By Caroline Dive, CBE, PhD, FMedSci,
and Kris Frese, PhD
Small cell lung cancer (SCLC) is aggressive, disseminates early, and has a dismal prognosis.1 Its genomic landscape which reveals little in the way of obvious druggable targets, presents a significant challenge. One obstacle to a more comprehensive understanding of the biology and behavior of this recalcitrant tumor has been the difficulty in routinely obtaining tumor biopsies of sufficient quantity and quality for productive research. Biopsies obtained at diagnosis are unlikely to represent the disease following relapse, which often occurs within only a few months after treatment with platinum-based doublet chemotherapy. As new therapeutics for SCLC will most likely be studied after debulking with first-line chemotherapy in a trial setting, it is the tumor biology with acquired chemotherapy resistance that we must better understand and target.
Several research groups, including that of the authors of this article, have demonstrated that in SCLC, the prevalence of circulating tumor cells (CTCs), detected using the EpCAM capture–based CellSearch platform, is high relative to other tumor types.2,3 It was subsequently shown that, following CTC enrichment from a simple 10 mL peripheral blood draw, CTC-derived tumors could be generated when implanted subcutaneously in the flanks of immune-compromised mice.4 These CTC-derived explant (CDX) tumors exhibited typical SCLC morphologic and histochemical properties, and their genomes correlated with those of the donor patient’s CTCs. CDXs are highly proliferative and faithfully reflect the donor patient’s depth and duration of response to platinum–etoposide double chemotherapy. The CDX approach has an advantage in that it can be implemented at the pre-treatment baseline and can be repeated when disease progresses after chemotherapy, which is when a tumor biopsy to generate a patient-derived xenograft is much more difficult to obtain.
Benefits and Applications
CDXs are now being derived in multiple research laboratories worldwide. The value of CDX tumors for SCLC research has been exemplified.5,6 There is now, to our knowledge, an extensive panel of over 60 SCLC CDX models in existence, encompassing baseline CDX from patients with disease that goes on to be chemosensitive or chemorefractory (progressing within 90 days of chemotherapy administration) and from patients with limited and extensive disease. Demonstrating the utility of CDX to investigate targeted therapies, baseline and progression CDX models have been used to examine the combination of the PARP inhibitor olaparib with the Wee1 inhibitor AZD1775. Although a range of responses were seen to this drug combination in 10 CDX models in vivo and/or in short-term cultures made from disaggregated CDX tumors, this combination demonstrated superior efficacy to chemotherapy for the majority of samples.7 The olaparib/Wee1 combination cured multiple mice bearing one patient’s CDX, and this “super-responder” model is providing insights for predictive biomarker discovery. Notably, a durable response seen at baseline was absent in the paired serial model made at progression, suggesting that, for this combination, durable benefit would be more likely in a clinical trial designed to facilitate early administration.
Using the CTC iChip technology,8 Drapkin et al.5 derived 17 CDX models, including paired pre- and post-treatment models from a patient recruited to a clinical trial. Importantly, this study showed that matched patient-derived xenograft s and CDXs derived from solid and liquid biopsies at baseline were faithful to the patients’ tumors in terms of shared mutations, supporting the low degree of clonal heterogeneity previously reported for SCLC.9 This study also showed that, in the patient for whom serial CDXs were generated, these serial models accurately recapitulated the evolving drug sensitivities of the donor patient’s disease to combination treatment with olaparib and temozolomide.5
CDX tumors can also be disaggregated, allowing short-term cultures to be derived.7 Gene expression profiling of these cultures reveals relatively few changes in protein-coding genes, many of which are reversed when cells are reimplanted in mice. Furthermore, these tumors grow with similar kinetics to those that have never been exposed to plastic, indicating that brief culturing under permissive conditions does not select for more aggressive clones. These short-term cultures can be subjected to genetic manipulation via lentiviral infection and facilitate chemical and genetic screens, as well as mechanism-based hypothesis exploration. CDX cultures can also be modified to reporters that facilitate assessment of in vivo disease burden and metastatic dissemination.
CDX can now be added to the research toolkit, augmenting established cell lines, patient-derived xenografts, and genetically engineered mouse models to support exploration of SCLC biology (including, for example, mechanisms of vasculogenic mimicry10) to test novel treatments, identify mechanisms of chemoresistance, and develop predictive and pharmacodynamic biomarkers that can be translated for clinical implementation as CTC-based assays.11 With a range of new candidate treatments entering SCLC clinical trials, CDXs derived from patients on clinical trials will facilitate studies to understand responses and resistance complemented by CTC-based biomarkers. This recalcitrant tumor has defeated all attempts to improve patient outcomes. It is our hope that the CDX approach, by allowing a more routine examination of the biology of SCLC throughout its disease course, will lead to new insights and next steps toward the collective overall goal of finding ways to extend patient survival. ✦
About the Authors: Prof. Dive is the deputy director of and a senior group leader at the Cancer Research UK Manchester Institute and professor of pharmacology at The University of Manchester. Dr. Frese is a clinical and experimental pharmacology preclinical team lead at the Cancer Research UK Manchester Institute.
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