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F. Di Giacomo
MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
MO01.10 - Integrated molecular characterization of Patient-Derived Tumorgrafts as innovative model for clinical management of Non-Small Cell Lung Cancer (ID 2919)
10:30 - 12:00 | Author(s): F. Di Giacomo
Lung cancer is the leading cause of death for cancer. Although impressive diagnosis and therapeutic achievements have been recently obtained, critical issues remain open. It is now believed that the generation of reliable preclinical models will provide the basis for new discoveries and to validate the clinical efficacy of known and novel compounds.
From 2010 to 2013, we have generated a biorepository of 190 frozen tumor samples and matched normal lung tissues, peripheral blood mononucleate cell collections, serum and plasma samples from patients who had undergone surgery with curative intentions (stage Ia, Ib, IIa mainly). This data set has been enriched with 480 additional archival tumors. The entire library, encompassing all major histotypes [adenocarcinomas (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)], covers the heterogeneous landscape of NSCLC. All tumors were characterized by immunohistochemistry (IHC) (TTF1, SPA, MUC5AC, CK5, CDX2, VILLIN, p53, p63, p16, ABCA3 and SOX2) and molecular analyses (EGFR, KRAS, BRAF and PI3K mutations). Considering that the pathogenetic role of many lesions is only in part elucidated, and that many lung cancers lack targetable mutations, we generated patient-derived tumorgrafts (PDTs), engrafting fresh and/or frozen tumor fragments in highly immunocompromised mice (NSG). Successfully grown tumors were propagated up to the third generation (T3). Primary versus PDT features were studied by histology, IHC and molecular profiling [Single Nucletoide Polimorphism (SNP), WES, RNA sequencing (RNAseq)] and HTP proteomic analyses.
A known distribution of mutations within the first 300 ADCs samples (17% EGFR; 35% KRAS; 2% PI3K; 1% BRAF) was observed. 26 PDT lines (9 adenocarcinoma, 14 squamous, 2 sarcomatoid, 1 mixed) have been propagated, showing that the time growth average required from engraftment was significantly longer for the ADC-lines than SCC-lines (ADC-lines 20 weeks vs SCC-lines 11 weeks). We demonstrated the strong correspondence of primary cancers and PDT tumors, highlighting primary tumor’s specific features or biomarkers. The SNP analysis has revealed the occurrence of stress engrafment events (i.e. loss of heterozigosity LOH) at the first PDT passage; these alterations, once acquired remain relatively stable along later passages. Preliminary data from proteomic profiling are demonstrating stable Phospho-Tyrosine-Kinase profiles in primary tumors compared to PDTs, reinforcing the idea that this PDT tumors aren’t drifted so far from primary cancer architecture.
To improve bio-molecular stratification, pathological classification and clinical treatments of lung cancers, a multiparametric approach is needed; this should depict a complete and integrated cancer network in each cancer patient. Nonetheless, reliable preclinical models are required to define the best treatment choices and to overcome the boundaries between basic knowledge and the clinical requirements.
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