Life is about stories, events and even coming back full circle sometimes. I experienced that moment of déjà vu this morning on opening a link to an article that a colleague kindly sent from Avrum Spira’s lab that was published in Science Translational Medicine, simply titled:

Airway PI3K Pathway Activation Is an Early and Reversible Event in Lung Cancer Development

Many moons ago I completed my doctoral thesis on the early detection of lung disease at King’s College London. Much of it was about the impact of smoking on the airways. Halfway through the 3 year MRC grant, while listening to some evening lectures at the Brompton Hospital by Prof Peter Barnes and Steven Holgate, I realised that the real answer lay in understanding the biochemical and molecular biology pathways… only we were working on the physiology of breathing patterns.  An a-ha moment to be sure.

Still, I was able to pick up differences in breathing patterns between healthy non-smokers and those who were medium to heavy smokers.

The unaswered question, though, was why?

Prof Barnes loved to put up charts of pathways with a black background and different targets meticulously coded with coloured highlighter pens… PDE, leukotrienes, cholinergic mast cell activation and many others sprang to life as he walked students through the various possible mechanisms where pharmaceutic intervention might have a role to play.

Fourteen years on, I don’t think a cure for asthma has been found and many of those pathways have not yielded much in chronic obstructive pulmonary disorder (COPD) either, except perhaps anti-cholinergics such as tiotropium bromide (Spiriva) as maintenance therapy in controlling bronchospasm. My suspicion at the time was that the mechanisms underlying inflammation and aggravation of the airways by chemicals was key to unlocking why some people get lung cancer, others COPD and still others were unaffected.

Fast forward to the article.

Last week, Gustafson et al., published a paper in Science Translational Medicine suggesting that phosphatidlyinositol 3-kinase (PI3K) pathway activation is an early event in the development of lung cancer.

In particular, they found elevated PI3K in the airways of smokers with lung cancer compared to smokers without lung cancer:

Source: Science Translational Medicine

The researchers validated their hypothesis that activation of PI3K is an early event in the development of lung cancer by comparing the cytology of airway epithelium from healthy smokers to those with mild to moderate airway dysplasia that reflects an early noncancerous abnormality, often considered a precancerous state.  The theory being that if smokers with dysplasia have higher PI3K pathway activation then this would suggest P13K pathway activation precedes the development of lung cancer.

The results showed increased expression of genes induced by PI3K pathway in high risk smokers and those with lung cancer. This may well explain the dysplasia and inflammation seen, which you can see in the chart below:

Source: Science Translational Medicine

One key question this research raises, but does not answer, is whether P13K pathway inhibitors have a role to play in the treatment of lung cancer?

Thinking about my doctoral research on early detection of lung disease, this statement made me sit up and pay attention:

“These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalized approaches to chemoprevention and therapy.”

Whoa!  Early detection of lung cancer?

Forgive my excitement and enthusiasm, but it’s kind of cool to see read that scientists can actually find something biochemically active that may represent a new target for intervention fifteen years after you realise that early detection might be possible, if only you knew what the target might be.  That’s the stuff of <goosebumps.

PI3-kinase is a fascinating target that quite a few biotech and pharma companies are looking at as a potential mechanism for the treatment of cancer. I’ve written and blogged extensively on this (see here, here, here, here and here) for some examples.

Interestingly, many of the PI3-kinase compounds in early clinical development are investigating the agents in leukemias, lymphomas, breast, ovarian and gastric cancer or basket solid tumour trials. Some of the interesting small biotech companies in this field include Calistoga, Semafore and Exelixis and big pharma is represented by Merck, Novartis, sanofi-aventis and Roche.  Only two agents seem to be specifically looking at non-small cell lung cancer (NSCLC) though – no prizes for guessing which ones:

1. Everolimus (Novartis), a combined mTOR-PI3 kinase inhibitor, in phase II development.
2. GDC-0941 (Roche/Genentech), which is looking at whether the new agent adds anything to the current standard of care in NSCLC ie carboplatin + paclitaxel + bevacizumab and is currently recruiting patients.

Novartis (a client) have completed their trial according to the clinical trials database, so it will be interesting to see if there are any data at ASCO in June that will help us learn more about the disease.

If the data from the Novartis or Roche trials are positive, the companies may be very interested to read Gustafson et al.’s suggestion:

“Our work further suggests that additional lung cancer chemoprevention trials either targeting the PI3K pathway or measuring airway PI3K activation as an intermediate endpoint are warranted.”

Chemoprevention is a big word in cancer research.

In two weeks time, I’ll be at the AACR annual meeting in DC (do let me know if you are going and would like to meet up for a coffee and chat) and hopefully there will be more about this fascinating pathway then.  Watch this space!

Gustafson, A., Soldi, R., Anderlind, C., Scholand, M., Qian, J., Zhang, X., Cooper, K., Walker, D., McWilliams, A., Liu, G., Szabo, E., Brody, J., Massion, P., Lenburg, M., Lam, S., Bild, A., & Spira, A. (2010). Airway PI3K Pathway Activation Is an Early and Reversible Event in Lung Cancer Development Science Translational Medicine, 2 (26), 26-26 DOI: 10.1126/scitranslmed.3000251