(P 383) AI ANALYSIS SHOWS ENHANCED CCNG1 ONCOGENE EXPRESSION IN SARCOMA TUMORS AND SUPPORTS THE USE OF DELTAREX-G, A CCNG1 INHIBITOR, AS PLATFORM THERAPY FOR ADVANCED SARCOMA

Objective: CCNG1 is an inducible proto-oncogene which is inactive in normal muscle and connective tissues. Enhanced CCNG1 expression has been reported in a variety of solid malignancies including breast cancer, prostate cancer, hepatocellular carcinoma, colon cancer, and recently, in chondrosarcoma.
Expanded access for DeltaRex-G, a CCNG1 inhibitor, is currently open for an intermediate-size population of advanced sarcoma (NCT04091295), based on Phase 1/2 studies wherein DeltaRex-G demonstrated safety and efficacy in advanced sarcoma (n=59), with four (7%) patients reported to be alive > 10 years from DeltaRex-G treatment initiation. However, additional data is needed to identify patients who will respond favorably to DeltaRex-G therapy.

Objective: To retrospectively analyze CCNG1 expression in tumors of sarcoma patients who are being followed at our Cancer Center.

Methods: Archived formalin-fixed paraffin-embedded (FFPE) tumor specimens (n=65) from patients with sarcoma who are actively followed at the Sarcoma Oncology Research Center were collected, processed, and subjected to RNA sequencing. Briefly, RNA-seq libraries were sequenced to generate 50 million reads, 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 levels in patients of the reference cohort are categorized as low/medium/high, defined by Low = < 17%; Medium-high = 50%-83%; Medium-low = 17%-49%; High = >83%.

Results: Thirty men and thirty-five women, ranging from ages 16 to 87 years were studied. All tumors showed enhanced CCNG1 expression. Fourteen (22%) tumors showed high CCNG1 expression, 18 (28%) tumors showed medium-high CCNG1 expression, 29 (44%) tumors showed medium-low CCNG1 expression and four (6%) tumors showed low CCNG1 expression (Figure 1). Forty-five (69%) patients had metastatic disease and 20 (31%) patients had localized disease. There was no correlation between CCNG1 expression and disease stage. PEComa had the highest (97%) CCNG1 expression, followed by myxoid liposarcoma, synovial sarcoma, clear cell sarcoma, uterine leiomyosarcoma, chondrosarcoma, mesodermal tumor, non-uterine leiomyosarcoma and desmoid tumor.
Six of 65 (9%) tumors were chondrosarcomas, 3 (50%) of which showed medium-high to high (74-88%) CCNG1 expression and 3 (50%) showed medium-low (21-35%) CCNG1 expression. One patient with metastatic chondrosarcoma was treated with DeltaRex-G under the Expanded Access program. This patient had stable disease and a 25% decrease in palpable chest mass while on DeltaRex-G treatment and lived >3 years after DeltaRex-G treatment initiation. AI analysis of his tumor showed 74% (medium-high) CCNG1 expression.

Conclusion: Taken together, these data suggest that (1) 100% of the analyzed sarcoma tumors have enhanced CCNG1 expression, and (2) DeltaRex-G, a CCNG1 inhibitor, may be used as the platform therapy upon which targeted therapies/immunotherapies could be added. Phase 2 studies are planned using DeltaRex-G plus an mTOR inhibitor or a tyrosine kinase inhibitor, with or without immunotherapy, for advanced sarcoma.