The DNA content of the cells are predictive ofthe risk for the development of carcinoma.

Treatment for oral leukoplakia is removal, when

feasible, via surgery or laser therapy.


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Inherited susceptibility as well as exposureto carcinogens such as tobacco andalcohol result in DNA damage and anincreased risk for the development ofinvasive cancer.

Much of what is known about head andneck cancer chemoprevention is based onstudies of patients with oral leukoplakia.


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AGENTS IN HEAD AND NECKCANCER CHEMOPREVENTION

The most well-studied agents in head and neckcancer chemoprevention include vitamin A, otherretinoids, beta-carotene, vitamin E, selenium,

and COX-2 inhibitors. In addition, the investigation of biomarkers has

led to the development of epidermal growthfactor receptor (EGFR), tyrosine kinase inhibitors

(TKIs) and farnesyl transferase inhibitors (FTIs)are new promising agents for chemoprevention.


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VITAMIN A

Vitamin A (retinyl palmitate) deficiency wasimplicated as a cause of head and neck cancerwhen low levels of serum vitamin A were found

twice as often in patients with stage III and IVdisease than in healthy individuals.

Lower levels of vitamin A were also found inhead and neck cancer patients with SPTs

compared with those without SPTs, suggesting apossible role in their etiology.


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It is thought that these agents restoreexpression of retinoic acid receptor-beta

(RAR-) mRNA, which may promotenormal tissue growth and differentiation.

In a randomized controlled trial of

smokeless tobacco users and betel nutchewers with oral leukoplakia, participantswere given either 200,000 IU of vitamin A

weekly for 6 months or placebo.


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Complete remissions occurred in 57.1% andsuppression of the development of new

leukoplakia occurred in 100% of the treatedgroup, versus 3% and 21% of the placebogroup, respectively.

This was confirmed by histologic and cytologicdifferences between biopsies taken at thebeginning and the completion of the trial.

(Stich HF, Hornby AP, Mathew B et al.

Response of oral leukoplakias to theadministration of vitamin A. Cancer Lett1988;40:93101.)


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European Study on Chemoprevention withVitamin A and N-acetylcysteine (EUROSCAN) is a

large randomized intervention study in over2,000 patients with head and neck cancer orlung cancer.

In that study, patients were randomized to

receive vitamin A (300,000 IU/day followed by150,000 IU/day in the second year), N-acetylcysteine (600 mg/day for 2 years), bothcompounds, or no intervention.

Unfortunately, recurrence, SPT, and death rateswere not better in any of the intervention groupswith a median follow-up of 49 months.


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OTHER RETINOIDS IN ORALLEUKOPLAKIA

Retinoids have been shown to have beneficialeffects on epithelial cancers in animal studies.

Compared with the approximately 15%

spontaneous regression rate of oral leukoplakia,Kochachieved complete or partial remissions in45% of patients with these premalignant lesionstreated with one of three retinoids13-cis-

retinoic acid (isotretinoin), trans-beta-retinoicacid, and aromatic retinoidafter follow-up ofup to 6 years.


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Hong et al. showed that high doses ofisotretinoin were active against oral

leukoplakia. There were significant decreases in the

sizes of lesions in 16 of 24 patients (67%)

receiving 12 mg/ kg/body weight/day,compared with only 2 of 20 patients(10%) receiving placebo.

Clinical response correlated with histologicresolution in nine of those 16 patients.


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However, toxicities were significant.

They included cheilitis, erythema and dryness of the

skin, and hypertriglyceridemia, which, in some cases,required reduction or cessation of the drug.

Furthermore, over 50% of patients with responsesrelapsed within 3 months after therapy was stopped.

However, since the study lasted only 9 months, it couldnot be determined whether leukoplakia regressioncorrelated with a decrease in future invasive cancers.

Hong WK, et al. 13-cis-retinoic acid in thetreatment of oral leukoplakia. N Engl J Med

1986;315:1501

1505.


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Adverse effects of high-dose isotretinoin and therelapse rate after discontinuation of the drug led

to the testing of another regimen with lowerdose of isotretinoin for a longer period of time.

Lippman et al., treated patients with leukoplakia

initially with isotretinoin at a high dose (1.5mg/kg) for 3 months.

Those who had stable or improved lesions thenproceeded to the maintenance phase - 30 mg of

beta-carotene versus isotretinoin (0.5 mg/kg) for9 months.


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55% patients had complete or partial clinicalresponses, 35% had stable disease, and sevenhad progression and did not proceed to the

maintenance phase. 92% patients on maintenance therapy with low-

dose isotretinoin and 45% patients who receivedbeta-carotene responded to the therapy or hadstable disease.

Additionally, there were minimal side effects inboth groups in the maintenance phase.(Lippman SM, et al. Comparison of low-dose isotretinoin with beta carotene toprevent oral carcinogenesis. N Engl J Med1993;328:1520.)


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RETINOIDS FOR SPT PREVENTIONIN HEAD AND NECK CANCER

HONG et al did a study on role of retinoids in theadjuvant setting in HNSCC.

103 patients with stage I-IV HNSCC received

either placebo or 50100 mg/m2 isotretinoindaily for 1 year.

Although there were no significant differencesbetween the two groups in the number of local,

regional, or distant recurrences of the primarycancers, the treatment group had significantlyfewer SPTs.


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After a median follow-up of 32 months, only twopatients (4%) in the isotretinoin group, versus

12 (24%) in the placebo group, had SPT. Long-term follow-up showed that, in the

treatment group, there was a 14% rate ofdevelopment of an SPT, versus 31% in the

placebo group after a median of 54.5 months. The toxicities encountered with high-dose

retinoids have prevented them from becomingthe standard of care, while low-dose retinoids

have been shown to be ineffective. An efficacious schedule with an adequate dose

of retinoids has not been achieved.


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A clinical trial was conducted by Kaugars et alon 79 patients with oral leukoplakia.

They received antioxidant supplements of 30 mgbeta-carotene as well as 1,000 mg ascorbic acidand 800 IU vitamin E or alpha-tocopherol (Alpha-TF) for 9 months.

There was clinical improvements in 56% ofthose patients.

(Kaugars GE, Silverman S Jr, Lovas JG et al.A clinical trial of antioxidant supplements

in the treatment of oral leukoplakia. OralSurg Oral Med Oral Pathol 1994;78:462468)


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In another study patients with early-stagehead and neck cancer received either 50

mg beta-carotene or placebo after beingcuratively treated with radiation and/orsurgery, showed no differences betweenthe two groups in mortality, time to SPTdevelopment, or local recurrences.

(Mayne ST, Cartmel B, Baum M et al.Randomized trial of supplemental

beta-carotene to prevent secondhead and neck cancer. Cancer Res2001;61:14571463.)


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In the Physicians Health Study, 12 years ofsupplementation with beta-carotene producedneither benefit nor harm in the incidence of

malignant neoplasms . Furthermore, the beta-carotene and retinol

efficacy trial (CARET) actually showed that thecombination of beta-carotene and vitamin A had

a relative risk of lung cancer and a relative riskof death from cardiovascular disease. Those trials prompted beta-carotene to be

removed from chemoprevention trials for oralpremalignancy in smokers.


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VITAMIN E AND SELENIUM

The antioxidant vitamin E (Alpha -TF) prevented thedevelopment of cancers in oral cavities in animal studies.

A phase II study showed that, among 43 patients withoral leukoplakia who took 400 IU of vitamin E twice daily

for 24 weeks, 20 (46%) had clinical responses and nine(21%) had histologic responses

(Benner SE, Winn RJ, Lippman SM et al. Regressionof oral leukoplakia with alpha-tocopherol: acommunity clinical oncology program

chemoprevention study. J Natl Cancer Inst1993;85:4447)


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The trace element selenium was proposed to be apotential agent for head and neck cancer

chemoprevention when epidemiologic studies showedthat death rates for head and neck cancer were lower inregions where soil contained higher levels of selenium.

In patients undergoing surgery and/or radiation therapyfor head and neck cancer, supplementation with 200 g

of selenium per day was found to be associated with asignificantly enhanced cell-mediated immuneresponsiveness. (Kiremidjian-Schumacher L, Roy M.Effect of selenium on the immunocompetence ofpatients with head and neck cancer and on

adoptive immunotherapy of early and establishedlesions. Biofactors 2001;14:161168.)


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BIOCHEMOPREVENTION

Biochemoprevention therapy combinedhigh-dose isotretinoin, alpha-TF, andinterferon-alpha (IFN-Alpha ).

Alpha-TF had been chosen because of its1.synergistic effects with retinoids,

2.its ability to decrease the toxicity of

isotretinoin,

3.its minimal side effect profile.


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In preclinical studies, this three-drugcombination showed a markedly better inhibitionof cell growth compared with each single agent

or two-drug combination. Cell cycle analysis showed that cells were

inhibited in the S phase, and a binding assayindicated greater apoptosis by the three-drug

combination. (Shin DM, Wang ZK, Feng C etal. Biochemopreventive combination (13-cis-retinoic acid, interferon- 2alpha andalpha-tocopherol) may have synergisticeffects over single-agents or 2-drug

combinations in vitro culture of squamouscell carcinoma of the head and neck cells.Proc Am Assoc Cancer Res 2002;43:311a).


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A prospective, nonrandomized phase IItrial by Papadimitrakopoulou et al.

enrolled patients with biopsy-provenadvanced premalignant lesions (e.g., mild,moderate, and severe dysplasia) of the

oral cavity, oropharynx, and larynx. In this study 4750% of patients with

laryngeal dysplasia, had completeresponses at 6 to 12 months.


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However, patients with oral cavity andoropharynx dysplasia did not achieve such.

Seven patients whose pretreatment biopsiesexpressed a mutant p53gene were found tohave had a reappearance of the wild-type p53gene in post treatment biopsies, suggestingbiochemoprevention may suppress the mutantp53gene.

(Shin DM, Mao L, Papadimitrakopoulou VMet al. Biochemopreventive therapy forpatients with premalignant lesions of thehead and neck and p53 gene expression. JNatl Cancer Inst 2000;92:6973).


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Adenovirus, ONYX-015 Approximately 40% to 50% of HNSCC carry an

inactivating mutation of the p53tumor suppressor gene. Altered p53 expression is found in up to 45% of

dysplastic mucosal lesions of the head and neck.

(Journal of Clinical Oncology, Vol 21, Issue 24(December), 2003: 4546-4552

2003American Society for Clinical OncologyAn Attenuated Adenovirus, ONYX-015, AsMouthwash Therapy for Premalignant OralDysplasia

Charles M. Rudin, Ezra E.W. Cohen, Vassiliki A.Papadimitrakopoulou, Sol Silverman, Jr, WendyRecant, Adel K. El-Naggar, Kirsten Stenson, ScottM. Lippman, Waun Ki Hong, Everett E. Vokes )
http://jco.ascopubs.org/misc/terms.shtmlhttp://jco.ascopubs.org/misc/terms.shtml


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Dysregulation of p53 in mucosal

epithelium correlates with increasedproliferation and dedifferentiation.

These findings suggest that mutationalinactivation of p53 is a critical andrelatively early event in oralcarcinogenesis, often preceding clinicallyevident malignant transformation.


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ONYX-015 is an attenuated adenovirus designedto preferentially replicate in and destroy p53-

mutant cells. ONYX-015 carries an inactivating deletion in thegene encoding the E1B 55-kd protein.

The E1B 55-kd protein binds to and inactivatescellular p53 and is required for efficient viralreplication in most human cells.

In cells lacking p53 function, adenoviralreplication can proceed in the absence of E1B55-kd protein.

Thus, ONYX-015 may be selectively lytic in cellsin which p53-dependent signaling pathways arenonfunctional.


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Recent studies demonstrate that ONYX-015 canreplicate in several tumor lines containing intact

p53, in contrast to initial expectations. Cell lines that support ONYX-015 replication

despite normal p53 genotype seem to carryother defects in p53-dependent response

pathways, including abnormal expression ofMDM2 and p14ARF.

These observations extend the potentialantitumor activity of ONYX-015 to include not

only cells with inactivating mutations of p53 butalso cells harboring other functional defects inp53-dependent response pathways.


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In a study conducted by Charles M. Rudin, etal concluded that ONYX-015 may have potential

synergy with retinoid therapy in oral cancerchemoprevention.

High-dose isotretinoin is primarily active againstdysplastic lesions without upregulated p53 anddoes not suppress p53 levels in dysplasia.

Through its differentiating activity, retinoidtherapy may promote transient resolution of the

hyperplastic and hyperkeratotic thickening ofmucosa associated with early dysplastic lesions.


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Retinoid therapy might be predicted to increasethe accessibility of the basal mucosal layers ofdysplastic lesions to viral infection with ONYX-

015. Topical administration of ONYX-015 for

chemoprevention in the oral cavity has sometheoretical advantages over systemic drug

therapy.1. topical ONYX-015 administration limitsexposure to the involved oral mucosa,minimizing the potential for adverse systemiceffects.

2. this approach targets a signaling pathwayimplicated in malignant transformation.


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Unlike isotretinoin, which functionsprimarily as a differentiating agent, ONYX-

015 has been shown to be selectivelycytotoxic for cells with defects in p53-dependent response pathways.

The lack of adverse effects with ONYX-015

combined with evidence of potentialefficacy supports the rationale for phase IIstudies of this agent both in patients with

oral dysplasia and as preventive therapy inpatients at high risk of local relapse afterresection of oral cancer.


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NEW TARGETS AND BIOMARKERSOF HNSCC

HNSCC develops after the accumulation ofgenetic changes in epithelia exposed tocarcinogens.

This multistep process has led to theinvestigation of biomarkers that may representdistinct alterations and may lead to thedevelopment of new chemopreventive agents aswell as serve as intermediate points in

chemoprevention trials.


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These biomarkers include oncogenes, growthfactors and growth factor receptors, and tumorsuppressor genes.

Expression of RAR- is selectively lost as tissueprogresses through dysplasia to invasivecarcinoma .

A tumor suppressor gene on chromosome 9p isalso lost in oral dysplastic lesions, and loss ofheterozygosity was found in 72% of HNSCCtumors.

Multistep process of the development of HNSCC.


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Multistep process of the development of HNSCC.Abbreviations: TGF- = transforming growth factor alpha;PCNA = proliferating cell nuclear antigen.


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H-RAS GENE

Members of the ras gene family areamong the most commonly alteredprotooncogenes in a variety of solid

tumors.

A mutation in the H-rasgene is found in27%61% of squamous cell carcinoma

cases and 30% of cases of oralleukoplakia.

O O


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EPIDERMAL GROWTH FACTORRECEPTOR

The EGFR is a 170-kDa transmembraneprotein that plays an important role inorganogenesis and tissue homeostasis and

is thought to be important in theproliferation and survival of cancer cells.

Overexpression of the EGFR has beenfound in several malignancies, includinghead and neck, lung, breast, prostate,bladder, and pancreatic cancers.


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Dysregulation of EGFR has been found in80%90% of HNSCC specimens and is felt

to correlate with a greater risk for diseaserecurrence.

Since the EGFR is frequently expressed in

HNSCC, blocking the EGFR is an excellentapproach to treat and prevent head andneck cancer.

One approach to block the EGFR includes

targeted agents that inhibit EGFR tyrosinekinase.


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These TKIs include gefitinib (Iressa;AstraZeneca Pharmaceuticals; Wilmington,

DE) and erlotinib (TarcevaTM; Genentech,Inc.; South San Francisco, CA).

In phase I trials, gefitinib has shown

antitumor activity in patients with non-small cell lung cancer.

Preliminary data from a phase II study

with 250 mg/day gefitinib support asuperior toxicity profile, but conclusionsregarding efficacy have not been made.


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p53GENE

p53is a tumor suppressor gene located on theshort arm of chromosome 17, and mutations inthis gene occur in 43% of HNSCC patients.

The expression of p53 protein in HNSCC hasbeen shown to be predictive of shorter survivaland may be a valuable marker for identifyingindividuals at high risk for developing recurrentdisease or SPTs.

p53status has also been shown to be anindependent indicator of response toneoadjuvant chemotherapy.


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CYCLOOXYGENASE-2 INHIBITORS

Selective COX-2 inhibitors are promising agentsin chemoprevention.

Mechanisms by which COX-2 activity contributes

to carcinogenesis are:1. COX-2 is thought to enhance the productionof vascular growth factors, leading toneoangiogenesis, as well as to mediate

cytokines involved in chronic inflammation,resulting in increased epithelial carcinogenesis.

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2. catalyzing the conversion ofprocarcinogens to carcinogens,

3. decreasing apoptosis, and4.stimulating the invasive phenotype ofcancer cells.

COX-2 is expressed in neoplastic cells inhead and neck, lung, colon, and breastcancer tissues.

Nearly 100-fold greater expression levels

of COX-2 were found in HNSCC cellscompared with normal oral mucosa.


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COX-2 inhibitors were first studied aschemopreventative agent in colonic polyps

and colorectal cancer and have anestablished use in familial adenomatouspolyposis.

Potential prevention of breasthepatocellular ,and bladder cancers hasalso been proposed.


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A randomized animal study by Wang et al.showed a significant difference between the

quantity of new vasculature at tumor sites inmice intradermally inoculated with oralcarcinoma cells and control mice, suggesting thechemopreventative efficacy of the COX-2

inhibitor celecoxib. In one study it was found that the combination

of the EGFR-TKI and celecoxib synergisticallyinhibited the growth of the HNSCC cell lines,

with apoptosis in 72% with combined treatment,21%50% with single-agent therapy, and 8%without treatment.


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This combined approach, with EGFR-TKIsand COX-2 inhibitors, has great promise inthe future chemoprevention of HNSCC.

Ch ti P ti f


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Chemopreventive Properties ofNSAIDs

Prostaglandins, especially PGE2, appear tobe important in the pathogenesis ofcancer secondary to effects on

mitogenesis, cellular adhesion, immunesurveillance and inflammation, andapoptosis.

Studies have shown that PGE2 and COX-2

are overproduced in colon neoplasticlesions.


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Additionally, COX-2 has been implicated intumorigenesis in a variety of tissues

including tumors of the head and neck. COX-2 is a member of a family of dual

function enzymes, PGH synthases, that

catalyze the formation of PGs from thefatty acid arachidonic acid.

COX-2 mRNA and protein expression isinducible in most tissues by externalstimuli such as tumor promoters, growthfactors, and cytokines.


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Overexpression of COX-2 is thought tocontribute to carcinogenesis by stimulating cell

proliferation, inhibiting apoptosis, and enhancingangiogenesis.

These effects are thought to be PG-dependenteffects.

COX-2 is also thought to hasten carcinogenesisby producing reactive oxygen products as a by-product of its catalytic function.

In addition, data suggest that PGs contribute tothe inhibition of antitumor immune defensemechanisms.

As a result cancer preventive and treatment


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As a result, cancer preventive and treatmentstrategies using NSAIDs, both nonselective andhighly selective COX-2 inhibitors, have been

focused on tissues that overexpress COX-2. Studies reveal increased levels of COX-2 inpremalignant and malignant lesions of the oralcavity, which is one rationale for testing thesecompounds in the treatment of lesions such as

oral leukoplakia.(Chan G., Boyle J. O., Yang E. K., Zhang F.,

Sacks P. G., Shah J. P., et alCyclooxygenase-2 expression up-

regulated in squamous cell carcinoma ofthe head and neck. Cancer Res., 59: 9991-9994, 1999).


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Additionally, immunohistochemicalevidence of expression of COX-2 protein in

oral mucosal lesions with a gradient ofincreasing COX-2 stain was foundincreasing from hyperplasia to dysplasiaand was highest in squamous cell

carcinoma .(Renkonen J., Wolff H., Paavonen T.

Expression of cyclooxygenase-2 in

human tongue carcinoma andprecursor lesions. Virchows Archiv.,440: 594-597, 2002).


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Direct evidence of COX in tongue carcinogenesishas been shown in a rat model with inhibition ofdysplasia occurring with the administration of

NSAIDs in animal models.Another study with COX-2 overexpression in

precancerous lesions and squamous cellcarcinomas in rat tongue revealed that the

administration of an NSAID reduced theincidence of squamous cell carcinoma in animalsto 2331% compared with 71% in untreatedcontrols .

These studies reveal that COX inhibition,particularly COX-2 inhibition, has a potential rolein the chemoprevention of head and necksquamous cell carcinomas.


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These data reveal a clear linkage betweenexpression of COX-2 and inhibition of

apoptosis.

Additionally, a correlation between p53and COX-2 expression has been reported

with cells that carry mutant p53expressing high levels of COX-2

Of note, NSAIDs induce apoptosis in

colon cancer cells and other tissues,regardless of p53 status.


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An additional cellular process by which NSAIDsmay inhibit tumor growth is through theinhibition of angiogenesis.

A correlation between COX-2 levels andangiogenesis has been shown in several studieswith increased production of vascular-endothelialgrowth factor by epithelial cells.

Additionally, increased levels of PG synthesis hasalso been shown to promote cell proliferationand angiogenesis.

Vascular-endothelial growth factor has been

shown to be elevated early in the progressionfrom dysplasia to carcinoma in oral squamouscell carcinoma.

h f d h


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These findings are consistent with priorreports that revealed overexpression of

COX-2 in epithelial cells led to enhancedproduction of vascular growth factors andthe formation of capillary-like networks.

The inhibition of COX has been shown tocause reductions in angiogenic activity andto reduce tumor invasiveness andmetastasis.


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The epidermal growth factor receptor (EGFR), aproduct of the erboncogene, is alsooverexpressed in the development of certainepithelial neoplasms early in the development ofcancers of the upper aerodigestive tract,including oral cancer.

It is also overexpressed in premalignant oral

leukoplakia as well. Furthermore, EGFR expression has been

correlated with lesion severity and proliferativecapacity.

EGF and the ligand of the EGFR induce COX-2,contributing to the increased levels of PG inpremalignant and malignant cells in head andneck tumors.


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NSAIDs and selective COX-2 inhibitors mayprevent carcinogenesis by affecting other non-COX-, non-PG-related molecular mechanisms.

The effects of these compounds on cellproliferation, cell survival, or transformation donot appear to be related to the expression ofCOX isoforms or PGs.

Many molecular pathways have been shown tobe affected by these agents associated withtheir effects on cell growth inhibition, includingperoxisome proliferator-activated receptors,nuclear factor- B, and apoptosis effectormolecules such as BAX, among others.

Limitations of NSAIDs for


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Chemoprevention in the Oral

Mucosa Transforming growth factor- (TGF- ), the

ligand of EGFR, is also overexpressed in

dysplastic oral leukoplakia. Significant overexpression of TGF- mRNA

was predictive of a response to

chemopreventive intervention with 13-cis-retinoic acid and its levels were alsomodulated by this treatment.


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Thus, agents that affect upstream factorsin the EGF signaling pathway may be

useful chemoprevention agents in oralcancer.

Although NSAIDs may be beneficial in

inhibiting EGF-induced increases in COX-2,they have not been shown to affect theexpression of TGF- mRNA.


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Whereas the NSAIDs are promising chemopreventiveagents, prolonged use of these agents is limited bygastric and renal toxicity.

As preventive agents, they must possess minimal toxicityfor long-term therapy.

Novel methods of administration have been evaluated tomaximize exposure while minimizing toxicity, with topical

therapy being an effective method of administration inanimal models.

(Clinical Cancer Research Vol. 10, 1561-1564,March 2004 2004American Association for Cancer Research

The Biology Behind NSAIDs for theChemoprevention of Oral Cancer: Promise orPessimism? )
http://clincancerres.aacrjournals.org/misc/terms.shtmlhttp://clincancerres.aacrjournals.org/misc/terms.shtml


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CONCLUSION

Chemoprevention is an attractive strategy inhead and neck cancer management, althoughpast trials have not demonstrated its feasibility.

Single-agent retinoids are active against oralpremalignant lesions, demonstrating a proof thathead and neck cancer chemoprevention ispossible.

Biochemoprevention (isotretinoin, IFN-alpha,alpha-TF) is a promising approach, but itsefficacy needs to be determined in phase IIItrials.

M l l t t d t h EGFR TKI FTI d


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Molecular targeted agents such as EGFR-TKIs, FTIs, andCOX-2 inhibitors are important potential treatments.

Future clinical trials should test these new agents and

combinations of these agents. Questions remain regarding the optimal dose and

duration of therapy with retinoids and other agents.

Other challenges include achieving efficacy while

maintaining acceptable toxicity levels and good patientcompliance.

Although vast advances have been made in theknowledge of head and neck carcinogenesis,chemoprevention for HNSCC remains investigational.

chemo prevention

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