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Mary Crowley s John Nemunaitis Discusses RNAi and Personalized Medicine

John Nemunaitis
medical director
Mary Crowley Medical Research Center

Name: John Nemunaitis

Position: Executive medical director, Mary Crowley Medical Research Center

Background: Fellow, University of Washington School of Medicine/Fred Hutchinson Cancer Research Center — 1985-1988

Resident/Intern, Boston City Hospital — 1982-1985

MD, Case Western Reserve University — 1982

BA, chemistry/psychology, Case Western Reserve University — 1978

At the Mary Crowley Medical Research Center in Dallas, John Nemunaitis oversees a clinical research site where various investigational cancer drugs are being evaluated. He is also conducting research into the use of personalized therapeutics, including siRNA-based drugs, to treat malignancies.

Recently, he spoke with RNAi News about his work.

Could you give an overview of your lab and what goes on there?

I actually established a phase I clinical research site, and that site involves a fairly large clinic now. It's about a 4,000-square-foot clinic and overall in total our program involves more than 70 research staff. They're exclusively devoted to research. Within the clinic, we manage patients with a variety of novel therapeutics. Our focus has generally been in targeted therapy and vaccines.

We also have a modest laboratory component to the program, which has two focuses. One is to support mechanistic questions dealing with targeted therapeutics, for instance … pharmacokinetics, pharmacodynamics, and gene-expression patterns when [a drug] is injected into tumors. The other part of the laboratory-based program involves a very focused program that we call our precision therapeutics program. In that part of the program we are actually determining genomic and proteomic profiles of patients, and through the process we are comparing the malignant tissue expression of RNA and protein to … normal cells … [from] the same organ. With that work we are able to focus on what proteins and what genes are unique or are signature genes for the malignant tissue.

The work we are doing now is to try to hone in on which proteins in genes are the higher priority targets and which are the lower priority targets. Obviously the higher priority targets are the ones we are going to endeavor to develop therapeutics to. These therapeutics may be [ones] that are already available, or [they may come from] the second part of the program, [which] involves siRNA shut-down. We are involved in construction of various siRNA constructs to shut down the genes we find up-regulated in individual patients.

Is the focus exclusively oncology?

I've got a friend with inclusion body myositis. It's like muscular dystrophy. She is very crippled from this and we are constructing a gene vector to try to treat her. About three years ago it was discovered what mutated gene was [causing] her disorder, and there aren't many programs in that field to build a vector and treat a patient with this kind of syndrome. So we're assisting in that work. But primarily we're [focused on] oncology.

In terms of cancer, do you have a defined focus?

It's pretty broad. The most common cancers we are involved with are lung cancer, prostate cancer, melanoma, and pancreatic cancer.

When you talk about looking at possible therapies including ones that already exist, what do you mean?

Our clinic, by being involved in translational research, has access every year to about 50 or 60 different molecules, none of which are approved by the FDA yet but all of which are undergoing FDA approval development. We can oftentimes, if we have the right information on a patient from the genomic/proteomic profiling, match a patient up to these novel targeted therapeutics.

So you do a lot of work on behalf of drug developers.


In terms of the RNAi aspect, could you talk about where that is in development?

When we identify the dominant expressed genes in a particular patient, we then identify cell lines that have the same gene abnormality and identify the siRNA that has been shown to knock down that gene expression pattern. [Then] we construct a vector — right now we're using adenoviral delivery vehicles — to deliver the siRNA particles. We are also contemplating nanoparticles as well.

Basically we synthesize the vector, which includes the delivery vehicle and the siRNA, and then move forward with validating the effect in cell lines and animal models.

So which cancers are you pursuing the RNAi work in?

There's nothing specific. We have tissue harvested from numerous patients that are undergoing evaluation right now, and we're not focusing on any one particular cancer. It's actually my belief that treatments of the future are going to involve molecular targeting, and molecular targets are going to cut across histologic barriers — the same gene that causes melanoma is highly likely, if it's abnormal in breast cancer, to also predispose that patient to developing breast cancer. We're really not focusing at all on the type of cancer, we're focusing on the molecular patterns that are coming out.

We're also using informatic technology to characterize those proteins that have high network connectivity.

How do you mean network connectivity?

There are many paths that these molecules have within the cell. When turned in one direction they'll cause one function, in another direction they'll [have] another functional effect. So the same protein may have several functions, depending on which path is activated at the time. For those proteins that are most highly connected to different paths, there is good literature support that they are critical proteins in cell survival. We are developing systems that will help us target that.

Do you anticipate these adenoviruses will be used therapeutically, or are these just for the in vitro and animal work?

It's definitely not the ideal delivery vehicle. I think it's effective in vitro and in vivo, but I think for the long run there are some limitations to that delivery vehicle, and that's why we're still exploring others. There are clearly adenoviruses I think are safe that will allow us to move into the clinic … and that's our goal and expectation over the next year, but we're continually evaluating better delivery vehicles.

So you anticipate phase I studies with an RNAi candidate within a year or so?


At that point, would you have identified a particular indication? How would that work?

The way it's going to work is we're going to look at that individual patient. We're actually not trying to build this into a treatment for lung cancer per se or melanoma per se. We're going to identify [a particular] patient.

If you sit back and think yourself, if you had cancer and we told you that, based on 2,000-patient trials, there was a 15-percent response rate [for a drug], which is typically what you hear for lung cancer, you're going to hope you're in that 15 percent. Or if you were told that we're going to look at the genetic pattern that is only unique to your cancer, and we're going to develop a treatment that's only for your cancer — and this hasn't been validated yet — you can see the comfort in realizing that if the targeted therapy is targeted to the genetic profile of your cancer, you're more likely to have an advantage with that therapy.

This is a personalized medicine approach.

That's exactly right.

We're hoping obviously that we're going to find recurrent molecular targets that are going to allow us to treat large subsets of patients either within a particular cancer histologic type or across histology — and by histology I mean lung cancer is one type of histology and melanoma is another histology.

Are you collaborating with any industry partners, or is that the idea for down the road?

We have several collaborations and I have to keep those confidential right now.

Are we talking big pharma/big biotech, or are these [collaborators] actual RNAi companies?

It's both.


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