Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Here’s an interesting paper in a new journal I recently signed up for, Science and Translational Medicine.  The journal provides little snapshots of how research can potentially be applied to real life disease.  Here’s a snippet from this particular abstract:

“Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations.

We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses.

We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases).”

Now, squamous cell histology tends to be more associated with smokers than non-smokers and chemotherapy has pretty much been the bedrock of treatment for this group, although it should be noted that in general, currently available therapies either have weak activity or are specifically contraindicated, as in the case of bevacizumab.

Compare this with non-squamous histology, particularly adenocarcinomas, where new molecular targeted therapies have begun to evolve that have extended life and the population tends towards more non-smokers.

Essentially, this is almost like treating two different diseases based on the underlying biology, but this is the first time I’ve seen a potential molecular target reported to be associated with squamous cell histology.

The researchers expanded on their finding that FGFR1 may be a useful target in squamous cell lung cancer by taking an FGFR inhibitor (PD173074) and testing it in an appropriate lung cancer model to see what happened:

“The compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1.”

Next, they looked at an in vivo model with the same FGFR inhibitor and found that it induced tumour shrinkage, which is very promising.

Meanwhile, I did a search in the literature and found a research paper from Pardo et al., who looked at the effects of the same FGFR inhibitor in small-cell lung cancer (SCLC), which accounts for approx. 15% of lung cancers, and is more commonly associated with smoking than non-smoking.  In this disease, many patients are chemo-sensitive, but tend to relapse as resistance sets in.  Pardo’s group found that the FGFRi potentiated the effects of cisplatin, the most commonly used chemotherapy in SCLC.

They also found something else of note:

“More dramatically, in H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors.”

Overall, it will be interesting to see what happens with FGFR inhibitors in the clinic going forward.  There are a number in development already, including the following:

  • TKI258 (dovitinib), Novartis
  • AP24534 (ponatinib)
  • AZD4547 (AstraZeneca)
  • FP-1039 (Five Prime)
  • XL999 (Exelixis/GSK) – may have been discontinued

Of note, some of these agents are multi-kinase inhibitors and target other kinases as well, some inhibit FGFR 1 or 2 or 3 and some inhibit FGFR1, 2 and 3, so it will be interesting to see how these shake out.  Advanced solid tumours, leukemia and breast cancer appear to be a common target, but few, if any are considering lung cancer (either squamous NSCLC or SCLC) as a possibility as far as I can see. Weiss, J., Sos, M., Seidel, D., Peifer, M., Zander, T., Heuckmann, J., Ullrich, R., Menon, R., Maier, S., Soltermann, A., Moch, H., Wagener, P., Fischer, F., Heynck, S., Koker, M., Schottle, J., Leenders, F., Gabler, F., Dabow, I., Querings, S., Heukamp, L., Balke-Want, H., Ansen, S., Rauh, D., Baessmann, I., Altmuller, J., Wainer, Z., Conron, M., Wright, G., Russell, P., Solomon, B., Brambilla, E., Brambilla, C., Lorimier, P., Sollberg, S., Brustugun, O., Engel-Riedel, W., Ludwig, C., Petersen, I., Sanger, J., Clement, J., Groen, H., Timens, W., Sietsma, H., Thunnissen, E., Smit, E., Heideman, D., Cappuzzo, F., Ligorio, C., Damiani, S., Hallek, M., Beroukhim, R., Pao, W., Klebl, B., Baumann, M., Buettner, R., Ernestus, K., Stoelben, E., Wolf, J., Nurnberg, P., Perner, S., & Thomas, R. (2010). Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer Science Translational Medicine, 2 (62), 62-62 DOI: 10.1126/scitranslmed.3001451

Pardo, O., Latigo, J., Jeffery, R., Nye, E., Poulsom, R., Spencer-Dene, B., Lemoine, N., Stamp, G., Aboagye, E., & Seckl, M. (2009). The Fibroblast Growth Factor Receptor Inhibitor PD173074 Blocks Small Cell Lung Cancer Growth In vitro and In vivo Cancer Research, 69 (22), 8645-8651 DOI: 10.1158/0008-5472.CAN-09-1576

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