Generation of a Circulating Tumour Cell (CTC)-Derived eXplant of a NeuroEndocrine Carcinoma of unknown origin

Melissa Frizziero, Elaine Kilgour, Kathryn Simpson, Kristopher Frese, Juan Valle, Mairead Mcnamara, Caroline Dive

Research output: Contribution to conferenceAbstractpeer-review

Abstract

Introduction:
NeuroEndocrine Carcinomas (NECs) are rare yet lethal diseases; they’re mostly metastatic and with limited treatment options. Whilst progress has been made in understanding the biology of Small Cell Lung Cancer (SCLC), a NEC from the lung, research in NECs from other anatomical sites is still lagging behind. In Small Cell Lung Cancer (SCLC), circulating tumour cells (CTCs) have proven effective for the generation of patient-relevant mouse models; termed CTC-Derived eXplants (CDX).

Material and method:
A pilot prospective study is on-going to assess feasibility of CTC and circulating tumour DNA (ctDNA) analysis, and CDX generation in patients with advanced stage NEC (lung origin excluded) undergoing palliative chemotherapy. CTCs are enumerated before and during treatment using CellSearch (CS) which selects for EpCAM-positive CTCs. RosetteSep enriched CTCs from parallel blood samples are implanted in immunodeficient mice to attempt CDX generation.

Results and discussion:
Twenty-one patients were recruited by Feb-21. CS-CTCs were present in most pre-treatment samples (15/21; 71.4%); mean 56.9 CTCs, median 2, range 0-685 (per 7.5mL of blood). CDX generation was successful from a pre-treatment CTC sample from a patient with a metastatic NEC of unknown origin who responded to platinum/etoposide (P/E). Histopathological analysis of the CDX tumour showed a small cell NEC morphology with Ki-67 positivity of 80%, and wide-spread expression of synaptophysin, chromogranin A and CD56, matching the donor patient’s biopsy. Additional IHC revealed CK20 positivity and TTF1 negativity in both the CDX and donor patient’s biopsy, raising the possibility of a Merkel Cell Carcinoma of unknown origin. The absence of TP53 and RB1 mutations in pre-treatment ctDNA also supports this hypothesis, which is being further explored. The CS-CTC count in a parallel blood sample was 1/7.5mL of blood, suggesting that EpCAM-negative tumourigenic CTCs are present in the donor patient’s bloodstream. The CDX showed in vivo sensitivity to P/E, mirroring the treatment response in the donor patient. CDX-derived cells have been successfully cultured and display a growth pattern (floating clusters) similar to that of ‘classic’ SCLC cell lines.

Conclusion:
Here, we report on the generation of the first CDX of a NEC of unknown origin. This CDX recapitulates the biology of the original donor patient’s tumour, holding the potential to serve as an avatar to guide future treatment of this donor.
Original languageEnglish
Publication statusPublished - 2021
EventEuropean Association for Cancer Research 2021 (virtual conference) -
Duration: 9 Jun 202112 Jun 2021

Conference

ConferenceEuropean Association for Cancer Research 2021 (virtual conference)
Period9/06/2112/06/21

Keywords

  • Neuroendocrine carcinoma
  • Circulating tumour cells
  • CDX

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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