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MD Anderson Team Preps for Phase I Testing of RNAi Cancer Drug


Researchers from the MD Anderson Cancer Center are poised to begin a phase I study of a novel siRNA-based therapeutic for cancer, opting to handle the first stage of human testing on their own before pursing an industry alliance, Gene Silencing News has learned.

The trial was expected to have already started, but an issue with the manufacturer of the drug’s siRNA payload led to a slight delay, MD Anderson investigator Anil Sood said. A new manufacturer has been found, however, putting the team on track to begin dosing patients before the end of the year.

The drug comprises unmodified siRNAs targeting EphA2 — a tyrosine kinase receptor in the ephrin family that plays a key role in neuronal development — incorporated into the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine, or DOPC.

According to Sood, EphA2 is a promising drug target because it is highly expressed in a variety of human cancers, particularly ovarian cancer, where its overexpression has been directly linked to poor clinical outcomes. Although its normal role is in neuronal cell migration and development, it can function as an oncoprotein and its suppression has been shown to reduce tumorigenicity in preclinical breast and pancreatic cancer studies.

Importantly, “in most normal adult tissues it is virtually absent,” making EphA2 especially attractive from a toxicology perspective, Sood explained.

Despite its therapeutic potential, EphA2 has largely been undruggable by traditional approaches, he added. There is a small molecule that targets its serine phosphorylation site, but the gene appears to have both phosphorylation-dependent and –independent functions.

“That’s part of the reason that we think an RNAi-based approach may be quite attractive,” Sood said.

The MD Anderson researchers have been working on the drug for a number of years, and in 2005 published in vivo data showing that the EphA2 siRNA/DOPC combination had a therapeutic benefit in an orthotopic mouse model of ovarian cancer.

Specifically, DOPC-formulated anti-EphA2 siRNAs were found to be taken up into tumors following tail vein injection, and reduced expression of their target 48 hours after a single dose, according to the paper, which appeared in Cancer Research. Twice weekly injections of the drug for three weeks resulted in reduced tumor growth — an effect that was “dramatically” enhanced when the treatment was combined with the chemotherapeutic paclitaxel.

Sood and his colleagues have since published additional data on the role of EphA2 in cancer, as well as a 2013 study examining a multistage vector system composed of discoidal porous silicon particles loaded with siRNAs against EphA2 in a metastatic cancer model.

In light of these and other data, the scientists had been aiming to move their RNAi drug into human trials this summer, but an undisclosed problem with the company that had been hired to produce the siRNAs forced them find a new GMP provider, Sood said.

The US Food and Drug Administration then requested a bridge study, he added. “We finally got some funding to make that happen, and we’re going to try to finish that up by November, at the latest,” he said. “The clinical trial should launch right after because everything else is ready.”

The phase I study is designed to enroll 40 patients with advanced solid tumors. The drug will be administered intravenously twice a week for three weeks at a starting dose of 450 micrograms per centimeter. The primary outcome measure of the open-label study is the maximal tolerated dose.

Sood said that he anticipates the study to conclude fairly quickly given MD Anderson’s access to cancer patients, and expects that follow-on studies would focus on specific cancers such as endometrial and ovarian because “clinically, [EphA2] seems to be particularly relevant for those” tumor types.

However, any trials beyond phase I would require the help of a partner.

“At this point, we wanted to work directly with the technology, so we didn’t pursue [industry deals] that aggressively,” Sood said. “In the long run, we would be looking for commercial opportunities.”