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CHAPTER 15  Molecular/Targeted Therapy of Cancer  261



                                                         G1       TABLE 15.2     Receptor Tyrosine Kinases Associated with
                                     Rb                                      Human Cancer
  VetBooks.ir                            E2F                       Tyrosine Kinase  Cancer Association
                                                                                 Breast, ovary, lung,  stomach, colon, glioblastoma
                                                                   EGFR family
                                                                                             a
                                            cdk4    Cyclin         Insulin receptor   Sarcomas, cervix, kidney
               p16 ink4                            D1, D2,           family
                                            cdk6     D3            PDGFR family  Glioblastoma, ovary, CMML, GISTs
                                                                   KIT           AML, GISTs,  seminoma, MCTs,  melanoma
                                                                                        a
                                                                                                    a,b
                                      P                            FLT3          AML a
                                        P
                                   Rb                                                    a,b
                                                                   VEGFR family  Angiogenesis,  Kaposi’s sarcoma, hemangiosar-
                                                                                                a
                                                                                  coma/angiosarcoma,  melanoma
                                                                   FGFR family   AML, lymphoma, breast, prostate, multiple
                p21                                                               myeloma, TCC
                                                    Cyclin
                                            cdk2    E1, E2         NGFR family   Thyroid cancer, neuroblastoma, fibrosarcoma, AML
                p27
                                                                   Met/Ron       Thyroid cancer, osteosarcoma,  rhabdomyosar-
                                                                                                    a
                                                                                  coma, liver, kidney, colon
                                     P
                                       P                           EPHR family   Melanoma, stomach, colon, breast, esophagus
                                   Rb   P                          AXL           AML
                                       P
                                     P                             Tie family    Angiogenesis, stomach, hemangioblastoma
                                                                   RET family    Thyroid cancer, multiple endocrine neoplasia
                                                                   ALK           Non-Hodgkin’s lymphoma, lung
                                                                   a Also associated with canine cancer.
                                                                   b Also associated with feline cancer.
                                                         S
                                                                   ALK,  Anaplastic lymphoma kinase;  AML, acute myelogenous leukemia;  CMML, chronic
                                         E2F                       myelomonocytic leukemia; EGFR, epidermal growth factor receptor; EPHR, ephrin recep-
                                                                   tor; FGFR, fibroblast growth factor receptor; GISTs, gastrointestinal stromal tumors; MCTs,
           • Fig. 15.8  Cyclin and CDK regulation of G1–S transition. CDK inhibitors   mast cell tumors; NGFR, nerve growth factor receptor; PDGFR, platelet-derived growth factor
           such as p16ink4 and p21 restrict the activity of cyclin D– and cyclinE–  receptor; TCC, transitional cell carcinoma; Tie, tyrosine kinase receptor on endothelial cells;
           dependent kinases. Progressive Rb phosphorylation by the cyclins results   VEGFR, vascular endothelial growth factor receptor.
           in liberation of E2F and the resultant transcription of S phase genes.
           (Reprinted with permission from Blackwell Publishing, London CA,  Vet
           Comp Oncol 2:177–193, 2004.)
                                                                 in tumorigenesis through direct effects on cancer cells or through
           resultant malignant transformation. Other examples of fusion   modulation of the local tumor microenvironment (stroma and
           proteins include TEL-PDGFR-β in CMML, FIP1-PDGFR-α in   neovasculature). The two most successful approaches to date have
           hypereosinophilic syndrome with mastocytosis, and EML4-ALK   been monoclonal antibodies (mAbs) and small molecule inhibitors.
           in non-small-cell lung cancer (NSCLC). 133              Several mAbs have been developed to target the extracellular
             Autocrine loops of activation primarily occur when the tumor   domain of RTKs known to be important in a variety of tumors.
           cell expresses both the RTK and the corresponding GF; in most   These antibodies may prevent the growth factor from binding,
           cases, one or the other usually is also overexpressed, resulting in   promote  internalization  of  the  RTK  and  subsequent  degrada-
           constitutive activation of the RTK. Examples include coexpres-  tion, or may induce an immune response against the cancer
           sion of transforming growth factor-alpha (TGF-) and EGFR in   cell. One of the most successful examples is a humanized mAb
           glioblastoma and squamous cell carcinoma, insulin-like growth   called  trastuzumab  (Herceptin).  This  antibody  targets  HER2,
           factor-1 (IGF-α) and its ligand, IGF-1R, in breast and colorectal   which as previously discussed is overexpressed in approximately
           cancer, and VEGF and VEGFR in melanoma. 73,134–136  In canine   30% of human breast cancers. 140  Initial clinical trials of trastu-
           cancers, possible autocrine loops have been documented in osteo-  zumab as single-agent treatment for HER2-positive breast cancer
           sarcoma (OSA) (coexpression of MET and its ligand, HGF) and   resulted in a response rate of approximately 25% in the setting
           hemangiosarcoma (HSA, coexpression of KIT and its ligand,   of metastatic disease. 141  The response rate approached 50% when
           SCF). 137–139                                         trastuzumab was combined with chemotherapy. 142  When  used
                                                                 in the adjuvant setting, multiple studies have demonstrated that
           Inhibition of Kinases                                 trastuzumab significantly improves survival rates of women with
                                                                 HER2-positive disease; consequently, it is now part of the rou-
           Given the detailed molecular characterization of signal transducer   tine standard of care for this type of cancer. 143,144  Other examples
           dysregulation in cancer cells, significant efforts have been directed   of mAbs that have significant activity in human cancers include
           at developing strategies to inhibit those transducers that participate   rituxumab (Rituxan), which targets CD20 expressed in a number
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