Marimastat

Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer

Srikala S. Sridhar, Frances A. Shepherd*

Summary

It has now been almost 30 years since Dr J. Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer; however, it is only recently that anti-angiogenesis agents have entered the clinical setting. The search for novel therapies is particularly important in lung cancer, where the majority of patients succumb to their disease despite aggressive treatments. Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP547,632 and ZD4190. Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin, angiostatin and interferons. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies. – 2003 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Lung cancer is the most common cause of cancer-related mortality in both men and women in North America [1]. Despite initial responses to aggressive treatments the majority of patients will eventually relapse and die as a result of their disease. This has led to the search for more effective therapeutic strategies. One such strategy involves interfering with the ability of a tumor to form new blood vessels, a process known as angiogenesis. This process plays a pivotal role in tumor growth, invasion and metastasis.
In the normal state endothelial cells are usually quiescent, dividing approximately every 7 years [2], but in the malignant state this growth rate is accelerated, sometimes occurring as rapidly as every 7/10 days [3]. This ‘angiogenic switch’ as compromised due to the lack of a smooth muscle wall, and an irregular leaky basement membrane, which may also facilitate tumor cell leakage into the circulation and development of metastatic disease [4,5].
Angiogenesis is a physiological process that is fundamental to normal healing, reproduction and embryonic development [6]. It is initiated by the release of proteases from activated endothelial cells, leading to degradation of the basement membrane, migration of endothelial cells into the interstitial space, with subsequent endothelial cell proliferation and differentiation into mature blood vessels [7]. Each of these processes is tightly regulated through the complex interplay of endogenous factors that promote and inhibit angiogenesis (Table 1).
Several agents targeting angiogenesis have been developed and can be grouped loosely into a few categories based on their mechanisms of action. This review will focus mainly on the angiogenesis inhibitors currently being evaluated in lung cancer.

2. Drugs inhibiting matrix breakdown

2.1. Matrix metalloproteinase inhibitors

Degradation of the extracellular matrix and basement membrane is one of the first steps in angiogenesis. The matrix metalloproteinases (MMPs) are a family of secreted zinc-dependent, neutral endopeptidases that are capable of degrading components of the extracellular matrix and basement membrane. They have been strongly implicated in tumor growth, invasion and metastasis [8]. They are expressed by proliferating endothelial cells and as such may play a direct role in neo-angiogenesis, through interactions with vascular endothelial growth factors (VEGF) and integrins [9/11]. Overexpression of MMPs in malignant tumors and their surrounding stroma appears to increase as tumors dedifferentiate and metastasize. Not surprisingly, therefore, increased MMP expression has been shown to be associated with a worse overall prognosis in many tumor types including lung cancer [12/16].
The MMP family includes four principal classes of molecules: collagenases, gelatinases, stromelysins, and membrane-type MMPs [17]. To date almost 30 MMPs have been identified and classified according to their substrate specificity [18]. Four endogenous tissue inhibitors of matrix metalloproteinases (TIMPs), have been described and may also be of prognostic significance [19].
In non-small cell lung cancer (NSCLC), increased MMP-2 within tumors is associated with an increased propensity for nodal metastases, while increased MMP-2 in serum is correlated with increased metastatic spread and resistance to chemotherapy [16]. MMP-9 overexpression may also be a negative prognostic indicator in NSCLC [20]. In small cell lung cancer (SCLC), high expression of MMP3 (P/0.077), MMP11 (P/0.031) and MMP 14 (P/0.019) have been shown to be independent negative prognostic indicators [16]. Several synthetic inhibitors of MMPs (MMPIs) have been developed and evaluated extensively in lung cancer. These trials are summarized in Table 2.

2.2. Marimastat (BB2516)

Marimastat is an orally administered, synthetic, broad spectrum MMPI capable of inhibiting the activity of MMPs 1, 2, 3, 7 and 9 [21]. In preclinical animal models, marimastat inhibited tumor growth and metastatic spread but did not have cytotoxic activity or induce tumor regression [22,23]. In Phase I studies, poly-arthritis limited the daily dose to 10 mg twice daily [24]. A Phase III randomized double blind, placebo controlled trial of marimastat in (SCLC) after response to first-line chemotherapy was undertaken by the National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG) and the European Organization for the Research and Treatment of Cancer (EORTC) [25].
The addition of marimastat did not prolong progression free survival (PFS) or overall survival (OS). Furthermore, significant musculoskeletal toxicity required discontinuation of therapy in almost 20% of patients [25]. An identical trial sponsored by British Biotech, in 350 patients with SCLC did not show a survival advantage. A second British Biotech trial in Stage III NSCLC patients randomized to marimastat 10 mg twice daily or placebo has not yet been reported.
Several reasons for the poor performance of Marimastat have been proposed. The most compelling of which is that we lack a good understanding of this complex MMP system, and its exact role in both angiogenesis and tumorigenesis. There is likely sufficient redundancy in the system to protect it against the effects of drugs such as MMPI’s that target only a few of these enzymes. Perhaps, combinations of several targeted therapies may prove to be more effective. It has also been suggested that MMP’s play a smaller role in advanced cancers, where angiogenesis, and metastasis have already occurred, making MMPIs less effective. Against this theory is the absence of any benefit in the setting of early stage disease or in patients in complete remission in the NCIC-CTG trial. Finally the toxicity of marimastat prevents long-term administration which would be necessary in the adjuvant setting.

2.3. Prinomastat (AG3340)

Prinomastat is a more targeted MMPI with activity specifically directed against MMP-2 and MMP-9. It has been evaluated in two Stage IIIB/IV NSCLC trials, where its addition to either paclitaxel and carboplatin, or gemcitibine and cisplatin, failed to show any survival advantage. In fact the latter study was closed prematurely after interim analysis in August 2000 [26,27]. No further lung cancer trials with prinomastat are planned.

2.4. BMS 275291

BMS 275291 is a new broad spectrum MMPI with activity against MMPs 1, 2, 8, 9, 13, 14 and to a lesser extent 3. It minimally affects other metalloproteases, including the sheddases, that are involved in the release of cell-associated molecules such as tumor necrosis factor alpha, tumor necrosis factor alpha receptor, interleukin 6 receptor and Lselectin, which may be responsible for the dose limiting joint toxicity seen with this class of compounds [28]. A phase III randomized trial in advanced NSCLC with paclitaxel and carboplatin completed accrual of 780 patients in the Spring of 2002, and results are awaited. It is anticipated that compliance with this agent will be better than that seen with either marimastat or prinomastat since it is not associated with the severe joint toxicity that was seen with both of these other agents.

2.5. BAY 12-9566

BAY 12-9566, an inhibitor of MMP-2, MMP-9, and MMP-3 has been evaluated in patients with SCLC in complete remission or near complete remission after chemotherapy and radiotherapy [29]. An interim analysis revealed no improvement in survival and this study was closed. The active treatment arm was also associated with an unexpected degree of thrombocytopenia.

2.6. Neovastat (AE-941)

Neovastat is a novel, naturally occurring antiangiogenic agent isolated from shark cartilage. In addition to its in vitro activity against MMP-2, MMP9 and MMP-12, it also inhibits VEGF binding to endothelial cells and VEGF-dependent tyrosine phosphorylation [30]. In the Lewis lung carcinoma murine model, orally administered Neovastat reduced pulmonary metastases by 70% when given alone and by 83% when combined with cisplatin. This is compared with only a 54% reduction when cisplatin was used alone [30]. Based on these encouraging preclinical results, a Phase III, double-blind placebo-controlled trial of Neovastat in locally advanced NSCLC was initiated in 2000, and aims to accrue 700 patients over 3/4 years.

3. Drugs blocking endothelial cellsignaling

Once degradation of the extracellular membrane and basement membrane occurs, the next step in angiogenesis is endothelial cell migration, proliferation and differentiation. Several endogenous angiogenesis inducers have been described which cooperate to tightly regulate this process. The first class of molecules specifically target endothelial cells and includes members of the VEGF family and angiopoietins. The second group consists of factors such as cytokines, chemokines and enzymes, such as fibroblast growth factor-2 (bFGF-2), which activate cells other than endothelial cells. Finally the third group of inducers includes tumor necrosis factor-alpha and transforming growth factor beta that act indirectly, by promoting the release of the direct acting factors [7]. Some of these angiogenesis inducers are currently being targeted by novel therapies.

3.1. VEGF

VEGF is known to be the most important proangiogenic factor, critical to the process of angiogenesis. Four alternatively spliced isoforms of VEGF exist, that bind to three receptors VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR), and VEGFR-3 (Flt-4) that are found on the surface of endothelial cells [31,32]. Receptor binding triggers kinase activation through tyrosine phosphorylation and begins the signaling cascade that initiates angiogenesis.
VEGF is expressed in normal tissues, and in almost every type of human tumor. Its expression is seen in alveolar macrophages, normal bronchiolar and differentiated columnar epithelial cells [4]. In addition it is found in both NSCLC and SCLC and over-expression is associated with a poorer prognosis. VEGF expression is regulated by a host of different factors including hypoxia that induces VEGF expression through both increased transcription and post-translational stabilization [33,34].
VEGF appears to play several key roles. It has been shown to increase vascular permeability, which may facilitate tumor dissemination via the circulation [35,36]. It may also inhibit endothelial cell apoptosis by inducing expression of the survival gene BCL-2 [37]. This may promote tumor growth, and also lead to resistance to cytotoxic chemotherapy. Clearly, VEGF and its receptors play a critical role in tumorigenesis and are therefore logical targets for novel anti-cancer therapies.

3.2. rhuMAb VEGF (avastin)

rhuMAb VEGF is a recombinant humanized monoclonal antibody to VEGF. Preclinical in vivo models demonstrate that rhuMAb VEGF inhibits growth of a variety of human cancer cell lines in a dosedependent manner, and may act synergistically with chemotherapy. In phase I trials, rhuMAb VEGF effectively reduced serum VEGF concentrations to undetectable levels when administered at doses of 3 mg/kg/week or more, and showed no pharmacologic interactions when studied in combination with doxorobucin, carboplatin, paclitaxel, 5FU or leucovorin [38,39]. In NSCLC, a small randomized, multicenter, three-arm, phase II study was performed [40]. Stage IIIB/IV NSCLC patients were randomized to standard therapy with carboplatin and paclitaxel alone or one of two experimental arms that included the same chemotherapy with rhuMAb 7.5 mg/kg or rhuMAb 15 mg/kg. On disease progression, the control group was allowed to cross over to the high dose rhuMAb arm. The results are summarized in Table 3. In the high dose rhuMAb arm, response rates were higher by approximately 10%; TTP and median survival were 1 and 3 months longer, respectively. An unusual and unexpected toxicity was the development of lifethreatening hemoptysis, resulting in four fatalities, mainly in patients with central tumours and squamous cell histology. Less severe bleeding including epistaxis has also been seen in trials of rhuMAb VEGF for other tumor types [41/43]. A Phase III trial of rhuMAb VEGF in advanced NSCLC is now ongoing through the Eastern Cooperative Oncology Group (ECOG). Patients with a history of hemoptysis and those with squamous cell histology are excluded from study. Patients are randomized to receive rhuMAb VEGF 15 mg/kg q 3 weekly or placebo with paclitaxel and carboplatin, and crossover of patients on the placebo arm is not allowed. An interim toxicity analysis has been performed, and although fatal hemoptysis was seen in the active treatment arm, the difference was not significant between the arms, and the trial continues. Regular safety analyses will continue to be performed during the conduct of the trial. A Phase II pilot trial (ECOG 1502) of q 3 weekly cisplatin, etoposide and rhuMAb (15 mg/kg day 1) is currently underway in patients with advanced SCLC.

3.3. VEGF receptor (VEGFR)

The VEGF system can also be targeted through inhibition of VEGFR, by the use of monoclonal antibodies or specific tyrosine kinase inhibitors. Several monoclonal antibodies are presently at the preclinical and early Phase I stages of development. Phase I trials are also ongoing for a number of different small molecules known to inhibit tyrosine kinases VEGFR1 (Flt-1), VEGFR2 (Flk-1), Tie-1 and Tie-2 which are directly or indirectly involved in angiogenesis. Of these, the VEGFR2 (Flk-1) is felt to be the most important in endothelial cell proliferation and chemotaxis, and thus a target for novel agents [44].

3.4. SU5416

SU5416 is a parenterally administered quinolone derivative, which is a potent inhibitor of VEGFR-2 (Flk-1) tyrosine kinase and also appears to inhibit ckit mediated signaling [45]. In vitro SU5416, inhibits endothelial cell proliferation, and in vivo, has shown broad anti-tumor activity [46]. In Phase I trials, the most common adverse effects were nausea, vomiting, headache, diarrhea, pain and fever. Dose limiting toxicities were headache and projectile vomiting [46]. SU5416 was evaluated in combination with gemcitibine and cisplatin in 19 patients with advanced malignancies. Numerous vascular events including pulmonary emboli, myocardial infarctions, and cerebrovascular events were seen [47]. This agent will not be developed further in view of its severe toxicity profile and requirement for frequent intravenous administration through central venous catheters.

3.5. SU6668

SU6668 is an oral small molecule tyrosine kinase inhibitor with multiple receptor targets including VEGFR-1 (Flk-1), platelet derived growth factor (PDGF), and fibroblast growth factor receptor (bFGFR) [31]. In preclinical testing, SU6668, inhibited the growth of established human tumor xenografts in mice. However, Phase I studies once again revealed an unacceptable toxicity profile, and so this agent will not be developed further.

3.6. ZD6474

ZD6474 is an orally administered small molecule inhibitor of VEGFR2 (KDR); and to a lesser extent the epidermal growth factor receptor (EGFR). In preclinical xenograft models ZD6474 showed dosedependent inhibitory effects on tumor growth, and in Phase I studies ZD6474 appeared to be well tolerated. With dose escalation, grade 3 thrombocytopenia, diarrhea and rash were observed (the latter, perhaps due to its anti-EGFR properties). Asymptomatic QTc prolongation was observed in 7/ 49 patients at varying dose levels [48]. A randomized Phase II trial examining ZD6474 in SCLC patients with limited or extensive disease who have achieved remission after induction chemotherapy and radiotherapy is under development by the NCIC-CTG, and will open shortly.

3.7. CP-547,632

CP-547,632 is another oral, anti-angiogenic small molecule inhibitor of VEGFR-2 tyrosine kinase activity, which also targets EGFR, PDGFR and other tyrosine kinases. In vitro, CP-547, 632 inhibits endothelial cell proliferation, and in xenografts including NSCLC retards tumor growth. Early Phase I data suggest an encouraging safety profile and pharmacokinetic parameters [49,50]. Phase II trials have not yet begun.

3.8. Other tyrosine kinase inhibitors

Other agents currently under investigation include CO-358, 774, PTK787/ZK225846, and ZD4190. Consideration is being given to designing a trial with ZD4190 in SCLC.

4. Endogenous inhibitors ofangiogenesis

The phenomenon of primary neoplasms inhibiting the growth of their metastatic lesions is thought to be related to the presence of tumor-derived inhibitors of angiogenesis such as endostatin and angiostatin [51]. These compounds are currently under intense study, but to date only recombinant endostatin has entered Phase I trials, and will be discussed here.

4.1. Endostatin

Endostatin, a carboxy-terminal 20 kDa fragment of collagen XVIII, inhibits endothelial cell proliferation and significantly increases the rate of apoptosis in tumor cells [52]. In murine Lewis lung cancer models, endostatin reduced tumor growth, and at doses of 20 mg/kg/day, induced nearly complete regression of established tumors [52]. Furthermore, repeated cycles of systemic endostatin treatment maintained tumor dormancy [53]. Recombinant human endostatin (rh endostatin), has entered Phase I trials in doses ranging from 15 to 600 mg/m2 and is generally well tolerated, with some evidence of minor anti-tumor activity [54]. Lung cancer trials with endostatin have yet to start.

4.2. Interferons

The interferons are a family of naturally occurring cytokines that possess immunomodulatory, anti-viral and anti-angiogenic properties. Interferon alpha inhibits angiogenesis by exerting antimitotic and antimigratory effects on endothelial cells, in part through blockade of bFGF production by parenchymal cells. Both IFN-b and IFN-g, inhibit endothelial cell proliferation and migration [55]. The anti-angiogenesis properties of interferons were first demonstrated in the treatment of lifethreatening hemangiomas of infancy [56]. A phase I/II study of sequential interferon alpha2b and weekly topotecan and vinorelbine in advanced NSCLC has shown this to be an active regimen with an acceptable toxicity profile. Survival data have not been reported [57]. Four randomized trials in SCLC patients, evaluating interferons as adjuvant therapy after response to chemotherapy have been reported (Table 4) [58/61]. Despite variations in the interferon preparations used in these trials, their results were essentially similar. There was no increase in overall survival in the interferon treated patients, and in fact in two of the trials, interferon treatment was associated with a poorer survival. Interferon was associated with considerable toxicity, interfering with completion of therapy. A trend toward superior longterm survival for patients with limited stage disease, achieving complete remission, was reported in the latter two studies. Once again, despite initial enthusiasm with the interferons, these studies do not support a role for it in SCLC at this time.

5. Novel agents inhibiting endothelialcells

5.1. Thalidomide

There has been renewed interest in the potent teratogen, thalidomide, since it has been shown to possess both immunomodulatory and antiangiogenic properties. Thalidomide may inhibit angiogenesis induced by bFGF and VEGF, inhibit tumor necrosis factor alpha and Cycloxygenase 2 (COX2), change ICAM expression, and modify the extracellular matrix [62]. Phase I/II trials showed that thalidomide 100/500 mg/day was generally well tolerated. The main toxicities were fatigue, nausea and vomiting. Similar results were seen in a dose escalation study of thalidomide given with paclitaxel and carboplatin in patients with stage III/IV NSCLC [63]. ECOG has opened a Phase III trial (ECOG E3598) in Stage IIIB NSCLC patients, of carboplatin, paclitaxel, and thoracic radiotherapy with or without thalidomide. The primary end point in this study is survival, and secondary endpoints are time to progression, overall response rate and safety. Results are not yet available. In SCLC a phase II trial, showed that carboplatin and etoposide with concurrent and subsequent maintenance thalidomide was a well-tolerated regimen without significant toxicity. A phase III trial is planned [64]. Also in SCLC, a phase III, randomized, double blind, placebo controlled trial is currently underway in France that evaluates a combination of cisplatin, cyclophosphamide, epirubicin and etoposide with and without thalidomide [65]. Following two courses of chemotherapy, responders are randomized to receive thalidomide 400 mg/day or placebo, initially concurrently with the remaining four courses of chemotherapy, then as maintenance therapy until progression or toxicity. The end point of this study is survival at 7 months after randomization, with a target accrual of 200 patients [66]. Study results are awaited.

5.2. Squalamine

Squalamine, is an aminosterol, originally derived from the liver of the dogfish shark, that shows potent anti-angiogenesis effects both in vitro and in vivo. Its mechanism of action is unique and appears to involve inhibition of mitogen stimulation of endothelial cells through modulation of cellular pH [67]. Three Phase I trials have been completed and show that squalamine is well tolerated, and demonstrates biologically relevant plasma concentrations approaching those required for antiangiogenic effects in vitro [68/70]. A Phase IIA trial of squalamine in advanced NSCLC in which chemotherapy naı¨ve stage IIIB/IV NSCLC patients received carboplatin and taxol followed by a 5 day infusion of squalamine every 3 weeks, has completed accrual, but survival data are not yet available [71].

5.3. Celecoxib

The enzyme cyclooxygenase 2 (COX2), involved in prostaglandin synthesis, is frequently upregulated in NSCLC, and may be a marker of poorer prognosis in surgically resected Stage I cancers. It also may promote angiogenesis, prevent apoptosis, and induce resistance to radiation therapy [72]. Inhibitors of COX2 have been designed, and used extensively in the setting of inflammatory conditions, but their potential anticancer effects have only recently been recognized. In both in vitro and xenograft studies, treatment with celecoxib, reduced growth of NSCLC tumors [73]. Phase II studies, suggest that celecoxib, may enhance response to preoperative paclitaxel and carboplatin in patients with Stage1-IIIA NSCLC [72]. A Phase II study in Stage III NSCLC patients receiving combined modality treatment examined the effects of celecoxib, on serum/plasma VEGF levels, but mature results are not yet available.

5.4. ZD6126

ZD6126, is a novel agent, with unique antiangiogenesis properties. Unlike other agents, previously discussed, which aim to prevent new vessel formation, ZD6126 selectively targets and induces direct damage to existing tumor endothelial cells [74]. ZD6126 binds to tubulin in the cytoskeleton of tumor endothelial cells, and induces morphological changes leading to vessel occlusion and extensive central tumor necrosis [75]. In vivo, ZD6126 also appears to enhance the antitumor effects of radiation therapy [76]. Phase I studies are underway and have shown the main adverse events are anorexia, constipation, dyspnea, fatigue, headache, nausea, vomiting and pain. There was, however, no relationship between the incidence of these adverse events and the dose of ZD6126 [75]. The highest dose reported to date is 7 mg/m2 which does not exceed the maximum tolerated dose. One surrogate marker of vascular damage currently being investigated is circulating endothelial cell level (CEC), which showed an approximate twofold increase 4/6 h after ZD6126 infusion [77]. Further studies are pending, for this new and potentially exciting agent.

5.5. Integrin antagonists

EMD121974 and SCH221153 belong to a class of novel antiangiogenesis drugs designed to target endothelial aV integrins. The integrins are heterodimeric endothelial cell surface adhesion receptors that play an important role in angiogenesis by controlling cell migration, differentiation, proliferation and apoptosis. Integrins also appear to associate both physically and functionally with VEGFR2, and may therefore modulate VEGFR2 mediated signaling [32]. Preclincial studies have shown these drugs to have both antiangiogenesis and profound growth inhibitory effects on tumor xenografts [78,79]. Preliminary phase I studies show EMD 121974 is tolerable at doses up to 1200 mg/m2, with the main toxicities being fatigue, rash, pruritis, nausea and vomiting [80]. Further studies are ongoing at this time.

5.6. TNP-470

TNP-470 is a synthetic analog of fumagillin, that blocks the growth of new blood vessels by inhibiting methionine aminopeptidase an enzyme that plays a key role in endothelial cell proliferation [81]. Preclinical studies, support a role for TNP470, in slowing tumor growth, but not causing shrinkage of existing tumors [82]. However, when used in combination with paclitaxel or other cytotoxic agents, tumor regression, disease stabilization and improved survival was seen [83,84]. TNP-470 combined with paclitaxel was recently evaluated in the Phase I setting in several tumor types including 16 patients with NSCLC [85]. Overall this regimen was well tolerated, with minimal pharmacokinetic interactions between the two drugs. Mild to moderate subclinical neurocognitive impairement was seen, but this was reversible. Of note, partial responses were reported in 6/16 NSCLC patients, 60% of whom had been pretreated with chemotherapy [85].

6. Conclusion

Angiogenesis plays a critical role in the growth and development of solid tumors, and over the past decade our understanding of the complex processes involved in new blood vessel development has increased dramatically. Several different classes of agents that target angiogenesis have been developed that have the potential to be effective in lung cancer where angiogenesis appears to be of primary importance. Although most agents under study to date have been designed to inhibit new vessel formation, other agents such as ZD6126, may be effective because they specifically target established blood vessels found mainly within tumors. These agents have demonstrated new and unusual toxicity profiles including doselimiting arthritis as well as unexpected bleeding and thrombotic complications. Therefore, clinical trials must be developed carefully with frequent monitoring for toxicity, and early stopping rules for safety clearly established before the study is opened. We await the results of the on-going trials of angiogenesis inhibitors, but it will likely be several years before the their role is clarified in the treatment of lung cancer.

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