NANETS2023 Basic Science (28 abstracts)
ATRX: a novel predictive biomarker for peptide receptor radionuclide therapy in neuroendocrine tumors
M. Hammad 1 , Z. Lee 2 , S.L. Asa 3 , K. Aboody 1 , A. Mahipal 4 , D. Bajor 4 , S. Chakrabarti 4 , J.E. Selfridge 4 , L.M. Ocuin 5 , R.S. Hoehn 2 , J. Winter 5 , J. Ammori 5 , J. Hardacre 5 , S.H. Tirumani 2 , L.E. Henke 6 & A. Mohamed 4
1Department of Stem Cell Biology and Regenerative Medicine, City of Hope National Medical Center & Beckman Research Institute, Duarte, CA; 2Department of Radiology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; 3Department of Pathology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; 4Department of Medicine, Division of Hematology and Medical Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; 5Department of Surgical Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; 6Department of Radiation Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH. Corresponding author: Amr Mohamed, MD, [email protected]
Background: Peptide receptor radionuclide therapy (PRRT) including Lutetium177 (Lu177) has changed the treatment landscape of metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). There is a subgroup of patients who are resistant or develop resistance after initial success to PRRT, indicating that accurate predictive markers are urgently needed to identify who will benefit from PRRT. We hypothesize that expression of ATRX (Alpha Thalassemia and Mental Retardation X-linked) could predict patients who might respond to PRRT.
Methods: A retrospective review at UH Seidman Cancer Center included clinical and radiological data review for patients with metastatic well-differentiated GEP-NETs who have received PRRT. We identified patients based on their response and performed bulk RNA sequencing (RNA-Seq) using RNAs extracted from formalin-fixed, paraffin-embedded tissue; candidates identified were then examined with IHC staining. We also examined the basal expression of ATRX in BON1 and QGP1 cell lines using western blot and qPCR analysis. Based on these results we then knocked out (KO) ATRX in the BON-1 cell line, exposed the KO cells to irradiation and then measured cell viability by Calcein AM viability day once daily for 3 days after irradiation. Statistical graphs were used to evaluate the hypothesis.
Results: Patient samples demonstrated that PRRT non-responders have higher ATRX expression compared to responders. BON1 cells exhibited a high basal ATRX expression; greater and more rapid cell death was seen in irradiated ATRX KO cells compared to non-irradiated KO cells and irradiated cells with normal ATRX expression. This cytotoxic effect peaked on day 3 post-irradiation, with 60% of cells in the irradiated KO group having died, which is 3 times and 1.5 times the cytotoxicity for the ATRX KO only and irradiation groups, respectively.
Conclusion: Overexpression of tissue ATRX mRNA in NETs is correlated with resistance to PRRT. Tissue ATRX mRNA and/or protein expression may be a useful biomarker for monitoring the response to PRRT. The addition of tissue ATRX expression measurement to future clinical trials as an exploratory biomarker seems warranted and may bring a novel targeted therapy to improve PRRT outcome.
Abstract ID 23662
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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