Abstract
Current systemic therapies for breast cancer are often limited by their nonspecific mechanism of action, unwanted toxicities on normal tissues, and short-term efficacy due to the emergence of drug resistance. However, identification of the molecular abnormalities in cancer, in particular the key proteins involved in abnormal cell growth, has resulted in development of various signal transduction inhibitor drugs as new treatment strategies against the disease. Protein farnesyltransferase inhibitors (FTIs) were originally designed to target the Ras signal transduction pathway, although it is now clear that several other intracellular proteins are dependent on post-translational farnesylation for their function. Preclinical data revealed that although FTIs inhibit the growth of ras-transformed cells, they are also potent inhibitors of a wide range of cancer cell lines that contain wild-type ras, including breast cancer cells. Additive or synergistic effects were observed when FTIs were combined with cytotoxic agents (in particular the taxanes) or endocrine therapies (tamoxifen). Phase I trials with FTIs have explored different schedules for prolonged administration, and dose-limiting toxicities included myelosuppression, gastrointestinal toxicity and neuropathy. Clinical efficacy against breast cancer was seen for the FTI tipifarnib in a phase II study. Based on promising preclinical data that suggest synergy with taxanes or endocrine therapy, combination clinical studies are now in progress to determine whether FTIs can add further to the efficacy of conventional breast cancer therapies.
Highlights
Farnesyltransferase inhibitors (FTIs), initially developed to target cancers in which the ras proto-oncogene was mutated and overactive, represent a novel form of anticancer therapy
In transgenic mouse mammary tumours, receptor tyrosine kinase pathways result in activated Ras protein signalling [2], whereas hormone-sensitive MCF-7 breast cancer cells have been shown to express high levels of Rasrelated proteins [3]
Whether the effect seen in these studies represents true synergy is sometimes unclear because formal mathematical methods of analysis have not always been employed. These emerging data have led to the initiation of several clinical trials in breast cancer to investigate the combination of an FTI with endocrine therapy
Summary
Farnesyltransferase inhibitors (FTIs), initially developed to target cancers in which the ras proto-oncogene was mutated and overactive, represent a novel form of anticancer therapy. Whether the effect seen in these studies represents true synergy is sometimes unclear because formal mathematical methods of analysis have not always been employed These emerging data have led to the initiation of several clinical trials in breast cancer to investigate the combination of an FTI with endocrine therapy (see below). A number of small phase I/II trials have been initiated with FTIs in combination with endocrine therapies, including tamoxifen, fulvestrant, or an aromatase inhibitor (Table 1) Some of these trials are in the post-tamoxifen setting, with at least one trial enrolling patients whose tumor is 266 progressing on tamoxifen, and adding the FTI tipifarnib to determine whether clinical responses can be observed and resistance reversed. Given the mechanism of action of these drugs in combination (i.e. enhanced G0/G1 arrest without enhanced apoptosis), an enhanced clinical benefit rate that includes an assessment of stable disease may be a better end-point for such randomized phase II trials, especially if FTIs contribute to prolonged control of the disease
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