A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma

Abstract

Background DNA aptamers represent a novel strategy in anti-cancer medicine. These compounds are short sequences of DNA that have protein binding effects via shape specific recognition of a target protein in an interaction which is analogous to antibody-antigen binding. AS1411, a DNA aptamer that targets nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, predominantly clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 previous tyrosine kinase inhibitor. We present the first manuscript reporting the use of this novel anti-cancer agent in humans. Methods In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1–4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints. Results 35 patients were enrolled and treated; 33 completed two treatment cycles. Median number of prior therapies was 2 (range 1–7). One patient (2.9%) had a response to treatment. The response was dramatic (84% reduction in the sum of longest diameters of selected target tumor lesions) and durable (the patient remains free of progression 2 years after completing therapy). No responses were seen in the other patients. Median PFS was 4 months. Only 34% of patients had an AS1411-related adverse event, all of which were mild or moderate. Conclusions AS1411 appears to have limited activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. Further studies with nucleolin targeted compounds may benefit from efforts to discover predictive biomarkers of response. Currently, promising pre-clinical studies are ongoing using AS1411 conjugated to traditional cytotoxic agents to selectively deliver these treatments to tumor cells. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

“…The c-MYC quadruplex was recently shown to be readily taken up by cells, where it destabilizes proteins that normally bind G4DNA in the cell (72). Indeed, the G4DNA oligonucleotide AS1411 has been developed as a possible treatment for cancer (67,73). G4 structures made up of DNA and In HeLa cells, 68% of the TIA1 foci co-localize with BG4 after 2 h of H 2 O 2 treatment, and 71% co-localize after 4 h of H 2 O 2 treatment.…”

Human anti-nucleolin recombinant immunoagent for cancer therapy

“…The widely demonstrated role of NCL in tumorigenesis suggests that inhibition of its oncogenic actions reduces tumor aggressiveness (9,13,19,24,32,34,47), and several studies have proposed NCL as an ideal target for antineoplastic therapies in different solid and hematological malignancies (9,19,25,34,37,38,41,42,48,49). Given the selective presence of NCL on cancer cells and cancer-associated endothelial cells, but not on normal cells, molecules targeting NCL might represent an effective approach for the selective delivery of drugs or toxins to tumors while minimizing side effects (25,41).…”

“…Several reports have shown that NCL inhibition by siRNAs or anti-NCL aptamers affects cell viability, proliferation, and migration (14,19,(37)(38)(39)(40)(41)(42)(43). To assess the effects of 4LB5 on cell viability and proliferation, we performed a dose-response (0.9-240 nM) experiment using the scFv on MDA-MB-231 triple-negative breast cancer (TNBC) cells at different time points (24,48, and 72 h).…”

Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis

“…33 The two FGFR2 mutations seen in cases 17 and 18 are identical. This mutation (p. A259V) is a confirmed somatic mutation in metastatic renal cell carcinoma 34 with a SIFT score of 0.07 and we regard it as a plausible, activating driver mutation. Finally, the ERBB2 mutation in case 14 is a previously confirmed somatic oncogenic mutation (SIFT score of 0) in breast, ovarian, and bladder carcinoma.…”