A third major goal of the Coordinating Center is to provide centralized tissue banking of SCLC samples including cell lines, in vitro and in vivo models, through maintenance of an updated and accessible virtual biospecimen database including tissue and model resources, to facilitate model sharing and distribution among collaborating SCLC investigators. Sharing of these models and resources may allow them to be used to address multiple hypotheses, by multiple investigators, simultaneously, and may minimize duplication of effort in regenerating similar datasets.
Cell lines
A primary resource of the Coordinating Center, immediately relevant to the SCLC research community, is the unique and extensive SCLC cell line collection established and maintained by Drs. Minna and Gazdar at UT Southwestern. This is by far the largest collection of SCLC lines in existence, and includes almost all of the SCLC lines in common use in laboratories around the world. The UTSW team has performed detailed morphological characterization, comprehensive mutational, expression, and proteomic profiling of these lines. Working with Ben Drapkin, new methods have been developed to facilitate creation of SCLC culture models from all of the SCLC PDXs. These cultures will both enable new avenues of research and the Coordinating Center will support distribution and use of these important new SCLC models.
The Coordinating Center helps defray the costs of banking, expansion, and distribution of SCLC lines to members of the Consortium at substantially reduced cost to the individual investigators.
PDX and CDX models
SCLC patient-derived xenografts (PDX) and circulating tumor cell-derived xenografts (CDX) are being generated by multiple investigators hoping to surface insights about the genesis, progression, and spread of cancer, and serve as a reliable testing ground for drug screening and new drug development.. The Coordinating Center will maintain and update a database of available PDX and CDX models, including where possible key patient demographics, tumor stage, treatment history prior to model generation, and response to prior treatments, with links to available sequencing data in our PDX/CDX cBioPortal site. We will promote access to models to investigators in the Consortium through MTA agreements and facilitate access to information about these models through our shared database.
Members of the SCLC Consortium including groups led by Coordinating Center PIs, Drs. Byers (MDACC), Rudin (MSKCC), Minna/Drapkin (UTSW), and Oliver (Duke), have established a collection of over 100 SCLC PDX/CDX models representing de novo chemo-sensitive, primary chemo-refractory, and secondary (acquired) chemo-resistant disease.. As a new shared initiative of the Coordinating Center, we propose an integrated multi-parameter analysis of these available models to further support an integrated dataset of resources for the community. Findings from these analyses will be analyzed with support of the SCLC Consortium Bioinformatics Group and published in one or more papers as a “SCLC PDX/CDX Atlas” to summarize key findings and to serve as a reference for investigators working in SCLC and be made centrally searchable through the Coordinating Center.
Genetically engineered mouse models (GEMMs)
One of the areas of most dramatic recent progress in SCLC research has been the expansion and characterization of genetically engineered mouse models (GEMMs). This has been driven in part by new technology for site-specific genome manipulation. Multiple laboratories have focused on generation of GEMMs assessing the contributions of different mutational drivers in the context of TP53/RB1 loss in SCLC.
The Coordinating Center will create and maintain a comprehensive database of SCLC GEMMs generated within, and to the extent possible beyond, the Consortium. This will include genes targeted, specifics on the targeting constructs, key observations including tumor latency and metastatic potential, histologic images of the resulting tumors, published references, available sequencing and gene expression data, availability of viably frozen fertilized oocytes or embryonic stem cells, and a contact for potential access to each model. This virtual tumor bank of GEMMs will be of substantial utility to investigators within the SCLC Consortium.
Target validation in human tumor microarrays (TMAs)
Dr. Dowlati has assembled a large collection of SCLC biopsies for construction of TMAs, representing de novo chemosensitive, primary chemorefractory, and secondary (acquired) chemoresistant disease. With SCLC Consortium support, this group is continuing to expand and genomically characterize this collection, with an associated IRB-approved prospectively maintained clinical and pathological database including patient demographics and outcomes including response and survival. The availability of these TMAs will provide the SCLC research community with clinically annotated patient tumors that can be interrogated by IHC and used to investigate correlations of IHC staining with patient features, outcomes and genomic alterations.