Abstract 3658: LINE1 ORF1P is a druggable target for early onset colorectal cancer and cancer prevention

Colorectal cancer is the second most common cause of cancer deaths in the United States. In recent years, there has been a surprising increase in early-onset colorectal cancer, making it the leading cause of cancer-related death in young men under 50 years old. With aging as the primary risk factor for human cancers, we argue that anti-aging agents are a viable option for cancer prevention. One common scientific approach in anti-aging is partial cell reprogramming using Yamanaka factors. However, there is concern that activation of stem cell-specific transcription factors may promote tumor formation. Transposable element LINE1 ORF1p expression has been reported to be elevated in both aging and cancer across multiple species and cancer types, making it a promising target to address both aging and cancer simultaneously. Interestingly, we discovered that LINE-1 expression is higher in the serum of early-onset colorectal cancer patients and hypothesize that ORF1p activation accelerates aging and promotes cancer progression. Using artificial intelligence-based small molecule drug screenings from 10 million compounds, we identified two LINE1 ORF1p targeting drugs, B7 and C1, that significantly kill cancer cells but not normal cells in vitro. A surface plasmon resonance (SPR) assay confirmed high binding affinity of B7 and C1 to the ORF1p protein. Consistently, B7 and C1 inhibited retrotransposition using a LINE1-specific retrotransposition reporter assay. When we transplanted ORF1p high-expressing human cancer cells into NSG mice, treatment with B7 or C1 significantly inhibited tumor growth by 57% (C1) and 75% (B7) and improved survival of tumor-bearing mice compared to vehicle control. Additionally, we designed an antibiotic-free nanoplasmid DNA vaccine targeting ORF1p. We confirmed its high expression level in vitro and then performed electroporation of the DNA vaccine using Ichor's TriGrid™ intramuscular electroporation technology. In a prophylactic model, we vaccinated the mice three times before inoculating them with syngeneic mouse colon tumor cells. The vaccination significantly delayed tumor onset and inhibited tumor growth by more than 50%. In conclusion, our data suggest ORF1p as a druggable target and a promising DNA vaccine target for both cancer prevention and treatment in human early-onset colorectal cancer. Citation Format: Dan Zhao, Yifei Wang, Praveen Neeli, Yong Li. LINE1 ORF1P is a druggable target for early onset colorectal cancer and cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3658.