Kenneth MK Mark, Dartmouth College


This thesis presents a comprehensive, multidisciplinary investigation into the development of personalized chemotherapy treatments for cancer patients, with a focus on predictive biomarkers, drug resistance mechanisms, and the regulation of multidrug resistance proteins. By integrating cutting-edge genomics, advanced molecular biology techniques, and sophisticated computational analysis, we have successfully unraveled the complex biological processes that underpin cancer treatment and drug resistance.

In Chapter 2, we identified and validated the E2F4 signature as a predictive biomarker for chemotherapy response in breast cancer patients. We demonstrated that the E2F4 signature is comparable in performance to other clinically available gene expression assays and should be considered when evaluating potential treatment options. This finding highlights the importance of developing genomic clinical assays that accurately categorize responders from non-responders, providing patients with the most effective therapy for their individual disease.

Chapter 3 investigates the molecular mechanisms underlying the emergence of drug-resistant prion strains and evaluates the efficacy of combination therapy with two oral drugs, IND24 and Anle138b, in scrapie-infected mice. We reported the formation of a new prion strain with specific resistance to combination therapy, suggesting that combination therapy may be less effective in treating prions than conventional pathogens.

Chapter 4 delves into the exploration of drug resistance mechanisms, focusing on the modulation of P-glycoprotein (P-gp) function in human neuroblastoma cells. Through a genome-wide CRISPR/Cas9 knockout screen, we identified novel regulators of P-gp and other multidrug resistance proteins, providing valuable insights into the complex regulation of P-gp expression and potential therapeutic targets for overcoming multidrug resistance.

Collectively, this thesis underscores the importance of a multidisciplinary approach in tackling the challenges of personalized cancer therapy. The findings presented herein contribute to the development of more effective, tailored cancer treatments that improve patient outcomes and minimize chemotherapy-associated toxicity. Moreover, this work emphasizes the need for collaborative efforts across disciplines to translate basic research findings into clinical practice for the benefit of patients undergoing chemotherapy.