British Journal ofCancer(2000) 82(4), 749-752
`®
`© 2000 Cancer Research Campaign
`DOI: 10.1054/ bjoc.1999.0991, available on line at http://www.idealibrary.com on I D E ~ l
`Commentary
`
`The promise of anti-angiogenic cancer therapy
`
`MK Oehler and R Bicknell
`
`Molecular Angiogenesis Laboratory, Imperial Cancer Research Fund, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford
`OX390S,UK
`
`It is now over 200 years since the British surgeon John Hunter first
`used the term angiogenesis to describe the growth of new blood
`vessels in the developing reindeer antler (Hunter, 1787) and some
`30 years since the possibility of antagonizing angiogenesis as a
`novel anticancer strategy first became recognized by the scientific
`community. It is only in the last 5 years, however, that the field of
`(anti)angiogenesis research has undergone an explosive growth
`in activity (Figure I). A primary reason for this has been an
`increasing optimism amongst researchers that anti-angiogenesis
`does indeed, at the present time, represent one of the most exciting
`opportunities for the development of completely new approaches
`to the treatment of cancer. The purpose of this commentary is to
`give an assessment of where we stand at present and of the future
`potential for angiogenic inhibitors in cancer therapy.
`
`CURRENT STATUS OF LEADING ANGIOGENESIS
`INHIBITORS
`
`At least 30 angiogenesis inhibitors are currently being assessed
`in clinical trials. Most are in clinical phase I or II studies. A few,
`however, have progressed to phase III evaluation, potentially
`leading to Federal Drug Administration (FDA) approval (Table I).
`Leading anti-angiogenic targets that have been identified are (I)
`the inhibition of matrix metalloproteinases, (2) antagonism of the
`VEGF pathway of angiogenic induction, and (3) inhibition of the
`av~3-integrin-vitronectin interaction that is pivotal in mediating
`endothelial cell adhesion to the extracellular matrix during neo(cid:173)
`vascularization.
`Some of the most advanced angiogenesis inhibitors currently
`being evaluated in clinical trials are matrix metalloproteinase
`(MMP) inhibitors. Marimastat (British Biotech, Annapolis, MD,
`USA) was the first MMP inhibitor to be involved in rigorous
`clinical trials. In a phase III study incorporating 400 patients with
`advanced pancreatic cancer, marimastat showed no single therapy
`benefit over gemcitabine, the 'drug of choice'. Nevertheless, mari(cid:173)
`mastat at 25 mg twice a day was as effective as gemcitabine and
`appeared to have an improved therapeutic index at lower doses
`(5 mg or IO mg) with fewer side-effects. It is clear that further
`studies of marimastat will be needed before a complete assessment
`of the efficacy, tolerability and dose regimen can be made. To this
`end, nine randomized controlled studies of marimastat in a range
`of solid tumours (pancreatic, non-small-cell lung, breast cancers)
`are ongoing and the current expectation is that these data will be
`available within the next 3 years.
`
`Received 30 July 1999
`Accepted 10 September 1999
`
`Correspondence to: R Bicknell
`
`Other metalloproteinase inhibitors in advanced trials are Bay
`12-9566 (Bayer, West Haven, CT, USA) and Ag3340 (Agouron,
`La Jolla, CA, USA). Several international phase III clinical trials
`using Bay 12-9566 against solid tumours including lung, ovarian
`and pancreatic cancer are being conducted. In addition, the
`National Cancer Institute (NCI) is currently performing phase I
`studies designed to evaluate a possible use of Bay 12-9566 in
`combination regimens with doxorubicin, fluorouracil or low-dose
`leucovorin. There are several phase III clinical trials underway to
`evaluate AG3340 alone or in combination with the anticancer
`drugs paclitaxel/carboplatin for the treatment of non-small-cell
`lung cancer and mitoxantrone/prednisone for hormone-refractory
`prostate cancer. It has been shown that the anti-tumour efficacy of
`AG3340 is associated with maintenance of a minimum plasma
`concentration but not total daily dose, exposure or peak plasma
`concentrations (Brekken et al, 1999).
`Attempts to abrogate the angiogenic activity of vascular
`endothelial growth factor (VEGF) have varied from inactivation of
`VEGF itself by using, for example, antibodies (Mordenti et al,
`1999) or soluble receptors to specific inhibition of the VEGF
`receptor tyrosine kinase (Lin et al, 1998). The latter includes
`ZD4I90, an anilino quinazoline derivative that specifically
`inhibits the VEGF receptor 2 (KDR) tyrosine kinase and has
`shown widespread anti-tumour activity in in vivo animal models
`following oral administration (Hennequin et al, 1999; Ogilvie
`et al, 1999). Another VEGF receptor tyrosine kinase inhibitor
`showing much promise is SU54I6 (Sugen Inc., CA, USA).
`The interaction of the angiogenic endothelial cell with extra(cid:173)
`cellular vitronectin mediated via the av integrin is crucial during
`angiogenesis. It follows that antibodies to the av~J integrin are
`strongly anti-angiogenic and mouse monoclonals have been
`humanized as 'Vitaxin' to permit clinical trials. Preliminary results
`have shown stable disease or shrinkage in eight of 14 late-stage
`cancer patients. No side-effects have been observed so far (Eliceiri
`and Cheresh, 1999).
`
`ANGIOSTATIN AND ENDOSTATIN, EMERGING
`ANGIOGENESIS INHIBITORS
`
`An area of intense current interest is that of potent naturally occur(cid:173)
`ring inhibitors of angiogenesis being encrypted within larger
`molecules with no angiogenic activity but having other functions.
`Proteolytic cleavage releases the active material. Such molecules
`include angiostatin, a fragment of plasminogen (O'Reilly et al,
`1997); endostatin, a fragment of collagen type 18 (O'Reilly et al,
`1997); a 16 kDa fragment of prolactin; and a fragment of throm(cid:173)
`bospondin. Attention has been most focused on endostatin, which
`is able to bring about successive waves of substantial tumour
`
`749
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`

`

`750 MK Oehler and R Bicknell
`
`1400
`
`1200
`
`Angiogenesis
`
`800
`
`U) 1000
`,:
`0
`j
`Zi
`:::, a.
`0
`l6
`.0
`E :::, z
`
`600
`
`400
`
`200
`
`0
`
`160
`
`140
`
`120
`
`1990
`
`1992
`
`1994
`
`1996
`
`1998
`
`Anti-angiogenesis
`
`80
`
`U)
`,:
`0
`~ 100
`.2
`Zi
`:::, a.
`0
`l6
`.0
`E :::, z
`
`60
`
`40
`
`20
`
`0
`
`1990
`
`1992
`
`1994
`
`1996
`
`1998
`
`Figure 1 Publications in angiogenesis and anti-angiogenesis between 1990 and 1998
`
`regression in animal models without the appearance of drug resis(cid:173)
`tance (Boehm et al, 1997).
`One year ago, a front page article in the New York Times
`(Kolata, 1998) initiated speculation that cancer could be treated
`with angiostatin and endostatin. That article, and coverage by
`other media, generated intense public interest in angiogenesis
`inhibitors and a subsequent controversial and emotional debate
`(Wadman, 1998; Cohen, 1999; Harris, 1999; Rowe, 1999). The
`controversy was fueled as studies on endostatin in laboratories
`outside Boston were unable to confirm the endostatin results,
`showing only a slight growth retardation of Lewis lung carcinoma
`(a difficult tumour to treat with chemotherapeutic agents) in mice.
`Members of the NCI went to Folkman's laboratory in Boston to
`clarify why the results differed from those in the original study. In
`Boston, subsequent results were consistent with previous experi(cid:173)
`ments, showing striking inhibition of tumour growth. Variations in
`experimental techniques between the two laboratories, such as
`injecting mice, as well as storage, handling and purification of
`endostatin, are assumed to have been responsible for the previ(cid:173)
`ously observed lack of agreement in results.
`The NCl's success with mouse endostatin - just a few months
`after it had been announced publicity that it could not replicate the
`
`results - allowed the Institute to initiate plans for the testing of
`human endostatin in patients, pending full-scale toxicology studies.
`In early fall of 1999 two sites were expected to conduct phase I
`studies with approximately 15-25 patients each in patients with
`solid tumours, including lung, breast, colon and prostate carcinoma.
`To launch clinical studies it has been necessary to scale up the
`production of endostatin. By applying a yeast expression system it is
`now possible to produce soluble human endostatin at quantities
`sufficient for clinical assessment in man (Sim et al, 1999).
`Animal studies with angiostatin and endostatin have so far been
`only with transplanted tumours, which show a different biology
`when compared to organ-specific, spontaneous tumours and are
`not necessarily accurate predictors of what will happen in natural
`human cancers. Thus, a transgenic mouse model of pancreatic islet
`carcinogenesis (RIPI-Tag2) was used as a model to examine the
`effect of several angiogenesis inhibitors on multistage tumorigen(cid:173)
`esis (Bergers et al, 1999). Apart from endostatin, angiostatin and a
`combination of both, AGM-1470 (TNP470; a furnagillin deriva(cid:173)
`tive which is thought to inhibit endothelial cell proliferation by
`irreversible binding to the enzyme methionylaminopeptidase-2)
`(Sin et al, 1997) and BB-94 (batimastat; a matrix metallopro(cid:173)
`teinases inhibitor) (Talbot and Brown, 1996) were tested for their
`
`British Journal of Cancer (2000) 82(4), 749-752
`
`@ 2000 Cancer Research Campaign
`
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`

`

`Table 1 Most advanced anti-angiogenic agents in clinical trials (source: NCI
`Cancer Trials - http://cancertrials.nci.nih.gov)
`
`Drug
`
`Trial
`
`Mechanism
`
`Marimastat
`
`Bay 12-9566
`
`AG3340
`
`Thalidomide
`
`Anti-VEGF
`antibody
`
`SU5416
`
`CAI
`
`Phase Ill against pancreas,
`non-small-cell lung, breast
`cancers
`Phase Ill against lung,
`ovary and pancreatic
`cancers
`Phase Ill against non-small(cid:173)
`cell lung; phase Ill against
`prostate cancer
`Phase II against Kaposi's
`sarcoma, glioblastoma,
`breast, prostate and lung
`cancers
`Phase 11/111 against lung,
`breast, prostate, colorectal
`and renal cancers
`Phase 1/11 against Kaposi's
`sarcoma, phase 1/11 against
`metastatic colorectal cancer,
`and phase 1/11 against
`advanced malignancies
`Phase 11/111 against ovarian,
`non-small-cell lung, and
`renal cell cancers
`
`Synthetic MMP inhibitor
`
`Synthetic MMP inhibitor
`
`Synthetic MMP inhibitor
`
`Unknown
`
`Monoclonal antibody to
`VEGF
`
`Blocks VEGF receptor
`signalling
`
`Inhibitor of calcium influx
`
`MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor.
`
`anti-angiogenic potency in a prevention, intervention and regres(cid:173)
`sion trial in the RIP-Tag mice. The four angiogenesis inhibitors
`examined showed distinct efficacy profiles varying from about
`60% to 85% depending on the stage of carcinogenesis being
`targeted. However, none of the agents tested completely prevented
`the angiogenic switch, blocked the growth of small tumours, or
`fully resolved lethal tumour burden. These results suggest that the
`prevention and treatment of human spontaneous organ-specific
`malignancies with anti-angiogenic agents is going to be more
`complex and difficult than was originally anticipated. For
`example, it is not possible to predict if human tumours are going to
`respond in vivo to human endostatin as do mouse tumours to
`mouse endostatin.
`The story of angiostatin and endostatin shows that much has yet
`to be learned about anti-angiogenic agents. Several years after the
`discovery of angiostatin and endostatin, recent reports began to
`give insight into the mechanism of anti-angiogenic action of those
`agents. Angiostatin has been shown to inhibit matrix-enhanced
`plasminogen activation, resulting in reduced invasive activity
`(Stack et al, 1999). Angiostatin's antiproliferative effect was
`reported to be mediated by binding to the a/~-subunits of ATP
`synthase (Moser et al, 1999). The last observation is noteworthy as
`it might be possible to develop small molecules that could mimic
`angiostatins effect on the ATP synthase-binding protein. Smaller
`molecules would reduce the problem of immunogenicity, might be
`more easy to synthesize and might be taken orally. Less is known
`about the mechanism of action of endostatin but it is believed to
`induce apoptosis of endothelial cells by reducing anti-apoptotic
`proteins like Bcl-2 (Dhanabal et al, 1999b).
`
`OTHER ANGIOGENESIS INHIBITORS
`It may not be the agents currently in trials that work best in the
`end. Several hundred angiogenesis inhibitors have been identified
`
`The promise of anti-angiogenic cancer therapy 751
`
`and the list is mushrooming, including exotic substances like those
`extracted from green tea (Cao and Cao, 1999). It is possible that
`some of the newly identified agents are going to be more potent
`than the currently known drugs. Although the chance of an anti(cid:173)
`angiogenic agent moving into standard medical practice is esti(cid:173)
`mated to be in the order of 1:10 000, a 'gold-rush' atmosphere has
`developed to detect or develop such a compound as the potential
`market is comparable to antibiotics and chemotherapeutics, that is
`of the order of billions of dollars per year (Brem, 1998).
`Some previously known drugs have also been shown to be
`angiogenesis inhibitors. For example thalidomide, a drug with a
`tarnished past, achieved a comeback after its antiangiogenic
`properties were identified. (D 'Amato, 1994 ), and it is almost no
`surprise that aspirin with its pleiotropic effects has been identified
`as an angiogenesis inhibitor (Tsujii et al., 1998).
`
`ANTI-ANGIOGENESIS AND CONVENTIONAL
`ANTICANCER THERAPIES
`
`traditional cancer therapies probably have an anti(cid:173)
`Many
`angiogenic component. Thus, chemotherapeutic agents such as the
`taxanes and camptothecins have anti-angiogenic properties that
`may, at least in part, account for their efficacy as anti-tumour
`agents (Belotti et al, 1996). It is possible that low-dose standard
`chemotherapeutic regimens may inhibit angiogenesis without
`being cytotoxic to the tumour. Anti-oestrogen therapy for the
`prevention or adjuvant treatment of breast cancer may also be
`mediated by affecting vascularity as tamoxifen has been shown to
`inhibit angiogenesis (Van der Schaft et al, 1999).
`Further evidence for the anti-angiogenic activity of conven(cid:173)
`tional as well as experimental cancer therapies comes from a
`growing number of studies that have shown that damage of blood
`vessels precede or accompanies tumour regression after radiation
`therapy, hyperthermia, photodynamic therapy or administration of
`a variety of biological response modifiers such as interferon,
`tumour necrosis factor, interleukins or endotoxin (Baillie, 1995).
`Finally, it is also known that many oncogenes modulate the expres(cid:173)
`sion of angiogenic factors, such as VEGF, and thus therapies
`targeting these genes may also be effective through the inhibition
`of angiogenesis (Rak et al, 1995).
`
`DESIGNING CLINICAL TRIALS OF
`ANGIOGENESIS INHIBITORS
`
`There are important differences between anti-angiogenic clinical
`trials and traditional trials of cytotoxics (Kerbel and Pluda, 1999).
`In phase I trials most of the anti-angiogenic agents have been
`exceptionally well tolerated, lacking many of the side-effects
`associated with conventional cancer chemotherapies (neutropenia,
`nausea and vomiting etc.). Due to this lack of measurable toxicity,
`it has been difficult to define the maximum tolerated dose and to
`identify a recommended drug dose. Further, in phase II studies it
`has proven a challenge to assess the effectiveness of angiogenic
`drugs. These relate to the observations that most of those agents
`do not necessarily cause tumour shrinkage but induce tumour
`dormancy leading to stable disease. Exceptions are agents used for
`vascular targeting (Huang et al, 1997) and the more recently
`described natural inhibitors, such as angiostatin and endostatin.
`Measuring time-to-progression is a parameter to determine stable
`disease but it tends to be a heterogeneous time point, with great
`
`© 2000 Cancer Research Campaign
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`752 MK Oehler and R Bicknell
`
`interpersonal variation (Kerbel and Pluda, 1999). Two methods
`have, however, been usefully applied to assess responsiveness to
`anti-angiogenic therapy: (i) measurement of serum levels of angio(cid:173)
`genic peptides and (ii) magnetic resonance imaging to detect
`contrast uptake and washout in tumours. Due to the difficulties of
`phase II trials, it seems likely that many anti-angiogenesis drugs
`will proceed rapidly from phase I to phase III.
`
`CONCLUSIONS
`
`For many years the perceived role for angiogenesis inhibitors in
`the clinic was either in the adjuvant situation or in combination
`with conventional cytotoxic's permitting use of lower doses of
`the latter. Recently, however, the arrival of new angiogenesis
`inhibitors such as endostatin that achieve substantial tumour
`regression points to a potentially greater role for angiogenesis
`inhibitors in oncology. Clinical application of anti-angiogenic
`agents looks an increasingly realistic prospect. Clearly, the next
`few years will see a period of intense research into the clinical
`potential for inhibitors of angiogenesis in the treatment of cancer.
`
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`British Journal of Cancer (2000) 82(4), 749-752
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`@ 2000 Cancer Research Campaign
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