Imatinib mesylate for melanoma: will a new target be revealed?

There are two general paradigms for clinical drug development. The first involves understanding a mechanism or pathway leading to disease, identifying a target, screening candidate drugs for target interaction, and then assessing efficacy in animal models and ultimately in clinical trials. This sequential process is time-consuming and expensive— successful development of a new drug can take decades and cost as much as $800 million (DiMasi et al, 2003). Nevertheless, this approach has led to the development of many successful drugs, such as those now used to treat many patients with hypertension and hyperlipidemia. A second, increasingly more common paradigm involves the unapproved (off-label) use of a drug developed for a different disease, such as use of imiquimod (initially developed to treat genital warts) for actinic keratoses and keloids. In some cases, an approved drug given to patients for one disease is serendipitously noted to improve a second condition in those patients, revealing a new target for drug action or a similar target in another disease. Another example is etanercept, which was initially used to treat rheumatoid and psoriatic arthritis, and later found to be effective in psoriasis (Goffe and Cather, 2003). This pathway to drug discovery, although unpredictable, is usually much quicker, since mechanistic studies and extensive screening of compounds have been bypassed. Imatinib mesylate (Gleevec, formerly known as STI571) is a drug that has taken both paths. It was originally developed by Novartis Pharmaceuticals as a specific inhibitor of the BCR-ABL tyrosine kinase, which arises from an acquired t(9;22) genetic translocation (Philadelphia chromosome) that causes chronic myelogenous leukemia. The constitutive tyrosine kinase activity drives proliferation of malignant cells and is sufficient to induce the disease (Daley et al, 1990). Imatinib mesylate competes for the ATP-binding site on BCR-ABL, disabling its kinase activity, and produces a complete hematologic response in most patients (Druker et al, 2001). Inhibition of additional protein tyrosine kinases (PTK), c-kit, and the platelet-derived growth factor (PDGF) receptor was also noted. Gastrointestinal stromal tumors often express mutated forms of c-kit, and patients with these tumors were also found to respond to imatinib mesylate (van Oosterom et al, 2001). When imatinib mesylate was found effective in patients with the hypereosinophilic syndrome (Gleich et al, 2002), investigation into the genetic basis of this disease revealed that many of these patients, as well as some with systemic mastocytosis, harbor a chromosomal deletion that gives rise to an oncogenic fusion protein (FIP1L1-PDGFRA) involving the PDGF receptor (Cools et al, 2004). Imatinib mesylate is thus now considered a first-line agent for many malignancies characterized by aberrant PTK signaling via ABL, c-kit, and PDGF receptor. We desperately need new agents to treat patients with advanced melanoma, and there is currently considerable interest in imatinib mesylate. There are several reasons to think that this drug may have therapeutic potential in melanoma. First, it is known that PTK signaling is critical for sustaining melanocyte proliferation in vitro and for migration of melanocytic cells in vivo (Halaban, 2000). Binding of ligands such as stem cell factor, hepatocyte growth factor, and fibroblast growth factor to their cognate PTK receptors on melanocytes triggers a phosphorylation cascade (mitogen-activated protein kinase pathway) that in turn activates additional kinases (PI3 and Akt) that promote cell proliferation and survival. In addition, overexpression of some PTK receptor ligands such as hepatocyte growth factor is associated with increased susceptibility to melanoma in mice (Noonan et al, 2001). All three known targets of imatinib mesylate (ABL, c-kit, PDGF receptor) are generally expressed in melanoma, although c-kit expression tends to be diminished in metastatic lesions (Shen et al, 2003). Imatinib mesylate is currently being tested in patients with metastatic melanoma, but preliminary results of Phase II trials have not been very impressive. One trial involving 26 patients from Vanderbilt-Ingram Cancer Center and Beth Israel Deaconess Medical Center did not produce any clinical responses, but the course of treatment was limited in most patients by drug toxicity. Data on expression of known drug targets in tumors was not reported. A second trial from MD Anderson Cancer Center was limited to 21 patients with biopsies demonstrating expression of relevant PTK in over 25% of tumor cells. A near complete response was seen in one patient with the strongest expression of c-kit, but the remaining 20 patients experienced progressive disease over 6–12 wk. There has been a concurrent effort in several laboratories to evaluate imatinib mesylate in mouse models of localized melanoma. In a recent issue of the Journal, McGary et al (2004) employed a xenograft model in which human