Traditional therapies for breast cancer have generally relied uponthe targeting of rapidly proliferating cells by inhibiting DNA replicationor cell division. Although this strategy has been effective, its innate lackof selectivity for tumor cells has resulted in diminishing returns, approachingthe limits of acceptable toxicity. A growing understanding ofthe molecular events that mediate tumor growth and metastases has ledto the development of rationally designed targeted therapeutics thatoffer the dual hope of maximizing efficacy and minimizing toxicity tonormal tissue. Promising strategies include the inhibition of growthfactor receptor and signal transduction pathways, prevention of tumorangiogenesis, modulation of apoptosis, and inhibition of histone deacetylation.This article reviews the development of several novel targetedtherapies that may be efficacious in the treatment of patients with breastcancer and highlights the challenges and opportunities associated withthese agents.
ABSTRACT: Traditional therapies for breast cancer have generally relied uponthe targeting of rapidly proliferating cells by inhibiting DNA replicationor cell division. Although this strategy has been effective, its innate lackof selectivity for tumor cells has resulted in diminishing returns, approachingthe limits of acceptable toxicity. A growing understanding ofthe molecular events that mediate tumor growth and metastases has ledto the development of rationally designed targeted therapeutics thatoffer the dual hope of maximizing efficacy and minimizing toxicity tonormal tissue. Promising strategies include the inhibition of growthfactor receptor and signal transduction pathways, prevention of tumorangiogenesis, modulation of apoptosis, and inhibition of histone deacetylation.This article reviews the development of several novel targetedtherapies that may be efficacious in the treatment of patients with breastcancer and highlights the challenges and opportunities associated withthese agents.In recent years, the strategy in cancertherapy in general and breastcancer in particular has shiftedfrom the use of high doses of toxic,nonspecific agents to a range of novelagents that target specific molecularlesions found in tumor cells. Advancesin molecular biology have allowedthe isolation of novel interactions anddownstream targets, driving the developmentof rationally designedtargeted therapies. The success oftrastuzumab (Herceptin) in breast cancerand imatinib mesylate (Gleevec)in chronic myelogenous leukemia andgastrointestinal stromal tumors providesproof of principle that such anapproach can have a marked impactwhen the mechanism of growth of aparticular cancer is understood andspecifically interrupted.This article will focus on new,molecular-targeted approaches to thetreatment of breast cancer. Of particularinterest are classes of drugs thattarget the tyrosine kinase signal transductionpathways, block tumor angiogenesis,modulate apoptosis, andinhibit histone deacetylation.Targeting the erbB1 ReceptorThe erbB family consists of fourclosely related transmembrane receptors:erbB1 (also termed epidermalgrowth factor receptor [EGFR] orHER1), erbB2 (also termed HER2 orneu), erbB3 (HER3), and erbB4(HER4). All four erbB receptors sharea common molecular architecturecomposed of three distinct regions:an extracellular ligand-binding domain,a transmembrane region, andan intracellular tyrosine kinase-containingdomain that is responsible forthe generation and regulation of intracellularsignaling (Figure 1). Theformation of erbB homodimers andheterodimers following ligand bindingand receptor aggregation activatesthe intrinsic receptor kinase activityvia intramolecular phosphorylationand generates a cascade of downstreamchemical reactions thattransmit a wide variety of cellulareffects.
The rationale for and developmentof therapeutics targeting erbB2, particularlytrastuzumab, have been reviewedelsewhere, and this sectionwill be limited to a discussion of therapeuticstargeting erbB1. The erbB1receptor is overexpressed in about40% of breast cancers.[2,3] The frequencyof overexpression variesdepending on the evaluation methodused and whether the truncatedEGFRvIII form-a constitutively activatederbB1 variant expressed in alarge proportion of breast cancers-isincluded.The overexpression of erbB1 hasbeen associated with increased proliferation,disease progression, and apoor prognosis in breast cancer.[3,4]ErbB1 expression has also been correlatedwith decreased estrogen-receptorexpression and increased resistanceto endocrine therapy.[2,3,5,6] ErbB2and erbB1 are commonly (10%-36%)coexpressed, and such coexpressionhas been correlated with a less favorableprognosis.[7,8] Given the wideexpression of erbB1 in breast cancerand the important role this receptorplays in signal transduction, the useof erbB1 inhibitors in the treatment ofbreast cancer has generated considerableinterest.The aberrant signaling that occursthrough the erbB1 pathway can becaused by high expression of erbB1,mutation of erbB1 (eg, EGFRvIII),decreased phosphatase levels, orheterodimerization of erbB1 withother members of the erbB receptorfamily (such as HER2). Severaldifferent strategies have been used todownregulate signaling through thispathway (Table 1). These includemonoclonal antibodies directedagainst erbB1 such as cetuximab(IMC-C225, Erbitux) and ABX-EGF,and small-molecule inhibitors oferbB1 tyrosine kinase such as gefitinib(ZD1839, Iressa) and erlotinib(OSI 774, Tarceva).Small Molecules TargetingerbB1 Tyrosine Kinase
Small-molecule inhibitors of erbB1receptor tyrosine kinase prevent receptordimerization, autophosphorylation,and the resulting downstreamsignaling. Hypothetically, this approachcould inhibit signaling mediatedby ligands as well as signalingthat is independent of growth factors.In contrast to monoclonal antibodies,such agents may also inhibit ligandindependentsignaling due to constitutivelyactive mutant receptors (eg,EGFRvIII). Several erbB1 tyrosinekinase inhibitors are under evaluation,but the anilinoquinazolines, gefitiniband erlotinib, are in the most advancedstages of development.
Targeting theRas/Raf/MAPK Pathway
The Ras proteins are guanine nucleotide-binding proteins that play apivotal role in the control of normaland transformed cell growth. Followingstimulation by several growthfactors and cytokines, Ras activatesmultiple downstream effectors. TheRas/mitogen-activated protein kinase(Ras/MAPK) pathway plays animportant role in breast cancer(Figure 2).Although
is functionally mutatedin < 5% of breast cancers, anupregulation of the classic mitogenicRas/Raf/MAPK cascade occurs, stimulatedby overexpression or amplificationof oncogenic proteintyrosine kinase activity (eg, erbB2 orerbB1). Phospholipase-C, one ofthe signaling proteins activated by receptordimerization of activated erbB1and erbB2 enhances Ras activitythrough its SH3 domain. In addition,the adaptor protein Grb2 thatlinks protein tyrosine kinases to Rasand is overexpressed in breast cancer,may amplify signaling through the Raspathway in response to growthfactors.The amplification of Ras signalingas a result of overexpression of theseoncogenes and intermediate signalingmolecules leads to increased stimulationof downstream effectormolecules including phosphatidylinositol3-kinase (PI3K) and proteinkinase B (Akt). Such oncogenic activationnot only confers a proliferativeand survival advantage to cancer cellsbut also supports tumor growththrough its proangiogenic effect.
Farnesyl Transferase Inhibitors
The Ras pathway may be targetedthrough the inhibition of farnesylation.This key step in the posttranslationalmodification of Ras is necessaryfor membrane localization and function.Initial studies of farnesyl transferaseinhibitors (FTIs) suggested thatthese agents selectively inhibit theanchorage-independent growth of rastransformedcells and reverse thetransformational phenotype of rasmutatedcells. Recently, the roleof Ras proteins in mediating the antitumoreffects of FTIs has become lesscertain.FTIs have demonstrated insufficientactivity in tumors with K-
mutations such as pancreas and colorectalcancers, presumably becauseanother prenylating enzyme, geranylgeranyltransferase, can alternativelyprenylate or activate K-
. Inaddition, FTIs have demonstrated antiproliferativeactivity in tumor cell
lines with wild-type Ras, suggestingthat mechanisms other than inhibitionof Ras farnesylation may beinvolved. The prevailing explanationfor the activity of FTIs in tumorssuch as breast cancer-whichrarely involves
mutations-includes the fact that FTIs preventsignaling through wild-type Rascaused by upstream aberrations (eg,erbB1, erbB2) or that they inhibit farnesylation(activation) of other criticalproteins.
Antiapoptotic mutations significantlycontribute to the malignant phenotypeby allowing the cell to surviveunder conditions that would normallytrigger its demise. The bcl-2 geneproduct has been implicated in thegrowth and development of a varietyof tumors including breast cancer andhas the potential to confer chemoresistanceand radioresistance to establishedtumors.[80-82] The Bcl-2protein dimerizes both with itself andwith other members of the Bcl-2 family(Bcl-xL, Bax, and Bcl-xS), andthe interaction of these protein dimersinfluences sensitivity to apoptoticstimuli.
Bcl-2 Antisense Therapy
Preclinical data demonstrate thatBcl-2 antisense therapy with oblimersen(G3139, Genasense) has antitumoreffects against breast cancer.Treatment with oblimersen is well toleratedand leads to a reduction in intratumoralBcl-2 protein levels.[80,84]Oblimersen has been combined withcytotoxic chemotherapy.[85,86] Inhuman breast cancer xenograft models,the combination of oblimersen anddocetaxel produced an enhanced antitumoreffect, leading to durable tumorregression. These preclinical dataprovided the basis for evaluation ofthis combination in breast cancer. In arecent phase I trial, oblimersen andweekly docetaxel were tolerable andresulted in a tumor response in two ofthe five patients with advanced breastcancer included in this study.These initial data support the furtherdevelopment of this combination formetastatic breast cancer.
TNF-Related Apoptosis Ligand
Mutations in survival factors at thecell surface including death receptorsof the TNF receptor family may alsolead to dysregulation of apoptosis. TheTNF-related apoptosis ligand (TRAIL)is a member of the TNF ligand superfamilywith high homology to theFas/Apo1 ligand. Although the biologicfunctions of TRAIL remain incompletelydefined, strong evidence ofTRAIL's ability to trigger apoptosisin numerous cancer cell lines supportsa physiologic role for TRAIL in mediatingapoptosis.TRAIL mediates apoptosis throughtwo death receptors, TRAIL-R1 (deathreceptor 4, DR4) and TRAIL-R2(death receptor 5, DR5). These receptorswere isolated and named basedon the presence of a death domain intheir cytoplasmic tails that is capableof initiating a cascade of caspase activationand ultimate cell death. Resistanceto TRAIL-induced apoptosis hasbeen demonstrated via in vitro studiesof breast cancer cell lines, with inactivatingmutations in the TRAIL-R1and -R2 genes being particularly important.[87,88]Therapies targeting TRAIL-R1 andTRAIL-R2 are under development.One such agent, TRM-1, a fully humanizedagonist monoclonal antibodyto the TRAIL-R1 receptor, is currentlyin phase I trials. TRM-1 has beenshown to induce apoptosis in cancercell lines, and investigators have predictedthat it will display activitiessimilar to the TRAIL-R1 agonisticligand.
Role of HistoneDeacetylase Inhibitors
Another attractive target for interventionin breast cancer is histoneacetylation. The acetylation anddeacetylation of histones plays animportant role in the regulation ofgene expression. Hypoacetylation ofhistones is associated with a condensedchromatin structure that resultsin the repression of gene transcription,whereas acetylated histones areassociated with a more open chromatinstructure and activation oftranscription.Histone deacetylase and the familyof acetyl transferases are involved indetermining the acetylation of histones.Inhibition of histone deacetylaseincreases histone acetylation, which,in turn, leads to the transcription of afew genes whose expression causesinhibition of tumor growth.[90-92]The mechanism of selectivity of geneexpression is currently not understoodbut is an area of intense study. Inhibitorsof histone deacetylase have beenshown to induce growth arrest, differentiation,and apoptosis in a varietyof tumors, including human breastcancer cell lines.[90,93]In preclinical studies, treatmentwith LAQ824, a hydroxamic acid analoginhibitor of histone deacetylation,led to downregulation of HER2in human breast cancer SKBR-3,BT-474, and MB-468 cells and sensitizedthese cells to the apoptotic effectsof trastuzumab and polymerizing agents(docetaxel and epothilone B).Histone deacetylase inhibitors causeacetylated histones to accumulate inboth tumor and peripheral circulatingmononuclear cells, and this accumulationhas been used as a markerof biologic activity. Several drugs thatinhibit histone deacetylation are beingevaluated in phase I/II clinical trialsas single agents or in combinationwith cytotoxic chemotherapy.[90-95]These include suberoylanilide hydroxamicacid, pyroxamide, depsipeptide,MS-275, CI-994, andLAQ824.Results of a phase I trial of suberoylanilidehydroxamic acid in heavilypretreated patients with hematologicmalignancies were recently reported. The major toxicities observedincluded fatigue, diarrhea, anorexia,dehydration, and myelosupression.Among the clinical responses in thisrefractory group of 29 patients was areduction in measurable tumor (seenin 6 patients). Encouraging data frompreclinical and phase I studies haveprompted further evaluation of thisclass of agents in patients with metastaticbreast cancer.
Improvements in our understandingof the molecular events that mediatetumor growth and metastases haveenabled the design and developmentof novel therapeutic agents that specificallytarget intrinsic aberrancies incancer cells. New combinations ofcytotoxic chemotherapy and targetedagents are being explored in breastcancer, generating much excitementand expectation that these innovativetherapies will improve the outcomeof patients with this disease. The increasinguse of molecular profilingtechniques should give us the opportunityto select the most active agentsfor a given tumor and thereby reduceunnecessary side effects. In addition,genomics and proteomics provide uswith the potential for discovering thehidden targets of our current therapeuticarsenal.In order to improve the efficiencyof the evaluation process and increasethe probability of success, the futuredevelopment of molecularly targetedagents needs to incorporate assays toassess the suitability of the patientpopulation, the target, and the effectsof the target. Such assays may lead toenrichment of early proof-of-principlestudies in patients who are mostlikely to benefit from these agents orwho might achieve responses that areeasy to detect in nonrandomized trials.New initiatives in clinical trialdesign including novel correlativeimaging, alternative end points suchas time to progression, and novel approachessuch as randomized discontinuationschemes, are needed todetermine the future utility of theseagents.
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Rowinsky EK: Signal transduction inhibitors.Horizons in Cancer Therapeutics 2:3-35, 2001.
Walker RA, Dearing SJ: Expression ofepidermal growth factor receptor mRNA andprotein in primary breast carcinomas. BreastCancer Res Treat 53:167-176, 1999.
Morris C: The Role of EGFR-directedtherapy in the treatment of breast cancer.Breast Cancer Res Treat 75 (suppl 1):S51-S55, 2002.
Fox SB, Leek RD, Smith K, et al: Tumorangiogenesis in node-negative breast carcinomas-relationship with epidermal growth factorreceptor, estrogen receptor, and survival.Breast Cancer Res Treat 29:109-116, 1994.
Klijn JG, Look MP, Portengen H, et al:The Prognostic value of epidermal growth factor(EGF-R) in primary breast cancer: Resultsof a 10-year follow-up study. Breast CancerRes Treat 29:73-83, 1994.
McClelland RA, Barrow D, Madden TA,et al: Enhanced epidermal growth factor receptorsignaling in MCF7 breast cancer cellsafter long-term culture in the presence of thepure antiestrogen ICI 182,780 (Faslodex). Endocrinology142: 2776-2788, 2001.
Osaki A Toi M, Yamada H, et al: Prognosticsignificance of co-expression of c-erbB-2 oncoprotein and epidermal growth factorreceptor in breast cancer patients. Am J Surg164:323-326, 1992.
Harris AL, Nicholson S, Sainsbury JR, etal: Epidermal growth factor receptors in breastcancer: Association with early relapse anddeath, poor response to hormones and interactionswith neu. J Steroid Biochem 34:123-131,1989.
Ciardiello F, Caputo R, Bianco R, et al:Antitumor effect and potentiation of cytotoxicdrugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. ClinCancer Res 6:2053-2063, 2000.
Normanno N, Campiglio M, SomenziG, et al: Cooperative inhibitory effect ofZD1839 (Iressa) in combination with trastuzumab(Herceptin) on human breast cancercell growth. Ann Oncol 13:65-72, 2002.
Moasser MM, Basso A, Averbuch SD,et al: The tyrosine kinase inhibitor ZD1839(Iressa) inhibits HER2-driven signaling andsuppresses the growth of HER2-overexpressingtumor cells. Cancer Res 61:7184-7188,2001.
Massarweh S, Shou J, Mohsin SK, et al:Inhibition of epidermal growth factor/HER2receptor signaling using ZD1839 (Iressa) restorestamoxifen sensitivity and delaysresistance to estrogen deprivation in HER2-overexpressing breast tumors (abstract 130).Proc Am Soc Clin Oncol 21:33a, 2002.
Ciardiello F, Caputo R, Borriello G, etal: ZD1839 (Iressa), an EGFR-selective tyrosinekinase inhibitor, enhances taxane activityin bcl-2 overexpressing, multidrug-resistantMCF-7 ADR human breast cancer cells. Int JCancer 98:463-469, 2002.
Ranson M, Hammond LA, Ferry D, etal: ZD1839, a selective oral epidermal growthfactor receptor-tyrosine kinase inhibitor, is welltolerated and active in patients with solid, malignanttumors: Results of a phase I trial. JClin Oncol 20:2240-2250, 2002.
Albain K, Elledge R, Gradishar WJ, etal: Open-labeled phase II multicenter trial ofZD 1839 (Iressa) in patients with advancedbreast cancer (abstract 20). Breast Cancer ResTreat 76:S33, 2002.
Hidalgo M, Siu LL, Nemunaitis J, et al:Phase I and pharmacologic study of OSI-774,an epidermal growth factor receptor tyrosinekinase inhibitor in patients with advanced solidmalignancies. J Clin Oncol 19:3267-3279,2001.
Winer E, Cobleigh M, Dickler M, et al:Phase II multicenter study to evaluate the efficacyand safety of Tarceva (erlotinib; OSI-774) in women with previously treated locallyadvanced or metastatic breast cancer (abstract445). Breast Cancer Res Treat 76:S115, 2002.
Slichenmyer WJ, Elliot WL, Fry DW:CI-1033, a pan-erbB tyrosine kinase inhibitor.Semin Oncol 28(5 suppl 16):S16; 80-85, 2001.
Allen LF, Lenehan PF, Eiseman IA, etal: Potential benefits of the irreversible panerbBinhibitor, CI-1033, in the treatment ofbreast cancer. Semin Oncol 28(3 suppl 11):11-21, 2002.
Gieseg MA, de Bock C, Ferguson LR,et al: Evidence for epidermal growth factorreceptor-enhanced chemosensitivity in combinationsof cisplatin and the new irreversibletyrosine kinase inhibitor CI-1033. AnticancerDrugs 12:683-690, 2001.
Garrison MA, Tolcher A, McCreery H,et al: A phase 1 and pharmacokinetic study ofCI-1033, a pan-erbB tyrosine kinase inhibitor,given orally on days 1, 8, and 15 every 28days to patients with solid tumors (abstract283). Proc Am Soc Clin Oncol 20:72a, 2001.
Shin DM, Nemunaitis J, Zinner RG, etal: A phase I clinical and biomarker study ofCI-1033, a novel pan-erbB tyrosine kinase inhibitorin patients with solid tumors (abstract324). Proc Am Soc Clin Oncol 20:82a, 2001.
Wissner A, Brawner Floyd MB, RabindranSK, et al: Syntheses and EGFR andHER-2 kinase inhibitory activities of 4-anilinoquiniline-3-carbonitriles: Analogues of threeimportant 4-anilinoquinazolines currently undergoingclinical evaluation as therapeutic antitumoragents. Bioorg Med Chem Lett12:2893-2897, 2002.
Xia W, Mullin RJ, Keith BR, et al:Anti-tumor activity of GW 572016: A dualtyrosine kinase inhibitor blocks EGF activationof EGFR/erbB2 and downstream Erk1/2and AKT pathways. Oncogene 21:6255-6263,2002.
Sivaraman VS, Wang H, Nuovo GJ, etal: Hyperexpression of mitogen-activated proteinkinase in human breast cancer. J ClinInvest 99:1478-1483, 1997.
Dy GK, Adjei AA: Farnesyltransferaseinhibitors in breast cancer therapy. CancerInvest 20(suppl 2):30-37, 2002.
Kim MJ, Chang JS, Park SK, et al:Direct interaction of SOS1 Ras exchange proteinwith the SH3 domain of phospholipase Cgamma1. Biochemistry 39:8674-8682, 2000.
Verbeek B, Adriaansen-Slot SS, RijksenG: Grb2 overexpression in nuclei and cytoplasmof human breast cells: A histochemicaland biochemical study of normal and neoplasticmammary tissue specimens. J Pathol183:195-203, 1997.
Sepp-Lorenzino L, Ma Z, Rands E: Peptidomimeticinhibitor of farnesyl: Protein transferaseblocks the anchorage-dependent and-independent growth of human tumor cell lines.Cancer Res 55:5302-5309, 1995.
Wang E, Casciano CN, Clement RP, etal: The farnesyl protein transferase inhibitorSCH66336 is a potent inhibitor of MDR1 productP-glycoprotein. Cancer Res 61:7525-7529,2001.
Ryan DP, Eder JP, Supko JG, et al:Phase I clinical trial of the farynesyl transferaseinhibitor BMS-214662 in patients withadvanced solid tumors (abstract 720). ProcAm Soc Clin Oncol 19:185a, 2000.
Johnston SRD, Hickish T, Houston S, etal: Efficacy and tolerability of two dosing regimensof R115777 (Zarnestra), a farnesyl proteintransferase inhibitor, in patients withadvanced breast cancer (abstract 138). ProcAm Soc Clin Oncol 2:35a, 2002.
Piccart-Gebhart MJ, Branle F, de ValeriolaD, et al: A phase I, clinical and pharmacokinetic(PK) trial of the farnesyl transferaseinhibitor (FTI) R115777 + docetaxel: A promisingcombination in patients with solid tumors(abstract 318). Proc Am Soc Clin Oncol20:80a, 2001.
Holden SN, Eckhardt S, Fisher M, et al:A phase I pharmacokinetic (PK) and biologicalstudy of the farnesyl tranferase inhibitor(FTI) R115777 and capecitabine in patients(Pts) with advanced solid malignancies (abstract316). Proc Am Soc Clin Oncol 20:80a,2001.
Dancey J, Sausville EA: Issues andprogress with protein kinase inhibitors for cancertreatment. Nat Rev Drug Discov 2:296-313, 2003.
Stevenson JP, Yao KS, Gallagher M etal: Phase I clinical/pharmacokinetic and pharmacodynamictrial of the c-raf-1 anti-senseoligonucleotide ISIS 5132 (CGP 69846A). JClin Oncol 17:2227-2236, 1999.
Moore M, Hirte H, Oza A, et al: Phase Istudy of the raf-1 kinase inhibitor BAY 43-9006 in patients with advanced refractory solidtumors (abstracts 1816). Proc Am Soc ClinOncol 21:2b, 2002.
Vincent P, Zhang X, Chen C, et al:Chemotherapy with the raf kinase inhibitorBAY 43-9006 in combination with irinotecan,vinorelbine or gemcitabine is well toleratedand efficacious in preclinical xenograft models(abstract 1900). Proc Am Soc Clin Oncol21:23b, 2002.
Strumberg D, Bauer RJ, Moeller JG, etal: Final results of a phase I pharmacokineticand pharmacodynamic study of the raf kinaseinhibitor BAY 43-9006 in patients with solidtumors (abstract 121). Proc Am Soc Clin Oncol21:31a, 2002.
Langdon S, McPhillips F, Mullen P, etal: Antisense oligonucletide (ISIS 5132) targetingof c-raf kinase in ovarian cancer models(abstract 833). Proc Am Soc Clin Oncol20:209a, 2001.
LoRusso PM, Adjei AA, Meyer MB, etal: A phase I clinical and pharmacokineticevaluation of the oral MEK inhibitor, CI-1040,administered for 21 consecutive days, repeatedevery 4 weeks in patients with advancedcancer (abstract 321). Proc Am Soc Clin Oncol21:81a, 2002.
Hidalgo M, Rowinsky ER: The rapamycin-sensitive signal tranduction pathway asa target for cancer therapy. Oncogene 19:6680-6686, 2000.
Gibbons JJ, Discafani C, Peterson R, etal: The effect of CCI-779, a novel macrolideanti-tumor agent, on the growth of human tumorcells in vitro and in nude mouse xenograftin vivo (abstract 2000). Proc Am Assoc CancerRes 40: 301, 1999.
Yakes FM, Chinratanalab W, Ritter CA,et al: Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt is requiredfor antibody-mediated effects on p27, cyclinD1, and antitumor action. Cancer Res 62:4132-4141, 2002.
CCI-779 investigational brochure. Collegeville,Pa, Wyeth Research, 2001.
Yu K, Toral-Barza L, Discafani C, et al:mTOR, a novel target in breast cancer: Theeffect of CCI-779, an mTOR inhibitor, in preclinicalmodels of breast cancer. Endocr RelatCancer 8:249-258, 2001.
Raymond E, Alexandre J, DepenbrockH, et al: CCI-779, a rapamycin analog withantitumor activity: A phase I study utilizing aweekly schedule (abstract 728). Proc Am SocClin Oncol 19:187a, 2000.
Raymond E, Alexandre J, DepenbrockH, et al: CCI-779, an ester analogue of rapamycinthat interacts with PTEN/PI3k kinase pathways:A phase I study utilizing a weeklyintravenous schedule. Proceedings of the 11thNCI EORTC AACR Symposium on NewDrugs in Cancer Therapy (abstract 414). ClinCancer Res 6 :4549s, 2000.
Hidalgo M, Rowinsky E, Erlichman C,et al: CCI-779, a rapamycin analog and multifacetedinhibitor of signal transduction: Aphase I study (abstract 726). Proc Am Soc ClinOncol 19:187a, 2000.
Hidalgo M, Rowinsky E, Erlichman C,et al: Phase I and pharmacological study ofCCI-779, a cell cycle inhibitor. Proceedingsof the 11th NCI EORTC AACR Symposiumon New Drugs in Cancer Therapy (abstract413). Clin Cancer Res 6:4548s, 2000.
Chan S, Scheulen ME, Johnston S, et al:Phase II safety and activity study of two doselevels of CCI-779 in locally advanced or metastaticbreast cancer failing prior anthracyclineand/or taxane regimens (abstract 774).Proc Am Soc Clin Oncol 22:193, 2003.
Shi Y, Frankel A, Radvanyi LG, et al:Rapamycin enhances apoptosis and increasessensitivity to cisplatin in vitro. Cancer Res55:1982-1988, 1995.
O'Reilly T, Vaxelaire J, Muller M, etal: In vivo activity of RAD 001, an orallyactive rapamycin derivative, in experimentaltumor models (abstract 359). Proc Am AssocCancer Res 43:71, 2002.
Lane H, Schnell C, Theuer A, et al:Antiangiogenetic activity of RAD 001, an orallyactive anticancer agent (abstract 922). ProcAm Assoc Cancer Res 43:184, 2002.
Clackson T, Metcalf III CA, RozamusLW, et al: Regression of tumor xenografts inmice after oral administration of AP23573, anovel mTOR inhibitor that induces tumor starvation(abstract 95). Proc Am Assoc CancerRes 43:2002.
Clackson T, Metcalf CA, Rivera HL, etal Broad anti-tumor activity of AP23573, anmTOR inhibitor in clinical development (abstract882). Proc Am Soc Clin Oncol 22:220,2003.
O'Donnel S, Faivre I, Judson C, et al: Aphase I study of the oral mTOR inhibitorRAD001 as monotherapy to identify the optimalbiologically effective dose using toxicity,pharmacokinetic and pharmacodynamic endpointsin patients with solid tumors (abstract803). Proc Am Soc Clin Oncol 22:200, 2003.
Zhang HT, Craft P, Scott PA, et al:Enhancement of tumor growth and vasculardensity by tranfection of vascular endothelialcell growth factor in to MCF-7 human breastcarcinoma cells. J Natl Cancer Inst 87:213-219, 1995.
McLesky SW, Kurebayashi J, HonigSF, et al: Fibroblast growth factor 4 transfectionof MCF-7 cells produces cell lines thatare tumorigenic and metastatic in ovariectomizedor tamoxifen-treated athymic nude mice.Cancer Res 53:2168-2177, 1993.
Sauer G, Deissler H, Kurzeder C, et al:New molecular targets of breast cancer therapy.Strahlenther Onkol 178:123-133, 2002.
Horak ER, Leek R, Klenk N, et al:Angiogenesis, assessed by platelet/endothelialcell adhesion molecule antibodies, as indicatorof node metastases and survival in breastcancer. Lancet 340:1120-1124, 1992.
Weidner N, Semple JP, Welch WR, etal: Tumor angiogensis and metastatic-correlationin invasive breast carcinoma. N Engl JMed 324:1-8, 1991.
Ellis LM: Angiogensis. Horizons inCancer Therapeutics 3:4-22, 2002.
Ferrara N, Houck K, Jakeman L, et al:Molecular and biological properties of the vascularendothelial cell growth factor family ofproteins. Endocr Rev 13:18-32, 1992.
Gerber HP, McMurtrey A, Kowalski J,et al: Vascular endothelial growth factor regulatesendothelial cell survival through thephoshatidylinositol-3Â´-kinase/Akt signal transductionpathway. J Biol Chem 273:30336-30343, 1998.
Margolin K, Gordon MS, Holmgren E,et al: Phase Ib trial of intravenous recombinanthumanized monoclonal antibody to vascularendothelial growth factor in combinationwith chemotherapy in patients with advancedcancer: Pharmacologic and long-term safetydata. J Clin Oncol 19:851-856, 2001.
Gordon MS, Margolin K, Talpaz M, etal: Phase I safety and pharmacokinetic studyof recombinant human anti-vascular endothelialgrowth factor in patients with advancedcancer. J Clin Oncol 19:843-850, 2001.
Borgstrom P, Gold DP, Hilan KJ, et al:Importance of VEGF for breast cancer angiogenesisin vivo: Implications from intravitalmicroscopy of combination treatments withan anti-VEGF neutralizing monoclonal antibodyand doxorubicin. Anticancer Res19:4203-4214, 1999.
Cobleigh MA, Miller KD, LangmuirVK, et al: Phase II dose escalation trial ofAvastin (bevacizumab) in women with previouslytreated metastatic breast cancer (abstract520). Breast Cancer Res Treat 69:301, 2001.
Miller KD, Rugo HS, Cobleigh MA, etal: Phase III trail of capecitabine (Xeloda) plusbevacizumab (Avastin) versus capecitabinealone in women with metastatic breast cancerpreviously treated with an anthracycline and ataxane (abstract 36). Breast Cancer Res Treat76:S37, 2002.
Fong TA, Shawver LK, Sun L, et al:SU5416 is a potent and selective inhibitor ofthe vascular endothelial growth factor receptor(Flk-1/KDR) that inhibits tyrosine kinasecatalysis, tumor vascularization, and growthof multiple tumor types. Cancer Res 59:99-106, 1999.
Tolcher A, Karp DD, O'Leary JJ, et al:A phase I and biologic correlative study of anoral vascular endothelial growth factor receptor-2 (VEGF-2) tyrosine kinase inhibitor, CP547,632 in patients with advanced malignancies(abstract 334). Proc Am Soc Clin Oncol21:84a, 2002.
Hurwitz H, Holden SN, Eckhardt SG, etal: Clinical evaluation of ZD6474, an orallyactive inhibitor of VEGF signaling in patientswith solid tumors (abstract 325). Proc Am SocClin Oncol 21:82a, 2002.
Drevs J, Schmidt-Gersbach CIM, MrossK, et al: Surrogate markers for the assessmentof biologic activity of the VEGF-receptor inhibitorPTK787/ZK 222584 (PTK/ZK) in twoclinical trials (abstract 337). Proc Am Soc ClinOncol 21:85a, 2002.
Baker CH, Solorzano CC, Fidler IJ:Blockade of vascular endothelial growth factorand epidermal growth factor receptor signalingfor therapy of metastatic humanpancreatic cancer. Cancer Res 62:1996-2003,2002.
Ciardiello F, Caputo R, Damiano V, etal: Antitumor effects of ZD 6474, a smallmolecule vascular endothelial growth factorreceptor tyrosine kinase inhibitor, with additionalactivity against epidermal growth factorreceptor tyrosine kinase. Clin Cancer Res9:1546-1556, 2003.
Mendel DB, Laird AD, Xin X et al: Invivo antitumor activity of SU11248, a noveltyrosine kinase inhibitor targeting vascularendothelial growth factor and platelet-derivedgrowth factor receptors: Determination of apharmacokinetic/pharmacodynamic relationship.Clin Cancer Res 9:327-337, 2003.
O'Farrell AM, Abrams TJ, Yuen HA, etal: SU11248 is a novel FLT3 tyrosine kinasewith potent activity in vitro and in vivo. Blood101:3597-3605, 2003.
Rosen L, Mulay M, Long J, et al: Phase1 trial of SU11248 a novel tyrosine kinaseinhibitor in advanced solid tumors (abstract765). Proc Am Soc Clin Oncol 22:191, 2003.
Morris MJ, Tong WP, Cordon-Cardo C,et al: Phase I trial of bcl-2 antisense oligonucleotide(G3139) administered by continuousintravenous infusion in patients with advancedcancer. Clin Cancer Res 8:679-683, 2002.
Leek RD, Kaklamanis L, Pezzella F, etal: bcl-2 in normal human breast and carcinoma,association with estrogen receptor-positive,epidermal factor receptor-negative tumorsin situ cancer. Br J Cancer 69:135-139, 1994.
Reed JC: Bcl-2: Prevention of apoptosisas a mechanism of drug resistance. HematolOncol Clin North Am 9:451-473, 1995.
Yang D, Ling Y, Almazan M, et al:Tumor regression of human breast carcinomasby combination therapy of anti-bcl-2 antisenseoligonucleotide and chemotherapeutic drugs(abstract 4814). Proc Am Assoc Cancer Res40:729, 1999.
Waters JS, Webb A, Cunningham D, etal: Phase I clinical and pharmacokinetic studyof bcl-2 antisense oligonucleotide therapy inpatients with non-Hodgkin's lymphoma. J ClinOncol 18:1812-1823, 2000.
Chen HX, Marshall J, Trocky N, et al:A phase I study of Bcl-2 antisense G3139(Genta) and weekly docetaxel in patients withadvanced breast cancer and other solid tumors(abstract 692). Proc Am Soc Clin Oncol19:178a, 2000.
Chi KN, Gleave ME, Klasa R, et al: Aphase I trial of an antisense oligonucleotide tobcl-2(G3139, Genta) and mitoxantrone in patientswith metastatic hormone refractory prostatecancer (abstract 1299). Proc Am Soc ClinOncol 19:330a, 2000.
Shin MS, Kim HS, Lee SH, et al: Mutationsof tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) andreceptor 2 (TRAIL-R2) genes in metastaticbreast cancers. Cancer Res 61:4942-4946,2001.
Keane MM, Ettenberg SA, Nau MM, etal: Chemotherapy augments TRAIL-inducedapoptosis in breast cancer cell lines. CancerRes 59:734-741, 1999.
Investigators brochure: TRM-1. Milan,Italy, Ichemco.
Marks PA, Richon VM, Breslow R, etal: Histone deacetylase inhibitors as new cancerdrugs. Curr Opin Oncol 13:477-483, 2001.
Marks PA, Rifkind RA, Richon VM, etal: Histone deacetylases and cancer: Causesand therapies. Nat Rev Cancer 1:194-202,2001.
Richon VM, O'Brien JP: Histonedeacetylase inhibitors: A new class of potentialtherapeutic agents for cancer treatment.Clin Cancer Res 8:662-664, 2002.
Donapaty L, Fuino S, Wittman R, et al:Histone deacetylase inhibitor LAQ824 downregulatesHER-2, induces growth arrest andsensitizes human breast cancer cells to herceptinand tubulin polymerizing agents (abstract805). Proc Am Soc Clin Oncol 22:201, 2003.
Ryan QC, Headlee D, Sparreboom A, etal: A phase I trial of a histone deacteylaseinhibitor MS-275 in advanced solid tumor andlymphoma patients (abstract 802). Proc AmSoc Clin Oncol 22:200, 2003.
Heaney M, O'Conner A, Richon V, etal: Clinical experience with the histonedeacetylase inhibitor suberoylanilide hydroxamicacid (SAHA) in heavily pretreated patientswith hematological malignancies(abstract 2321). Proc Am Soc Clin Oncol22:577, 2003.