All of the key advances made in the prevention, detection, and treatment of cancer over the last several decades would not have been possible without the significant investment in cancer research – research that moves from basic discoveries of the molecular drivers of cancer to translation of these findings into the clinic to development of large-scale clinical trials.
During the month of May, we celebrate National Cancer Research Month.
We will highlight recent research accomplishments from the University of Chicago Medicine Comprehensive Cancer Center investigators and how our patients have directly benefited from broad investment in cancer research. We will also include a banner from the American Association for Cancer Research’s month-long campaign to raise awareness of the need for research funding.
As a kickoff to this series, we share four recent studies that shed light on the mechanisms by which tumor cells respond to various types of therapies and innovative strategies to develop more effective treatments.
Deciphering the Keys to Cancer Therapeutic Response
A major challenge facing oncologists is the lack of tools for predicting how patients will respond to specific chemotherapeutic agents or targeted therapies in terms of both eradicating their disease and preventing side effects.
Researchers at the University of Chicago Medicine Comprehensive Cancer Center are tackling this problem from multiple angles, including dissection of the genetics and molecular pathways involved in determining therapeutic sensitivity, as well as developing more effective novel therapy combinations. The goal is to translate these pre-clinical and early-stage clinical findings into clinical practices to aid oncologists in decision-making and, ultimately, produce better outcomes for patients.
In a recent paper published in Science Translational Medicine, a research team led by Philip Connell, MD, associate professor of radiation and cellular oncology, and including Ralph Weichselbaum, MD, D.K. Ludwig Professor of Radiation and Cellular Oncology, explored the role of DNA repair pathways in determining patient response to platinum-based chemotherapy drugs.
They developed a novel methodology for quantifying the efficiency of DNA repair pathways and generated a recombination proficiency score (RPS) based on the expression of four genes (Rif1, PARI, RAD51, and Ku80) involved in DNA repair.
Analysis of patients with breast and non-small cell lung cancer revealed that tumors with low RPS were associated with higher levels of gene mutations, adverse clinical features and decreased survival rates.
Importantly, the ability of the RPS to predict the sensitivity to platinum-based chemotherapy was validated, specifically that treatment significantly improved the 5-year overall survival in low-RPS tumors but not in high-RPS tumors.
Therefore, the RPS may be a new, powerful tool to help oncologists select therapies that would be the most effective and appropriate for individual patients. (Pitroda et al., Sci Transl Med 6:229ra42, 2014)
Two collaborative projects have been recently published that specifically address the impact of an individual’s genetic make-up on the response to chemotherapy and uncovered new targets to modify drug sensitivity.
A study by Eileen Dolan, PhD, professor of medicine, and involving Kevin White, PhD, professor of human genetics, identified novel relationships between protein factors, genetic variants and sensitivity to paclitaxel and cisplatin, two commonly used chemotherapeutic agents.
Beyond their large-scale approach analyzing hundreds of signaling proteins and transcription factors and using dozens of cell lines, the research team functionally validated two genes, SMC1A and ZNF569, which are associated with sensitivity to cisplatin and paclitaxel, respectively. (Stark et al., PLoS Genet, 10:e1004192, 2014)
Stephanie Huang, PhD, assistant professor of medicine, and Nancy Cox, PhD, professor of medicine, collaborated to develop an integrative approach to combine genome-wide genetic, gene expression, and microRNA expression to determine the molecular basis for carboplatin and cisplatin sensitivity.
They identified five single-nucleotide polymorphisms, or small gene changes, associated with 10 miRNAs and the expression level of 15 genes, all of which were linked to carboplatin sensitivity.
Functional studies confirmed that two candidates, ABCD2 and miR-30d, robustly controlled the response of ovarian cancer cells to cisplatin, and did so by working together. (LaCroix et al., BMC Genomics 15:292, 2014)
Maciej Lesniak, MD, professor of surgery, and his research team have been exploring ways to optimize the therapeutic response for glioblastoma multiforme (GBM), the most common form of malignant brain tumors in adults, and one that is particularly challenging to treat.
They recently reported the effectiveness of a novel triple-combination immunotherapy in GBM preclinical models. Specifically, the combination of inhibiting indoleamine 2,3 dioxygenase 1 (IDO), CTLA-4 and PD-L1, all of which control tumor-infiltrating immune cells, resulted in potent antitumor activity and long-term survival in animal models.
This study provides critical proof-of-concept evidence to pursue this therapeutic strategy in patients with GBM in early-phase clinical trials. (Wainright et al., Clin Cancer Res Apr 1 Epub ahead of print, 2014)