Signal Transduction Targeted Therapies

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Elucidation of the signal transduction cascade downstream from growth factors and membrane receptor tyrosine kinases has revealed several key proteins involved in this malignant transformation, including the guanine nucleotide-binding proteins encoded by the ras proto-oncogene (Figure 5.1). Following posttranslational processing and addition of a hydrophobic 15-carbon farnesyl moiety, Ras is localized to the

FIGURE 5.1. The signal transduction inhibitors.

FIGURE 5.1. The signal transduction inhibitors.

inner plasma membrane and acts as a molecular switch that plays a crucial role in linking tyrosine kinase activation at the cell membrane to downstream cytoplasmic and nuclear targets, ultimately resulting in cell differentiation, proliferation, and survival.36 Farnesylation has attracted attention because of its critical role for Ras signaling,37 and farnsesyl transferase inhibitors (FTIs) were initially developed as a novel therapy to target aberrant Ras function in cancer.

Farnesyltransferase Inhibitors

As farnesyltransferase inhibitors (FTIs) have been developed and entered clinical trials, a fundamental research goal has been to understand their exact mechanism of action. Although FTIs clearly inhibit Ras farnesylation, it is unclear whether the antiproliferative effects of these compounds result exclusively from their effects on Ras alone. Other targets for FTIs include RhoB, a 21-kDa protein that regulates receptor trafficking and cell motility, and two centromere-associated proteins (CENP-E and CENP-F) that play a role in attaching centromeres to microtubules in early G2 phase.38

The FTI lonafarnib (SCH66336 or sarasar) is a tricyclic compound that inhibits the growth of several tumor cell lines as well as K-ras-transformed xenografts in vivo.39 In human xenograft studies a wide variety of tumors including colon, bladder, lung, prostate, and pancreas were growth inhibited in a dose-dependent manner, while prophylactic administration of SCH66336 delayed both tumor onset and growth.40 In patients with solid tumors, efficacy has been reported in early Phase I clinical studies in a variety of tumor types including lung and head and neck cancer,41 and confirmation of biologic efficacy has been demonstrated by inhibition of prenylation of prelamin A in buccal mucosa cells in treated patients42 (Table 5.5). Based on promising preclinical evidence that lonafarnib may synergize with taxane-based chemotherapy,43 randomized Phase II/III trials were initiated in NSCLC to investigate whether lonafarnib could further enhance the efficacy of standard taxane platinum-based chemotherapy. Tipifarnib (R115777 or zarnestra) is an imidazole-containing heterocyclic compound that is a potent and selective, orally active, nonpeptidomimetic inhibitor of the farnesyl protein transferase (FPTase) enzyme.44 There is considerable evidence that tipifarnib may have promising activity in hematologic malignancies, in particular, newly diagnosed acute myeloge-nous leukemia (AML) and myelodysplasia (MDS)45,46 (see Table 5.5).

In view of the higher incidence of Ras mutations in gastrointestinal malignancies, two randomized double-blind placebo-controlled Phase III trials of tipifarnib were conducted in colorectal and pancreatic cancer. There was no significant improvement in overall survival versus best supportive care for tipifarnib as monotherapy in advanced refractory colorectal cancer,47 or for gemcitabine plus tipifarnib versus gemcitabine plus placebo in 688 patients with advanced pancreatic cancer.48 Although several Phase I studies have assessed combinations of FTIs with various cyto-toxic agents, it remains unclear whether they will significantly enhance the efficacy of standard cytotoxic regimens. Several issues have arisen, including competing toxicities (i.e., myelosuppression) and uncertainty on the optimal sequence/schedule for FTI-chemotherapy combinations. There may be more promise for combining FTIs with noncy-totoxic therapies. In breast cancer, preclinical data have shown additive or synergistic interactions of FTIs with endocrine therapy,49 and in view of this, randomized Phase II studies of both tipifarnib and lonafarnib with letrozole are in progress. Evidence has also emerged that FTIs may be radiosensitizers in selected cancer cell lines, and Phase I trials have investigated the feasibility of this combined modality in

TABLE 5.5. FTI Phase I/II clinical trials.

Drug

Author

Dose range

Schedule

No. patients (pts)

Dose-limiting toxicities

Clinical/biological activity

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