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

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.