In July, investigators at Arizona State University and Texas A&M received a two-year grant from the National Cancer Institute to develop a microfluidics-based platform for screening combinatorial drug treatments. The amount of the award for FY 2008 is $210,215.
The goal of this work is to develop an integrated screening technology based on well plates and microfluidic cell arrays for the discovery of small molecules from combination treatments and 20 to 50 novel candidates that enhance cell death in combination with death receptor agonists.
To those ends, the researchers are developing a cancer-based screening technology that integrates traditional well plate-based screening and microfabrication and microfluidics technologies for the identification and mechanistic evaluation of small molecules that sensitize cancer cells to death receptor-mediated apoptosis.
The investigators will use 96-well-plate screening methods to screen a library of approximately 2,500 US Food and Drug Administration-approved drugs to identify lead candidates. They then will use microfluidic cancer cell arrays to perform a secondary screen of leads identified in that primary screen.
Principal investigators Kaushal Rege, an assistant professor in the department of chemical engineering at Arizona State University, and Arul Jayaraman, an assistant professor in the department of chemical engineering at Texas A&M University, spoke with CBA News this week about their work and their plans for the technology that they are developing.
Please give me a little background on this work.
Arul Jayaraman: Basically, our work involves trying to use a microfluidic-based platform for identifying interactions between drug molecules. That is the long-term goal of this work — to be able to identify what combinations of drugs would work in order to tackle specific cancers, or any other disease for that matter.
This is more of a proof-of-principle type project where we want to use microfluidic methods to generate the different drug combinations. One of the things about combination therapies is that the combinations that need to be screened are large, and when you are trying to screen a library of 100 molecules, for example, suddenly the combinations you need to screen become really large and hard to handle.
Our approach is that we plan to use microfluidics as a way to facilitate such high-throughput combinatorial studies. Microfluidics offers a way to mix different compounds or candidate molecules, easily expose them to cancer cells or any target cell line, and then investigate the effect of that drug combination on the cells’ survival.
What we hope to establish is that screening combinatorial treatments, facilitated by microfluidics, is a viable and feasible alternative for screening molecule libraries.
Kaushal Rege: Another thing that we have discussed in the proposal itself is that we envision this as being a very good tool for secondary screening. It can be integrated eventually into some of the existing robotics platforms out there that companies would use for screening molecules.
We certainly discuss some of the advantages of going with microfluidic and microfabricated platforms for drug screening, and combination drug screening in particular.
Can you use this to screen potential monotherapies?
KR: Yes, the device that we designed can be used to screen just single agents, but the overall advantage is that we designed the device in such a way that we can screen combinations of compounds as well.
How does this improve upon current methods to screen combination therapies?
KR: Let me explain that a little bit, in that it is not necessarily a fixed-dose combination that we are looking at. What we are looking at is an array of combinations. So you can have multiple combinations of drug one times multiple combinations of drug two. So its not just one combination versus another.
In a single device, you can screen this whole array of concentrations.
What is your timeline for this project?
AJ: We just recently started, but we already have some prototypes that we are working on, and that we are testing right now. We expect that by the end of year one, and this may be a little optimistic, we will have a fully functional platform that can screen a 10 x 10 array of conditions. Then the trick is to integrate that further.
KR: We have designed the device based on two different generations, as we call it. The first-generation device is rather simplistic and it can be done within a few months to a year from now, in the sense that we already have the device working, and we are validating the device with some combinations.
In the second year of the project we will focus on some of the complicated microfluidics that may be complicated in the beginning, but will facilitate the throughput later on.
That is the second part of the project, which will be integrated into what we are saying will be the second-generation device.
Will this be something that you plan to commercialize or identify a commercial partner with which to further develop it?
KR: We are both talking to the IP departments at our respective institutions. We have started that ball rolling.
Do you think that this is something where you would work with a partner to commercialize the technology, or you would spin out a company to market it?
KR: We have not really worked out the details on that yet. I am talking to IP people here and attorneys to see what we can best do in collaboration with Texas A&M. We just do not have a firm answer on that yet.
AJ: It’s too preliminary. Our first goal is to establish the IP part of it and make sure that the respective parties are OK with that, and then once that happens, we can think of other modalities.
Has this work been published?
AJ: In this format it has not been published. The concept is out there and there are parts of it that are out there in different shapes and forms, but the way in which we are proposing to do this, to our knowledge, has not been published. For example, scientists have known about the use of microfluidics to generate a range of concentrations for quite a few years, at least 10 years, I would say.
But the design that we are proposing to generate an array of conditions, that has not yet been published.
KR: As in many cases, everything is in the details. Some of the enabling concepts, I would say, are in the literature, but I do not think it will be evident, even to people working in the area, to put them together for screening drug combinations. I think that is where the novelty will lie.
We’ll see what we hear from our respective IP departments, but so far the feedback has been pretty positive regarding the landscape. This is just based on a couple of meetings that I had with them, however.
What is the next step in this project?
KR: There are multiple things that we are doing. One is making sure that the first generation device works robustly, for which we are looking at established combination treatments. The second part, which is happening in parallel, involves developing our own new combination treatments, for which we are looking at new drugs for certain types of cancers.
We are trying to integrate both of these — once we have the device working the way we want it to, and we have some of these combinations that we want to test with the device. I think they go hand-in-hand, where we look at kind of merging both of these things.