Chapter 081. Principles of Cancer Treatment (Part 18)

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Site of action of targeted agents. Signals proceeding from growth factor– related receptor tyrosine kinases (RTKs) such as EGF-R, erbB2, or c-kit can be interrupted by lapatinib, erlotinib, gefitinib, and imatinib, acting at the ATP binding site; or by cetuximab, trastuzumab, or panitumomab. Tyrosine kinases (TKs) that are not directly stimulated by growth factors such as p210 bcr-abl or src can be inhibited by imatinib, dasatinib, or nilotinib. Signals projected downstream from growth factor receptors can be affected by the multitargeted kinase inhibitor sorafenib, acting on c-raf, and, upon arrival at the nucleus, affect gene expression, which can be...

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Chapter 081. Principles of Cancer Treatment (Part 18) Site of action of targeted agents. Signals proceeding from growth factor– related receptor tyrosine kinases (RTKs) such as EGF-R, erbB2, or c-kit can be interrupted by lapatinib, erlotinib, gefitinib, and imatinib, acting at the ATP binding site; or by cetuximab, trastuzumab, or panitumomab. Tyrosine kinases (TKs) that are not directly stimulated by growth factors such as p210 bcr-abl or src can be inhibited by imatinib, dasatinib, or nilotinib. Signals projected downstream from growth factor receptors can be affected by the multitargeted kinase inhibitor sorafenib, acting on c-raf, and, upon arrival at the nucleus, affect gene expression, which can be affected by the targeted transcriptional modulators vorinostat (targeting histone deacetylase), azacytidine derivatives (targeting DNA
methyltransferase), or retinoid receptor modulators all-trans-retinoic acid (ATRA) or bexarotene. Cytokine receptors (CkRs) are one stimulus for degradation of the inhibitory subunit of the NFκB transcription factor by the proteosome. Bortezomib inhibits this process and can prevent activation of NFκB-dependent genes, among other growth-related effects. Sorafenib and sunitinib, acting as inhibitors of VEGF receptors, can modulate tumor blood vessel function through their action on endothelial cells, while bevacizumab targets the same process by combining with VEGF itself.Hematopoietic Neoplasms Imatinib targets the ATP binding site of the p210bcr-abl protein tyrosine kinase that is formed as the result of the chromosome 9,22 translocation producing the Philadelphia chromosome in CML. Imatinib is superior to interferon plus chemotherapy in the initial treatment of the chronic phase of this disorder. It has lesser activity in the blast phase of CML, where the cells may have acquired additional mutations in p210bcr-abl itself or other genetic lesions. Its side effects are relatively tolerable in most patients and include hepatic dysfunction, diarrhea, and fluid retention. Rarely, patients receiving imatinib have decreased cardiac function, which may persist after discontinuation of the drug. The quality of response to imatinib enters into the decision about when to refer patients with CML for consideration of transplant approaches. Nilotinib is a tyrosine protein kinase inhibitor with a similar spectrum of activity to imatinib, but with increased potency and perhaps better tolerance by certain patients. Dasatinib, another
inhibitor of the p210bcr-abl oncoproteins, is active in certain mutant variants of p210bcr-abl that are refractory to imatinib and arise during therapy with imatinib or are present de novo. Dasatinib also has inhibitory action against kinases belonging to the src tyrosine protein kinase family; this activity may contribute to its effects in hematopoietic tumors and suggest a role in solid tumors where src kinases are active. Only the T315I mutant is resistant to dasatinib; a new class of inhibitors called aurora kinase inhibitors is in development to address this problem. All-trans-retinoic acid (ATRA) targets the PML-retinoic acid receptor (RAR) α fusion protein, which is the result of the chromosome 15,17 translocation pathogenic for most forms of APL. Administered orally, it causes differentiation of the neoplastic promyelocytes to mature granulocytes and attenuates the rate of hemorrhagic complications. Adverse effects include headache with or without pseudotumor cerebri and gastrointestinal and cutaneous toxicities. Another active retinoid is the synthetic retinoid X receptor ligand bexarotene, which has activity in cutaneous T cell lymphoma. Bortezomib is an inhibitor of the proteasome, the multi-subunit assembly of protease activities responsible for the selective degradation of proteins important in regulating activation of transcription factors, including NFκB and proteins regulating cell cycle progression. It has activity in multiple myeloma and certain lymphomas. Adverse effects include neuropathy, orthostatic hypotension with or without hyponatremia, and reversible thrombocytopenia.
Vorinostat is an inhibitor of histone deacetylases, responsible for maintaining the proper orientation of histones on DNA, with resulting capacity for transcriptional readiness. Acetylated histones allow entry of transcription factors and therefore increased expression of genes that are selectively repressed in tumors. The result can be differentiation with the emergence of a more normal cellular phenotype, or cell cycle arrest with expression of endogenous regulators of cell cycle progression. Vorinostat is approved for clinical use in cutaneous T cell lymphoma, with dramatic skin clearing and very few side effects. DNA methyltransferase inhibitors including 5-aza-cytidine and 2'-deoxy-5- azacytidine can also increase transcription of genes "silenced" during the pathogenesis of a tumor by causing demethylation of the methylated cytosines that are acquired as an "epigenetic" (i.e., after the DNA is replicated) modification of DNA. These drugs were originally considered antimetabolites but have clinical value in myelodysplastic syndromes and certain leukemias when administered at low doses. Combinations of DNA methyltransferase inhibitors and histone deacetylase inhibitors may offer new approaches to reregulate chromatin function. Targeted toxins utilize macromolecules such as antibodies or cytokines with high affinity for defined tumor cell surface molecules, such as a leukemia differentiation antigen, to which a therapeutic antibody can deliver a covalently linked potent cytotoxin (e.g., gemtuzumab ozogamicin, a drug linked to anti- CD33), or a growth factor such as IL-2 to deliver a toxin (in the form of diphtheria
toxin in denileukin diftitox) to cells bearing the IL-2 receptor. The value of such targeted approaches is that in addition to maximizing the therapeutic index by differential expression of the target in tumor (as opposed to nonrenewable normal cells), selection of patients for clinical use can capitalize on assessing the target in the tumor.