Targeting the Acidic Microenvironment of Prostate Cancer Using Chemical Shift-Based, Clinically Translatable Hyperpolarized 13C MRI Biomarkers
Abstract
The goal of this proposal is to develop new imaging agents to distinguish small and indolent tumors from aggressive tumors, which are resistant to treatments with surgery, radiation, hormones, or chemotherapy and will ultimately prove fatal. Our new agents are isotopically labeled versions of carbonated molecules, dicarboxylic acids, and biological buffers. Solid tumors typically have a rapid cell division and consequently develop and acidic microenvironment. We hypothesize that the use of our new chemical probes would serve to detect the slight change of pH in the microenvironment of tumors. Moreover, interstitial acidity is thought to induce resistance to chemotherapeutic agents, and many small molecule agents targeting acid transporters are currently under development. Therefore, acidic extracellular pH represents both a potential biomarker as well as a therapeutic target. Several magnetic resonance techniques have been developed for the purpose of imaging acidic interstitial pH, including methods based on magnetic resonance spectroscopy (MRS). A central requirement for these techniques is accuracy, since the pH change between healthy and diseased tissues is small. In the MRS strategy, a chemical probe that has a known chemical shift response to pH changes is administered systemically. The chemical shift is then measured using MRS, and by comparison to a standard curve, the pH can be determined. While these previous techniques have provided important insights in animal model systems, they have various limitations, including long scan time, requirement for high dose of probe administration, and in some cases, poor spatial resolution. Hyperpolarized 13C MRS is an emerging technology that has been applied to numerous chemical substrates and successfully translated to the clinic for use in men with prostate cancer. However the molecules that serve as sensors still suffer from limitations. The agents we target are promising, owing to properties considered in their initial design coupled with the vast experience of their use. Distinguishing between the different types of prostate cancer is an important problem for clinical oncologists since the treatment varies widely between tumor subtypes. We are convinced our method will help oncologists to rapidly decide which treatment is the most appropriate. This method is non-invasive and based on the use of biocompatible molecules, which decreases the risks of unpredictable side effects and consequently improves the compliance of the patients and the quality of their life. This consideration elevates the likelihood of near-term clinical translation. The training component of this proposal is an extension of the relationship I have built with Drs. Wilson, Flavell, and Kurhanewicz. The proposal will consolidate our collaboration, while further advancing my career to my ultimate goal of supervising an academic laboratory at a research center or university in the USA. Because of Drs. Wilson, Kurhanewicz, and Flavell?s expertise in preclinical pharmacology, imaging, and prostate cancer cell biology, I expect that their mentorship will round out my training, allowing me to become a leader in new biomarker and therapy development for prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710352
Entities
People
- Céline Taglang
Organizations
- United States Army
- University of California, San Francisco