Receptors for luteinizing hormone-releasing hormone (LH-RH) are expressed on the plasma membranes of most prostate cancer cells. The expression of these receptors appears to persist despite prolonged exposure to LH-RH agonists, as demonstrated by our preliminary data. This is in contrast to pituitary LH-RH receptors, which are down-regulated. These findings support the use of LH-RH receptors as a viable target in the treatment of advanced prostate cancer. AN-152 [AEZS-108] is an agent that can effectively exploit this target due to its design combining an LH-RH agonist with the cytotoxic doxorubicin moiety. Extensive preclinical data provide evidence that AN-152 has anti-tumor activity against prostate cancer cells. Phase I studies conducted in women with gynecologic tumors show AN-152 is well-tolerated. In this application, we propose to conduct an accelerated Phase I lead-in to a Phase II trial of AN-152 in men with advanced prostate cancer previously treated with taxane chemotherapy. We will assess the efficacy of this agent as well as its toxicity in men. We will also use a new method to collect circulating tumor cells (CTCs) employing new membrane filter technology that will permit direct evaluation of LH-RH receptor expression. We will correlate CTC LH-RH receptor expression with outcomes in an attempt to identify a predictive marker of response to AN-152. Internalization of AN-152 by captured CTC will be quantified in a novel approach to studying kinetics exploiting the auto fluorescence of the agent. This new CTC capture method will be validated using concurrent CTC measurements by the established Veridex CellSearch(R) CTC assay. Positron emission tomography (PET) will also be incorporated to clarify its role in evaluating response to AN-152. In conclusion, this proposal will employ a new targeted cytotoxic agent directed to LH-RH receptors as a therapeutic target in prostate cancer and will also incorporate several correlative studies including a new method to collect CTCs, unique analyses of these CTCs and a novel method of studying drug kinetics.
Though prostate cancer is the most common cancer in men, there is only one option for men who require chemotherapy. In an effort to identify a new treatment option for these men, this proposal explores a novel agent that targets LH-RH receptors, which are highly expressed on prostate cancer cells but not on normal tissues. Correlative studies will investigate several novel assessment techniques, including a new technique to collect circulating tumor cells that allows visualization of drug internalization into tumor cells by exploiting the auto fluorescence of the agent.
|Liu, Stephen V; Tsao-Wei, Denice D; Xiong, Shigang et al. (2014) Phase I, dose-escalation study of the targeted cytotoxic LHRH analog AEZS-108 in patients with castration- and taxane-resistant prostate cancer. Clin Cancer Res 20:6277-83|