ISTM

Following a PhD and post-doctoral work in pharmacology at Cambridge, Alan completed his post-doctoral training at the University of Virginia, USA. Following several years leading drug discovery programs in industry (Johnson & Johnson, Belgium and OSI pharmaceuticals, Oxford) he returned to academic research at the Institute of Cancer Research in London. At Keele, he is module leader and a lecturer on three pharmacology modules and a final year module option on oncology molecular therapeutics. He also makes teaching contributions to the School of Life Sciences and the School of Medicine. He is currently second year tutor.  His research interests focus on discovering new therapeutic targets and drugs for the treatment of ovarian cancer. He has received funding from charities and Research Councils.

ISTM Research themes: 1. Clinical & Diagnostic Science 
2. Bioengineering & Therapeutics

Research interests:

Cancer therapy is entering an exciting era. The fundamental research performed over the last 30 years or so has been translated into new therapies that are now becoming available to treat patients. We are witnessing the arrival of several new “targeted therapies” in the clinic. These targeted therapies differ from traditional chemotherapy by exploiting specific defects in cancer cells. For example, cancer cells may become overly dependent on one particular signalling pathway, and so are susceptible to drugs that target those pathways. Non-cancerous cells may be less dependent on these pathways, and so “normal tissue” may be less sensitive to the effects of the targeted therapies. As a consequence, targeted therapies often have milder side effects than traditional chemotherapy.

But that is not to say that chemotherapy is obsolete. Far from it, in fact. For example, the current therapy for many ovarian cancer patients remains surgery and chemotherapy and this is likely to remain the case until new targeted therapies have been proven in large scale clinical trials to be as effective as chemotherapy. And even after targeted therapies become the preferred treatment option, there will still be a place for chemotherapy. One of the reasons for this is a phenomenon known as drug resistance. After exposure to a drug, cancer cells may become resistant to the effects of the drug. This can occur with both chemotherapy and with the newer targeted therapies. Thus, even when targeted therapies become the standard treatment option, chemotherapy will remain a potent weapon in the clinician’s arsenal to treat disease that has become resistant to a targeted therapy. However, once cancer cells become resistant to chemotherapy, the treatment options may be more limited. One solution to this problem is to develop agents that “reverse” drug resistance – making the cells that are resistant to the drugs sensitive to them once again.

The work in my group is focusing on ovarian cancer.  Many patients initially respond well to chemotherapy, but the emergence of drug resistance may hamper a long-term cure.  To address this, we are pursuing two goals.

Firstly, to identify the molecular mechanisms that lead to drug resistance. This will allow us to identify targets for new drugs that can be used to resensitize drug-resistant cancer cells to chemotherapy. We have conducted a RNAi-based screen, and have identified several genes that appear to contribute to sensitivity to carboplatin and paclitaxel in ovarian cancer cell lines. We are “validating” these as potential drug targets and seeking collaborations to develop drugs inhibiting these targets.

Secondly, we are investigating several new targeted therapies that we anticipate may be used to increase the sensitivity of drug-resistant cancers to chemotherapy. We compare the effects of the chemotherapy alone to the effect of the chemotherapy in combination with a targeted therapy. Where synergy between these two drugs is identified, we seek to identify the underlying molecular mechanism, anticipating that this will help the identification of individual patients who will benefit from combination therapy.

An example of the second approach is shown in the figure below. Cells treated with carboplatin (chemotherapy) are starting to die, but substantially more cells die if they are treated with a combination of carboplatin and ABT-737 (a “BH-3 mimetic” from Abbott laboratories). Chemotherapy can kill cells through a process called apoptosis. ABT-737 prevents the “apoptosis inhibitors” from sequestering the “apoptosis activators” that are generated by carboplatin and that cause cell death by stimulating the “apoptosis effectors” in the mitochondrion. In effect, ABT-737 lowers the threshold for carboplatin to induce cell death by apoptosis.

Collaborators:

Dr Charles Redman, ISTM Keele and University Hospital of North Staffordshire

Dr Nicholas Forsyth, ISTM, Keele.