Page 282 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

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