CCNG1 oncogene: a novel biomarker for cancer therapy /gene therapy

Abstract

Background: Metastatic cancer is associated with an invariably fatal outcome. However, DeltaRex-G, a tumor-targeted retrovector encoding a gene-edited dominant-negative CCNG1 inhibitor gene, has induced long term (>10 years) survival of patients with chemo-resistant metastatic pancreatic adenocarcinoma, malignant peripheral nerve sheath tumor, osteosarcoma, B-cell lymphoma, and breast carcinoma. Objective: To evaluate the level of CCNG1 expression in tumors as a potential biomarker for CCNG1 (Cyclin G1-blocking) inhibitor therapy. Methods: CCNG1 RNA expression levels that were previously measured as part of whole genome molecular profiling of tumors (TCGA, N=9161), adjacent “tissues” (TCGA, N=678) and GTEx normal tissues (N=7187) across 22 organ sites were analyzed. Differential expression of CCNG1 and Ki-67 in primary (N= 9161) vs metastatic (N= 393) tumors were also compared in primary (N=103) vs. metastatic (N=367) skin cancers (i.e., melanoma). Statistical Analysis: To detect systematically differential expression of CCNG1 and Ki-67 expression between populations (e.g. tumor vs. normal), unpaired Student's t-tests were performed. Results: Enhanced CCNG1 RNA and Cyclin G1 protein expression were noted in tumors compared to normal analogous counterparts, and CCNG1 expression correlated significantly with that of Ki-67. Moreover, CCNG1 expression tended to be higher than that of Ki-67 in metastatic vs primary tumors. Conclusions: Taken together with the emerging Cyclin G1 / Cdk / Myc / Mdm2 / p53 Axis governing Cancer Stem Cell Competence, this supportive data indicates: (1) CCNG1 expression is frequently enhanced in tumors when compared to their normal analogous counterparts, (2) CCNG1 and Ki-67 expressions are higher in metastatic vs primary tumors, (3) CCNG1 expression is significantly correlated with that of Ki-67, and (4) CCNG1 may actually be a stronger prognostic marker of stem cell competence, chemo-refractoriness, and EMT/metastasis than Ki-67. Phase 2 studies are planned to identify patients most likely to respond favorably to CCNG1 inhibitor therapy.