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Traversa Founder Says Multi-Targeting Approach Key to RNAi-Based Cancer Drugs

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By Doug Macron

Given the rate at which cancer cells mutate, any successful RNAi-based oncology drug will need to down-regulate a number of targets at the same time, Traversa Therapeutics founder Steven Dowdy told RNAi News this week.

"The problem with cancer is that there are very few [wherein] a single genetic lesion" is entirely responsible for the disease, he said. In the "vast majority" of cases for a given cancer, patients have a small number of mutated genes in common, but also mutations in "a ton of genes that have no relationship to each other."

Meanwhile, if a patient fails primary treatment and the disease recurs, it is often "completely resistant to whatever the [initial] treatment was … [since] the recurrent disease … is entirely different genetically than the primary disease," Dowdy, who is also a researcher at the University of California, San Diego, noted.

As a result, highly selective drugs might work for one patient but not another because of the particular genetic background of each patient's tumor, Dowdy explained. At the same time, existing treatments such as small molecules, peptides, and tumor-suppressor proteins "don't have the ability to evolve" with the cancer.

But Dowdy says RNAi can offer a solution to these problems.

A targeted small-molecule drug, for instance, may only inhibit three to five members of a kinase family and only offer a moderate therapeutic benefit.

Chemotherapeutics and radiation, on the other hand, "work on a wide variety of pathways, inducing DNA damage and … apoptosis, and probably work in the clinic only because they hit so many different pathways," he said. "The down side is that they are not selective and cause a lot of contralateral damage to the patient."

With an RNAi-based drug, however, "you can go after [specific] multiple pathways … [but also] evolve the drug as rapidly as a patient's tumor evolves by … [seeing] what oncogenes have been selected for in the recurrent disease … [and] re-designing RNAs to go back after it."

Dowdy's comments follow a presentation he gave last week at the annual meeting of the American Society of Gene and Cell Therapy in Washington, DC. There he described how his lab developed an siRNA cocktail against glioblastoma that incorporates a proprietary delivery technology.

According to Dowdy, while the brain malignancy is one of the most "devastating" of all cancers, the indication is promising because even a small increase in patient survival, four to six months, for example, is "a really big thing" if the quality of additional life is good.

At the same time, because the tumor is contained within the brain, it is amenable to local drug delivery, which will allow researchers to "learn something about how patients respond and we can tune [therapies] easier" before tackling systemic delivery, he said.

In their experiments, Dowdy and colleagues administered siRNAs targeting epidermal growth factor receptor contained in so-called PTD-DRBD molecules to animal models via an intracranial catheter.

According to Traversa, which holds the exclusive worldwide rights to the PTD-DRBD technology for therapeutic applications, the approach involves protein transduction domains linked with a double-stranded RNA-binding domain.

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An siRNA coated with PTD-DRBD molecules binds to cell-surface proteoglycans, which stimulates macropinocytosis. The drug then enters the cell inside a macropinosome, at which point the pH inside the vesicle drops and the siRNA is released from the PTD-DRBD molecules into the cytoplasm.

"We fixed on the EGF receptor because it's mutated in half of glioblastomas, so that's an easy one to genetically prescreen your patients for," Dowdy said. However, both in culture and in the animal models the EGFR-targeting siRNA "doesn't do very much to induce apoptosis."

Looking to achieve greater efficacy through a synthetic lethal response, the team then screened libraries of pro-survival oncogenes and "hit on AKT2 because that one combined the best in cells we looked at with EGFR," he said. "We had such a massive induction of apoptosis — greater than 95 percent in culture — we went into the animals" and saw significant apoptosis in the tumor but not in surrounding normal tissue.

Despite the increase in apoptosis, knocking down the two targets only resulted in a two-and-a-half-fold increase in longevity, Dowdy noted. The treatment "didn't work quite well enough because the tumor cells that survived — the one percent or two percent — continued to divide. And they're dividing on a daily basis because they are very aggressive tumors, so it doesn't take too many days to catch back up."

To address the issue, the investigators conducted a second screen, keeping "AKT2 and EGFR constant … to see what fishes out," he said. The result was the identification of "a couple of promising genes" that appear to confer an even stronger therapeutic benefit when combined with AKT2 and EGFR alone. Dowdy, however, declined to specify them.

When it comes to an actual RNAi drug, Dowdy told RNAi News that he expects a candidate would need at least five gene targets, which would allow the drug to be highly effective while "encompassing the genetic backgrounds of more patients' tumors then if you just went with three" — a necessity when it comes to achieving statistically significant results in a clinical trial setting.

In the end, "the synthetic lethal approach, no matter what your delivery agent is, is going to be the way you go to treat cancer," he said.

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