Initiation and Characterization of Small Cell Lung Cancer Patient-Derived Xenografts from Ultrasound-Guided Transbronchial Needle Aspirates

Abstract

Small cell lung cancer (SCLC) is a devastating disease with limited treatment options. Due to its early metastatic nature and rapid growth, surgical resection is rare. Standard of care treatment regimens remain largely unchanged since the 1980’s, and five-year survival lingers near 5%. Patient-derived xenograft (PDX) models have been established for other tumor types, amplifying material for research and serving as models for preclinical experimentation; however, limited availability of primary tissue has curtailed development of these models for SCLC. The objective of this study was to establish PDX models from commonly collected fine needle aspirate biopsies of primary SCLC tumors, and to assess their utility as research models of primary SCLC tumors. These transbronchial needle aspirates efficiently engrafted as xenografts, and tumor histomorphology was similar to primary tumors. Resulting tumors were further characterized by H&E and immunohistochemistry, cryopreserved, and used to propagate tumor-bearing mice for the evaluation of standard of care chemotherapy regimens, to assess their utility as models for tumors in SCLC patients. When treated with Cisplatin and Etoposide, tumor-bearing mice responded similarly to patients from whom the tumors originated. Here, we demonstrate that PDX tumor models can be efficiently established from primary SCLC transbronchial needle aspirates, even after overnight shipping, and that resulting xenograft tumors are similar to matched primary tumors in cancer patients by both histology and chemo-sensitivity. This method enables physicians at non-research institutions to collaboratively contribute to the rapid establishment of extensive PDX collections of SCLC, enabling experimentation with clinically relevant tissues and development of improved therapies for SCLC patients.

A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo

“…S1A). Notably, the cisplatin and etoposide (C/E) refractory PDX tumor model LU86 (14) had high NEUROD1 and DLL3 expression despite low ASCL1 expression. Collectively, our data show high expression of DLL3 in most of classic SCLC, with lower levels in variant SCLC.…”

Identification and Targeting of Long-Term Tumor-Propagating Cells in Small Cell Lung Cancer

“…PDX and CDX models were generated from extensive stage SCLC patients after ethical approval and patient consent as previously described (Anderson et al, 2015; Hodgkinson et al, 2014). Rb/p53/p130 triple knockout (TKO) mice that model human SCLC have been described extensively before (Gazdar et al, 2015; Jahchan et al, 2013; Park et al, 2011; Schaffer et al, 2010).…”

Patient-derived xenografts: a relevant preclinical model for drug development

“…In particular, the authors reported only one exception to this concordance, as one PDX was resistant to the treatment, while the patient from which this PDX was derived, elicited a good response. They hypothesized that these differences could be due to establishing a more aggressive clone in mice or that additional mutations may have occured during the growth of the PDXs [22]. …”