Chapter 080. Cancer Cell Biology and Angiogenesis (Part 6) potx

Cancer Cell Biology and Angiogenesis Part 6 Imatinib has also demonstrated targeted activity in other diseases, including gastrointestinal stromal tumors GIST, rare mesenchymal tumors

Chapter 080 Cancer Cell Biology

and Angiogenesis

(Part 6)

Imatinib has also demonstrated targeted activity in other diseases, including gastrointestinal stromal tumors (GIST), rare mesenchymal tumors of the GI tract (stomach and small intestine) The pathogenic molecular event for most patients

with this disease is mutation of the proto-oncogene c-Kit, leading to the

constitutive activation of this receptor tyrosine kinase without the binding of its physiologic ligand, stem cell factor About 10% of GISTs encode activating

mutations of the PDGFRα instead of c-Kit GISTs are thought to arise from or

share a common stem cell with the interstitial cells of Cajal, which give rise to the myenteric plexus of the GI tract Imatinib, which inhibits the c-Kit kinase domain, has demonstrated significant activity (>50% partial responses usually lasting 1–2 years) in this chemotherapy-refractory tumor Resistance to imatinib develops due

to secondary mutations in c-Kit, and many of these tumors are susceptible to

treatment with the multitargeted TK inhibitor sunitinib that has activity against c-Kit as well as the PDGF and vascular endothelial growth factor (VEGF) receptors Sunitinib is approved by the U.S Food and Drug Administration for treatment of patients with imatinib-resistant GIST or who are intolerant of imatinib (Table 80-2) Interestingly, tumors with mutations in exon 11 of c-Kit's juxtamembrane region are particularly sensitive to imatinib, whereas those with exon 9 mutations (extracellular domain) respond better to sunitinib than imatinib In the future, primary therapy for GIST may be determined by the specific molecular defect in c-Kit Patients with chronic myelomonocytic leukemia (CMML, a myeloproliferative disorder) often harbor a Tel-PDGFR translocation that results

in constitutive activation of the PDGFR kinase domain exclusively in the leukemic cells Imatinib inhibits this kinase and has demonstrated significant activity in this

disease These examples extend the proof of principle that targeting of signaling

pathways in cancer cells can be highly efficacious with minimal toxicity, even when the drug does not have absolute target specificity Imatinib has become the

paradigm of targeted drug development in other diseases

Targeting Other Receptor Tyrosine Kinases

Epidermal growth factor receptor (EGFR) mutations define a novel subset

of lung cancers Clinical studies of two high-affinity competitive inhibitors of the ATP binding site in the EGFR kinase domain, gefitinib and erlotinib, have provided important insights into the pathogenesis of different subsets of patients

with non-small cell lung cancer (NSCLC) Phase III studies led to FDA approval after ~10–20% of advanced-stage patients treated with single-agent gefitinib or erlotinib had objective tumor responses Responders tended to have adenocarcinoma or bronchoalveolar histology (not squamous or large cell), and were never-smokers, women, and of Eastern Asian origin DNA sequence analysis

of the EGFR gene isolated from the tumors of responding patients (mostly

nonsmokers) demonstrated that most had acquired mutations of the kinase domain that led to increased tyrosine kinase activity Frequently, patients with mutated

alleles also had evidence of EGFR gene amplification by fluorescence in situ

hybridization (FISH) These tumors exhibited euploid chromosome content, in contrast to tumors from smokers, which were most often aneuploid and harbored

mutations in the K-Ras oncogene In fact, mutated K-Ras, which occurs to the

exclusion of EGFR mutation, appears to define a subset of patients with low likelihood of response to EGFR inhibitors Thus the model has been proposed that the pathogenesis of NSCLC in never-smokers occurs through a novel pathway that

is dependent on activated EGFR, and that tumors are addicted to this oncogene,

rendering them highly susceptible to its inhibition (see Fig 80-7) No EGFR

kinase domain mutations have yet been found in tumors other than NSCLC Thus,

these studies define a novel oncogenic pathway for an important human cancer, and provide a mechanism to identify subsets of patients likely to respond to the targeted therapy The wild-type EGFR is expressed by many other human cancers,

and in colon cancer and head and neck cancers, targeting of the EGFR with a

monoclonal antibody (cetuximab) has demonstrated improved survival when combined with chemotherapy or radiation therapy

HER2/neu is a target in human breast cancer The gene encoding HER2/neu, a member of the EGFR family, is amplified in ~20% of breast cancers Tumors that overexpress HER2/neu are less responsive to chemotherapy, and

patients with these tumors have a reduced survival compared with patients with

normal levels of HER2/neu Trastuzumab (Herceptin) is a humanized monoclonal antibody that binds HER2/neu on the surface of tumor cells and induces

internalization of the receptor, thereby reducing the level of surface expression This leads to inhibition of cell cycle progression and renders cancer cells more susceptible to the induction of apoptosis Phase III clinical trials demonstrated that combining trastuzumab with chemotherapy significantly improved response rates and overall survival in patients with metastatic HER2-positive disease, leading to FDA approval In addition, five randomized trials demonstrated that the addition

of trastuzumab to chemotherapy in the adjuvant setting for patients with HER2-positive disease reduces the risk of recurrence by nearly 50% These studies emphasize the critical pathogenic role of HER2-overexpression in a subset of breast cancer patients

The PDGFR and its ligand, platelet-derived growth factor (PDGF), are overexpressed in many glioblastomas and in subsets of melanoma, ovarian, pancreatic, gastric, lung, and prostate cancers Overexpression of the hepatocyte

growth factor receptor c-MET has been observed in many human cancers and correlates with a poor prognosis, perhaps due to its role in invasion and metastasis Small-molecule inhibitors of these RTKs are being developed for clinical use As described below, the vascular endothelial growth factor receptor (VEGFR), TIE, and EPH RTK families have been identified as important therapeutic targets for inhibition of angiogenesis