The performance of current prostate cancer (PCa) imaging is unsatisfactory. Clinicians need a diagnostic imaging approach that reveals primary PCa location, its clinical significance and predicts its malignant potential. Furthermore, the detection of recurrent disease is often difficult after definitive treatment, hampering effective local salvage treatments. Also given new systemic treatment option in metastatic PCa, the selection of treatment options and monitoring of treatment success early (via imaging) may benefit patients and reduce costs by avoiding ineffective systemic treatments. Using metabolomic profiling, tissue levels of sarcosine have been identified to be elevated in primary PCa with further increase during PCa progression. Our preclinical data show that micro-PET with 11C- sarcosine outperforms 11C-choline in prostate cancer tumor models. Based on these encouraging data, we hypothesize that PET imaging with 11C-sarcosine is able to identify primary and metastatic PCa for staging and response evaluation in humans. The study goals are to conduct a pilot trial using 11C- sarcosine as PET tracer for PCa and to evaluate the uptake mechanisms and metabolic pathways of 11C-sarcosine in human PCa tissue. Objectives: (1) Development of 11C-sarcosine as PET tracer for human use, (2) conduction of a pilot study with 11C-sarcosine in human prostate cancer subjects to collect preliminary efficacy and to assess feasibility, (3) measurement of the human radiation dosimetry of 11C-sarcosine, and (4) assessment of sarcosine uptake regulation in human prostate cancer tissue samples. Study design: The current 11C-sarcosine production will be modified according to GMP standards (aim 1). To assess aim 2, human prostate cancer subjects will undergo PET/CT imaging with 11C-sarcosine and 11C-choline to directly compare biodistribution and tumor uptake. The study will include PCa subjects undergoing prostatectomy (group A) and recurrent and/or metastatic disease (group B). The human radiation dosimetry of 11C-sarcosine is determined in normal volunteers (aim 3).
For aim 4, tumor tissue samples will undergo standard pathology and target metabolite analysis based on liquid-and-gas- chromatography mass spectrometry techniques to specifically assess the metabolic pathways for sarcosine in prostate cancer and to compare these with 11C-sarcosine uptake measurements. Impact: If successful, this study would lead to a novel molecular imaging strategy for PCa, differentiating PCa from normal benign tissues, and overcome current limitation in staging and monitoring prostate cancer treatments.
In 2014 an estimated 233,000 men will be newly diagnosed with prostate cancer (PCA) and almost 30,000 men will die from PCA in the United States. One in seven men will develop invasive prostate cancer during life, highlighting the tremendous relevance of PCA for the health care system. Despite remarkable progress in medical imaging, the ability to detect and accurately stage primary prostate cancer is still limited. The current diagnostic approach based on PSA screening and subsequent prostate biopsy identifies a large subgroup of individuals with cancers that pose little threat to life, but may trigger unnecessary treatment, while at the same time too many aggressive cancers remain undetected at early stages. A diagnostic imaging approach that reveals prostate cancer location, its clinical significance and predict its malignant potential would therefore be a tremendous clinical asset for staging and management of primary prostate cancer. Similarly, medical imaging fails to provide sufficiently accurate guidance for the clinical management of recurrent and metastatic prostate cancer. Neither MRI nor the elsewhere widely used 11C/18F choline PET tracers identify recurrent disease early enough for salvage curative treatment. While several new (expensive) systemic treatment options are available in the metastatic disease state, their effectiveness cannot be predicted or assessed early to select optimal treatment options for individual patient. Given that our metabolomic profiling data reveal elevated tissue levels of sarcosine in primary prostate cancer and during prostate cancer progression to metastatic disease, and given that preclinical PET imaging data show increased tumor visualization in prostate tumor models, 11C-sarcosine may be the answer to the above clinical need.
| Piert, Morand; Shao, Xia; Raffel, David et al. (2017) Preclinical Evaluation of 11C-Sarcosine as a Substrate of Proton-Coupled Amino Acid Transporters and First Human Application in Prostate Cancer. J Nucl Med 58:1216-1223 |
| Xing, Junhao; Brooks, Allen F; Fink, Dylan et al. (2017) High-Yielding Automated Convergent Synthesis of No-Carrier-Added [11C-Carbonyl]-Labeled Amino Acids Using the Strecker Reaction. Synlett 28:371-375 |
