Combinatorial Inhibition of Complement Factor D and BCL2 for Early-Onset Colorectal Cancer.

Abstract

The tumor immune microenvironment is distinct between early-onset and late-onset colorectal cancer which facilitates tumor progression. We previously identified several genes, including complement factor D, as having increased expression in patients with early-onset colorectal cancer. This study aimed to assess and validate differential expression of immune genes in early and late-onset colorectal cancer. We also aimed to test known drugs targeting genes increased in early-onset colorectal cancer in preclinical mouse models. Retrospective cohort study with analysis performed using tumor RNA from formalin-fixed paraffin-embedded, cell culture and immunohistochemistry to validate gene expression and gene function. In vivo preclinical tumor study to assess drug efficacy. Oregon Colorectal Cancer Registry was queried to find patients with colorectal cancer. Study included 67 patients with early and 54 patients with late-onset colorectal cancer. Preclinical animal models using the HCT-116 colon cancer cell line were treated with complement factor D inhibitor danicopan and BCL2 inhibitor venetoclax, or with vehicle controls. Elevated RNA signatures using NanoString data was evaluated from the retrospective cohort. When inhibiting these markers in the mouse preclinical model, tumor volume and weight were the main outcome measures. After updating our sample size from our previously published data, we found that complement factor D and BCL2, genes with known function and small molecule inhibitors, are elevated in patients with early-onset colorectal cancer. When inhibiting these markers with drugs danicopan and venetoclax in a mouse model, we found that the combination of these drugs decreased tumor burden but also resulted in toxicity. This study is limited by small sample size and a subcutaneous tumor model. Combinatorial inhibition of early-onset associated genes complement factor D and BCL2 slows growth of early-onset colorectal cancer in a mouse preclinical model. See Video Abstract.