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To Be or Not to Be Small-Cell Lung Cancer?

Lung cancer, one of the most deadly killers worldwide, comprises two histological subtypes: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). SCLC and NSCLC are classified as different diseases because of their distinct biology and genomic abnormalities; therefore therapeutic strategies for these two pathologies differ substantially. A recent review published by The Lancet Oncology has challenged the commonly accepted view of NSCLC and SCLC as two separated diseases highlighting the importance of improving diagnostic tools and encouraging the use of a personalized medicine approach.

SCLC accounts for 15% of lung cancer cases while NSCLC manifests as adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma and represents the remainder 85% of lung cancer cases. Although these diseases originate within the same tissue they are viewed and treated as very distinct pathologies. SCLC treatment depends on stage of disease with chemotherapy and radiation being widely used options. Most forms of NSCLC instead benefit from the use of targeted therapies that inhibits the function of EGFR, a surface receptor aberrantly activated in this type of cancer.

The common view of SCLC and NSCLC as separate diseases, deriving from distinct cellular lineages, has been recently challenged by a team of researchers headed by Dr. Engelman from the Massachusetts General Hospital Cancer Center who collated unexpected findings about a subset of NSCLCs with mutated EGFR that recurs as SCLC once resistance to EGFR tyrosine kinase inhibitors (TKIs) has developed. Most of the cases described follow a similar pattern: patients who were diagnosed EGFR mutated NSCLC were treated with TKIs and initially showed a favorable response. However, after a progression-free survival of 10–38 months they came back with disease progression, and repeated biopsies confirmed transformation to SCLC. Evidences of EGFR mutant cancers that become resistant even to new third generation TKIs are increasing, suggesting that although EGFR inhibition may not be absolutely essential for SCLC transformation, it favors or accelerates this transition.

Examples of transformation that are independent of acquisition of resistance to EGFR inhibitors have been reported as well. In a correspondence addressed to Dr. Engelman and coauthors and published by the same journal the case of an 80-year-old man with lung adenocarcinoma carrying EGFR mutation (exon 19 deletion) was discussed as an example of transformation that occurred before the initial treatment with TKIs. In this patient the disease had progressed during 1 month of TKIs therapy and later, repeated biopsies of the metastatic and primary lesions identified a pathological transformation from adenocarcinoma to SCLC, which retained the same EGFR mutation.

One of the proposed mechanisms of transformation alternative to EGFR inhibition is the loss of RB1, a powerful tumor suppressor gene whose function has been shown to be frequently lost when EGFR mutant NSCLCs evolve into SCLC. RB-1 is required for regulating cellular division and its loss drive cells into continuous multiplication.

Since the therapeutic approaches for SCLC and NSCLC differ substantially, the authors of both reports urge the identification of non-invasive methods for detecting potential disease transformation that could replace repeated biopsy. They presented and discussed the interesting idea of using small-cell serum markers as early predictors of transformation to capture tumor heterogeneity and overcome the limitations of biopsies of a single lesion, which might miss a different metastatic lesion that has transformed.

Crown Bioscience has developed the largest portfolio of commercially available NSCLC and SCLC models within our HuPrime® and PDXact collections of patient derived xenografts (PDX), with each model representing the biological characteristics and genetic diversity of the original tumor and patient. Our PDXs can be used to run HuTrial, Phase II-like mouse avatar trials to identify the responder population before entering late phase human clinical trials. Our HuSignature, and HuMark translational platforms further allow our clients to identify molecular biomarkers and genetic signatures of response before entering the clinic.

We have also recently validated the use of liquid biopsies for detecting circulating tumor cells (CTCs) and their genetic characterization helped the identification of the responder population in our pre-clinical models.

Crown Bioscience can be contacted at busdev@crownbio.com for further information on our lung cancer PDX models, our translational platforms or for any other enquiry.


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