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

Generally, solid tumors (\u3e400 mm3) 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 64Cu 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

Applying PET to Broaden the Diagnostic Utility of the Clinically Validated CA19.9 Serum Biomarker for Oncology

UnlabelledDespite their considerable advantages, many circulating biomarkers have well-documented limitations. One prominent shortcoming in oncology is a high frequency of false-positive indications for malignant disease in upfront diagnosis. Because one common cause of false positivism is biomarker production from benign disorders in unrelated host tissues, we hypothesized that probing the sites of biomarker secretion with an imaging tool could be a broadly useful strategy to deconvolute the meaning of foreboding but inconclusive circulating biomarker levels.MethodsIn preparation to address this hypothesis clinically, we developed (89)Zr-5B1, a fully human, antibody-based radiotracer targeting tumor-associated CA19.9 in the preclinical setting.Results(89)Zr-5B1 localized to multiple tumor models representing diseases with undetectable and supraphysiologic serum CA19.9 levels. Among these, (89)Zr-5B1 detected orthotopic models of pancreatic ductal adenocarcinoma, an elusive cancer for which the serum assay is measured in humans but with limited specificity in part because of the frequency of CA19.9 secretion from benign hepatic pathologies.ConclusionIn this report, a general strategy to supplement some of the shortcomings of otherwise highly useful circulating biomarkers with immunoPET is described. To expedite the clinical validation of this model, a human monoclonal antibody to CA19.9 (a highly visible but partially flawed serum biomarker for several cancers) was radiolabeled and evaluated, and the compelling preclinical evidence suggests that the radiotracer may enhance the fidelity of diagnosis and staging of pancreatic ductal adenocarcinoma, a notoriously occult cancer

Applying PET to Broaden the Diagnostic Utility of the Clinically Validated CA19.9 Serum Biomarker for Oncology

Despite their considerable advantages, many circulating biomarkers have well-documented limitations. One prominent shortcoming in oncology is a high frequency of false-positive indications for malignant disease in upfront diagnosis. Because one common cause of false positivism is biomarker production from benign disorders in unrelated host tissues, we hypothesized that probing the sites of biomarker secretion with an imaging tool could be a broadly useful strategy to deconvolute the meaning of foreboding but inconclusive circulating biomarker levels. METHODS: In preparation to address this hypothesis clinically, we developed (89)Zr-5B1, a fully human, antibody-based radiotracer targeting tumor-associated CA19.9 in the preclinical setting. RESULTS: (89)Zr-5B1 localized to multiple tumor models representing diseases with undetectable and supraphysiologic serum CA19.9 levels. Among these, (89)Zr-5B1 detected orthotopic models of pancreatic ductal adenocarcinoma, an elusive cancer for which the serum assay is measured in humans but with limited specificity in part because of the frequency of CA19.9 secretion from benign hepatic pathologies. CONCLUSION: In this report, a general strategy to supplement some of the shortcomings of otherwise highly useful circulating biomarkers with immunoPET is described. To expedite the clinical validation of this model, a human monoclonal antibody to CA19.9 (a highly visible but partially flawed serum biomarker for several cancers) was radiolabeled and evaluated, and the compelling preclinical evidence suggests that the radiotracer may enhance the fidelity of diagnosis and staging of pancreatic ductal adenocarcinoma, a notoriously occult cancer

Noninvasive Imaging of PSMA in Prostate Tumors with ⁸⁹Zr-Labeled huJ591 Engineered Antibody Fragments: The Faster Alternatives

Engineered antibody fragments offer faster delivery with retained tumor specificity and rapid clearance from nontumor tissues. Here, we demonstrate that positron emission tomography (PET) based detection of prostate specific membrane antigen (PSMA) in prostatic tumor models using engineered bivalent antibodies built on single chain fragments (scFv) derived from the intact antibody, huJ591, offers similar tumor delineating properties but with the advantage of rapid targeting and imaging. ⁸⁹Zr-radiolabeled huJ591 scFv (dimeric scFv-C_H3; ⁸⁹Zr-Mb) and cysteine diabodies (dimeric scFv; ⁸⁹Zr-Cys-Db) demonstrated internalization and similar <i>K</i>_ds (∼2 nM) compared to ⁸⁹Zr-huJ591 in PSMA­(+) cells. Tissue distribution assays established the specificities of both ⁸⁹Zr-Mb and ⁸⁹Zr-Cys-Db for PSMA­(+) xenografts (6.2 ± 2.5% ID/g and 10.2 ± 3.4% ID/g at 12 h p.i. respectively), while minimal accumulation in PSMA(−) tumors was observed. From the PET images, ⁸⁹Zr-Mb and ⁸⁹Zr-Cys-Db exhibited faster blood clearance than the parent huJ591 while tumor-to-muscle ratios for all probes show comparable values across all time points. <i>Ex vivo</i> autoradiography and histology assessed the distribution of the probes within the tumor. Imaging PSMA-expressing prostate tumors with smaller antibody fragments offers rapid tumor accumulation and accelerated clearance; hence, shortened wait periods between tracer administration and high-contrast tumor imaging and lower dose-related toxicity are potentially realized