Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer.
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.
Program in Molecular Pharmacology and Chemistry, andDepartments of Radiology.
Nerissa Therese
NT
Viola-Villegas
Program in Molecular Pharmacology and Chemistry, andDepartments of Radiology.
Sean D
SD
Carlin
Medical Physics.
Ellen
E
Ackerstaff
Departments of Radiology.
Kuntal K
KK
Sevak
Departments of Radiology.
Vadim
V
Divilov
Neurology, and.
Inna
I
Serganova
Medical Physics.
Natalia
N
Kruchevsky
Department of Physics, University of Rhode Island, Kingston, RI 02881; and.
Michael
M
Anderson
Program in Molecular Pharmacology and Chemistry, andDepartments of Radiology,Neurology, and.
Ronald G
RG
Blasberg
Department of Physics, University of Rhode Island, Kingston, RI 02881; and.
Oleg A
OA
Andreev
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520 donald.engelman@yale.edu lewisj2@mskcc.org.
Donald M
DM
Engelman
Program in Molecular Pharmacology and Chemistry, andDepartments of Radiology,Medical Physics,Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
Jason A
JA
Koutcher
Department of Physics, University of Rhode Island, Kingston, RI 02881; and.
Yana K
YK
Reshetnyak
Program in Molecular Pharmacology and Chemistry, andDepartments of Radiology, donald.engelman@yale.edu lewisj2@mskcc.org.
Jason S
JS
Lewis
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D005710:Gallium Radioisotopes / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010641:Phenotype; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging*; D019275:Radiopharmaceuticals / Q000494:pharmacology*
D000951:Antigens, Neoplasm; D002614:Chelating Agents; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D007527:Isoenzymes; D008565:Membrane Proteins; D019275:Radiopharmaceuticals; C533201:pHLIP protein; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases