Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer.

Abstract

Generally, solid tumors (>400 mm(3)) are inherently acidic, with more aggressive growth producing greater acidity. If the acidity could be targeted as a biomarker, it would provide a means to gauge the pace of tumor growth and degree of invasiveness, as well as providing a basis for predicting responses to pH-dependent chemotherapies. We have developed a (64)Cu pH (low) insertion peptide (pHLIP) for targeting, imaging, and quantifying acidic tumors by PET, and our findings reveal utility in assessing prostate tumors. The new pHLIP version limits indiscriminate healthy tissue binding, and we demonstrate its targeting of extracellular acidification in three different prostate cancer models, each with different vascularization and acid-extruding protein carbonic anhydrase IX (CAIX) expression. We then describe the tumor distribution of this radiotracer ex vivo, in association with blood perfusion and known biomarkers of acidity, such as hypoxia, lactate dehydrogenase A, and CAIX. We find that the probe reveals metabolic variations between and within tumors, and discriminates between necrotic and living tumor areas.

• Authors: Nerissa Therese Viola-Villegas, Sean D Carlin, Ellen Ackerstaff, Kuntal K Sevak, Vadim Divilov, Inna Serganova, Natalia Kruchevsky, Michael Anderson, Ronald G Blasberg, Oleg A Andreev, Donald M Engelman, Jason A Koutcher, Yana K Reshetnyak, Jason S Lewis
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 20 Pg. 7254-9 (May 20 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24785505 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, Neoplasm
• Chelating Agents
• Gallium Radioisotopes
• Heterocyclic Compounds, 1-Ring
• Isoenzymes
• Membrane Proteins
• Radiopharmaceuticals
• pHLIP protein
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases

Topics

• Animals
• Antigens, Neoplasm (metabolism)
• Carbonic Anhydrase IX
• Carbonic Anhydrases (metabolism)
• Cell Line, Tumor
• Chelating Agents (pharmacology)
• Gallium Radioisotopes (pharmacology)
• Heterocyclic Compounds, 1-Ring (pharmacology)
• Humans
• Hydrogen-Ion Concentration
• Hypoxia
• Isoenzymes (metabolism)
• L-Lactate Dehydrogenase (metabolism)
• Lactate Dehydrogenase 5
• Male
• Membrane Proteins (pharmacology)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Phenotype
• Positron-Emission Tomography
• Prostatic Neoplasms (diagnostic imaging)
• Radiopharmaceuticals (pharmacology)