Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic

Reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease (Ref-1/APE1) is a critical node in tumor cells, both as a redox regulator of transcription factor activation and as part of the DNA damage response. As a redox signaling protein, Ref-1/APE1 enhances the transcriptional activity of STAT3, HIF-1α, nuclear factor kappa B, and other transcription factors to promote growth, migration, and survival in tumor cells as well as inflammation and angiogenesis in the tumor microenvironment. Ref-1/APE1 is activated in a variety of cancers, including prostate, colon, pancreatic, ovarian, lung and leukemias, leading to increased aggressiveness. Transcription factors downstream of Ref-1/APE1 are key contributors to many cancers, and Ref-1/APE1 redox signaling inhibition slows growth and progression in a number of tumor types. Ref-1/APE1 inhibition is also highly effective when paired with other drugs, including standard-of-care therapies and therapies targeting pathways affected by Ref-1/APE1 redox signaling. Additionally, Ref-1/APE1 plays a role in a variety of other indications, such as retinopathy, inflammation, and neuropathy. In this review, we discuss the functional consequences of activation of the Ref-1/APE1 node in cancer and other diseases, as well as potential therapies targeting Ref-1/APE1 and related pathways in relevant diseases. APX3330, a novel oral anticancer agent and the first drug to target Ref-1/APE1 for cancer is entering clinical trials and will be explored in various cancers and other diseases bringing bench discoveries to the clinic

Multicenter Trial of EC145 in Advanced, Folate-Receptor Positive Adenocarcinoma of the Lung

BackgroundEC145 is a novel folate-receptor targeted agent consisting of a folate molecule linked to a vinca alkaloid. EC20 is a technetium-labeled folate that assesses the presence of folate receptors (FR) in vivo. The objective of this study was to determine the activity of EC145 in patients with chemotherapy refractory lung adenocarcinoma, whose tumors expressed the FR as determined by EC20 imaging.MethodsPatients with advanced adenocarcinoma of the lung, Eastern Cooperative Oncology Group performance status 0 to 2, normal organ function, those who had progressed after at least two prior cytotoxic regimens, and with EC 20 uptake in at least one index lesion were eligible. The primary objective of the study was the ability to receive four or more cycles of therapy.ResultsSixty patients were screened and 43 patients were enrolled. Eleven patients (26%) received more than four cycles (95% confidence interval [CI] 14%, 41%), and one patient had partial response (response rate (RR) = 2.3%, 95% CI 0%, 12%). Patients in whom all target tumor lesions expressed FR by EC 20 scans had a trend toward superior results in terms of clinical benefit response (50% versus 14.3 %; p = 0.10) and survival (47.2 weeks versus 14.9 weeks [HR = 0.539, p = 0.101]) compared with those in whom at least one but not all target lesions were positive for FR (FR+).ConclusionEC145 demonstrated clinical activity with a good toxicity profile in this population. Uniform uptake of EC20 may predict activity of EC145 and be useful for prospective selection of patients in future trials