Pharma Strategy Blog

“Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes–WHSC1L1, LETM2, and FGFR1–is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas.”

Dutt et al., (2011)

This snippet from a paper in PLoSOne caught my attention, because while we have seen a number of molecular targets identified and therapies developed for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma.

Squamous cell carcinomas account for 25% of new lung carcinoma cases and 40,000 deaths per year in the United States, a not inconsiderable number of patients.

This isn’t a new finding per se, as we have discussed FGFR1 amplification in lung cancer previously on this blog.  However, what was also interesting and novel about the paper, is that the authors went on to note:

“Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition.”

In this study, the pan-FGFR inhibitor PD173074 (Pfizer) was used to test whether cell growth was attenuated or not.  There are a number of FGFR inhibitors in development, which we discussed in the last blog post on this topic in December.

All this sounds very encouraging indeed, although there are caveats that should be stated, for example, preclinical research is no guarantee of success in the clinic and amplification of a mutation or gene (as opposed to mutation) does not mean that it is a driver of the disease – it could be a passenger or overexpression as a consequence of other things happening as a result of the tumour proliferation.

Still this is a promising finding well worth exploring, because as the authors rightly point out, “no FDA-approved targeted therapies for squamous cell lung cancer.”

The critical key to exploring mutations, amplifications and targeted therapies in the clinic going forward will be to have well designed iterative phase II trials with very careful patient selection based on the known biology to tease out the patients most likely to respond rather than catch-all studies where the chances of finding responders over non-responders is much lower.

Why do this?  Overall, I think it is better to have high response rates in a small subset than a low response rate in an unselected population where people who have no chance of doing well are exposed to the systemic side effects unnecessarily.

We can see this trend clearly emerging with the well designed trials ELM4-ALK translocations for crizotinib, for example.  Interestingly, ALK and lung cancer mutations (seen in adenocarcinomas) are very much in the news this month, following some excellent data at ASCO for Pfizer’s crizotinib that augers well for FDA approval and Ariad announcing that they are progressing their dual ALK-EGFR inhibitor, AP26113, into the clinic. Preclinically, this agent has also been shown to inhibit the T790M mutant that is resistant to EGFR inhibitors.  You can read more from Ariad on their EGFR-ALK inhibitor.

Oddly, Ariad’s other drug in phase II clinical development for CML, ponatinib, also inhibits FGFR and FLT3 as well as BCR-ABL, the critical target in CML; this will be an interesting company to watch out for over the next few years.

References:

Dutt A, Ramos AH, Hammerman PS, Mermel C, Cho J, Sharifnia T, Chande A, Tanaka KE, Stransky N, Greulich H, Gray NS, & Meyerson M (2011). Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer. PloS one, 6 (6) PMID: 21666749