Current status of clinical trials of farnesyltransferase inhibitors

Abstract

Farnesyltransferase inhibitors represent a new class of agents that target signal transduction pathways responsible for the proliferation and survival of diverse malignant cell types. Although these agents were developed to prevent a processing step necessary for membrane attachment and maturation of Ras proteins, recent studies suggest that farnesyltransferase inhibitors block the farnesylation of additional cellular polypeptides, thereby exerting antitumor effects independent of the presence of activating ras gene mutations. Clinical trials of two farnesyltransferase inhibitors--the tricyclic SCH66336 and the methylquinolone R115777--as single agents have demonstrated disease stabilization or objective responses in 10 to 15% of patients with refractory malignancies. Combinations of farnesyltransferase inhibitors with cytotoxic chemotherapies are yielding complete and partial responses in patients with advanced solid tumors. A phase I trial of R115777 in refractory and relapsed acute leukemias induced responses in 8 (32%) of 25 patients with acute myelogenous leukemia (including two complete remissions) and in two of three with chronic myelogenous leukemia in blast crisis. In patients with solid tumors, accessible normal tissues such as peripheral blood lymphocytes or, perhaps more germane to epithelial malignancies, buccal mucosa have provided surrogate tissues that allow confirmation that farnesyltransferase is inhibited in vivo at clinically achievable drug doses. In conjunction with the R115777 acute leukemia trial, serial measurements provided evidence of farnesyltransferase enzyme inhibition, interference with farnesyltransferase function ( ie, protein processing), and blockade of signal transduction pathways in leukemic bone marrow cells. Preclinical studies of farnesyltransferase inhibitor resistance and clinical trials of farnesyltransferase inhibitors in combination with other agents currently are in progress.

K-ras activation generates an inflammatory response in lung tumors

“…Activated Ras protein is known to directly interact with a number of distinct effectors to trigger downstream signaling pathways, including activation of the RAF/MEK/ERK, PI3K/AKT and RAL-GTP pathways, to impact cellular proliferation, apoptosis and neoplastic transformation (Vojtek and Der, 1998;Adjei, 2001). Despite years of intense effort, therapeutics targeted against oncogenic K-ras have failed to prolong patient survival in tumors harboring activated K-ras mutations (Karp et al, 2001;Doll et al, 2004). Thus, a more detailed understanding of the downstream effectors of oncogenic K-ras is required to identify additional targets for the development of novel therapeutics.…”

In vitro antiproliferative activity of the farnesyltransferase inhibitor R115777 in hematopoietic progenitors from patients with myelofibrosis with myeloid metaplasia

“…22,23,25,26 Subsequent studies, however, have demonstrated that FTIs inhibit the proliferation of transformed cells in vitro and in vivo even if ras mutations are absent. 27,28 Along with H-ras, other farnesylated proteins, including rhoB, the centromere proteins CENP-E and CENP-F, and a currently unidentified molecule in the phosphatidylinositol-3 (PI-3) kinase/Akt pathway, have been implicated as potential FTI targets in neoplastic cells that lack ras mutations. [27][28][29][30] On the basis of the presence of ras mutations in a subset of acute myeloid leukemias, 31 as well as patient tolerance of nonmyeloid drug side effects in solid tumor patients, 32,33 R115777 was examined in a phase I trial in acute leukemia.…”

“…27,28 Along with H-ras, other farnesylated proteins, including rhoB, the centromere proteins CENP-E and CENP-F, and a currently unidentified molecule in the phosphatidylinositol-3 (PI-3) kinase/Akt pathway, have been implicated as potential FTI targets in neoplastic cells that lack ras mutations. [27][28][29][30] On the basis of the presence of ras mutations in a subset of acute myeloid leukemias, 31 as well as patient tolerance of nonmyeloid drug side effects in solid tumor patients, 32,33 R115777 was examined in a phase I trial in acute leukemia. 34 Responses were observed in 29% of patients with relapsed or primary refractory acute myeloid leukemia, none of whom had ras mutations.…”

Perspectives on the treatment of chronic phase and advanced phase CML and Philadelphia chromosome positive ALL

“…55 In addition to combinations with chemotherapy, farnesyltransferase inhibitors (FTI) represent a new class of agents that target signal transduction pathways responsible for proliferation and survival of diverse malignant cell types. FTIs have shown activity in advanced leukaemia 66 and the combination with imatinib may be another rational strategy to increase the Table 3 Phase II results of imatinib in accelerated phase CML 400 mg (%) 600 mg (%) Overall (%) …”