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Targeted Therapy for Cancer 193 CHAPTER 14 Targeted Therapy for Jeffrey S. Ross, MD Albany Medical College, Albany, New York Cancer: Integrating and Millennium Pharmaceuticals, Inc., Diagnostics and Cambridge, Massachusetts Therapeutics The recent regulatory approval in the United administration of both previously approved States and Europe of imatinib mesylate traditional agents and new therapeutics in (Gleevec®) for patients with bcr/abl transloca- clinical trials; and truly personalize medical tion positive chronic myelogenous leukemia care for the cancer patient.5–8 (FIG. 14.1) and the subsequent approval for gastrointestinal stromal tumors featuring an activating c-kit growth factor receptor muta- Targeted Therapies for Cancer: Definitions tion infused the oncology drug development During the last several years, multiple defini- community with enthusiasm for anticancer tions for the term “targeted therapy” have 1,2 targeted therapy. Recent major news maga- emerged. From the regulatory perspective, zines have headlined the considerable public targeted therapy has been defined as a drug in interest in new anticancer drugs that exploit whose approval label there is a specific refer- disease-specific genetic defects as the target of ence to a simultaneously or previously ap- 3,4 their mechanism of action. Many scientists, proved diagnostic test that must be performed clinicians, and pharmaceutical company execu- before the patient can be considered eligible tives now believe that in the next 5 to 10 years, to receive the drug. The classic example of the integration of molecular oncology and mo- this definition for targeted therapy is the lecular diagnostics will further revolutionize coapprovals of the anti-breast cancer an- oncology drug discovery and development; cus- tibody trastuzumab (Herceptin®) and the eli- tomize the selection, dosing, and route of gibility tests (Herceptest®, Pathway®, and Pathvysion®) (see Chapter 16 and below). For many scientists and oncologists, targeted ther- apy is defined as a drug with a focused mecha- nism that specifically acts on a well-defined target or biologic pathway that, when inacti- vated, causes regression or destruction of the malignant process. Examples of this type of targeted therapy include hormonal-based therapies (see Chapter 15), inhibitors of the epidermal growth factor receptor (EGFR) pathway (see Chapter 17), blockers of inva- sion and metastasis enabling proteins and FIGURE 14.1 Chronic myelogenous leukemia and imatinib (Gleevec®) therapy. Photomicrograph demonstrates a bcr/abl enzymes (see Chapter 18), antiangiogene- translocation detected by FISH in a patient with a packed bone sis agents (see Chapter 19), proapoptotic marrow biopsy diagnostic of chronic myelogenous leukemia drugs (see Chapter 21), and proteasome in- (inset). Note the yellow “fusion” gene product, indicating the ap- position of one green (chromosome 22) and one red (chromo- hibitors (see Chapter 24). In addition, most some 9) resulting from the translocation.This patient was treated scientists and oncologists consider anticancer with single agent imatinib (Gleevec®) and achieved complete antibody therapeutics that seek out and kill remission of bone marrow histology and absence of bcr/abl by routine cytogenetics and FISH assessment. See Plate 30 for malignant cells bearing the target antigen as color image. another type of targeted therapy. 192 Chapter 14 Targeted Therapy for Cancer 193 The Ideal Target creating enough fresh tissue to perform the assay.10 The drug tamoxifen (Nolvadex®), which The ideal cancer target (Table 14.1) can be de- has both hormonal and nonhormonal mecha- fined as a macromolecule that is crucial to the nisms of action, has been the most widely pre- malignant phenotype and is not significantly scribed antiestrogen for the treatment of expressed in vital organs and tissues; that has metastatic breast cancer and chemoprevention biologic relevance that can be reproducibly of the disease in high risk women.11,12 Although, measured in readily obtained clinical samples; ER and progesterone receptor testing is the that is definably correlated with clinical out- front line for predicting tamoxifen response, ad- come; and that interruption, interference, or ditional biomarkers, including HER-2/neu inhibition of such a macromolecule yields a (HER-2) and cathepsin D testing, have been clinical response in a significant proportion of used to further refine therapy selection.13 The patients whose tumors express the target with introductions of specific estrogen response mod- minimal to absent responses in patients whose ulators and aromatase inhibitors such as anas- tumors do not express the target. For antibody trozole (Arimidex®), letrozole (Femara®), and therapeutics, additional important criteria in- the combination chemotherapeutic, estramus- clude the use of cell surface targets that when tine (Emcyt®)14–18 have added new strategies for complexed with the therapeutic naked or con- evaluating tumors for hormonal therapy. jugated antibody, internalize the antigen– antibody complex by reverse pinocytosis, thus facilitating tumor cell killing. Leukemia and Lymphoma Lead the Way The introduction of immunophenotyping for The Original Targeted Therapy: leukemia and lymphoma was followed by the Antiestrogens for Breast Cancer first applications of DNA based assays, the polymerase chain reaction, and RNA based Arguably the first type of targeted therapy molecular technologies in these diseases that in oncology was the development of antiestro- complemented continuing advances in tumor gen therapies for patients with breast cancer cytogenetics.19,20 In addition to the imatinib that expressed the estrogen receptor (ER) pro- (Gleevec®) targeted therapy for chronic mye- tein (see Chapter 15) (FIG. 14.2).9 Originally logenous leukemia, other molecular targeted developed as a competitive binding bioassay therapy in hematologic malignancies includes performed on fresh tumor protein extracts and the use of all-trans-retinoic acid (ATRA) for the used to select for hormone production ablation treatment of acute promyelocytic leukemia21; by surgery (oophorectomy, adrenalectomy, and anti-CD20 antibody therapeutics targeting hypophysectomy), the ER and progesterone re- non-Hodgkin lymphomas, including rituximab ceptor test format converted to an immunohis- (Rituxan®)22; and the emerging Flt-3 target for tochemistry (IHC) platform when the decreased a subset of acute myelogenous leukemia pa- size of primary tumors enabled by mass screen- tients (see below).23 ing programs produced insufficient material for Thirty Years Later: HER-2 and Trastuzumab Table 14.1 Features of the Ideal Anticancer Target (Herceptin®) After the introduction of hormone receptor test- • Crucial to the malignant phenotype ing, some 30 years then elapsed before the next • Not significantly expressed in vital organs and tissues major targeted cancer chemotherapy program • A biologically relevant molecular feature for a solid tumor was developed. In the mid- • Reproducibly measurable in readily obtained clinical samples 1980s, the discovery of the HER-2 (c-erbB2) • Correlated with clinical outcome gene and protein and subsequent associa- • When interrupted, interfered with, or inhibited, the result is tion with an adverse outcome in breast cancer a clinical response in a significant proportion of patients provided clinicians with a new biomarker whose tumors express the target that could be used to guide adjuvant chemo- • Responses in patients whose tumors do not express the therapy.24 The development of trastuzu- target are minimal mab (Herceptin®), a humanized monoclonal 194 MOLECULAR ONCOLOGY OF BREAST CANCER Relative ER mRNA Expression 25 20 15 10 5 0 + + + + + + + + + + + + + + + + + + + + + + + + +-------------------+ -+ -- ER Status by IHC on Core Needle Biopsies A FNA115 FNA154 FNA126 FNA111 FNA102 FNA120 FNA136 FNA133 FNA153 FNA116 FNA135 FNA127 FNA150 FNA159 FNA155 FNA117 FNA139 FNA158 FNA157 FNA106 FNA128 FNA123 FNA108 FNA110 FNA113 FNA156 FNA130 Inositol triphosphate receptor MGC17687 GATA-binding protein 3 Hs 347271 DKFZp667D095 DKFZp43N2412 FNA115 FNA154 FNA126 FNA111 FNA102 FNA120 FNA136 FNA133 FNA153 FNA116 FNA135 FNA127 FNA150 FNA159 FNA155 FNA117 FNA139 FNA158 FNA157 FNA106 FNA128 FNA123 FNA108 FNA110 FNA113 FNA156 FNA130 Tyrosine phosphatase IVA.1 N-myc down-stream regulated gene 2 Tyrosine phosphatase IVA.2 Homolog mouse quaking OKI Protein kinase X-linked.1 DKFZp564F053 Protein kinase X-linked.2 Interleukin 6 signal transducer.1 UNIGENE - ambiguity GS1999full Interleukin 6 signal transducer.2 Gamma aminobutyric acid A receptor Reticulon 1 Potassium intermediate FLJ20005 Androgen induced protein Ataxaia telangiectasia group D associated protein Ctyochromeb5 reductase 260170 Profilin 2 v-myb BAF 53 Ribosomal protein L44 N-acetyltransferase 1 Keratin 6B X-box binding protein 1 Proteasome sub-unit beta Heterogeneous nuclear ribonucleotprotein D Adipose specific 2 Adenylate kinase 2 EST EST Cellular retinoic acid-binding protein 1 DKFZp586J2118 BTG family member 3 Lymphocyte antigen 6 complex Non-metastatic cell 3 MGC5350 Estrogen receptor 1 PH domain containing protein in retina 1 28kD interferon responsive protein KIAA0632 protein KIAA0179 protein LIV-1 protein Chitinase 3-like 2 Amyloid beta (A4) precursor like protein 1 Duodenal cytochrome B EST Flap structure-specific endonuclease1 Vav 3 oncogene Stathmin 1 cDNA FLJ10561 CDK-associated protein 1 Enolase 1 GDNF family receptor alpha 1 CCAAT/enhancer binding protein BC FIGURE 14.2 ER status determination.(A)
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