Chapter 080. Cancer Cell Biology and Angiogenesis (Part 5)

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Targeting BCR-ABL with Imatinib: Proof of Principle The protein product of the Philadelphia chromosome occurs in all patients with chronic myeloid leukemia (CML) and in ~30% of patients with adult acute lymphoid leukemia (ALL) and encodes the fusion protein Bcr-Abl. Although the c-Abl protooncogene is a nuclear protein whose kinase activity is tightly regulated as a part of the DNA damage response pathway (and actually induces growth arrest), the Bcr-Abl fusion protein is largely cytoplasmic with a constitutively activated tyrosine kinase domain. The deregulated tyrosine kinase activity of BcrAbl is required for its transforming activity. The Abl tyrosine kinase...

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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 5) Targeting BCR-ABL with Imatinib: Proof of Principle The protein product of the Philadelphia chromosome occurs in all patients with chronic myeloid leukemia (CML) and in ~30% of patients with adult acute lymphoid leukemia (ALL) and encodes the fusion protein Bcr-Abl. Although the c-Abl protooncogene is a nuclear protein whose kinase activity is tightly regulated as a part of the DNA damage response pathway (and actually induces growth arrest), the Bcr-Abl fusion protein is largely cytoplasmic with a constitutively activated tyrosine kinase domain. The deregulated tyrosine kinase activity of Bcr- Abl is required for its transforming activity. The Abl tyrosine kinase inhibitor, imatinib mesylate (Gleevec), has validated the concept of a molecularly targeted approach to cancer treatment.
Imatinib is a low-molecular-weight competitive inhibitor of the ATP binding site of Bcr-Abl, c-Abl, platelet-derived growth factor receptor (PDGFR), and c-Kit; hence it is not absolutely specific for the Bcr-Abl oncogene product (Table 80-2). Clinical studies have demonstrated remarkable activity of this agent in CML. In phase II studies of 532 chronic phase CML patients in whom interferon treatment had failed, 95% obtained a hematologic complete response, with only 9% relapse after a median follow-up of 18 months. With longer follow- up, 75% of patients treated with imatinib in chronic phase remain in remission after nearly 4 years. Imatinib was also active in CML blast crisis with a 52% response rate, although the responses were short-lived (78% relapse within 1 year). Relapse during treatment with imatinib was associated with reactivation of the tyrosine kinase either by amplification of the Bcr-Abl locus leading to increased levels of Bcr-Abl protein or, more commonly, by point mutations within the Bcr-Abl kinase domain that decreased imatinib binding without loss of Bcr- Abl kinase activity. These data constitute genetic proof that the target of imatinib is the Bcr-Abl tyrosine kinase, and that Bcr-Abl kinase activity is still required by imatinib-resistant cells. Two drugs have been developed (dasatinib and nilotinib) that are potent inhibitors against most imatinib resistant mutants; these compounds have demonstrated significant activity in patients with imatinib-resistant CML. Table 80-2 FDA-Approved Molecularly Targeted Agents for the
Treatment of Cancer Drug Molecular Disease Mechanism of Target Action All-trans PML-RARα Acute Inhibits retinoic acid oncogene promyelocytic transcriptional (ATRA) leukemia M3 repression by the AML; t(15;17) PML-RARα Imatinib Bcr-Abl, c- Chronic Blocks ATP (Gleevec) Abl, c-Kit, myelogenous binding to tyrosine PDGFR-α/β, leukemia; GIST kinase active site. Sunitinib c-Kit, GIST; Inhibits (Sutent) VEGFR-2, renal cell cancer activated c-Kit and PDGFR-β, Flt-3 PDGFR in GIST; inhibits VEGFR in RCC. Sorafinib RAF, RCC; Targets VEGFR
(Nexavar) VEGFR-2, may have pathways in RCC. PDGFR-α/β, Flt-3, activity in Possible activity c-Kit melanoma when against BRAF in combined with melanoma, colon chemotherapy cancer, and others. Erlotinib EGFR Non- Competitive (Tarceva) small cell lung inhibitor of the ATP cancer; binding site of the pancreatic EGFR. cancer Gefitinb EGFR Non- Inhibitor of (Iressa) small cell lung EGFR tyrosine kinase. cancer Bortezomib Proteasome Multiple Inhibits (Velcade) myeloma proteolytic degradation of multiple cellular proteins.
Monoclonal Antibodies Trastuzumab HER2/neu Breast Binds HER2 on (Herceptin) (ERBB2) cancer tumor cell surface and induces receptor internalization. Cetuximab EGFR Colon Binds (Erbitux) cancer, extracellular domain of squamous cell EGFR and blocks carcinoma of the binding of EGF and head and neck TGF-α; induces receptor internalization. Potentiates the efficacy chemotherapy and radiotherapy. Panitumomab EGFR Colon Like cetuximab; (Vectibix) cancer likely to be very similar in clinical
activity Rituximab CD20 B cell Multiple (Rituxan) lymphomas and potential mechanisms leukemias that including direct express CD20 induction of tumor cell apoptosis and immune mechanisms. Alemtuzumab CD52 Chronic Immune (Campath) lymphocytic mechanisms leukemia and CD52- expressing lymphoid tumors Bevacizumab VEGF Colon, Inhibits (Avastin) lung, breast angiogenesis by high- cancers; data affinity binding to pending in other VEGF. tumors
Note: PML-RARα, promyelocytic leukemia–retinoic acid receptor-alpha; AML, acute myeloid leukemia; t(15;17), translocation between chromosomes 15 and 17; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet- derived growth factor receptor; Flt-3, fms-like tyrosine kinase-3; GIST, gastrointestinal stromal tumor; RCC, renal cell cancer; EGFR, epidermal growth factor receptor; TGF-α, transforming growth factor alpha.