The relatively poor prognosis of patients with advanced non-small cell lung cancer (NSCLC) indicates an obvious need of more effective treatments. Our laboratory recently discovered that (a) acidic and basic fibroblast growth factors (aFGF and bFGF) that are expressed in solid tumors induce a broad spectrum anticancer drug resistance, (b) FGF inhibitors including monoclonal antibodies and suramin completely reversed the FGF-induced resistance, (c) the suramin concentration required to reverse the FGF-induced resistance (i.e., 10-15 pM) in cultured cells is between 5 to 10 percent of the concentration that shows cytotoxicity in cultured cells and in patients, (d) a low suramin dose, which yields about 10 percent of the suramin concentration used in previous clinical trials, significantly enhanced the efficacy without enhancing the toxicity of chemotherapy and resulted in eradication of well established human xenograft lung tumors in mice, and (e) FGF expression was a better predictor of paclitaxel resistance in 96 human tumors, as compared to the status of p53, Bc12, mdr 1 p-glycoprotein. We propose to test the hypotheses that FGF are a clinically important mechanism of resistance to chemotherapy and that suramin can enhance the efficacy of chemotherapy, in stage IIIB/IV NSCLC patients. Phase I/II trials of suramin plus paclitaxel/carboplatin and the accompanying pharmacokinetic studies are proposed. In addition, we will determine (a) FGF levels in tumors, effusion fluid, plasma and urine in individual patients, (b) extent of chemoresistance induced by the FGF levels found in patients, and (c) whether suramin at the plasma concentration found in individual patients is sufficient to reverse the FGF-induced resistance. The pharmacologic data will be evaluated together with the clinical outcome to determine whether suramin enhances the therapeutic efficacy of chemotherapy and whether the enhancement is due to reversal of the FGF-induced resistance. The proposed research may identify a new treatment for advanced NSCLC, provide the first proof-of-concept in humans on the importance of the FGF-induced chemoresistance mechanism and its reversal, and lead to a new treatment paradigm of solid tumors.
| Villalona-Calero, M A; Otterson, G A; Wientjes, M G et al. (2008) Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study. Ann Oncol 19:1903-9 |
| Chen, Danny; Song, Sae Heum; Wientjes, M Guillaume et al. (2006) Nontoxic suramin as a chemosensitizer in patients: dosing nomogram development. Pharm Res 23:1265-74 |
| Villalona-Calero, Miguel A; Wientjes, M Guillaume; Otterson, Gregory A et al. (2003) Phase I study of low-dose suramin as a chemosensitizer in patients with advanced non-small cell lung cancer. Clin Cancer Res 9:3303-11 |
