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MD Anderson Researchers Discuss RNAi Drug Development Hurdles, Strategies

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NEW YORK (GenomeWeb) – With recent advances in RNAi therapeutic payload design and delivery, the gene-silencing technology's potential as a key part of cancer management continues to grow. Yet careful target selection and delivery system validation, as well as a thorough understanding of target biology, are required to realize this promise, according to a team from MD Anderson Cancer Center.

"RNAi technology represents a rapidly emerging platform for personalized cancer therapy," Anil Sood and colleagues wrote in a perspective piece appearing this week in Science Translational Medicine. But despite encouraging signs in early-stage clinical studies, "seminal work is required for siRNAs to revolutionize the clinical care of cancer patients."

Meanwhile, an RNAi-based cancer drug under development at MD Anderson continues to move toward Phase I testing, as the institute wraps up additional animal studies requested by the US Food and Drug Administration following an siRNA manufacturing hiccup last year, Sood noted.

That study is on track to begin before the end of the year.

Since the discovery of RNAi, a number of drug candidates based on the technology have advanced into human testing, including several for cancer from companies such as Alnylam Pharmaceuticals and Calando Pharmaceuticals.

But delivery has continued to be an issue for such programs, the MD Anderson group wrote. For instance, in a Phase I trial, Alnylam's hepatocellular carcinoma treatment ALN-VSP proved capable of cutting target gene levels in only a small percentage of patient tumor samples examined. And in Phase I testing of Calando's CALAA-01, there was "minimal evidence of mRNA cleavage products in the tumors, which is a critical indicator of RNAi activity."

Calando's parent firm Arrowhead Research has since shelved CALAA-01, while Alnylam has stopped working on ALN-VSP unless it can find a partner for the drug.

To Sood, these setbacks reflect a sort of rush into the clinic amid the early hype surrounding RNAi, which led to human trials without rigorous consideration of the details. But he views these as learning experiences that has put the field in "a much better position to identify the best [delivery] approaches in a clinical setting," he told Gene Silencing News this week.

In Science Translational Medicine, the MD Anderson scientists focused on nanoparticle-based delivery and highlighted four key areas of consideration for RNAi-based cancer therapies including tumor localization, intratumoral mobility, tumor cell uptake, and intracellular trafficking.

"The size, shape, surface charge, and composition of nanocarriers are critical factors in tumor localization," they noted. At the same time, "detailed preclinical nanoparticle characterization and investigation of the effects of nanoparticles on siRNA distribution patterns in vivo are critical for increasing the chances of clinical success."

Once inside of tumors, nanocarriers must be efficiently taken up in target cell populations — an effect controlled by their physicochemical properties including size, charge, and the extent of their interaction with the extracellular matrix and soluble factors present in the tumor microenvironment, the investigators wrote.

Attempts to improve tumor cell uptake have included the use of targeting ligands on the surface of the delivery nanoparticles, but while these have been tested extensively preclinically and clinically, their use is limited by heterogeneity in tumoral expression and lack of tumor specificity of the targeted protein.

RNAi cancer drug development can benefit from high-throughput screening approaches for targeting ligands such as aptamers and peptides, which can help identify highly tumor-specific ones, but careful characterization of the ligand-to-nanoparticle ratio is required for clinical translation.

Furthermore, the assessment of delivery efficacy of such tumor-targeted nanocarriers in vivo requires tumor models that mimic the heterogeneity in ligand binding partners observed in human tumors, Sood and the other researchers wrote.

Lastly, once a drug has entered a target cell, the ability of a nanocarrier to mediate the appropriate release of its RNAi payload is paramount, and strategies for endosomal escape must be considered, the team pointed out. "We still need high-throughput techniques for identifying new biomaterials that can promote efficient intracellular trafficking of siRNAs."

In addition to delivery, the success of an RNAi cancer therapy requires careful target selection, Sood said. "In my view, there are very few [targets] that are going to be tumor-specific. A lot of targets that are important for tumor biology are going to have some level of function for normal physiology, as well."

"An ideal target should have a biomarker that can predict the biological and clinical response of RNAi; cause tumor regression upon silencing; and be preferentially expressed in tumors," the MD Anderson group wrote in their report. "Many of the RNAi targets currently being evaluated in clinical trials fall short of these criteria, resulting in complications such as on-target toxicity or lack of an effective strategy for patient selection."

In terms of designing a development strategy for RNAi cancer therapeutics, Sood highlighted the need for a "true biological validation of delivery." Rather than assuming a gene-silencing payload will reach its tissue of interest and knock down its gene target, there needs to be strong evidence confirming delivery and target engagement, he said.

Doing this could include the use of Phase 0 clinical trials, which are designed to examine the pharmacodynamics and pharmacokinetics of an exploratory therapy. Because these studies involve subtherapeutic doses, they yield no safety or efficacy data.

"When coupled with planned surgery after treatment, sufficient tumor samples can be obtained to carefully assess tumor localization of the nanocarriers, as well as the effectiveness of target modulation," according to the Science Translational Medicine report.

In-house cancer drug

As reported by Gene Silencing News last year, Sood and a team from MD Anderson have been developing an siRNA-based cancer drug designed to silence EphA2 — a tyrosine kinase receptor in the ephrin family that plays a key role in neuronal development — and incorporated into the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine, or DOPC.

They had been on track to begin clinical testing last summer, but an undisclosed problem with the manufacturer of the drug's siRNA component forced the researchers to find a new GMP provider. After doing so, the FDA asked the researchers to run a bridge study to generate additional animal data, Sood said.

Dosing in the bridge study has been completed and histopathology work is underway, he said. Once completed, MD Anderson expects to finalize its investigational new drug application for its therapy and begin Phase I testing. The trial is still expected to begin before year-end.

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