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Drug Discovery Today: Disease Mechanisms

Vol. 1, No. 2 2004

DRUG DISCOVERY

TODAY

Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Tamas Bartfai – Harold L. Dorris Neurological Research Center and The Scripps Research Institute, USA

DISEASE Cancer MECHANISMS

Mechanisms of breast cancer
Evgeny N. Imyanitov*, Kaido P. Hanson
Group of Molecular Diagnostics, N.N. Petrov Institute of Oncology, St. Petersburg 197758, Russia

Breast cancer is the first human tumor for which targeted therapies have been developed. The most impressive success stories include estrogen receptor pathway downregulators (tamoxifen and aromatase inhibitors) and HER2 antagonists (Herceptin). The development of dozens of other targeted treatments for breast cancer is underway. Unfortunately, some intrinsic features of breast cancer biology compromise the efficiency of current therapeutic strategies. Introduction
Breast cancer is the most common malignancy among females affecting approximately one out of ten women. Ageing of population in the industrialized world is the most obvious cause of increased breast cancer occurrence; indeed, the risk of developing breast cancer after 65 years of age is 5.8 times higher than before 65, and 150-fold higher than before 30 years of age. In addition to advanced age, a few dozens of other breast cancer predisposing factors have been identified; however, all these diverse risks can be assigned to either of two major categories: excessive exposure to estrogens and deficiency in maintenance of genomic integrity (Fig. 1) [1]. The proliferative effect of estrogens on breast epithelium has been acknowledged for decades. It is suggested since recently, that tumor promotion is not the only mechanism of estrogens action: some of estrogen metabolites were shown to cause DNA damage directly (i.e. contribute in the breast cancer initiation). Selected causes of estrogen overload (e.g. early menarche or late menopause) are at least in part attributed to inherited genetic variations. However, most of determinants of hyperestrogenia are related to the modern, Western lifestyle including low parity, delayed age at first
*Corresponding author: (E.N. Imyanitov) evgeny@imyanitov.spb.ru 1740-6765/$ ß 2004 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddmec.2004.09.002

Section Editor: Silvio Gutkind – National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
Breast cancer is the most common malignancy among females and affects approximately one in every ten women worldwide. It is the first human tumor for which targeted therapies have been developed. Some notable successful therapies include tamoxifen, aromatase inhibitors – both estrogen receptor pathway downregulators – and Herceptin, a HER2 antagonist. However, despite some spectacular examples of prolonged disease remission in selected women, the statistical survival benefit in metastatic breast cancer patients is estimated in months and not years. In this article, Evgeny Imyanitov and Kaido Hanson describe the progress of targeted treatments for breast cancer that are already underway, and discuss the particular features of breast cancer biology that compromise the efficiency of current therapeutic drugs.

delivery, short duration of breastfeeding, overeating, limited exercise and so on. Interestingly, the obesity correlates with hyperestrogenia and excessive breast cancer risk only after the menopause; in pre-menopausal women, overweight is associated with anovulatory cycles and reduced probability of acquiring breast cancer disease. The adverse impact of oral contraception and hormone replacement therapy has been confirmed in some but not all epidemiological studies. The role of exogenous endocrine disruptors in breast cancer incidence remains to be proven [1–4]. The second group of breast cancer predisposing properties – deficiency in maintenance of genomic integrity – has been recognized only recently (Fig. 1). There are two lines of supporting arguments: first, all of the identified breast cancer susceptibility genes contribute to the sensing or repair of DNA damage; second, there is an impressive reproducibility of phenotyping studies demonstrating relationships between breast cancer risk and constitutional chromosomal instability [5–7]. Unlike lung or bladder cancers, none of environmental carcinogens has been convincingly linked to breast cancer
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some recent findings have resumed the debate on the viral etiology of breast cancer [8. predisposing to ataxiatelangiectasia and Li-Fraumeni hereditary syndromes. However. specific fraction of cells forming breast cancer lump is highly tumorigenic [43]. Some founder mutations can be classified as middlepenetrance polymorphisms. the outcome of these studies remains to be seen [7]. in intriguing accordance with the viral hypothesis. Intriguingly. which seem to be somewhat less penetrant than non-founder defects. and the spectrum of these genetic alterations is different from those observed in cancer cells [22]. However. The bestknown highly penetrant breast cancer genes are BRCA1 (GenBank accession number NM_007294) and BRCA2 (GenBank accession number NM_000059).Drug Discovery Today: Disease Mechanisms | Cancer Vol.9] (Box 1). etiology. There are surprisingly few reports in modern scientific literature assessing the relationship between breast trauma and subsequent cancer development. they account for approximately 20% of familial breast cancer clustering [10]. Interestingly. there are also some negative reports on this subject [8.2. many aspects of breast cancer prevention and treatment will need to be re-analyzed.drugdiscoverytoday. NM_000051) and p53 (GenBank accession number NM_000546) germ-line mutations. stromal cells surrounding breast cancer epithelium also carry somatic mutations. Does all tumor mass possess a danger? Recent experiments show that only a minor. Although early studies carried out on breast cancer families suggested that BRCAs are associated with nearly fatal risk of the disease. 1. If the contribution of viruses in breast cancer etiology will be confirmed. There is more hope to detect breast cancer genedisease interactions within the class of hormone metabolizers. It is frequently stated that the majority of breast cancer cases are related to the disadvantageous ‘‘genetic passport’’ (i. breast cancer lump appears to arise from several independent progenitors. As already mentioned above. Wide-spread hypermethylation of regulatory regions of genome is another mandatory peculiarity of breast tumors [13]. many breast cancer researchers have recently re-located the efforts to the analysis of DNA repair gene polymorphisms. based on convincing evidence for heritability of individual features of hormonal portrait coupled with the proven role of hyperestrogenia in breast cancer development. Chromosomal instability manifested by enormous number of gross chromosomal abnormalities appears to be the most characteristic feature of breast cancer genome [12]. worldwide breast cancer spread appears to parallel the geographical distribution of one species of house mouse. Polyclonal origin of breast cancer? Monoclonal origin of breast cancer is believed to be a wellestablished fact. No. The results of the studies on dietary factors have been inconclusive as well. can also be considered as breast cancer-associated genetic defects.e. limitations in currently available methodologies force to abstain from the . Challenging the dogmas in breast cancer research: recent unexpected findings Viral theory revisited? There are several independent reports claiming that in some groups of patients roughly a third of breast carcinomas contain DNA sequences homologous to the well-known Mouse Mammary Tumor Virus (MMTV). owing to their noticeable occurrence in the population (1%) and modest but clinically meaningful influence on the breast cancer risk increase. Tumor heterogeneity might compromise the search for new therapeutic targets. 2 2004 Box 1. 1). The intrinsic resistance of particular intratumoral cell subsets to the treatment might explain a discordance between high frequency of short-term partial tumor responses and low rate of prolonged breast cancer remissions.com Somatic events in breast cancer pathogenesis Interaction between various breast cancer predisposing factors leads to accumulation of somatic mutations in breast epithelial cells (Fig. thus supporting the cancer field theory [42]. which are situated in between rare catastrophic germ-line mutations and frequent normal gene polymorphisms. Following the success in identifying breast cancer-associated germ-line mutations within genome safeguards in addition to relying on the consistency of the results of phenotyping tests (see the text above and Fig.4]. Contrary to beliefs of many patients. no reproducible associations have been revealed over the decade-long research in this field. breast cancer represents a classical hereditary disease with mendelian mode of transmission. all high. respectively. ATM (GenBank accession number 236 www. However. In a broad sense. unfavorable combination of low-penetrant gene polymorphisms).and middle-penetrant genes with proven breast cancer-associated significance participate in various aspects of maintenance of genomic integrity. as the current approaches are almost always based on the analysis of crude tumor material. Mus domesticus. recent reports indicate that their penetrance in unselected breast cancer series approaches to 65% for BRCA1 and only to 45% for BRCA2 (by age 70 years) [11]. such as colorectal or lung cancer. 1). the examples include CHEK21100delC (GenBank accession number NM_007194) and NBS1657del5 (GenBank accession number NM_002485) [7]. psychological stress is not associated with breast cancer risk [1. owing to the increased incidence of breast neoplasia in their heterozygous carriers [5]. Contribution of inherited features In some instances. Single nucleotide instability appears to be less common in breast cancer than in other major cancer types.9]. however. The attempts to link breast cancer risk to polymorphisms in carcinogen metabolizing enzymes have been unsuccessful. recent data cast some doubt on this confidence: at least in some cases. In addition to Jewish founder mutations in BRCA genes. There is a growing class of breast cancer-associated genetic variations.

No. Hundreds of reports have been devoted to the cataloging of breast cancer-associated genetic abnormalities (e. although it was demonstrated in a small portion of bilateral breast tumors [15]. It was shown recently that many breast carcinomas carry alterations in mitochondrial DNA [16]. These DNA alterations activate oncogenes and inactivate tumor suppressor genes. 1. which eventually results in the manifestation of ‘The hallmarks of cancer’ [21].drugdiscoverytoday. During the malignant transformation process. Two groups of predisposing factors have a major role in breast cancer etiology: excessive breast exposure to estrogens and deficiency in maintenance of genomic integrity.Vol. definitive conclusion [12. 2 2004 Drug Discovery Today: Disease Mechanisms | Cancer Figure 1.14]. ‘‘Classical’’ type of microsatellite instability does not occur in breast cancer.g. breast epithelial cells accumulate high number of somatic genetic events (mainly gross chromosomal alterations and methylation abnormalities). Somatic Mutations www.com 237 . Discrete alterations in breast cancer-specific genes can serve both as the triggers of somatic genetic instability and as consequences of increased mutation rate. Breast cancer mechanisms. Molecular determinants of the most essential tumor properties might serve as potential therapeutic targets.

ac. Breast carcinomas share all characteristics of malignancy. CCNE. RAR-beta. 17q12–21: HER2. STMY3. 53BP2 Refs. TGFBR3. SPR1. 9p (9p21. insensitivity to antigrowth signals.17]. Conditionally. 8p (8p21. 16q (16q21–23. In 1990s and early 2000s many researchers tried to locate breast cancer-specific losses of heterozygosity (LOH). Frequently. TIMP3. THBS.1).3. 7q (7q31. the decreased expression of suppressor genes is associated with the methylation of their promoter regions [13]. ITGA6. mutations in RAS family oncogenes occur in a negligible fraction of breast cancer [20].uk/nomenclature/. 2q (2q22. SRBC.2). GZMH. The p53 238 www. 8q (8q24). SYK.1). NES1. GSTP1. IGF1R. it remains to be established whether they do contain activated oncogenes or simply reflect the background noise of somatic chromosomal instability [12]. [12] [12. B94.drugdiscoverytoday. CCND1 (GenBank accession number NM_053056). it has turned out that conventional PCR allelotyping can not discriminate between inactivating and activating mutations (e. Rantes.onco-is. RASSF1A. 11q (11q22–23. TMS1. 1. 11q13: CCND1. evasion from apoptosis. BRCA1.32). 6q21–23. 20q (20q13) 1p (1p36.1).gov/entrez/query.nlm. Maspin. see http://www. However. 6q (6q25. SOCS1. neurosin.nih.ncbi.3). limitless replicative potential. 16q24.3). GPC3. C-MYC (GenBank accession number NM_002467)] followed by their overexpression is a distinct feature of breast cancer. OXTR. and include self-sufficiency in growth signals. http://www.3). Noticeable frequency of amplifications of selected oncogenes [HER2 (also known as ERBB2) (GenBank accession number NM_004448). NOEY2. 1q41).2).17] Gains of genetic material Events of uncertain significance Losses of heterozygosity (allelic imbalances) reflecting either allelic deletion or gain of the remaining allele Inactivating events Losses of genetic material [12] [18] [12] Intragenic mutations Promoter methylation followed by the loss of gene expression [20] [13] Loss of gene expression a [12. BAX. and http://www.3. an active and essential component of neoplastic evolution [22.3). 21q (21q11.com). MUC1.3). 19p (19p13). PR. CCND2. POH1. 16q24. instead. in Human Cancers Database. there are several other regions in the genome that repeatedly demonstrate extra copies in breast cancer. TWIST.gene. RFC.2). but. 16p (16p11). TOP2A. however systematic picture of upregulated transcripts has yet to be drawn [17]. lipocalin 2. 2 2004 Table 1. claudin-7. Cathepsin D. CIP1. 18p (18p11. The genome-wide approaches led to the identification of dozens breast cancer-associated deletions. However. 8p (8p21. HIN1. BCSG1. they can be classified into activating and inactivating events (Table 1). 17p (17p13.1. 13q (13q14). there is also a growing list of genes whose transcription is downregulated in breast cancer [12. 17p13. PAI2. CTSD.23]. INK4. 16q (16q22. 17p (17p13. SPARCL1. Similarly to the progress in understanding of tumor angiogenesis. CRABP2. Intragenic mutations are relatively uncommon for breast cancer. 20q13: AIB1 BCL2. 13q (13q12–13.com (GenBank accession number NM_000546) gene is mutated only in 20% of breast carcinomas. TFAP4. 1q32. KIP1. hTERT.ucl. RIZ1. HOXA5. plakophilin 1.3). DAPK.3). 14-3-3sigma ATM. which have been defined as ‘The Hallmarks of Cancer’ in already-classical work of Hanahan and Weinberg [21]. 6q (6q13–21. PS2. ZAC. Prostasin. In addition to identified oncogenes. MYBL2. RB1. RBL2. Various combinations of activating and inactivating mutations and epigenetic events lead to the spectrum of properties of tumor cells. SIX1. 4q (4q35. Genetic alterations in breast carcinomas Type of genetic event Activating events Gene amplification followed by over-expression Gene over-expression Chromosomal regions or genes involveda 8q24: MYC. SMARCD2. 6q25–27). CDH1. 3p (3p14. No. RIG-like7-1. VEGF 1q (1q21.fcgi?db=OMIM&itool=toolbar. MGST1.19]. 11q (11q13). with one important reservation: more than 50% of breast cancers retain at least partial dependence from estro- . the attempts to identify new suppressor genes by LOH mapping have largely failed: in addition to enormous variability of LOH patterns due to admixture of non-specific allelic imbalances. 18q (18q21. 17q24). lactoferrin. genomic instability and sustained angiogenesis. 1p36).Drug Discovery Today: Disease Mechanisms | Cancer Vol. FHIT. it is becoming apparent that the contribution of surrounding stroma in tumor growth is not a merely passive process. Recent developments in expression profiling have significantly enlarged the list of genes overexpressed in breast cancer.1). NM23-H1. TGFBR2. PAI1. 22q (22q13) p53 APC. invasion and metastasis. EMS1. Ki-67. TNXA. CD63. 11q24–25). molecular techniques enabling global mapping of hypermethylated regions are not yet as efficient as expression profiling or array-based comparative genomic hybridization. ER. 13q14. 17q (17q11. CDH13.1) 1p (1p31–35.1.17] For more information of these genes. loss of the allele versus amplification of the remaining allele) or between homozygous deletion and retention of both gene copies [18. GATA3. 8p22–23).g.2. MDM2.

their targeting possesses a risk of adverse effects. the intervention with breast cancer initiating cascades might have some potential for breast cancer prevention. Noticeably. which demonstrated evident survival benefit for patients suffering from HER2-positive breast cancer [29]. With some reservations. however. being a non-toxic precursor of 5-fluorouracil.30. because it does not require functional evidence but solely relies on the proof of breast cancer-specific expression. This concept certainly enlarges the list of potentially relevant targets. surprisingly. while the specific targeting of upregulated molecules has become a realistic approach. Other targeted approaches such as HER1 or pan-HER inactivation [26]. All of the approaches mentioned above are based on the suppression of molecules essential for breast cancer maintenance. the substitution of downregulated enzymes) is not achievable for the time being. 1) [26]. the opposite (i. The somatic genomic instability might represent not only the dangerous property of tumor phenotype. Activation of the HER2 pathway in breast cancer is often associated with an upregulation of other members of HER receptor family. many of breast cancer signatures identified by array expression profiling tend to group around long-known disease markers. Two molecules appear to be truly specific for breast cancer. 2 2004 Drug Discovery Today: Disease Mechanisms | Cancer genic growth stimulation.Vol. However. a key enzyme of estrogen synthesis. Targeted therapies The web of signaling cascades Owing to the rapid accumulation of data in signal transduction research. Interestingly. Therefore. Aromatase inhibitors have shown more favorable results than tamoxifen in several randomized breast cancer trials [24]. cyclin-dependent cascades. the spectrum of candidate targets is limited by those molecules. antiapoptotic and metastatic cascades has also been acknowledged [27]. including breast cancer [12. inhibition of molecules involved in tumor metastasis and angiogenesis [29. therefore. it might soon be replaced by inhibitors of aromatase. such as estrogen receptor (ER) or HER2 oncogene status [25]. the comprehensive description of breast cancer-associated signaling pathways and their cross-talk has become a difficult challenge. In postmenopausal women. First. Another success story concerns Trastuzumab (Herceptin). Although it failed to control fertility in humans. this complexity is not as high as it might appear. This benign feature of some breast cancer accounts for remarkable efficiency of the antiestrogenic treatment approaches [24].drugdiscoverytoday. COX2 is mentioned most frequently in the context of tumor angiogenesis. its involvement in autoproliferative. as well as some additional strategies [27. Although the diversity of molecular portraits of breast cancer is extraordinary. due to increased expression of thymidine phosphorylase in the neoplastic tissue [38]. Xeloda undergoes topical conversion to the cytostatic drug in tumors. owing to the multifunctionality of many signaling proteins and pathways. the initial inclusion criteria for the target usually are its breast cancer specificity and involvement in the disease maintenance. Third. These molecules are not indeed specific for breast cancer. Downstream parts of HER-initiated signaling cascades include RAS–RAF–MEK–MAPK pathway. More general approaches are based on the use of breast cancer-specific antibodies conjugated with various toxins [39]. but also an www. recently introduced Capecitabine (Xeloda) could be considered as a relevant example. are in early clinical trials or pre-clinical studies (Table 2). interference with downstream participants of receptor tyrosine kinase signaling [29– 33].28. Second. it is usually difficult to precisely assign the molecule of interest to the defined biological outcome(s). and is involved in transcriptional regulation of many essential genes.29]. The first example of selective breast cancer therapy emerged several decades ago owing to an accidental finding. No. Tamoxifen had been initially tested with the intention to develop a contraceptive pill. host factors appear to play an essential role in determining the molecular variant of breast cancer pathogenesis [15]. especially HER1. 1. indeed. The alternative strategy suggests the use of breast cancer-specific proteins as the anchors for site-specific delivery of toxic compounds [38–40] (Table 2). and both of them are receptors: ER and HER2. however HER1 overexpression occurs in breast cancer significantly less frequently than in several other cancer types. the members of HER receptor family appear to contribute into all cancer hallmarks (Fig. In addition to ER and HERs. these cascades appear to be upregulated in many cancer types. applied breast cancer research is more interested in tumor-activated pathways than in those that are suppressed in breast cancer cells. For example.26. they do have regulatory functions in normal cells as well.34].28.35–37]. which has an essential role in the regulation of cell survival. which are essential for the maintenance of breast cancer cells. mTOR). its inhibitory effect on breast cancer cell growth led to the rapid introduction of this drug in the treatment of ER-positive breast cancer.com 239 . there is an increasing attention to the angiogenic pathways triggered by vascular endothelial growth factor (VEGF). ER is a member of the family of nuclear receptors. in the light of potential therapeutic relevance. they appear to fit into the limited number of distinct disease subsets. and phosphatidylinositol 3kinase (PI3-K) pathway (AKT. which potentiates cellular proliferation through modification of The description of breast cancer-specific molecular targets and corresponding therapeutic compounds is presented in the Table 2. Although the utmost importance of comprehensive functional description of potential breast cancer targets is beyond any doubt.e. but not for the cure of already existing disease.

Roche http://www. alkylating drugs. antimetabolites. 2 2004 On the market AstraZeneca http://www. Orion http://www. vinca alkaloids) On the market for a long time Clinical response can be achieved in more than 80–90% cases. more than a third of breast cancers are resistant to antiestrogen therapy. limited duration of response. 1. toxins. radioactive isotopes. However. overlapping spectrum of drug resistance. molecules essential for breast cancer development and maintenance) Estrogen receptor pathway ER pathway downregulators show high efficiency combined with good safety profile. taxanes.drugdiscoverytoday.lilly. [40] Genuine targets (i. [38] Molecular targets as tumor-specific anchors for delivery of cytostatic substances Thymidine phosphorylase Capecitabine (Xeloda) On the market Thymidine phosphorylase converts Xeloda to the cytostatic drug.com Drug Discovery Today: Disease Mechanisms | Cancer Table 2. Selective estrogen receptor modulators (SERMs) Tamoxifen Toremifene (Fareston) On the market for a long time On the market Almost complete cross-resistance with tamoxifen Almost complete cross-resistance with tamoxifen Many pharmaceutical companies Schering-Plough. However. Breast cancer targets and related therapies Target Therapy against target Stage of developmenta Advantages and/or disadvantages Who is working on the target Many pharmaceutical companies and research groups Website Refs.e. 5-fluorouracil.com [24] . disadvantages include severe adverse effects.com [38] Several research groups [39] Sodium–iodide symporter Laboratory studies Adverse effects on thyroid gland are probable. attractants of tumor-killing cells) Radioactive iodide Phase I–II Presumably large spectrum of candidate molecules. No.scheringplough. limited ability to predict response and/or non-response to a given cytostatic compound.240 www. Breast cancer-specific antigens Immunoconjugates (with cytotoxic drugs.roche.com http://www.fi http://www.astrazeneca.orion. since the target does not need to be essential for tumor growth.com [24] [24] Raloxifene (Evista) Selective estrogen receptor downregulators (SERDs) Faslodex (Fulvestrant) Chemoprevention trials Eli Lilly [24] Vol.b Properties of cancer cells as a target Genetic instability and/or Conventional cytostatic high proliferation drugs (anthracyclines. high tumor specificity is attributed to the preferential expression of this enzyme in cancer tissues.

roche.com http://www. Genentech.com http://www.com http://www. induce tumor response in a subset of tamoxifen-resistant tumors.roche.gene. efficient only in postmenopausal patients.astrazeneca.com http://www. However. 1.roche.com http://www. Genentech.com [29] [29] AstraZeneca OSI.com [31] http://www.gene. Roche http://www. No.com 2C4 (Omnitarg.com http://www.astrazeneca. Gefitinib) OSI-774 (Tarceva. Roche http://www.com [29] [29] EKB-569 HER2 and HER1 HER kinases VEGF www. Wyeth GlaxoSmithKline Pfizer Genentech AstraZeneca [29] [26] [26] [30] [29] Drug Discovery Today: Disease Mechanisms | Cancer GW572016 (GW2016) CI-1033 (PD183805) Bevacizumab (Avastin) ZD6474 VEGFR2 Farnesyl transferase R115777 (Zarnestra.jnj.pfizer. lonafarnib) CDK kinases Flavopiridol (Alvocidib) Phase I–II Phase I Johnson and Johnson Schering-Plough Aventis http://www.drugdiscoverytoday.gene.com [31] [32] 241 .com http://www. On the market On the market On the market HER2 is activated only in one out of four breast tumors. AstraZeneca Novartis Pfizer http://www.astrazeneca.novartis.pfizer.pfizer. Notice that HER2+ tumors represent the most aggressive subset of breast cancer.takeda.gsk. Erlotinib) Phase I–II Genentech.wyeth. Tipifarnib) Phase II SCH66336 (Sarasar.com http://www.com [29] Phase I Phase I HER1 is rarely overexpressed in breast cancers.Aromatase inhibitors Superior when compared with tamoxifen.com http://www.com http://www.com http://www.com Phase I Phase II Phase II Phase II Phase II Trials on several farnesyltransferase inhibitors have been discontinued due to high-toxicity and lack of clinical effect.com [24] [24] [24] Vol.com http://www. Phase II Phase II Pfizer Takeda http://www. 2 2004 Anastrozole (Arimidex) Letrozole (Femara) Exemestane (Aromasin) HER2 (ERBB2) Antibodies Trastuzumab (Herceptin) On the market High-efficiency combined with good safety profile. Pertuzumab) Small molecule inhibitors CP-724714 TAK-165 HER1 (EGFR) ZD1839 (Iressa.gene. Roche http://www.schering-plough.com http://www.osip.

Several research groups and pharmaceutical companies Geron http://www. Target Therapy against target UCN-01 CYC202 (Roscovitine) BMS-387032 mTOR kinase CCI-779 (Temsirolimus) RAD001 (Everolimus. the information was updated using the websites of pharmaceutical companies. 1.kosan.com http://www.com Bryostatin-1 Bay 43-9006 CI-1040 (PD184352) Perifosine 17-AAG Phase II–III Phase I Clinical trials on other cancer types Clinical trials on other cancer types Phase II Phase II Phase I High toxicity but limited therapeutic efficiency in initial clinical trials Vernalis Bristol-Myers Squibb.com [30] [33] [29] [33] [33] [33] [30] Stage of developmenta Phase I Phase II Phase I Advantages and/or disadvantages UCN-01 inhibits several other kinases.com [28] [27] [34] Wyeth Novartis GPC Biotech Onyx.drugdiscoverytoday. Pfizer http://www.gov/clinicaltrials).com http://www. 2 2004 Stage of development’’ applies mainly for breast cancer but not for other cancer types. Celltech http://www. MS-275 GRN163 Phase I–II Laboratory studies Laboratory studies Laboratory studies Inhibition of chemokine receptors might interfere with metastatic process.com http://www.gov/scripts/cder/drugsatfda).bms. LAQ-824.242 www. including PKC.aeterna. but still remain at the stage of clinical trials for the use in adjuvant therapy and/or chemoprevention. Certican) PKC RAF MEK Akt Hsp90 Matrix metalloproteinases BB-2516 (marimastat) BMS-275291 c-Kit and/or PDGFR COX2 STI571 (Gleevec. thus COX2 inhibitors have good safety profile.accessdata.novartis. Glivec.com [32] [35] [36] [37] Vol.com Drug Discovery Today: Disease Mechanisms | Cancer Table 2 (Continued).pfizer. CI-994.com http://www.fda.celltechgroup.wyeth.geron. Notice that some of the already licensed compounds have been approved for the treatment of metastatic breast tumors.b [32] [32] [30] Histone deacetylases Telomerase Prolactin receptor Chemokine receptors a SAHA. and the Catalog of FDA Approved Drug Products (http://www. Who is working on the target Kyowa Hakko Kogyo Cyclacel Bristol-Myers Squibb Website Refs. Bayer Pfizer Aeterna Zentaris Kosan Biosciences http://www. .com http://www. Clinical Trials site of the National Cancer Institute (http://www. PXD101. No. this is especially true for phase II/III trials and already marketed drugs. b In addition to the literature references indicated in the table.com http://www.vernalis.pfizer.cancer. Imatinib) Celecoxib (Celebrex) Phase II Phase II Phase II Phase II–III COX2 is selectively expressed in tumors.

HER2 and COX2.drugdiscoverytoday. It is probable that the mechanism of action of conventional non-specific cytostatics utilizes this weakness. its extent could have been underestimated. thus supporting the theory of tumor field [42]. some compounds with broader substrate specificity have been recently tested (e. administration of signal transduction modifiers (Table 2) often results in noticeable adverse effects. one would expect higher rate of prolonged breast cancer remissions than the one currently observed. With the possible exception of ER. therefore. non-selective COX2 inhibitors and so on). sophisticated combinations of targeted drugs [41]. dual HER1–HER2 inhibitor GW572016 and CDKs–PKC inhibitor UCN-01) (Table 2). most of upregulated target molewww. 2). The antitumor specificity is warranted if none of normal cells (depicted at the four corners) carries the same set of targets. unlike the cancer cells. it also increases the risk of undesirable consequences. in attempt to prevent cancer cell from rescuing from target inhibition. Unfortunately. Towards curable breast cancer: how long is the road? Modern therapeutic combinations can induce tumor response in more than 80–90% of breast cancer patients. Unfortunately. Although the relaxed drug specificity might render higher antitumor activity [29]. therefore. and inevitably develop drug-resistant phenotype. that normal tissues do not carry exactly the same set of vital molecules. because they are almost always based on the analysis of gross primary tumor mass and.Vol. furthermore. potentially metastatic cells constitute only a negligible fraction of crude breast cancer lump [43]. most of the detected variations are usually quantitative but not qualitative. some of the recent evidence suggests that a notable portion of breast cancer might be polyclonal in their origin. indeed. HER2 antagonists. vise versa. at least in part. simply reflects the selection of pre-existing fatal cell subsets. Furthermore. However. the tumor specificity is achieved by fine adjustment of the multidrug panel to the unique spectrum of survival determinants detected in malignant tissue by expression profiling (Fig. However. Tumor heterogeneity might compromise current efforts of molecular portraying of neoplastic disease. previously. This model is in concordance with the clinical experience. selective and. or. The intrinsic genomic instability of cancer cells certainly facilitates this process. Interestingly. where the therapy saves the lives in a certain (still frustratingly small) number of otherwise relapsed patients [38]. Not surprisingly. To the great surprise of scientific audience. The situation is slightly better in adjuvant breast cancer treatment. the statistical survival benefit in metastatic breast cancer patients is estimated in months and not years. it is not immediately clear whether the treatment-related drug resistance is truly attributed to the adaptive genetic flexibility of tumor cell clones. they can tolerate the cocktail of signal transduction modifiers. 2 2004 Drug Discovery Today: Disease Mechanisms | Cancer Achilles’ heel of neoplasia. In this approach. No. it is difficult to differentiate between tumor evolution and tumor heterogeneity.g. The concept of combined cancer therapy implies that all survival determinants of the tumor cell (depicpted in the center) can be efficiently blocked by the individually matched cocktail of signal transduction modifiers. sometimes comparable with toxicities of conventional cytostatics. Although the tumor heterogeneity has been acknowledged for a long time. 1. might miss the targets in the most destructive cancer subclones (Box 1). It is assumed at the same time. Figure 2. cytotoxic agents with various mechanisms of action. combined therapy of breast cancer is definitively superior when compared with the monotherapy. Choice of the targets: cancer-specific or breast-specific? The initial phase of the search for cancer targets is usually based on the comparison of expression profiles in tumor versus corresponding normal tissues. molecular portrait-based. The promise of drug combinations. most of the currently available cytotoxic agents have a low therapeutic index [38]. despite some spectacular examples of prolonged disease remission in selected women.g. Another group of difficulties is related to the tumor ability to evolve over selective pressure of cancer treatment. However. There are several concerns related to the future of breast cancer therapy. Following the logic described above. ER pathway downregulators. there are an impressive number of entirely distinct therapeutic modalities whose combinations have already been used in breast cancer treatment or trials (e. pan-HER inhibitor CI-1033. It is hoped that ongoing efforts in expression array profiling will help to increase the list of genuine breast cancer-specific targets. most of the currently considered targets are not truly cancer-specific because they are involved in the functioning of vital human tissues.com 243 . It is often suggested that the future of breast cancer therapy lies in the use of individualized. there are experimental data demonstrating that truly dangerous. In other words.

it has a reasonably favorable prognosis. and genetics. J. 9–23 17 Bertucci. Oncogene 21. N. Eur.P. Crit. Cancer Lett. as a result of the deficiency in systematic understanding of molecular physiology of normal human cells. K. Oncol. It has been demonstrated that even transformed cells stably retain major lineage-specific molecular markers [44]. risk factors. 7. Cancer 40. References 1 Singletary. At the clinical level.N. et al. (2002) Molecular alterations in sporadic breast cancer. Rev. However. metastatic breast cancer remains largely an incurable disease. S. 2 2004 cules occur only in a subset of carcinomas. B. and Cason. 1117–1130 12 Lerebours. et al. Nat. A. selective ablation of particular cell lineage) can be more achievable than specific elimination of cancer cells [45]. J. 624–628 3 Clemons. In contrast to many other epithelial tumors.drugdiscoverytoday. 3–14 8 Mant. et al. 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