ImmunoPET Imaging Identifies the Optimal Timepoint for Combination Therapy in Xenograft Models of Triple-Negative Breast Cancer.

(1) Purpose: The glycoprotein non-metastatic melanoma B (gpNMB) is a type 1 transmembrane protein that is overexpressed in numerous cancers, including triple-negative breast cancer (TNBC). Its overexpression is associated with lower overall survival of patients with TNBC. Tyrosine kinase inhibitors such as dasatinib can upregulate gpNMB expression, which has the potential to enhance therapeutic targeting with anti-gpNMB antibody drug conjugates such as glembatumumab vedotin (CDX-011). Our primary aim is to quantify the degree and identify the timeframe of gpNMB upregulation in xenograft models of TNBC after treatment with the Src tyrosine kinase inhibitor, dasatinib, by longitudinal positron emission tomography (PET) imaging with the 89Zr-labeled anti-gpNMB antibody ([89Zr]Zr-DFO-CR011). The goal is to identify the timepoint at which to administer CDX-011 after treatment with dasatinib to enhance therapeutic efficacy using noninvasive imaging. (2) Methods: First, TNBC cell lines that either express gpNMB (MDA-MB-468) or do not express gpNMB (MDA-MB-231) were treated with 2 µM of dasatinib in vitro for 48 h, followed by Western blot analysis of cell lysates to determine differences in gpNMB expression. MDA-MB-468 xenografted mice were also treated with 10 mg/kg of dasatinib every other day for 21 days. Subgroups of mice were euthanized at 0-, 7-, 14-, and 21-days post treatment, and tumors were harvested for Western blot analysis of tumor cell lysates for gpNMB expression. In a different cohort of MDA-MB-468 xenograft models, longitudinal PET imaging with [89Zr]Zr-DFO-CR011 was performed before treatment at 0 (baseline) and at 14 and 28 days after treatment with (1) dasatinib alone (2) CDX-011 (10 mg/kg) alone, or (3) sequential treatment of dasatinib for 14 days then CDX-011 to determine changes in gpNMB expression in vivo relative to baseline. As a gpNMB-negative control, MDA-MB-231 xenograft models were imaged 21 days after treatment with dasatinib, combination of CDX-011 and dasatinib, and vehicle control. (3) Results: Western blot analysis of MDA-MB-468 cell and tumor lysates showed that dasatinib increased expression of gpNMB in vitro and in vivo at 14 days post treatment initiation. In PET imaging studies of different cohorts of MDA-MB-468 xenografted mice, [89Zr]Zr-DFO-CR011 uptake in tumors (SUVmean = 3.2 ± 0.3) was greatest at 14 days after treatment initiation with dasatinib (SUVmean = 4.9 ± 0.6) or combination of dasatinib and CDX-011 (SUVmean= 4.6 ± 0.2) compared with that at baseline (SUVmean = 3.2 ± 0.3). The highest tumor regression after treatment was observed in the combination-treated group with a percent change in tumor volume relative to baseline (%CTV) of -54 ± 13 compared with the vehicle control-treated group (%CTV = +102 ± 27), CDX-011 group (%CTV = -25 ± 9.8), and dasatinib group (%CTV = -23 ± 11). In contrast, the PET imaging of MDA-MB-231 xenografted mice indicated no significant difference in the tumor uptake of [89Zr]Zr-DFO-CR011 between treated (dasatinib alone or in combination with CDX-011) and vehicle-control groups. (4) Conclusions: Dasatinib upregulated gpNMB expression in gpNMB-positive MDA-MB-468 xenografted tumors at 14 days post treatment initiation, which can be quantified by PET imaging with [89Zr]Zr-DFO-CR011. Furthermore, combination therapy with dasatinib and CDX-011 appears to be a promising therapeutic strategy for TNBC and warrants further investigation.

Comparing PET and MRI Biomarkers Predicting Cognitive Decline in Preclinical Alzheimer Disease.

OBJECTIVE: To compare how structural MRI, Fluorodeoxyglucose (FDG), and Flortaucipir (FTP) PET signal predict cognitive decline in high-amyloid versus low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials. METHODS: In this prospective cohort study, we analyzed data from clinically-normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and PiB-PET acquired within a year, and prospective cognitive evaluations over a mean three-year follow-up. We focused analyses on pre-defined regions-of-interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed using the Preclinical Alzheimer's Cognitive Composite (PACC5). We evaluated the association between biomarkers and cognitive decline using linear-mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials. RESULTS: Data from 131 participants [52 females, 73.98±8.29 years old] were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high-PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high-PiB. DISCUSSION: In preclinical Alzheimer's disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with preclinical Alzheimer's disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.

The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography.

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-ß (Aß) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aß in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, Aß burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked Aß-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global Aß burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer's disease: findings from the Colombia-Boston (COLBOS) biomarker study.

BACKGROUND: Neuroimaging studies of autosomal dominant Alzheimer's disease (ADAD) enable characterization of the trajectories of cerebral amyloid-ß (Aß) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD. METHODS: Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2-3 sessions of Aß (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2-4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers. RESULTS: Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aß accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers. CONCLUSIONS: Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aß burden and neocortical tau accumulation in ADAD.