An Interview with Dr. Hakim Djaballah | Biowire Spring 2011

Biowire Spring 2011 — Cell Lines — Models of Disease

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Dr. Hakim Djaballah 

Dr. Hakim Djaballah - Director of the High-Throughput Screening Facility at the Memorial Sloan-Kettering Cancer Center (MSKCC) in Manhattan, New York

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High-throughput compound screening for drug discovery has traditionally been the preserve of large pharmaceutical companies, due to the high infrastructure costs and difficulty in accessing compound and clinical libraries. However, the decreasing cost of automation together with changing attitudes within the pharmaceutical industry have seen a recent surge in the number of academic institutes conducting screening operations. Hakim Djaballah, Ph.D., is Director of the High-Throughput Screening Facility at the Memorial Sloan-Kettering Cancer Center (MSKCC) in Manhattan, New York, helping oncology clinicians and researchers harness the power of high-throughput technologies to develop new clinical strategies, as well as furthering our understanding of various types of cancer.

Dr. Djaballah joined MSKCC in 2003 with a wealth of experience in the pharmaceutical and biotechnology sectors, but his interest in biology didn’t begin as early as might be expected. Dr. Djaballah explained:

Dr. Hakim Djaballah:
Although my parents wanted me to be a medical doctor, I actually started out studying architecture in my native Algeria before receiving a government scholarship to go and study overseas. The subject of the grant was Biochemistry with Biotechnology, and, although my knowledge of biological sciences was very limited at the time, I seized the opportunity. After finishing my degree, I went on to do a Ph.D. in enzymology, as I was fascinated by the interaction between enzymes and their inhibitors. It was this interest that took me into the pharmaceutical industry as, in the mid-1990s, I felt it was the best place to continue this kind of work, in the guise of drug discovery.

However, the 2004 launch of the National Institutes of Health (NIH) Roadmap for Medical Research led to a shift in the way early-phase drug discovery was conducted in the U.S.

Dr. Hakim Djaballah:
With the introduction of the NIH Roadmap, many universities began screening programs, setting up dedicated facilities with high-throughput capabilities. Around the same time, there was a paradigm shift in the mindset of the pharmaceutical industry. Where historically there had been a reluctance to share any data or material with collaborators in academia, the changing intellectual property landscape meant pharmaceutical companies began to move away from early-phase drug discovery, as it became easier and cheaper to in-license compounds from third parties. This change in attitude has led to something of a revival for the service industry within the sector, allowing academic laboratories to offer contract services, which today help fund other research initiatives and cover overheads for costly high-throughput equipment. One of the major benefits of this from a clinical perspective has been that academic laboratories are not as bound by financial constraints and business models as pharmaceutical manufacturers, allowing investment in higher-risk projects, particularly for neglected diseases.

The shift in attitudes has been further eased by a migration of expertise to academia, as pharma companies have downsized their screening operations. This experience has been vital to harnessing high-throughput tools in a research environment. For example, the multidisciplinary team in my laboratory provides a consultancy service to other researchers within the MSKCC, allowing scientists to come to us with anything — from a rough concept to an existing assay — which we can then help develop into a high-throughput format. Although simple in theory, this can be difficult to achieve in practice, as it is very easy to introduce bias or artifacts in large-scale studies.

Research at the MSKCC can directly benefit cancer patients in the neighboring Memorial Hospital, ensuring high levels of collaboration between researchers and clinical oncologists.

Dr. Hakim Djaballah:
The close links with clinicians at Memorial Hospital was one of the things that first attracted me to the MSKCC. Researchers in the pharmaceutical industry are insulated from the benefits of their work, only learning about how they have helped patients through reading clinical trials reports and press releases. By comparison, we are almost “on the ground” in the fight against cancer. Most of our collaboration is with clinicians, so we hear first-hand what they are trying to achieve in the clinic, what is working, and what we should be focusing our research on.

Technological development has also had a large influence on the landscape of high-throughput technologies.

Dr. Hakim Djaballah:
A significant change over the last few years has been the push towards high-content screening and cell-based assays. Working with live cells introduces a new level of complexity in terms of minimizing intra- and inter-plate variability; the advantage over biochemical techniques, however, is that you are able to investigate secondary metabolism and downstream effects of a compound or biological agent. This is particularly important when investigating candidate drugs that have failed during clinical trials, and we perform a large number of drug modifier studies to understand why these compounds do not have the expected effects.

A good example of this is drugs against epidermal growth factor receptor (EGFR). This is a very important drug target in many forms of cancer, and there have been some very successful chemotherapy drugs that target the tyrosine kinase activity of EGFR in the past. Unfortunately, due to the high rate of EGFR mutation in many cancers, most of these drugs are now ineffectual, as they no longer bind or inhibit EGFR signaling. To avoid this issue, we need to identify novel molecules that do not target the kinase activity, by preventing internalization or initialization of the signaling cascade. Studying these aspects of EGFR activity cannot be achieved without whole cell systems. These highly uniform reporter cells incorporate specific fluorescent markers which allow us to monitor the effect of candidate compounds on all aspects of EGFR activity — including dimerization, trafficking, phosphorylation, etc. — in their natural environment.

Similarly, KRAS is another important target for cancer therapy that could benefit from using commercially prepared cell lines. Activating mutations in the KRAS gene are linked to several common cancers, making them very difficult to treat. Despite millions of dollars spent on attempting to counteract the effects of these mutations, there are still no effective candidate drugs which directly target KRAS, due to its complex secondary metabolism and signaling. Although there has only been very limited investigation of KRAS using cell-based systems, there have already been some promising results in terms of disrupting KRAS metabolism, and further studies are required to understand how these molecules affect cellular signaling. Use of engineered biosensor cell lines here would allow us to follow signaling and dissect individual pathways, which would be almost impossible in a native cell system. By introducing predefined break points in the signaling cascade, we can prevent the cell’s natural tendency to recalibrate through redundant pathways and feedback loops.

These are just two examples of the potential of this approach, and commercially prepared cell lines are emerging as powerful new tools for investigating secondary metabolism. Technological developments like these greatly simplify large-scale studies and give academic institutes — with or without experience in cell line engineering — the capabilities and flexibility to conduct novel investigations. Where historically pharma companies once dominated, a role for academic institutes in early-phase drug discovery is now firmly established with the help of highthroughput technologies such as these.

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