Chemoresistance in Renal Cell Cancer

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DESCRIPTION (provided by applicant): Patients with metastatic renal cell cancer (RCC) have a bleak prognosis with an average survival time of less than 18 months. Hence, there is an urgent need of more effective treatments. RCC show an overall response rate of <10% to chemotherapy and is resistance to different classes of drugs that do not share the same action or resistance mechanisms. We recently discovered a new epigenetic mechanism of anticancer drug resistance, that is caused by two fibroblast growth factors expressed in solid tumors, i.e., acidic and basic fibroblast growth factors (aFGF and bFGF). These two proteins at clinically relevant concentrations induce an up to 10-fold resistance to drugs with diverse structures and action mechanisms. Inhibitors of these FGF, including the monoclonal antibodies and suramin (at low concentrations with no cytotoxicity), completely reverse the FGF-induced resistance and enhance the activity of chemotherapy. In animals, low and nontoxic doses of suramin significantly enhanced the efficacy of chemotherapy, resulting in eradication of well- established tumors in immunodeficient mice. In addition to these earlier studies conducted with prostate tumor cells, we have obtained data showing the following. (a) RCC cell lines and RCC tissues obtained from patients contained high levels of aFGF/bFGF. (b) The FGF-induced resistance was observed for drugs that have been used to treat RCC, and was reversed by FGF inhibitors. (c) aFGF/bFGF induced chemoresistance in other human solid tumor cells (i.e., lung ovarian, colon, pharynx). (d) FGF inhibitors (suramin and/or pentosan polysulfate) enhanced the antitumor activity of 5-fluorouracil and gemcitabine in two RCC cell lines and histocultures of RCC patient tumors. (e) bFGF expression was a better predictor of paclitaxel resistance in multiple types of human tumors, compared to other known prognostic indicators (i.e., mutated p53, overexpression of Bcl2 and the mdr1 p-glycoprotein, and tumor pathology). (e) Results of cDNA microarray analysis show that bFGF enhanced the expression of genes involved in several known chemoresistance mechanisms (GST, Bcl-2 family proteins, topoisomerase, and drug efflux proteins), whereas suramin reduced the expression of these genes and FGF receptors. To evaluate the clinical application of our findings, we initiated a phase I/Il trial using low dose suramin to enhance the efficacy of paclitaxel and carboplatin, in advanced non-small cell lung cancer patients. The preliminary results of the completed phase I trial support the hypothesis that low and nontoxic doses of suramin enhanced the response rate, prolonged the progression-free survival and prolonged the median survival time, as compared to the historical data in this patient group treated with only paclitaxel/carboplatin. Based on these findings, we hypothesize that (a) aFGF/bFGF is an important resistance mechanism of RCC to chemotherapy, and (b) aFGF/bFGF inhibitors can enhance the efficacy of chemotherapy in RCC. The overall goal of this application is to test these hypotheses in preclinical (Aims 1 to 3) and clinical (Aims 4 and 5) studies. The proposed research has the potential of identifying a new treatment paradigm for RCC.