Combination Therapy

Effective clinical chemoprevention may require combination therapy rather than single-agent regimens (Dragnev et al. 2003c). One way to limit clinical toxicities of cancer chemopreven-tive agents would be through combining agents targeting different chemopreventive pathways, each administered at dosages lower than when these are typically used as single agents. For each chemopreventive agent used in a combination regimen, a validated target can be selected based on preclinical and clinical activities. An active combination regimen should be associated with a tolerable toxicity profile as well as a safe and convenient schedule of chronic administration. Ideally, synergistic or additive effects would first be observed in in vitro and animal models. Animal model testing could establish that a combination regimen is potentially safe for clinical use. If available, clinical evidence for drug synergy in treatment of advanced stage cancer might provide a basis for use of a regimen in cancer che-moprevention.

The findings already summarized directly implicated cyclin D1 as a key downstream signaling species in the EGFR pathway (Lonardo et al. 2002; Petty et al. 2004). This indicated that targeting cyclin D1 with a combination regimen that independently affected this cyclin would augment clinical activity of an EGFR-TKI. It was hypothesized that combining an EGFR inhibitor with a rexinoid would coordinately repress cyclin D1 expression and thereby confer cooperative clinical anti-tumor effects (Dragnev et al. 2003b, 2004; Petty et al. 2004; Fan et al. 2004). To explore this mechanistically, in vitro studies revealed that combining the rexinoid, bexarotene, with the EGFR-TKI, erlotinib (tarceva), yielded at least additive growth inhibitory effects and cooperative repression of cyclin D1 immunob-lot expression in examined bronchial epithelial and lung cancer cells (Dragnev et al. 2005). This regimen has the added therapeutic advantage of using a nonclassical retinoid, a rexinoid that activates the retinoid X receptor (RXR) pathway and thereby overcomes the block to classical retinoids that occurs in cells that aberrantly express the retinoic acid receptor-^ (RAR^), as has been reported to occur in lung carcinogenesis (Petty et al. 2005). The clinical rationale for this regimen is summarized in Fig. 3.

A recent clinical trial investigated bexarotene (targretin) and erlotinib (tarceva) in patients with advanced aerodigestive tract cancers and demonstrated clinical efficacy of this hypothesis-driven combination regimen (Dragnev et al. 2005). Clinical findings indicated that combining these agents broadened activity of single agent erlotinib (tarceva). Results from this trial pro-

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