Artificial intelligence analysis of CCNG1 expression in tumors: A novel biomarker in development for anti-CCNG1 targeted therapy.

Abstract

e15083 Background: Metastatic cancer is associated with an invariably fatal outcome. Therefore, innovative therapies are urgently needed. Although expanded access for DeltaRex-G, a tumor targeted retrovector encoding a CCNG1 inhibitor gene, is on-going for an intermediate-size (n = up to 40) population of advanced sarcoma and pancreatic cancer, more data is needed to identify patients who are likely to benefit from DeltaRex-G gene therapy. In this study, we retrospectively analyzed CCNG1 expression in archived tumors of patients who were previously treated with DeltaRex-G and who are active candidates for DeltaRex-G therapy. Methods: Archived formalin-fixed paraffin embedded (FFPE) tumor specimens (n = 58) from patients with solid malignancies who are actively followed at the Cancer Center of Southern California were collected, processed, and subjected to RNA sequencing. Briefly, RNA-seq libraries were sequenced to generate 50 million reads that were aligned using Kallisto v0.42.4 to GENCODE v23 transcripts with default parameters. Only protein-coding, IGH/K/L- and TCR-related transcripts were retained for downstream processing, resulting in 20,062 protein coding genes. Gene expression was quantified as transcripts per million (TPM) and log2-transformed (Goldman et al., 2020). A gene expression level is presented as low/medium/high depending on the expression level of a such gene in patients of the reference cohort. Low = < 17%; Medium = 17%-83%; High = > 83%. Results: Thirty-two male and 26 female subjects, ages ranging from 16 to 86 years were studied. Forty-nine (84.4%) patients had sarcoma, 3 (5.2%) had urothelial carcinoma, 2 (3.5%) had breast carcinoma, 2 (3.5%) had pancreatic cancer, 1 (1.7%) had Sertoli cell tumor, 1 (1.7%) had adenocarcinoma of appendix. Eleven (19%) tumors showed high CCNG1 expression, 44 (76%) tumors had medium expression, and 3 (5.2%) tumors had low CCNG1 expression. Of note, the tumor of one 14-year survivor with metastatic pancreatic adenocarcinoma in sustained remission had 24 % CCNG1 expression, one 3-year survivor with metastatic chondrosarcoma metastatic to lung with stable disease had 74% CCNG1 expression, one 2-year survivor with early stage HR+ HER2+ breast cancer in remission had 23% CCNG1 expression, and one 2-year survivor with early stage triple negative breast cancer in remission had 74% CCNG1 expression. Conclusions: Taken together, these data indicate that (1) Medium to high CCNG1 expression was found in 95% of tumors studied, and (2) Patients with medium CCNG1 expression who received DeltaRex-G had clinical benefit and are alive in sustained remission or with stable disease 2-14 years from DeltaRex-G treatment initiation, and (3) Prospective studies are warranted to correlate CCNG1 expression level and response to DeltaRex-G therapy.