Clinical Cancer Research Vol. 10, 4249S-4253S, June 15, 2004
© 2004 American Association for Cancer Research
Proceedings of the First International Conference |
Molecularly Targeted Approaches to the Chemoprevention of Lung Cancer
Fadlo R. Khuri1 and
Victor Cohen2
1 Winship Cancer Institute, Emory University, Atlanta, Georgia, and 2 Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada
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ABSTRACT
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Large, randomized trials have been conducted in the primary prevention of lung cancer using micronutrients or derivative agents for which epidemiological data suggested a potential role in lung cancer prevention. The disappointing primary prevention trials of ß-carotene, 
-tocopherol, and retinyl palmitate have led to the development of a more compact, biomarker-driven series of translational trials of lung cancer prevention that target reversal of premalignancy as the primary end point. Serial trials of 13-cis-retinoic acid (isotretinoin) and other retinoids have failed to show a difference in reversal of premalignancy in active smokers or in second primary tumor prevention. However, a trial of 9-cis-retinoic acid, a pan retinoid/rexinoid agonist, showed up-regulation of retinoic acid receptor ß (RAR-ß), a potentially important intermediate marker of response in lung cancer premalignancy. Other planned or ongoing trials currently target important molecular markers of lung carcinogenesis and progression including cyclooxygenase-2, the ras-signaling pathway through farnesyl transferase inhibitors, and the tyrosine kinase/epidermal growth factor receptor pathway (gefitinib, erlotinib). Early results of bioadjuvant trials in head and neck cancer suggest that combination chemoprevention will ultimately be an important option.
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INTRODUCTION
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Lung cancer is by far the leading cause of cancer-related death worldwide, with about 1,240,000 cases of lung cancer diagnosed in 2001 and close to 1,500,000 anticipated by 2003 (1)
. The devastating 5-year survival rates for this disease in the United States including all stages is 16.8% (2)
, with 5-year survivals in Great Britain approximately 7% (1)
. Most of the progress in this disease during the last decade relates to the introduction of novel agents, improved surgical techniques, and increased utilization of concomitant chemoradiotherapy for locally advanced lung cancer (3)
. However, the results remain quite dismal, and many believe the best approach to this disease is to intervene in the premalignant stage.
Cancer chemoprevention was first defined by Michael Sporn as attempts to "reverse, suppress, or prevent progression of disease from preinvasive cancer to frank malignancy" through pharmacological interventions (4)
. The field was largely pioneered by Waun Ki Hong, who, in his seminal studies in upper aerodigestive tract cancer, showed that high doses of synthetic retinoids, namely 13-cis-retinoic acid, were effective in reversing upper aerodigestive tract premalignancy [Hong et al. (5)
] and in preventing second primary tumors in advanced head and neck cancer (6)
. Subsequent results in this area with low-dose retinoids, which have been shown to be well tolerated but ineffective, have been somewhat disappointing. With the advent of novel targeted agents, there has been a push to consider molecularly targeted approaches to non-small cell lung cancer. The success of these agents remains open to question at this time. First, it might be worthwhile to discuss the biology of lung cancer, give an overview of the chemopreventive trials completed to date in this area, and finally conclude with planned trials and future directions in lung cancer chemoprevention.
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LUNG CANCER BIOLOGY AND CHEMOPREVENTIVE APPROACHES
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Lung carcinoma seems to develop from a pleuripotent stem cell that is involved in the generation of the bronchial epithelium and that is capable of differentiating along several different pathways. The multistep process of carcinogenesis can be viewed as progressive disorganization characterized by the occurrence of initiation, promotion, and progression events happening over latent periods of a decade or more and resulting from exposure to a variety of environmental insults (7
, 8)
. These events result in the accumulation of genetic and epigenetic alterations of at least three groups of genes, proto-oncogenes, tumor suppressor genes, and mutator genes, resulting in imbalances between cellular proliferation, apoptosis, and shedding. Malignant lesions can develop from multiple genetically distinct clones in diverse areas, defined as field carcinogenesis, and lateral intra-epithelial spread of genetically related preinvasive clones. Field carcinogenesis denotes the process of diffuse epithelial tissue injury resulting from carcinogenic exposure in an entire epithelial field or region in which tissue changes can be detected at the gross, microscopic, and molecular levels (9)
. Recent observations detecting extensive genetic alterations in histologically normal-appearing tissue from high-risk individuals has provided strong support for this notion (10)
. The clinical importance of these phenomena is best illustrated in aerodigestive tract cancers in which both synchronous and metachronous second primary tumors are common (10)
. These two basic concepts of multistep carcinogenesis and the diffuse field-wide carcinogenic process provide an excellent model for prevention studies and have guided the development of lung cancer chemoprevention efforts.
The essential principle of chemoprevention is to intervene within the multistep carcinogenic process and throughout the tobacco/carcinogen-damaged field. Using pharmacological or natural compounds, secondary chemoprevention is designed to interrupt the clonal propagation of aberrant cells by blocking DNA damage, retarding or reversing the malignant phenotype, or inducing apoptosis in the damaged cells of premalignant lesions (11)
. Primary prevention of lung cancer involves intervening with pharmacologically or chemically active compounds with an acceptable level of tolerance in patients considered to be at high risk for the development of lung cancer. Preventive measures would include smoking cessation or prevention of smoking initiation. Chemopreventive approaches would include intervening with minimally toxic compounds, such as nonsteroidals or cyclooxygenase-2 (COX-2) inhibitors or potentially vitamin A derivatives, if they were effective to prevent the development of lung cancer in this patient population, with that being the primary end point. Chemoprevention of second primary tumors in patients treated for, or cured of, an initial malignancy is a good example of tertiary prevention, whereas normal, healthy individuals, or individuals at increased risk for cancer, including former active smokers, are the targets for primary preventive interventions, such as smoking prevention and cessation or the use of chemoprevention drugs in a group of asymptomatic smokers.
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LUNG CANCER CHEMOPREVENTION STRATEGIES: LIMITED SUCCESS, IMPORTANT CLUES
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To date, several agents have been tried for primary prevention of lung cancer. These include compounds targeting several important developmental proteins. Of these, by far the most widely studied have been the retinoids, synthetic or natural vitamin A derivatives meant to prevent the progression from premalignancy to invasive cancer (11)
. Several chemoprevention trials have been carried out to date in lung cancer, and they are summarized in Table 1
. Among these, several large trials randomizing high-risk individuals in the primary prevention setting to ß-carotene and/or retinol (12
, 13)
have resulted in increased risk of developing lung cancer in those individuals randomized to these agents (14)
. Secondary prevention trials have generally attempted to reverse premalignant lesions (15, 16, 17, 18, 19, 20)
. Most of these trials with various retinoids, including isotretinoin, fenretinide, etretinate, or retinol, have had negative outcomes, whereas in a small trial by Heimburger et al. (19)
results with vitamin B12 and folic acid were noted to be positive (Table 1)
. However, a subsequent reanalysis of this one positive trial using standard analytical methods found a negative outcome. Finally, large randomized tertiary prevention trials in former cancer patients have been mostly negative (21
, 23)
. Although the initial trial of retinyl palmitate in the prevention of second primary lung cancers in individuals who had a prior history of a stage I non-small cell lung cancer had a positive initial result (21)
, subsequent studies, including the EUROSCAN study (22)
and the United States Intergroup Study (23)
, showed no benefit for intervening with retinoids in individuals known to have a prior history of lung cancer. In fact, these trials continue to suggest that individuals who maintained their smoking behavior and were given supplementation with vitamin A derivatives might have had an enhancement of their risk of developing lung cancer. However, there were supportive trends for decreases in primary tumor recurrence in individuals who were never smokers and were randomized to a retinoid in the United States Intergroup Study (Table 1)
.
Among recent studies targeting the reversal of premalignancy, one trial randomized former smokers to 13-cis-retinoic acid plus -tocopherol versus 9-cis-retinoic acid, a pan-retinoid agonist, versus placebo in an attempt to reverse premalignancy in former smokers, with the desired biomarker being the up-regulation of retinoic acid receptor ß (RAR-ß) in the bronchial epithelium of former smokers (20)
. Although 9-cis-retinoic was more effective than placebo in up-regulating RAR-ß, our own data implicate the maintenance of RAR-ß intratumorally in stage I lung cancers in individuals with a poorer prognosis. Additional work from our group indicated that RAR-ß expression in stage I non-small cell lung tumors correlated with cyclooxygenase-2 (COX-2) expression, which was also an indicator of poor prognosis (24
, 25)
.
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NOVEL AGENTS IN THE CHEMOPREVENTION OF LUNG CANCER: PROMISE, BUT LIMITED PROGRESS?
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The data from our group, showing that expression of COX-2 mRNA correlated with RAR-ß expression and portended a poorer survival, have enhanced interest in examining selective COX-2 inhibitors in the secondary chemoprevention of lung cancer (24
, 25) . Clinical trials of celecoxib and rofecoxib are ongoing at the University of California-Los Angeles and at the University of Texas M. D. Anderson Cancer Center, seeking to evaluate whether premalignant lesions in the lung can be reversed, using these compounds to down-regulate COX-2-dependent cell signaling pathways (Ref. 26
; Fig. 1
). Additional studies of prostacyclin inhibitors are being conducted through the Lung Cancer Biomarker Chemoprevention Consortium (LCBCC), which includes several leading lung cancer research institutions in North America. Randomized trials of iloprost, a prostacyclin inhibitor, versus placebo, initiated at the University of Colorado by Dr. Paul Bunn, are being expanded to several other research institutions.
Two proposed trials testing novel signal transduction inhibitors have been stalled because of disagreements between the National Cancer Institute (NCI) and the Food and Drug Administration (FDA) as to the relative safety profile of these agents. These two trials, part of the STOP (Selective Trials of Prevention) Lung Cancer program, examine an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib, and a farnesyl transferase inhibitor (FTI), tipifarnib, in the reversal of premalignant lesions of the lungs. Randomized trials are planned to run in parallel for a target accrual of 150 patients with a 2:1 randomization favoring active drug versus placebo (Fig. 2)
. The primary end point in the STOP trial is the reversal of dysplasia and the secondary endpoints are biomarker-related changes. These trials propose to recruit individuals with a prior history of a tobacco-related cancer (non-small cell lung, head and neck squamous cell, small cell lung, bladder, or esophagus) who have had definitive therapy, either surgery or chemoradiation therapy for prior early-to-intermediate-stage disease and who are 1–3 years out from their last treatment. Those individuals who have a 30-pack-year smoking history and evidence of sputum atypia will also be eligible for these two randomized trials. These trials are currently under discussion among FDA, NCI, and Specialized Programs of Research Excellence (SPORE) investigators, with the hope that these studies will eventually be activated in the United States and possibly in Europe (27)
. One major question is, given that the fastest increasing histology of lung cancers is adenocarcinoma, when premalignant progression to overt disease has been less well described than in squamous cell cancers and are generally peripheral lesions at their outset, a new model will need to be developed to assess improvement or reversal in premalignancy. It may ultimately be that serial computed tomography-guided biopsies of peripheral lesions, such as atypical alveolar hyperplasia, will be necessary to evaluate premalignancy and response to treatment in a comprehensive manner.
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Fig. 2. This figure shows the tandem trial schema of the two lung cancer biomarker chemoprevention consortium Selective Trials of Prevention (STOP) Lung Cancer Trials. In both of these trials [STOP FTI (farnesyl transferase inhibitor, tipifarnib); and STOP TKI (tyrosine kinase inhibitor, gefitinib)], the plan is to accrue 150 patients, of whom two-thirds will be randomized to active drug (Rx) and one-third to placebo. All of the patients undergo a bronchoscopy at baseline, and have a repeat bronchoscopy at 6 months, using the combined placebo groups to enhance the statistical power of study.
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CONCLUSIONS
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Lung cancer chemoprevention studies have thus far failed to yield substantial evidence of compounds that can reverse, suppress, or prevent cancer progression. The introduction of novel agents targeting important cellular signaling pathways, such as retinoid-based differentiation and apoptosis, the EGFR, the ras signaling pathway, and the COX-2 pathway, may enhance our therapeutic index and accelerate the discovery of novel chemopreventive agents. There needs to be collaborative development of acceptable standards for reasonable safety and toxicity profiles for the enrollment of patients in these trials, and this discussion is ongoing between the FDA, NCI, and selected investigators in the field.
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OPEN DISCUSSION
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Dr. Thomas Lynch: Where do we stand with the STOP-FTI (farnesyl transferase inhibitor) and STOP-TKI (tyrosine kinase inhibitor) trials? I thought these represented a wonderful trial design for asking questions of chemopreventive agents. What do you think the hurdles are?
Dr. Paul Bunn: I don’t think the FTI trial will go anywhere. The FDA refused to allow the agents to go forward if the mouse studies showed any evidence of toxicity, no matter how many patients had been treated. They wanted the company to go back and study huge numbers of animals to show that the cataracts, for example, were in only one strain of mice. The company was unwilling to do that. The data with gefitinib were somewhat less troubling and of course, they have already approved the adjuvant trial in the same patient population. So I’m hopeful that the discussions about using gefitinib preventively in that patient population will go forward. The FDA has been looking at this as though these are normal populations, and you can’t give drugs to normal populations unless you have an incredible safety database. Most of the data would suggest that if you picked a very high-risk smoking group (prior cancer, 30 pack-years, and sputum atypia), over 20% will have cancer in 5 years. We need to convince the FDA that a group with a 20% incidence of cancer in 5 years is not a normal population, and that the risk assessment should be different.
Dr. Lynch: What do you see as the potential of antisense oligonucleotides, particularly the bcl-2 compound, to be translated into a meaningful chemopreventive compound in non-small cell lung cancer?
Dr. Geoffrey Shapiro: These pathways and groups of proteins are extremely complex; with inhibition of only bcl-2, we do not know what is happening to the expression of a number of the apoptosis regulators. There certainly are data showing bcl-2 overexpression in non-small cell lung cancer. But people who overexpress bcl-2 actually live longer, with more slowly growing tumors, so I do have some concerns about the approach. In addition, it is going to be important to document target inhibition in tumor tissue as these studies progress forward. I don’t think we have shown that we are killing enough malignant or premalignant cells to know that these agents are the most logical for chemoprevention.
Dr. David Gandara: Sometimes prognostic factors are paradoxical under the influence of therapy. bcl-2 predicts a better survival for the natural history, for instance, after surgery with breast cancer, but it may be a bad predictive factor for therapy. In data that Dr. Bunn will show tomorrow using bortezomib, when we transfected bcl-2 into cancerous cell lines, every single chemotherapeutic drug class lost activity, but bortezomib did not, presumably because it is able to shut off bcl-2. I think this theme can carry forward to other markers.
Dr. Mark Socinski: Concerning bcl-2 as a target, the CLGB [cyclo-epsilon-(L-lysine, glycine6-bradykinin] trial is a good design and it is over halfway to completion. We might look to see whether there is any signal there before expanding this approach. The melanoma data look intriguing, but they are not the most compelling data we have seen. I know there is discussion of expanding to Phase II, but would you do that if you did not see a signal from the ongoing trial?
Dr. Bunn: With regard to chemoprevention, EGFR expression is the highest in the premalignant lesions, and so it’s possible that inhibitors could work preventively. It may be one of the main reasons for resistance in advanced diseases, but there are many other genetic pathways, so it’s actually possible that the drugs work better in preneoplastic disease.
Dr. Raymond DuBois: From our experience in mouse models, when we knock out ligands for the EGFR, the other ones always compensate, so when there are multiple members of a pathway, at least in the mouse models, it’s hard to see a phenotype.
Dr. Roman Perez-Soler: We have to be careful because these nucleic acids do a variety of other things. They are potent immunostimulants, and the reason we see an effect in melanoma may be precisely because of that. In 1983, we were using small random nucleotide sequences as immunostimulants.
Dr. Alex Adjei: That’s a very good point, because it has been show that this antisense is dependent on the sequence. When you have a number of CGs in the chain, you tend to have a lot more immunostimulation. People have theorized that these are sequences that are common in bacteria. So when you have an oligonucleotide with those sequences, your body thinks it’s some bacteria and makes a lot of antibodies against it. I don’t know that to be true, but there have been some anecdotal reports that bcl-2 antisense has a lot of immunomodulatory effects.
Dr. Giorgio Scagliotti: Being the president of the pessimistic party, I will be short. You are already too much optimistic. We need to keep the Phase II studies as a base for clinical research, but again, it is extremely important to check for the target. Even more for the antisense technology, because if the target is not there, I don’t know what we will be able to block. The model that Dr. Khuri proposed, using adjuvant chemotherapy followed by chemoprevention, is already in use, because the study BR319 done by the National Cancer Institute of Canada is following exactly this model. I’m not sure that gefitinib would be an adjuvant treatment, but it could be a good chemopreventive agent.
Dr. Fadlo Khuri: That is exactly the point. The only way we are going to get anything into a chemoprevention trial that is more toxic than celecoxib is under the adjuvant umbrella. I would comment on the importance of international multicenter trials, not just in Europe or the United States, because, for example, you can get significant surgical samples from induction trials. Dr. Giaccone pointed out earlier that Japanese response rates to gefitinib are dramatically different from American response rates. I think we would learn a lot, not just about population science, but about differences in the biology of the disease.
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ACKNOWLEDGMENTS
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We thank Judie Wells for transcription and editing of the manuscript.
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FOOTNOTES
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Presented at the First International Conference on Novel Agents in the Treatment of Lung Cancer, October 17–18, 2003, Cambridge, Massachusetts.
Requests for reprints: Fadlo Khuri, Professor of Hematology, Oncology, Medicine, Otolaryngology and Pharmacology, Winship Cancer Institute/Emory University, 1365 Clifton Road NE, Building C 3094, Atlanta, GA 30322. Phone: (404) 778-4250; Fax: (404) 778-5520; E-mail: fkhuri{at}emory.edu
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ABSTRACT
INTRODUCTION
B, nuclear factor