Madeleine Rance

Program: Cancer Biology

Current advisor: David G. DeNardo, PhD

Undergraduate university: Rice University, 2021

Enrollment year: 2022

Research summary
Targeting Tumor-Stromal Signaling to Increase Radiation Efficacy in PDAC

Pancreatic ductal adenocarcinoma (PDAC) is traditionally resistant to radiation therapy (RT); however targeted inhibition of oncogenic KRAS signaling and tumor-stromal crosstalk has the potential to make RT a viable therapeutic option and is actively being tested in clinical trials. My thesis work interrogates the mechanism of dual Focal Adhesion Kinase (FAK) and Mitogen-Activated Protein Kinase (MAPK) inhibition in enhancing RT-induced PDAC cell death and long-term tumor control, and how direct versus downstream inhibition of oncogenic KRAS in this setting shapes tumor responses to therapy. Through profiling of cell signaling and DNA damage pathways, survival studies in murine models, and in-depth characterization of patient samples from an active clinical trial using this treatment approach, I hope to better understand how inhibition of these integrated kinase cascades can improve responses to DNA-damaging therapies in PDAC and provide patients with better long-term outcomes.

Graduate publications
Liu X, Baer JM, Stone ML, Knolhoff BL, Hogg GD, Turner MC, Kao YL, Weinstein AG, Ahmad F, Chen J, Schmidt AD, Klomp JA, Coho H, Coho KS, Coma S, Pachter JA, Bryant KL, Kang LI, Lim KH, Beatty GL, DeNardo DG. 2024 Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy. Sci Transl Med, 16(770):eado2402. PMCID: PMC12376167