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 Target Disease Mechanism of Action All-trans retinoic acid (ATRA) PML- RARα oncogene Acute promyelocytic leukemia M3 AML; t(15;17) Inhibits transcriptional repression by the PML-RARα Imatinib (Gleevec) Bcr-Abl, c- Abl, c- Kit, PDGFR-α/β, Chronic myelogenous leukemia; GIST Blocks ATP binding to tyrosine kinase active site. Sunitinib (Sutent) c-Kit, VEGFR-2, PDGFR-β, Flt-3 GIST; renal cell cancer Inhibits activated c- Kit and PDGFR in GIST; inhibits VEGFR in RCC. Sorafinib RAF, RCC; Targets VEGFR (Nexavar) VEGFR-2, PDGFR-α/β, Flt- 3, c-Kit may have activity in melanoma when combined with chemotherapy pathways in RCC. Possible activity against BRAF in melanoma, colon cancer, and others. Erlotinib (Tarceva) EGFR Non- small cell lung cancer; pancreatic cancer Competitive inhibitor of the ATP binding site of the EGFR. Gefitinb (Iressa) EGFR Non- small cell lung cancer Inhibitor of EGFR tyrosine kinase. Bortezomib (Velcade) Proteasome Multiple myeloma Inhibits proteolytic degradation of multiple cellular proteins. Monoclonal Antibodies Trastuzumab (Herceptin) HER2/neu (ERBB2) Breast cancer Binds HER2 on tumor cell surface and induces receptor internalization. Cetuximab (Erbitux) EGFR Colon cancer, squamous cell carcinoma of the head and neck Binds extracellular domain of EGFR and blocks binding of EGF and TGF- α; induces receptor internalization. Potentiates the efficacy chemotherapy and radiotherapy. Panitumomab (Vectibix) EGFR Colon cancer Like cetuximab; likely to be very similar in clinical activity Rituximab (Rituxan) CD20 B cell lymphomas and leukemias that express CD20 Multiple potential mechanisms including direct induction of tumor cell apoptosis and immune mechanisms. Alemtuzumab (Campath) CD52 Chronic lymphocytic leukemia and CD52- expressing lymphoid tumors Immune mechanisms Bevacizumab (Avastin) VEGF Colon, lung, b reast cancers; data pending in other tumors Inhibits angiogenesis by high- affinity binding to VEGF. 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. . Chapter 080. Cancer Cell Biology and Angiogenesis (Part 5) Targeting BCR-ABL with Imatinib: Proof of Principle The protein. Breast cancer Binds HER2 on tumor cell surface and induces receptor internalization. Cetuximab (Erbitux) EGFR Colon cancer, squamous cell carcinoma of the head and neck Binds extracellular. Possible activity against BRAF in melanoma, colon cancer, and others. Erlotinib (Tarceva) EGFR Non- small cell lung cancer; pancreatic cancer Competitive inhibitor of the ATP binding