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

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

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 Bcr-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 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 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

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,

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

(Nexavar) VEGFR-2,

PDGFR-α/β, Flt-3, c-Kit

activity in melanoma when combined with chemotherapy

pathways in RCC Possible activity against BRAF in melanoma, colon cancer, and others

Erlotinib

(Tarceva)

Non-small cell lung cancer;

pancreatic cancer

Competitive inhibitor of the ATP binding site of the EGFR

Gefitinb

(Iressa)

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)

cancer, squamous cell carcinoma of the head and neck

Binds extracellular domain of EGFR and blocks binding of EGF and

receptor internalization

Potentiates the efficacy chemotherapy and radiotherapy

Panitumomab

(Vectibix)

cancer

Like cetuximab; likely to be very similar in clinical

activity

Rituximab

(Rituxan)

lymphomas and leukemias that express CD20

Multiple potential mechanisms including direct induction of tumor cell apoptosis and immune mechanisms

Alemtuzumab

(Campath)

lymphocytic leukemia and

CD52-expressing lymphoid tumors

Immune mechanisms

Bevacizumab

(Avastin)

lung, breast 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