This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lung cancer remains the leading cause of cancer death worldwide. In the United States approximately 170,000 new cases are diagnosed annually with over 85% of patients eventually dying of their disease. The vast majority (80%) of lung cancer is non-small cell lung cancer (NSCLC). NSCLC is rarely detected in its early stages. Nearly a third of patients present with metastatic disease and most will relapse. We know from a meta-analysis of eight randomized trials comparing Cisplatin-based combination chemotherapy with best supportive care in advanced NSCLC that treatment improves median survival. In those studies best supportive care arms achieved median survival of 4 months with 1-yr survival of only 5%. Two recent large trials of chemotherapy in advanced NSCLC found median survival of 8 months with 1-yr survival rates of 33%-38%. The role of second line chemotherapy in relapsing or refractory NSCLC has only recently been established with studies using docetaxel. A recent review looked at the results of 34 single-agent studies in this setting. Docetaxel is currently the only agent approved for the second-line treatment of NSCLC. That approval was based on two Phase III trials. Docetaxel response rates of 7-10% were reported with median survival of 24-33 weeks (6-8 months) and 1 yr survival of 21-37%. For the third-line therapy of patients with advanced NSCLC, the FDA-approved ZD1839 (Iressa). ZD1839 achieved a 12-18% overall response rate and 6.5 to 7.6 month median survival, but leaves significant room for improvement. Traditional chemotherapeutics are unlikely to be tolerated in this heavily pretreated population, which makes combination with other well-tolerated, biologically targeted agents attractive. Combination studies of bexarotene with chemotherapy in NSCLC have been conducted. Bexarotene (Targretin) is a retinoid. Retinoids function by altering gene expression mediated through 2 families of intracellular receptors; the retinoic acid receptors and the retinoid-X receptors. In vivo studies have shown bexarotene to induce apoptosis (cell death) in tumor cell lines. Phase I studies have demonstrated bexarotene's tolerability and possible activity. Activities seen in Phase I studies in cutaneous T-cell lymphomas led to Phase II-III trials in patients with refractory advanced-stage cutaneous T-cell lymphomas with Bexarotene at 300 mg/m2/d orally. Responses seen in those trials led to FDA approval of oral bexarotene for this disease. The most frequent drug-related adverse events included hypertriglyceridemia (associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache. Studies have demonstrated the addition of bexarotene to traditional chemotherapy in a front-line treatment study yielded a 3 month improvement in median survival compared to historical controls (14 versus 11 months). Encouraging survival data was also seen in the Phase I studies of Bexarotene for very heavily pretreated NSCLC patients (11 months with 42% 1-yr and 15% 2-yr survival). The potential for Bexarotene to add in the third line treatment of NSCLC is therefore very promising. The mechanisms of action of the 2 agents, Bexarotene and ZD 1839, are not entirely understood, but there is reason to believe that they may have additive or synergistic effects. ZD1839's primary activity is as an epidermal growth factor receptor (EGFR) inhibitor, but it also leads to cell cycle inhibition and other changes in cellular metabolism. The exact mechanism by which ZD1839 leads to apoptosis is not understood, but is not entirely through inhibition of EGFR. ZD1839 showed similar antitumor activity in xenograft models with differing levels of EGFR expression indicating that factors other than the number of EGFRs per cell influences cancer cell sensitivity to EGFR targeted therapies. ZD1839 has been shown to block tumor-induced angiogenesis, with a dose and time dependent growth inhibition accompanied by a decrease of vascular endothelial growth factor (VEGF) and TGF production in vitro and in vivo in several human cancer cell lines. Synergism with other agents that alter expression of EGFR and its ligands is theoretically possible. Bexarotene is a rexinoid (RXR-specific retinoid) and therefore alters several cellular pathways. It has been shown to downregulate both TGF and EGFR expression. It also inhibits the cell cycle through regulation of several cyclins and cyclin dependent kinase inhibitors. It leads to apoptosis in tumor cells, though the exact mechanism is unknown. While the combination of ZD1839 and Bexarotene has not been studied pre-clinically, the combination of Bexarotene and another small molecule EGFR inhibitor showed additive effects in vitro (K. Dragnev personal communication). Given the proven safety of both of the agents, the potential overlapping actions of the agents, and the need for further improvement in survival of NSCLC patients, it seems reasonable to clinically study the combination. Bexarotene is known to upregulate CYP 3A4, the main enzyme responsible for ZD1839 metabolism, so the Phase I portion of the study will include pharmacokinetics. It is important to note that the two agents have non-overlapping toxicities with diarrhea and acneiform rash seen with ZD1839 and lipid abnormalities, thyroid suppression, headache and dry skin noted with Bexarotene. They are both well tolerated oral agents well suited for trials in heavily pre-treated NSCLC patients.
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