Outsmarting Prostate Cancer with an RNA Aptamer
November 2014
The ability to target a specific cell type is the Holy Grail for current cancer therapy. This reduces the side effects that are common with traditional therapies that are broadly cytotoxic. Over the past decade several so-called “smart drugs”, designed to target a cell surface molecule that is distinct or highly upregulated in the malignant cell, have been developed. However, despite being the second most prevalent malignancy in males worldwide, no such treatment has been developed for prostate cancer (PC), a cancer that often progresses quickly into metastatic castration-resistant prostate cancer (mCRPC). Currently there are limited therapeutic options for mCRPC. Furthermore, these options only prolong the life of the patient for 6-12 months, emphasizing the need for additional treatment options.
Responding to this need, Dassie et al. recently developed an RNA aptamer-based smart drug that targets cells expressing prostate specific membrane antigen (PSMA), a cytosolic glyco-protein that converts to a transmembrane isoform in PC cells. Although smart drugs have traditionally been small molecules or antibodies, aptamers are becoming a more popular option. Aptamers are often compared to antibodies and have similar profile of target recognition, though they offer several distinct advantages such as greater affinity, increased stability and ease of synthesis.
A previous study headed by Paloma Giangrande described the clinical optimization of the PSMA targeted aptamer, A9g. Using this information, Dassie et al. were able to show a dose-dependent reduction in PSMA enzymatic activity (NAALADase) and a concurrent reduction in cell migration and invasion after treatment with A9g. However, they were surprised A9g had no effect on cell proliferation or survival. Previously this effect was noted in a PSMA -/- cell line, thus indicating that A9g may be affecting downstream effectors of the focal adhesion kinase pathway.
Next Dassie et al. tested the efficacy of the A9g aptamer in a mouse model of metastatic PC. After intracardial administration of PC cells, the authors treated the mice with 1 nmol of aptamer once every 24 hours for the first four days. After the fourth day they then treated the mice once a week for 4 weeks. Administration of A9g significantly reduced the spread of PC cells in the mouse model. Only 2 of 18 mice developed visible metastases, compared to 8 out of 10 in the vehicle control group and 13 of 16 mice in the non-active aptamer (A9g.6) control group. Additional experiments indicated the aptamer showed no signs of toxicity after four weeks of treatment. A biodistribution study showed that A9g selectively targets PSMA (+) tumors and is retained for 72+ hours while control A9g.6 is efficiently cleared in less than 8 hours.
Finally, the authors examined the stability and safety of A9g in human serum and human peripheral mononuclear blood cells (PBMC). The stability of the RNA aptamer in serum is adversely affected by nuclease activity, however modifications, such as 2′ F and 2′ O-Me are often employed to increase stability. Here, the authors found that 2′ O-Methylation of all the purines resulted in a non-functional aptamer and partial 2′ O-Methylation did not increase stability. This highlights the importance of including desired modifications during aptamer selection. Regardless, Dassie et al. found that the unmodified aptamer was stable for 72 hours and had no toxic effects when incubated with PBMCs. This study demonstrates the safety and efficacy of A9g and supports further therapeutic testing. A9g may be the first effective smart drug for the treatment of advanced stage PC.
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