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Targeted Therapy: Its Status and Promise in Selected Solid Tumors Part IPublished on Physicians Practice (http://www.physicianspractice.com)

Targeted Therapy: Its Status and Promise in Selected SolidTumors Part IReview Article [1] | October 23, 2012By Jennifer Wu, MD [2], Sasha O. Joseph, MD [3], and Franco M. Muggia, MD [4]

We describe areas where major inroads were initially achieved by targeting angiogenesis and byunraveling pathways in the heterogeneous tumors of mesenchymal origin—spurred by theidentification of c-Kit–activating mutations in GIST and the regressions that ensued when tumorsharboring these mutations were exposed to the tyrosine kinase inhibitor imatinib (Gleevec).

Introduction

Clinical cancer therapeutics has entered an era[1] in which advances by means of targeted therapiesare leading to unprecedented successes—from the impact of imatinib (Gleevec) in chronic myeloidleukemia and gastrointestinal stromal tumor (GIST) in 2004, the striking cure rates achieved withadjuvant trastuzumab (Herceptin) for human epidermal growth factor receptor 2 (HER2)-amplifiedbreast cancer in 2005, and convincing improvements via novel agents in outcomes for hepatocellularand renal cell cancers from 2006 on—to the groundbreaking inroads into successful palliation ofaggressive phases of malignant melanoma[2] and new efficacious endocrine and immunologiccontrol of prostate cancers in the past 2 years. Personalized medicine and the need for molecularprofiling have justifiably become the Holy Grail for the development of future successful weaponsagainst cancer.[3,4]

As has often been the case, hematologic malignancies have led the way in the introduction of thisnew generation of therapeutics—perhaps because of easy access to tumor samples forpharmacodynamics, and the narrow spectrum of cells of origin. The situation with solid tumors isconsiderably more complex, and the evolution of targeted therapies for these cancers is still in itsinfancy. Consequently, this review (which is being presented in two parts) consists of a perspectiveon current opportunities and the “work in progress” and is not a compendium of clinical trials withnovel targeted agents still seeking an indication. In fact, we shall focus on integrating emergingtreatments with therapeutic strategies that include both the older endocrine therapies (the “originaltargeted therapies”) against breast and prostate cancers, and the empirically-derived successfulchemotherapies, such as platinums, that are used in gynecologic cancers. At present, and for someyears to come, the treatment of most solid tumors will continue to rely on a patchwork of empiricallyderived and newly introduced molecularly targeted agents. However, prospective identification oftargets in the clinic will not only illuminate their clinical significance, but will also further acceleratedrug development—witness the way in which the introduction of gefitinib (Iressa) for lung cancerwas followed in less than a decade by the identification of driver mutations, new targeted drugs, andthe universal adoption of molecular profiling for treatment selection. (Lung cancer will be covered inPart II).

Questions addressed

There are four fundamental questions that need to be answered about any targeted therapy.1. What is the underlying tumor biology that is being targeted?2. How “targeted” are the so-called “targeted drugs”?3. Is the targeted therapy also suitable for immunomodulation and/orimmunoconjugation?4. In what way does the targeted therapy constitute a meaningful improvement overchemotherapy?For most of the tumors we will consider, all of these questions will be covered, even though the areaof immunomodulation is currently in its infancy and experimental in most instances. However, theremarkable developments in immunomodulation in a number of diseases—for example,immunotherapy in melanoma (which is covered below), and immunoconjugates in certain forms ofbreast cancer (covered in Part II) and in Hodgkin lymphoma represent just the beginning of a role for

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“targeted” immunotherapy. In fact, great excitement has been generated by the identification ofnew T-cell and antigen-presenting−cell stimulatory pathways targeting Programmed Death (PD)-1 orits ligand, although it is too early in the development of these pathways to assess their impact on thetreatment of specific cancers.

Major impact areas

Selected solid tumor groupings best illustrate the various stages in the evolution of this targetedtherapy revolution. In this review—part I of the two-part series—we consider targeted therapies forrenal cell carcinoma, hepatocellular carcinoma, melanoma, and sarcomas. We have chosen to focuson these cancers because the systemic treatment of these tumors is dominated by recentlyintroduced molecularly targeted drugs. We describe how the tumor biology in each of these cancershas been largely responsible for the therapeutic advances.Prostate cancer (although not covered in this series) affords another example of the connectionbetween tumor biology and the development of targeted therapies. Endocrine therapy (which targetsandrogen-dependent growth) has been the hallmark of the treatment of prostate cancer for severaldecades. During the past 2 years, refinements in targeting have led to the introduction ofabiraterone (Zytiga; a steroid synthetic pathway inhibitor) and enzalutamide (Xtandi [formerlyMDV3100]; an androgen receptor inactivator). Treatment of this cancer is also relying onimmune-stimulation and bone-seeking radio-immunoconjugates—with all of these advances openingup new therapeutic landscapes.While Part I highlights the way in which targeted therapies have led to unprecedented therapeuticadvances in previously erratically responsive areas, Part II will deal with areas in which targetedtherapies have had a major impact in special subsets of patients (eg, in breast and lung cancers),and with those areas where we expect evolving integration into treatment as molecular pathwaysbecome better understood (eg, colorectal cancer and gynecologic cancers).

Targeted therapy: how revolutionary is it?

It is important to keep in mind that some older, empirically discovered agents are actually quitetargeted—eg, camptothecin derivatives that target topoisomerase I.[5] On the other hand, some“targeted therapies” that were designed to be directed against a specific target have been shown tohave clinical utility for unrelated reasons (eg, sorafenib [Nexavar] was not effective as a BRAFinhibitor; its utility likely stemmed instead from effects on the vascular endothelial growth factor[VEGF] receptor [VEGFR]). Finally, recent successes in cancer treatment may yet come fromempirically derived chemical entities (eg, bendamustine [Treanda], which is active against a numberof hematologic malignancies).

Renal Cell Carcinoma

1. What is the underlying tumor biology that is being targeted?

Early observations that patients with metastatic renal cell carcinoma (RCC) who underwentnephrectomy could experience spontaneous regression of pulmonary metastasis aroused interest inimmune therapy in RCC. In fact, the only US Food and Drug Administration (FDA)-approvedmedications before targeted therapies were all immune therapies. However, the toxicities of suchtreatments were often formidable, and the responses were low and unpredictable.Preclinical studies by Kaelin et al established a relationship between mutations in von Hippel-Lindau(VHL) genes and the failure of cells to degrade hypoxia-inducible factor-1α (HIF-1α).[6] This insightinto RCC biology eventually established it as the poster child for heretofore largely resistant diseasesin which a targeted therapy had demonstrated success: its median overall survival of 9 months inpre−targeted drug therapy trials[7-9] has been superseded by a median overall survival time of 22months, with rapidly evolving diverse options for targeted therapies that are refining concepts ofpathway inhibition.FIGURE 1

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Angiogenic Pathways and Inhibitors Used in the Treatment of Renal Cell Carcinoma

In addition, RCC is a striking example of how knowledge of hereditary cancers has led to insight intopathways that are deranged in sporadic cancers. One common mutation in hereditary RCC (in VHL)results in an autosomal-dominant disease with a high lifetime likelihood of RCC.[10] VHL mutationsalso occur in up to three-quarters of sporadic RCC with clear-cell histology,[11] and accumulation ofHIF-1α is a powerful activator of downstream signals involved in angiogenesis. These factors includenot only VEGF, but also platelet-derived growth factor (PDGF) and the corresponding receptors(VEGFR and PDGFR). VEGF, PDGF, VEGFR, and PDGFR have all now become the therapeutic targetsof tyrosine kinase inhibitors (TKIs). A second prominent pathway in RCC development was revealedin another autosomal-dominant inherited disease that frequently co-occurs with non−clear-cell RCC:tuberous sclerosis. Genetic mutations in tuberous sclerosis lead to inactivation of downstream Rhebprotein, which in turn causes activation of mammalian target of rapamycin (mTOR) (Figure). mTORplays a critical role in the development, progression, and metastatic potential of RCC, and it has alsoserved as a successful target in the treatment of RCC, including the non−clear-cell subtype. mTORexists in two forms: mTOR complex 1 (mTORC-1) and mTOR complex 2 (mTORC-2). mTORC-1 is thebest understood form of mTOR, and it is downstream of the phosphatidylinositol-3'-kinase (PI3K)/AKTpathway. Its activation leads to activation of the p70 ribosomal protein S6 kinase (p70S6K) pathway,and activates angiogenesis through transcription of HIF-1α.[12,13]

2. How ‘targeted’ are the so-called ‘targeted drugs’?

TABLE 1

Targeted Small-Molecule Inhibitors With Major Impact

The first approved targeted therapy in RCC was sunitinib (Sutent), a multitargeted TKI that focusesmostly on the angiogenesis pathway, which encompasses VEGFR and PDGFR. In a 2005 clinicaltrial,[14] it demonstrated progression-free survival (PFS) and response advantages over the oldstandard therapy, interferon alfa (IFN-α), in treatment-naive patients with RCC. This was soonfollowed by the approval of a number of somewhat related agents that have different toxicity profilesand that may be active after the failure of other agents (Table 1). For example, sorafenib, a TKI thatpotently blocks VEGFR-2, VEGFR-3, PDGFR, and fibroblast growth factor receptor (FGFR), wonapproval for superior PFS, compared to placebo, in patients who had been exposed to cytokinetherapies.[15] FGFR is a receptor that activates an alternate angiogenic pathway after theVEGF-related axis has been inhibited, and the fact that sorafenib targets FGFR may explain theactivity of this agent in sunitinib failures. In addition, bevacizumab (Avastin; a monoclonal antibodyagainst VEGF) and pazopanib (Votrient; a TKI that blocks all three isoforms of VEGFR [1,2, and 3])both showed activity either in combination with IFN or as single agents in treatment-naiveRCC.[16,17] In 2011, axitinib (Inlyta; a TKI targeting VEGFR-1, -2, -3, and PDGFR), anotheranti-angiogenic drug, showed longer PFS than sorafenib in the second-line setting.[18] In 2012,tivozanib, a TKI targeting VEGFR-1, -2, and -3, with potent activity and a long half-life, offered longerPFS than sorafenib as first-line treatment in patients with RCC,[19] again indicating the pivotal role oftargeted therapy in combating angiogenesis in the treatment of RCC.As the only first-line targeted therapy in RCC with an overall survival advantage over IFN-α,temsirolimus (Torisel), the first mTOR inhibitor to target mTORC-1, brought hope to patients withRCC, including to those with the non–clear-cell subtype.[20] Not surprisingly, everolimus (Afinitor),the first oral mTOR inhibitor that also targets mTORC-1, now is approved for patients who failed ananti-angiogentic drug, since it demonstrated a PFS advantage in the second-line setting.[21]

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3. Is the targeted therapy also suitable for immunomodulation and/orimmunoconjugation?

This progress based on TKIs and mTOR inhibitors should not blunt further research into immunemodulation; IFN-α and interleukin-2 (IL-2) were the FDA-approved medications for RCC until theemergence of targeted therapy. The anti-angiogenic agent sunitinib has been shown to inhibitmyeloid-derived stromal cells; this inhibition in turn reduces regulatory T-cell function, thus alsoproviding immunomodulatory effects.[11] On the other hand, sorafenib inhibits theimmunosuppression induced by myeloid-derived stromal cells, and can therefore potentially enhanceimmune function.[11] The mTOR inhibitor temsirolimus is derived from rapamycin analogs(“rapalogs”); it has been the chief component in immune modulation post organ transplantation, andit could have a significant role in immune modulation in RCC as well. Consequently, targetedtherapies may also contribute to immune modulation, and their immunomodulatory effects can beutilized in the design of combination novel targeted therapies in RCC.

4. In what way does the targeted therapy constitute a meaningful improvement overchemotherapy?

Targeted therapy has changed metastatic RCC from a disease with nearly invariable and earlyfatality and with extremely limited yet very toxic treatment options (such as IL-2 and IFN) into acondition that is treatable for several months to years with a variety of therapeutic agents that offerreproducible efficacy to the majority of patients, with less toxicity. Before these agents wereintroduced, no prior chemotherapy trial had demonstrated even a prolongation in PFS, either aloneor in combination, while this endpoint has been met by all FDA-approved targeted therapies, some ofwhich have also demonstrated overall survival advantages. Of additional importance, theseachievements have led to separate RCC treatment strategies based on histology and prognosticfeatures, and to the application of different targeted therapies in sequence. This conceptualadvance—coupling treatment to the biology of RCC—represents a key direction of future cancertherapy. RCC is also leading the way in the drive to establish a rational sequential use of thesetherapies on the basis of biological features; IFN has been successfully displaced, and only highlyselected patients now receive interleukin-2 (IL-2).

Hepatocellular Carcinoma


Systemic therapy of advanced hepatocellular carcinoma (HCC) had left behind a long record ofnegative phase III trials until the landmark placebo-controlled Sorafenib Hepatocellular CarcinomaAssessment Randomized Protocol (SHARP) trial demonstrated an impact of sorafenib on survival.[22]Advances in the imaging studies used in both the diagnosis and therapy of HCC had identified thedevelopment of the typical hypervascularity of HCC in the arterial phase, which is followed by rapidwashout in the venous phase on a contrast-enhanced CT scan of the liver on a cirrhotic background.Such findings not only spurred the use of local measures against these lesions, but also gave rise totrials targeting tumor angiogenesis. The tumor itself carries frequent mutations in many tumorsuppressor genes throughout its development and progression; these, coupled with the frequentlycompromised liver function (varying with the etiology of the liver disease), account for HCC’snotorious chemotherapy resistance. In fact, as the tumor progresses and acquires adverseprognostic features, such as vascular invasion and portal vein thrombosis, angiogenesis continues toplay a critical role in metastasis and invasion. VEGF-A is one of the most potent angiogenetic factorsin HCC; consequently, inhibition of VEGF-A is a key targeted therapy in HCC. In addition, basicfibroblast growth factor (bFGF) is also over expressed in HCC, and it may, along with VEGF-A, furtherenhance angiogenesis.[23,24] There are at least two other types of growth factor that play animportant role in angiogenesis in HCC: PDGF, which stimulates formation of blood vessels, andangiopoietins, which modulate blood vessel vascularity to enhance nutrient delivery to tumorcells.[25] In addition to contributing to angiogenesis, epidermal growth factor receptor (EGFR) mayalso be important to the growth and metastasis of some HCCs: EGFR activation leads to activation ofthe downstream RAF/extracellular signal–regulated kinase (ERK) pathway and the PI3K/mTORpathway. The mTOR pathway is a crucial part of hepatocyte malignant transformation into HCC.[26]Aberrant expression of mTOR has been demonstrated in up to 50% of HCC tissues,[27] and whenmTOR becomes constitutively activated, it is associated with activation of the insulin-like growthfactor (IGF) axis and upregulation of the PI3K pathway.[28] The mTOR pathway has become one of

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the therapeutic targets in HCC clinical trials. Raf kinase is also upregulated in HCC, representinganother rational target for HCC treatment. Another possible therapeutic target—c-MET—the solereceptor of hepatocyte growth factor, is overexpressed in up to 49% of HCCs, and is associated withworse overall survival.[29]


In 2006, a new stage in HCC treatment unfolded when sorafenib improved overall survival in patientswith unresectable HCC. Sorafenib is the first and only agent in the history of HCC therapy that hasdemonstrated an overall survival benefit; this targeted treatment—which inhibits VEGF-2, VEGF-3,PDGFR, and Raf kinases—has transformed the landscape of HCC treatment. Subsequent phase IIstudies using bevacizumab and erlotinib (Tarceva; a TKI targeting EGFR) in HCC have shown promisewith regard to disease stabilization and PFS. Current studies of a PI3K inhibitor and mTOR inhibitorsare ongoing, making treatment of HCC the prototype for targeted therapy.


Similar to RCC, HCC is a tumor with potential to respond to immunomodulation, and there are casereports of spontaneous regression. Immune therapy has figured prominently in past HCC treatments:IFN was tested as a component of combination therapy for HCC (IFN, cisplatin, doxorubicin, andfluorouracil [5-FU]), but high response rates did not confer an overall survival benefit. New studiesare focusing on glypican-3, a member of the proteoglycan family that is found on the surface of HCCcells, and which is not present in nonmalignant tissue.[30] A phase I study in patients with advancedHCC used a peptide vaccine against glypican-3; the study demonstrated that patients with acytotoxic T-cell lymphocyte frequency (percentage of both glypican-3 peptide+ and CD8+ T cellspre- and post-vaccination) of ≥ 50 had longer overall survival than those whose cytotoxic T-celllymphocyte frequency did not reach 50.[31] There is potential interest in immunotherapy for thetreatment of HCC because of the possibly lesser risk of incurring toxicities in the setting ofprecarious liver dysfunction.


The key feature of targeted therapy in HCC has been the demonstration that it can offer clearsurvival advantages to patients undergoing treatment. With sorafenib, for the first time, patientswith limited options because of known liver disease have been able to experience clinical benefit.This experience highlights the inadequacies of response rate as a reflection of benefit for patientswith this disease. In fact, lack of objective tumor regression should not diminish our confidence in theefficacy of targeted therapy. By contrast, while chemotherapy drug regimens could claim higherresponse rates, they all failed to prolong overall survival in HCC patients.

Malignant Melanoma


Other than the known propensity of melanoma to accelerate its growth years after a latent stage,virtually little information of much therapeutic use had been assembled in at least three decades.Two breakthroughs initiated a cascade of events leading to successful clinical applications that werecovered by both The New York Times and the American Society for Clinical Oncology (ASCO) in 2010.One powerful lead was related to a BRAF mutation. BRAF, a member of the MAP kinase signalingpathway, is involved in cell proliferation, differentiation, and apoptosis. Up to 60% of melanomashave a V600 mutation in BRAF, leaving the kinase in a constitutively active form.[32] Identification ofthis pathway as one that confers a growth advantage, leading to accelerated growth in the presenceof additional mutations, was demonstrated in mouse models [33].TABLE 2

Targeted Monoclonal Antibodies With Major Impact

Another approach—trying to harness immunity against tumors—led to investigation of the

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importance of the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor on T cells. Antibodies toCTLA-4 prevent the negative regulation of the T-cell interactions with antigen-presenting cells.Antigen-presenting cells use CD-28 to help bind T cells while presenting peptide fregments to T cellsduring this positive interaction. CTLA-4 expression then becomes upregulated on the T-cell surface,and CTLA-4 binds B7 on tumor cells, which bears the antigen more tightly than CD-28 (Table 2),thereby effectively slowing the activated immune system, acting in a manner similar to that of abrake. The immunologic consequence of removing the “brake” that CTLA-4 puts on the immunesystem is the unleashing of T-cell–mediated immunity; this stimulation was further shown to beclinically relevant. The intense interest emanating from the unprecedented clinical successes thatfollowed these discoveries has resulted in further inquiries into the tumor biology of melanoma andin additional developments, such as the simultaneous use of B-raf and MEK inhibitors.[34]


Until the introduction of targeted therapy with ipilimumab (Yervoy; an antibody against CTLA-4) andvemurafenib (Zelboraf, a B-raf inhibitor), the treatment of malignant melanoma in the adjuvantsetting was limited to IFN—and in the metastatic setting to high-dose IL-2, radiation, and cytotoxicchemotherapy. All of these therapies, even though some were “targeted,” had minimal impact onoverall survival.Vemurafenib is an extremely potent and specific inhibitor of the BRAF V600E activating mutation,providing an effective blockade of the downstream MAP kinase pathway. This compound, introducedby Plexxikon, as well as the similarly targeted drug by GlaxoSmithKline (dabrafenib), represent aremarkably successful feat in drug development. Compared to dacarbazine, vemurafenib increased6-month overall survival: 84% of vemurafenib-treated patients survived compared with 64% ofpatients treated with dacarbazine.[35] Of interest, future directions of therapy include other methodsof blockading the MAP kinase pathway, such as with new inhibitors of MEK.[36] Studies are underwayto investigate whether dual blockade of both B-raf and MEK can overcome acquired resistance toB-raf inhibition.Ipilimumab does not directly target melanoma; instead, by targeting CTLA-4, it prevents applicationof the “brake” and allows the body’s immune system to sustain an attack on malignant cells. At thesame time, it allows the immune system to attack a number of other tissues—a cause of toxicmanifestations (and paradoxically an indication of “non-specific targeting”). Compared withadministration of a gp100 vaccine alone, ipilimumab increased overall survival in metastaticmelanoma by close to 5 months.[37] While this effect is not specifically limited to melanoma,malignant melanoma is the first tumor in which deregulating the immune system has proveneffective at curbing malignant cell growth. In a similar manner, more recent data have shown thatcurbing the negative regulation of T cells by inhibiting PD-1 or the PD-1 ligand (PD-L1) may alsoimprove the cytotoxic attack of T cells on a number of malignant cells, including melanomacells.[38,39]


Immunomodulation has a place in the treatment of malignant melanoma, and has been proveneffective with the advent of CTLA-1 and PD-1 inhibition. Ipilimumab is likely to be a prototype for theharnessing of the immune system to target malignancies. Allowing T cells to act without functionalinhibition leads to improvements in overall survival in patients with melanoma.


For a decade, cytotoxic chemotherapy had minimal benefit in the treatment of melanoma. Even thecombination of chemotherapy and nonspecific immunotherapy proved futile. BRAF and MEKinhibition have shown their impressive power in halting disease progression. Vemurafenib has beenproven to be more effective in the treatment of this disease than the standard cytotoxic agent,dacarbazine. Furthermore, with research in melanoma focusing squarely on targeting the MAP kinasepathway and harnessing the immune system to combat the disease, it is likely that we have seen theend of cytotoxic chemotherapy use for melanoma. In malignant melanoma, targeted therapy is theonly meaningful treatment option currently available.

GIST and Other Sarcomas

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We include sarcomas as a “major impact area” because even the notoriously chemo-resistanttumors that are prevalent in adults are increasingly being reclassified based on molecular profiling,leading to totally new therapeutic paradigms. GIST was the initial major success of targetedtherapy—once a potent inhibitor of an activated tyrosine kinase such as imatinib was identified inlaboratory studies[40] and tried in a patient with advanced GIST while the drug was being tested asan inhibitor of BCR/ABL in chronic myeloid leukemia. GIST became the prototype for a notoriouslychemo-resistant sarcoma that yielded to a targeted agent; the approach that led to imatinib’ssuccess in GIST was subsequently extended to other c-kit–activating mutations. Sunitinib, sorafenib,and more recently regorafenib[41] have shown efficacy in GIST imatinib failures—regorafenibpresumably by successfully targeting PDGFR-A as well as KIT, which are implicated in GIST growthand imatinib resistance.[42] In addition, other tumors of mesenchymal origin, such asdermatofibrosarcoma protuberans, have been shown to be responsive to imatinib because theirgrowth is in part driven by PDGFR.[43] A number of sarcoma subtypes have been defined bychromosomal translocations coding for chimeric oncoproteins that promote abnormal transcription;typical translocations have been described in synovial sarcoma, epithelioid sarcoma, and Ewingsarcoma. Ewing sarcoma is associated with the rearrangement of the EWS gene, which results inIGF-1 or IGF-2 hyperactivation and susceptibility to inhibitors of the IGF pathway.[44] Alveolar softpart sarcoma’s translocation results in a fusion protein that is associated with METautophosphorylation and activation of downstream pathways, which promote growth andangiogenesis; it has been successfully targeted by sunitinib, as well as other drugs that inhibitVEGFR-1.[45,46] The growth of giant-cell tumors is mediated by RANK-ligand (RANKL)-inducedosteoclast activation; denosumab (Xgeva), an inhibitor of RANKL, is able to reverse this tumor’slocally aggressive behavior.[47] The perivascular epithelioid cell tumors (PEComas) and relatedlymphangioleiomyomatosis occur as part of tuberous sclerosis complex (TSC), in which mutations in TSC1 or TSC2 result in defective negative regulation of mTOR; treatment with rapalogs has beeneffective.[48] Trabectedin (Yondelis) is a marine product that inhibits transcription-coupled DNArepair, leading to responses in myxoid liposarcoma,[49] a tumor with a unique chromosomalrearrangement that also confers increased sensitivity to ifosfamide and doxorubicin.[50] Pazopanibhas recently been approved as a systemic treatment for the notoriously drug-resistantleiomyosarcomas.[51] Finally, paclitaxel—as well as anti-angiogenic strategies—althoughdisappointing in many forms of sarcoma,[52] has activity against angiosarcomas.[53]Considered in perspective, the systemic treatment of sarcomas had changed little since thelandmark introductions of doxorubicin and ifosfamide for soft-tissue sarcomas and cisplatin for bonesarcomas. It is now mandatory to consider specific therapeutic targets when a tumor ofmesenchymal origin requiring systemic therapy is first identified.Financial Disclosure: Dr. Muggia has served on safety data monitoring committees for Bayer, Lilly,Pfizer, and Roche. Dr. Wu and Dr. Joseph have no significant financial interest or other relationshipwith the manufacturers of any products or providers of any service mentined in this article. References: REFERENCES

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targeted therapy: its status and promise in selected solid ...€¦ · clinical cancer therapeutics...

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