One of the best-recognized downstream events resulting from the tyrosine kinase activity of BCR-ABL in chronic myelogenous leukemia patients is the activation of ras. Ras, which is synthesized as an inactive protein in the cytoplasm, is activated through a prenylation process that allows attachment to the cellular membrane. This process is mediated most prominently by farnesyl transferase and alternatively through geranyl protein transferase. Mutations of ras and Ras protein activation are frequent features of malignant transformation. Approximately 30% of human cancers have been associated with ras mutations. The frequency of these mutations varies in hematologic malignancies from 5% to 15% in acute lymphoblastic leukemia and up to 65% in chronic myelogenous leukemia. Therefore, inhibition of Ras activation has been investigated as an antineoplastic therapy. One approach to ras inhibition is inhibiting farnesyl transferase via farnesyl transferase inhibitors (FTIs). Preclinical studies have demonstrated that FTIs have significant anti-chronic myelogenous leukemia activity.
Mechanism Of Action
The actual mechanism of action of FTIs is not yet clear because the inhibition of Ras farnesylation does not account for all of the FTIs’ actions. For example, FTIs do not require the presence of mutant Ras protein to produce antitumor effects. Several other proteins have been implicated as downstream targets that mediate the antitumorigenic effects of FTIs. The regulation of RhoB, a small GTPase that acts downstream of Ras and is involved in many cellular processes, including cytoskeletal regulation and apoptosis, has been proposed as a mechanism of FTI-mediated antitumorogenesis. Additional proteins involved in cytoskeletal organization are also known to be farnesylated, including the centromere proteins CENP-E and CENP-F, protein tyrosine phosphatase, and lamins A and B. Therefore, one possible mode of action of FTIs may be their inhibiting effects on cellular reorganization and mitosis.
In addition to inhibiting cellular reorganization and mitotic pathways, it is known that FTIs indirectly modulate several important signaling molecules, including transforming growth factor (TGF) βRII, MAPK/ERK, PI3K/AKT2, Fas (CD95), and vascular endothelial growth factor. The regulation of these effectors can lead to the modulation of signaling pathways involving cell growth, proliferation, and apoptosis.
Janssen Pharmaceutica and its parent company, Johnson & Johnson, are developing tipifarnib (R-115777, Zarnestra), an orally bioavailable non-petidomimetic FTI for the treatment of various hematologic malignancies, including acute myelogenous leukemia, myelodysplastic syndrome, and chronic myelogenous leukemia. Tipifarnib inhibits farnesyl transferase, preventing Ras from being altered and locating in the cell membrane. Therefore, Ras is not activated, and the signal for cell growth is not transmitted.
A Phase I study suggested that tipifarnib’s mechanism of action may involve inhibiting angiogenesis and decreasing the expression and secretion of vascular endothelial growth factor. This study investigated the tolerability and efficacy of tipifarnib + imatinib in patients with chronic-phase chronic myelogenous leukemia who have failed imatinib. The starting dosage was tipifarnib 300 mg twice daily for 14 days every 21 days and imatinib 300 mg daily, with subsequent levels 300 mg + 400 mg once daily, 400 mg + 400 mg twice daily, and 500 mg + 400 mg three times daily, respectively. The median age was 63 years, and the median time from diagnosis was 68 months. All the patients had failed imatinib, nine had failed interferon-a, and six had failed other therapies. The maximally tolerated dose (MTD) was imatinib 400 mg daily and tipifarnib 400 mg twice daily. One patient died early (16 days on treatment) of unknown causes, nine discontinued therapy after a median of 12 three-week cycles, and six continued therapy after a median of 11+ cycles. Eleven patients started with abnormal WBC counts and nine achieved normalization during therapy. One patient achieved a cytogenetic response, one patient achieved an major cytogenetic response (with a T315I mutation), and two patients displayed minor cytogenetic responses. Two patients lost the response after nine months, and two had ongoing responses more than 12 months after commencing therapy. The researchers concluded that this combination is well tolerated and demonstrates antileukemia activity.
Schering-Plough’s lonafarnib is an orally bioavailable nonpetidomimetic FTI. The compound is in Phase II trials for a variety of difficult-to-treat solid tumors and leukemias and in Phase I for chronic myelogenous leukemia.
Lonafarnib inhibits the proliferation of imatinib-resistant, BCR-ABL-positive cell lines as well as colony formation of cells from imatinib-resistant chronic myelogenous leukemia patients. It also sensitizes imatinib-resistant cells to apoptosis with imatinib.
A Phase I study investigated lonafarnib in combination with imatinib for patients with chronic myelogenous leukemia who had failed imatinib therapy. The starting dosage for chronic-phase chronic myelogenous leukemia was imatinib 400 mg daily + lonafarnib 100 mg twice daily; for the accelerated and blastic phases dosage was 600 mg daily and 100 mg twice daily. A total of 22 patients were treated: 9 in the chronic phase, 10 in the accelerated phase, and 3 in the blastic phase. Prior therapy included imatinib (n = 22), interferon-a therapy (n = 16), and other agents (n = 7). Median age was 59 years, and median time from diagnosis was 51 months. Patients received therapy for a median of 23 weeks.
Among 6 patients in the chronic phase evaluable for hematologic response, 1 patient had a CHR and 1 patient achieved an major cytogenetic response. Among patients in the accelerated and blastic phases, 4 had hematologic responses: one CHR (with mutation F359V), one partial hematologic response (no mutation), and two hematologic improvements (one patient with lymphoid blastic-phase disease achieved marrow cytogenetic response, and one patient with accelerated-phase disease achieved CHR with incomplete platelet recovery). The researchers concluded that the combination of lonafarnib and imatinib is well tolerated and shows early evidence of activity in this refractory population.