REACH

Rationale. While pancreatic ductal adenocarcinoma (PDAC) is not a common cancer, it is one of the most lethal and hard-to-treat tumors with a 5-year survival rate of 10-11%. Apart from the addition of FOLFIRINOX and nab-Paclitaxel, the standard of care for PDAC has not substantially changed over the past 30 years, and overall survival (OS) continues to hover around 6-12 months. The latter is primarily due to the inherent chemo/radio-resistance of this tumor and the presence of highly tumorigenic and chemoresistant stem-like cells, known as cancer stem cells (CSCs), with unique transcriptional features under epigenetic and epitranscriptomic regulation. However, PDAC epitranscriptomics and their translational potential remain vastly unexplored.
Hypothesis. Based on emerging evidence, we hypothesize that the epitranscriptomic landscape [regulated by N6-Methyladenosine (m6A) marks on mRNAs] of PDAC tumor cells and CSCs modulates key transcripts that drive PDAC chemoresistance, and targeting m6A with inhibitors of the “writer”, “eraser” and “reader” enzymes of these m6A marks will render PDAC cells and CSCs highly sensitive to standard chemotherapeutics.
Aims. The Main Aim of REACH is to make epitranscriptomic-based therapies in PDAC a clinical reality, by altering the epitranscriptomic nature of PDAC tumor cells and CSCs with targeted therapies to modulate m6A marks, the main epitranscriptomic modification that shapes the PDAC transcriptional landscape. Specifically, REACH will use functionalized tumor-tropic nanoparticles (NPs) to both penetrate the impermeable PDAC stroma and home to PDAC cells to deliver epitranscriptomic modulators of m6A “writers”, “erasers” and/or “readers. The ability of our approach to sensitize PDAC tumors to chemotherapy will be tested in advanced preclinical animal models.
Methods. Patient-derived xenografts (PDXs) and PDX-derived primary 3D cultures are powerful tools with translatable potential to dissect the role of m6A marks in PDAC, discover novel targets, and test NP-delivery. Thus, we will take advantage of these pre-clinical models as well as patient samples to test our functionalized NPs, coated with a PDAC tumor-cell homing antibody (anti-CAPRIN-1) and loaded with the aforementioned epitranscriptomic modulator(s) for their ability to enter the tumor, recognize PDAC cells and CSCs, effectively modulating the epitranscriptomic and mRNA landscape of the tumor and thus sensitize PDAC to chemotherapy.
Expected results and potential impact. As the social, economic and healthcare impact of PDAC are significant, novel ideas are required to make this tumor more sensitive to currently available therapies. If successful, REACH will make PDAC chemo-sensitive, providing an effective therapeutic solution to a currently unsolvable health care problem, with a true possibility of extending the overall survival of PDAC patients, even of those with advanced disease, who currently rely only on palliative treatment options.