The New Era in Cancer Research by fad10689



                                                                                                                         message has been driven home, gradually but
       PERSPECTIVE                                                                                                       effectively, by a variety of new and less toxic
                                                                                                                         agents for treating cancers-hormones,      antihdies,
       The New Era in Cancer Research                                                                                    and enzynie-inhibitory drugs-and especially, by
                                                                                                                         the h i a t i c arid of a near-mimulous drug,
       Harold Varmus                                                                                                     imatinib (Gleevec), a “molecule-specific” agent
                                                                                                                         that induces nearly complete and sustained
       For many years, discoveries about the genetic determinants of cancer appeared to be having                        mnissions in nearly all patients in the early stages
       only minor effects on efforts to control the disease i n the clinic. Following advances made over the             of chronic myeloid leukemia (CML), by blocking
       past decade, however, a description of cancer i n molecular terms seems increasingly likely to                    a protein-tyrosine kinase activated by a well-
       improve the ways in which human cancers are detected, classified, monitored, and (especially)                     studied chromosomal translocation (f).
       treated. Achieving the medical promise of this new era i n cancer research will require a deeper                       These new therapiesare ofien called “targeted.”
       understanding of the biology of cancer and imaginative application of new knowledge i n the clinic,               E h t in a sense they are not any more targeted than
       as well as political, social, and cultural changes.                                                               the conventionalchemothempies that inta-fere with
                                                                                                                                                               DNA @
                                                                                                                         components of the DNA i~plicatioi~ E, or
               he conquest of cancer continues to pose          notion that biology and chemistry could be               mitotic machineries or than radiotherapies that

       T       great challenges to medical science. The
               disease is notably coniplex, affecting nearly
       every tissue lineage in our bcdies and arising fiom
                                                                harnessed to benefit patients with cancer ()
                                                                    At the time that Burchenal began treating

                                                                leukemias, little was known abut the causes of
                                                                                                                         damage DNA in a focused field. The new breeds
                                                                                                                         of treatmentsusually have specificity for individ-
                                                                                                                         ual cancers, reflecting the particular mutations
       nonnal cells as a consequence of diverse mutations       cancers or abut the genetic and molecular mech-          responsible for that tumor or variations in gene
       affecting inany genes. It is also widespread and         anisms by which they arise from nomal cells. His         expression-distinctive molecular attributes that
       lethal; currentlythe secondmost common cause of          therapeutic strategy was based largely on the            are increasingly used to subdivide cancers as-
       death in the United States, it is likelyto become the    pmnise that cancer cells replicate their DNA and         signed to the same standard histopathological
       most common in the near hm . Despite large
                                         i e                    divide more freguentlythanmost nonnal cells and          subtype (6, 7). These attributes include the pres-
       federal and industrial investments in cancer             hence would be more sensitive to DNA damage.             ence or absence of receptors that bind to lionnones
       research and a wealth of discoveries abut the            Although this concept has proven to be an overly         or to derivative antagonists; the amplification or
       genetic, biochemical, and functional changes in          simplistic explanation, an emphasis on damage to         efficient expression of genes encoding cell surface
       cancer cells, cancer is commonly viewed as, at           DNA and the mitotic apparatus has guided the             proteins that are recognized by antibodiesthat may
       best, minimally controlled by modem medicine,                               h
                                                                development of t e many chemothempeutic regi-            inhiiit cancer cells (directly or through damaging
       especially when compared with other major                mens and radiotherapies that have been used for          toxins or isotopes); or the activation of intracellular
       dwases. Indeed, the age-adjusted mortality rate          nearly all t y p of cancers over the past 50 years.      signaling pathways by mutant proteins that are
       for cancer is about the same in the 21st century as it   The results have ranged fmm modest at best (in the       sensitive to niolecule-specific drugs.
       was 50 years ago, whereas the death rates for            advanced stages of some of the most common                                                              n
                                                                                                                              Thempatic successes, however limrteed i some
       cardiac, cerebrovascular, and infectious diseases        carcinomas of adults), to partially protective           situations, have prompted optimism about other
       have declined by about hvo-thirds (I).                   a m subsequent metastasis (when used as an               uses of genetic and biochemical information-
                                                                adjuvant to surgery in the early stages of such          to classify tumors, to detect them early and
       A Perspective on the History of                          diseases), to highly effective (in the treatment of
       Cancer Research                                          even advanced stages of testicular cancers, some
       The recent death of Joseph Burchenal(2), one of          lymphonm. and a few other tumor types).
       the pioneers in the use of chemotherapy, provides            h i n g most of those 50 years, pharmaceuti-
       a vantage point for thinlung about the hstory and        cal chemistry continued to serve cancer patients
       the future of cancer research and its implications       much more effectivelythan did cancer biology.
       for control of the disease. Just over 50 years ago,      Laboratory-based investigationsinto the nature
       Burchenal (Fig. 1) and his colleagues used analogs       of cancer cells and clinical efforts to control cancer
       of folic acid, methotrexate, and of a nucleoside, 6-     often seemed to inhabit separate worlds. In the
       mercaptopurine, to induce profound and sustained         world of labomtov research, the characterization
       remissions in children with aggressive leukemias         of cancer viruses of aninmls in the 1960s and 70s,
       (3). This event-viewed in combination with re-            h                 h is
                                                                te discovery of t e frt protooncogenes and tu-
       lated, contemporaneouswork by Sidney Farber and          mor suppressor genes in the 1970s and 8Os, the
       by Emil Frei and Emil Frekickwas revolution-             integration of the p&cts of those genes into cell
       ary: For the fm time, drugs of known chemical            sipding pathways m the 199Os, and even the
       composition ta interfered with enzymes engaged
                      ht                                        repeated unveilings of mutant genes implicated in
       in a specific biological process, DNA replication,       human cancm beginning in the early 1 9 8 O s 4
       were used to treat cancers successfully in a rational    seemed to have little or no impact on the methods
       manner. The sevtral successfid cases T i r e d the       used by clinicians to diagnose and treat cancers.
       design of clinical trials, pem~ttingthe mea-
       surement of gractual improvements in treatment           The Rise of Molecular Oncology
       protocols. The resulting progress against childhood      During the past decade, perceptions about this sit-
       leukemias, despite the toxicity of the drugs and the     uation have been changmg rapidly. Understanding
       lethality of the diseases built confidence in the        the genetic and biochemical mechanisms by which
                                                                cancers arise and behave is now widely believed to
       Memorial Sloan-Kettering Cancer Center, New York, NY     paend improvements in the way we detect,                 Fig. 1 Ioseph H. Burchenal. [Photo: courtesy of
       10021, USA E-mail                       classify, monitor, and treat these diseases. This        Memorial Sloan-Kettering Cancer Center]

1162                                                26 MAY 2006         VOL 312        SCIENCE
monitor their growth, and to devise more in-             era in cancer research are promised, not acheved.          Several other issues require attention be-
genious ways to inhibit or reverse their growth,         Classificationof tumors based on analysis of DNA       fore oncogene dependence can be adequately
Two broad areas of knowledge about cancer in             and RNA is stlll an uncertain art and practiced only   exploited for diagnostic and therapeutic
general-and about individual cancers arising             in a few academic centers, largely on an               purposes:
in different cell lineages-have been especially          experimental basis. Development of reliable new             1) The mutational repeitok. Most obviously,
significant in t h s transformation of thnking           biomarkeix for detection of tumors and of novel,       the catalog of oncogenicmutations associated with
about cancer:                                            hgh-aflinity ligands for imaging, based on evi-        the many forms of human cancer is far from
     1) The genetic basis of cancer. Mutations are       dence of changes in the structure or production of     complete. The Cancer Genome Atlas (TCGA)
now recognized to be the h b e n t a l lesions           ceaain proteins in specific cancers, has yet to        initiative, recently announced by the National
driving neoplasia (8). The mutations are largely         occur. The impact of the new generation of mo-         Institutes of Health (NIH) (19j, should substantial-
somatic, but sometimes heredimy; they affect             lecularly targeted therapies on overall cancer mor-    ly improve this situation over the next decade. The
proto-oncogenes, producing a dominant gain-              tality rates remains neghgible, because imatinii is    high-throughput technologies that make this initia-
of-function, and tumor suppressor genes, result-         effective only in CML and a few other relatively       tive possible can, in principle, be used to survey
ing in a loss of function. The Cancer Gene               uncommon cancers; because other tyrosine kinase        sets of hundreds of tumors, each set representing
Census maintained by the Sanger Center of the            inhibitors dramatically Shrink only those lung         one of the common malignancies, for determi-
Wellcome Trust (9) now lists over 350 genes,             cancers with mutations in the epidermal growth         nation of gene copy number, gene expression
situated on every chromosome (except Y), that            factor receptor (13). and the impact on survival in      at i
                                                                                                                p ten and sequences of the exons of 10oO to
have been causally implicated in human cancer            this group of patients has yet to be established in    2000 genes (20). Development of new methods
because they have been repeatedly encountered in         prospectivestudies;and because antibcdiesa    -        for DNA sequencing (21j could appreciably drive
mutant form--amplified, deleted, translocated, or        cell surface proteins that are effective as adjuvant   down costs of TCGA, and faster methods for
damaged by missense, nonsense, or frameshift             therapies, such as anti-HER2 in early breast cancer    karyotyping could extend the project to detect
mutationsin one or more cancer types. The mu-            (14, Is), have not yet been used long and wide-        chromosomal reanangements,which are proving
tations are supplemented by epigenetic variations        ly enough to affect public health data.                to be very common mechanisms of oncogenic
(methylation of DNA or nidfications of Manes                                                                    mutation (9). TCGA is intended to assist the
or transcription factors) that affect gene expression    Oncogene Dependence                                    development of therapeutic strategies, but the
(10).The mutations and the secondary changes in          So why is there so much excitement about new           portraits of molecular changes in many cancer
gene expression provide new tools for classifLrng        cancer thmpies? One reason is based on an              types should also offer new ideas about diagnos-
tumors, for predicting their behavior, for antic-        unexpected consequence of interfering with acti-       ing and classlfylng cancers, detecting them earlier
ipating means to detect them early, for designing        vated oncogenes. The remarkable reduction in the       with biornarkers, and monitoring them during
new tools for imagng, and for developing the             number of cancer cells observed after treatment        therapy with novel imaging methods.
rapeutic strategies. In additioi~gem1 line muta-         with in~tiniband some other tyrosine kinase                 2) Mutational hiemchies. Most if not all tu-
tions associated with cancers have been observed         inhibitors implies that such drugs do not simply       mors have multiple mutations affecting hown
in 66 genes (9), n&ing them canddates for as-            mt tumor cell prohfaation when they block
                                                             s                                                  cancer genes, but the relative importance of such
sessment of genetic risks of certain cancers (11).       oncogeneactivity; they eliminate tumor cells, most     mutant genes in maintaining the oncogenicity and
    2) The physiology of cancer. The biological          likely by programmed cell death. The idea that         viability of a cancer cell is not known. The loss of
behavior of cancer cells ha$ increasingly been           cancer cells are dependent on mutant oncogenes         responsiveness to anti-HER2 antibody after a
llnked to underlying niutations through an un-           for viability, not j s growth+often called ‘‘onco-
                                                                             ut                                 tumor suppressor gene ( P E N ) is mutated in hu-
derstanding of the signaling pathways that govern        gene dependence” ( I @ or “oncogene addiction”         man breast cancers (22), and loss of dependence
the cell cycle and cell growth, programmed cell          ( I v i s also supported by studies of cancer cell     on the c4Qc oncogene in mouse breast tumors
death (apoptosis), longevity, motility, metabolisni,     lines and anjmals. In mice carrying oncogenes as       when a mutation occurs in another oncogene
and genome integrity. Furthermore. in addition to        transgenes that can be regulated by transcrip          (ku)(23), imply that thaapies addressing mul-
the physiological cha~acteristics cancer cells
                                      of                 tional control, a wide variety of tumor types          tiple genetic changes will be required. On the other
themselves, components of a cancer cell’s envi-          swiftly regress, mainly by apoptosis, when the         hand, in some genetically enpeered mice, onco-
ronment are now recognized to be important for           oncogenic proteins are de-induced (16, 18).            gene dependenceis not affected by the coexistence
u n m d i n g cancer and considering new means                The concept of oncogene dependence encour-        of an oncogenic mutation in another gene (24).
to attack it. The swalled hallmarks of cancer (12)       ages efforts to destroy cancer cells with new          Experiments that explore the h i m h y of mu-
include the acquisition of self-sufficient signals for   therapeutics directed specifically against the         tations in Merent types of tumors could guide the
growth, the capacity for extended proliferation,         products of mutant oncogenes, but it is still a        selection of t e most appropriate molecular
resistance to pwth-inhibiting signals, the ability       poorly und-                         t
                                                                               phenomenon A its heart is a      targets and the design of multi-agent therapies.
to evade cell death signals, the potential for tissue    vexing question: How did a cell that was originally         3) Secondary resistance. AU targeted therapies
invasion and nietastasis, and the power to induce        content without an oncogene become ready to die        are limited by the appearance of resistance to drugs
blood-vessel formation (angiogenesis). Some                                               hs
                                                         if deprived of it? Answers to ti question could        or antibodies. In some highly instructive cases,
of these traits are the properties of the cancer         guide shtegies for exploiting a cancer cell’s          resistance can be amibuted to a limited repertoire
cells themselves, but others depend on com-              dependence on some of the most ftequently              of secondary mutations in targets such as onco-
munication between the cancer cells and their            encountered oncogenes, such as members of the          genic tyrosine kinases (25, 29, providing a basis
cellular and macromolecular environments. Each           RAS and MYC gene families, for which therapeu-         for screening for drug resistance and for
property constitutes a vulnerability in a tumor,         tic agents are c ~ t l lacking. This will entail
                                                                                     y                          seeking new agents that can prevent or over-
to be exploited by new therapies, especially             learning more about the vulnerabilities of cells       come it. Deciphering mechanisms of resistance
when the underlying mutations and signaling              dependent on oncogenic proteins that do not            and developing multi-agent treatment protocols,
aberrations are known.                                   function as enzymes (e.g., Myc and other               resembling the anti-HIV combination therapies
    Still, despite all this new knowledge and de-        oncogenic transcripton factors) or those that have     that reduce the ldcelihood that drug resistance
spite the startling success of imatinib in the           lost a catalytic activity (e.g.,mutant Ras proteins    will emerge, will be essential to achieve Iong-
treatment of CML, most of the effects of the new         lacking guanosine triphosphatase activity).            term control of cancers.

                                             SCIENCE VOL 312              26 MAY 2006                                                     1163

           4) Heterogeneity and stem cells. The use of           Other means to control cancer have also            deployment of the limited financial resources
       differentiation markers reveals heterogeneity         been developed, improved, or more widely               and human talent devoted to cancer. From that
       among neoplastic cells in a single tumor (-77, 28).   used in recent years. These include strategies         perspective,there is a great deal to wony about.
       Some if not all tumors arc thought to contain a       for prevention [such as smoking cessation pro-              The major public support for cancer research in
       minor population of cells (so-called cancer stem      grams, vaccines against cancer-promoting               the United States comes froni the National Cancer
       cells) that are responsible for the tumor’s           viruses (hepatitis B and papilloma viruses),           Ins$itute (NCI) an& to lesser degrees, from several
       continued expansion and for its regeneration          and methods for detection of premalignant le-          other components of the NIH. Despite a much
       when once-effective therapies fail (29,30). Better    sions and early cancers (e.g., colonoscopies,          welcomed doubling of the NIH budget koni 1998
       characterization of cancer stem cells and the         mammography, and PAP smears)]; neurotropic             to 2003, appropriationsto the NCI specif~cally,   and
       means to isolate them may help to monitor this        medications to control the ancillary symptoms          to the NIH generally, have not kept pace with in-
       subset of cells during treatment and to design        of cancer, most obviously pain and nausea;             flation since then (40). As a result, the buying pow-
       treatments that selectively kill them, thereby        hematopoietic growth factors to blunt the side-        er of the NIH has been substantially eroded, and
       eliminating a tumor’s potential for regrowth.         effects of cytotoxic treatments, such as anemia        the success rates for grant applications have fallen
           T h s list is, of course, incomplete. It re-      and leukopenia; and psychosocial methods for           to discouraging levels. In this atniosphere, it is
       mains to be established, for example, whether         managing the response of patients and families         diflicult to take on new and expensiveprojects and
       all cancers show oncogene dependence;wheth-           to the diagnosis and treatment of cancers.             to ath-dct the best young talent even to this exciting
       er there is a relationship between oncogene               Furthermore, as a recent inventory of U S .        and important area of research. Furthennore, the
       dependence and metastatic potential; and              cancer rates and trends makes evident (38),            leadership of the nation’s cancer efforts has been
       whether components of signaling mechanisms            successful control of cancer will require more         poorly defined in recent months and will remain so
       “downstream” of mutant oncogenic proteins             than just new technologies, whether molecular-         until a new NCI director is appointed (41,42).
       (31) can commonly serve as targets for ther-          ly based or not. It also calls for elimination of           Traditionally, the public has looked to the
       apeutic intervention.                                 disparities in care-and in access to ciue-that         pharmaceutical and biotechnology industries for
                                                             are based on racial and economic factors.              new tools to detect and treat a wide spectrum of
       Attacking Cancer Cells Indirectly                                                                            diseases, based largely on the results of publicly
       An enlarged understanding of the tissue en-           Gauging the Future                                     h d e d basic science.But a nuniber of factors raise
       vironment in which cancers grow is providing          It is &cult to appraise the progress that has been     questions about how, in oncology, this tradition
       new opportunities to develop therapies that are       made against cancer over the past hdf-century, but     may be challenged by a future increasingly
       not targeted at the tumor cells themselves.           even more so to predict the progress that should be    influenced by a molecular view of cancer. Will
       Best known among these novel approaches is            anticipated over the next 10 or 50 years, because      industry lose incentives to develop targeted
       the anti-angiogenicstrategy,for which drugs and       cancer is such a complex problem, with hundreds        therapies that address small, precisely &fined
       antibodies have already been approved by the          of fomq diverse means of controlling it, and           classes of tumors? Or will commonalities among
       Food and Drug Administration(FDA) (32).               daunting s c a barriem to reducing its burdens. To
                                                                         oil                                        tumors, such as the high frequency of mutations in
             the^ are grounds for optinism about other       argue ta the fight against cancer has been dis-
                                                                      ht                                            RAS genes (43), sustain n ~ e sizes? Will the
       approaches that address the tumor’s milieu: (i) by    appointing, one can simply recall that age-adjusted    high prices of some recently approved cancer
       interFering with growth-promotingsignals supplied     mortality mtes now are about the same as they          therapies (44)be sustainable, given increasing pres-
       by non-neoplastic “stromal cells” that m u n d a      were 50 years ago. But it is also legitinlate to       sures on health care financing? Will govemment
       tumor (33); (ii) by inhibiting specific proteases     supprt a more optinnstic view by noting the            agencies and private i n s m continue to provide
       that mold a tumor’s environs to promote the dan-      recent annual 1% declines in mortality rates after     adequate r e i m b m e n t for molecular methcds for
       gerous escap of tumor cells into the circulation      seveid decades of steady i n c m s (38); the           detecting diagnosing, and monitoring tumors as thc
       (34, 35) or by using those proteases to activate      enormous improvements in treatments of a               use of these cimntly expensive technologies
       molecules usefulfor imaging tumors (36); and (iii)    few adult and several pediatric cancers; the           expands?Will rebylatory agencies and industry find
       by promoting an immune response against tunior        large increases in 5-year patient survival rates       common ground to allow affordable and interpret-
       cells-for example, by inactivating factors. such      for many cancers (39); the recent development          able clinical trials for drugs for uncommon cancers,
       as the T cell surface protein CTLA4 ( 3 3 , that      and FDA approval of several narrowly targeted          perhaps by using early indicatm of tlimpeutic
       restrict the immune response to cancer cells.         therapies wt mild side-effects: and the several
                                                                          ih                                        success, such as biomarkers in m’? will      And
                                                             ways in which living with advanced cancer has          companies collabomte to test multi-agent thempies
       Placing Selective Therapies i n Perspective           been made better by controlling the symptoms           directed at multiple targets?
       Despite these encouraging ideas, enthusiasm for       of even resilient underlying disease.                       Finally, the new em in cancer research calls for
       harnessing new knowledge to combat cancer                  Regardless of how the current situation is        changes in the culture of oncology. These include
       clinically can seem naively ovqronising; sim-         viexved, the United States and many other              swonger working relationdups between bench
       plistic about the medical aid social amibutes of      countries are faced with a daunting demographic        scientists and their clinical colleabwes, between
       cancer; unperceptive about the history of in-         reality: With the continued aging of the population,   oncologists in academia and those in community
       corporating complex technical changes into the        the absolute number of cancer diagnoses will very      hospitals, and between oncologists and other
       g e n d practice of medicine; and neglectfd of the    likely rise substantiallyin the coming decades. So,    physicians, new iraining programs that provide
       many other ways cancer can be conhdled. Surgery,      for the foreseeablefuture, we will need better ways    graduate students in the basic sciences with an
       chemotherapy, radiation, histopathology, and con-     to detect and treat cancers, especially the solid      opportunity to understand the dilemmas posed by
       ventionalimaging a~ likely to remain the staplesof    tumors of the lung, breast, prostate, colon, pan-      cancer as a human disease; grant m e h s m s and
       cancer c a for many years. And they too are be-       creas,ovary, and other organs that are common in       criteria for advancement in academia that support
       coming more effective,even without any molecular      older age pups. Aaicles in this issue provide          the kind of teamwork traditionallyassociated with
       advances,through image-guidedand minimally in-        groundsfor optimism about the prospects for better     inchshy; and guarantees of access to the molecular
       vasive surgery, positron emission tomography-         means to control such cancers if new research          data sets genwdted with public funding,to enhance
       computed tomography scanning, dose-moctulated         opportunities are fully exploited. But science         their usefulncss for investigators,practitioners,and
       radiothempy, and other technologies.                  operates in a cultural context that affects the        patients and their advocates.

1164                                             26 MAY 2006         VOL 312       SCIENCE
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