Todd Peterson

Background It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME‐HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME‐HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects. Methods We developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME‐HAP …

Prolonged inflammatory expression within the central nervous system (CNS) is recognized by the brain as a molecular signal of “sickness”, that has knock‐on effects to the blood–brain barrier, brain‐spinal barrier, blood‐cerebrospinal fluid barrier, neuro‐axonal structures, neurotransmitter activity, synaptic plasticity, neuroendocrine function, and resultant systemic symptomatology. It is concurred that the inflammatory process associated with cancer and cancer treatments underline systemic symptoms present in a large portion of survivors, although this concept is largely theoretical from disparate and indirect evidence and/or clinical anecdotal reports. We conducted a proof‐of‐concept study to link for the first time late non‐CNS cancer survivors presenting chronic systemic symptoms and the presence of centralized inflammation, or neuroinflammation, using TSPO‐binding PET tracer [11C]‐PBR28 to visualize …

BackgroundRadiopharmaceuticals capable of targeting the fibroblast activation protein have become widely utilized in the research realm as well as show great promise to be commercialized; with [68Ga]Ga-FAPI-46 being one of the most widely utilized. Until now the synthesis has relied on generator-produced gallium-68. Here we present a developed method to utilize liquid-target cyclotron-produced gallium-68 to prepare [68Ga]Ga-FAPI-46.ResultsA fully-automated manufacturing process for [68Ga]Ga-FAPI-46 was developed starting with the 68Zn[p,n]68Ga cyclotron bombardment to provide [68Ga]GaCl3, automated purification of the [68Ga]GaCl3, chelation with the precursor, and final formulation/purification. The activity levels produced were sufficient for multiple clinical research doses, and the final product met all release criteria. Furthermore, the process consistently provides < 2% of Ga-66 and Ga-67 at the …

BackgroundAlterations in glutamine metabolism have been proposed to play critical roles in cancer cell growth and survival. Mitochondrial glutaminase is a key enzyme in the conversion of glutamine to glutamate and is highly expressed in colorectal cancer (CRC). CB-839 is a potent and selective inhibitor of glutaminase, and synergistic activity in vitro and in vivo have been seen with CB-839 in combination with chemotherapy. We also demonstrated synergy between CB-839 and anti-EGFR monoclonal antibody therapy in multiple human CRC cell lines and that the combination could overcome anti-EGFR resistance. Given this preclinical data, we conducted a phase I/II study evaluating CB-839 with panitumumab. Our phase I results were presented earlier; here we present phase II.MethodsStudy enrolled adult patients with metastatic, RAS wildtype CRC who achieved at least stable disease from prior anti-EGFR …

L‐ergothioneine (ERGO) is a potent antioxidant with cytoprotective effects. To study ERGO biodistribution and detect oxidative stress in vivo, we report an efficient and reproducible preparation of [11C]‐labeled ERGO PET radioligand based on protecting the histidine carboxylic group with a methyl ester. Overall, this new protection approach using methyl ester improved the chemical yield of a 4‐step reaction from 14% to 24% compared to the previous report using t‐butyl ester. The [11C]CH3 methylation of the precursor provided the desired product with 55 ± 10% radiochemical purity and a molar activity of 450 ± 200 TBq·mmol−1. The [11C]ERGO radioligand was able to detect threshold levels of oxidative stress in a preclinical animal model of Alzheimer’s disease.

Altered metabolism is a hallmark of cancer. In addition to glucose, glutamine is an important nutrient for cellular growth and proliferation. Noninvasive imaging via PET may help facilitate precision treatment of cancer through patient selection and monitoring of treatment response. l-[5-11C]-glutamine (11C-glutamine) is a PET tracer designed to study glutamine uptake and metabolism. The aim of this first-in-human study was to evaluate the radiologic safety and biodistribution of 11C-glutamine for oncologic PET imaging. Methods Nine patients with confirmed metastatic colorectal cancer underwent PET/CT imaging. Patients received 337.97 ± 44.08 MBq of 11C-glutamine. Dynamic PET acquisitions that were centered over the abdomen or thorax were initiated simultaneously with intravenous tracer administration. After the dynamic acquisition, a whole-body PET/CT scan was acquired. Volume-of-interest analyses …

(R)‐[18F]MH.MZ ([18F]MH.MZ) is a promising positron emission tomography (PET) radiotracer for in vivo study of the 5‐HT2A receptor. To facilitate clinical trials, a fully automated radiosynthesis procedure for [18F]MH.MZ was developed using commercially available materials on the iPhase Flexlab module. The overall synthesis time was 100 min with a radiochemical yield of 7 ± 0.9% (n = 3). The radiochemical purity was greater than 99% for [18F]MH.MZ with a molar activity of 361 ± 57 GBq/μmol (n = 3). The protocol described herein reliably provides [18F]MH.MZ that meets all relevant release criteria for a GMP radiopharmaceutical.

Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood–brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer’s disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [11C]PIB, [11C]ERGO, and [18F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy.

EphA2 receptor tyrosine kinase (RTK) is highly expressed in breast tumor cells across multiple molecular subtypes and correlates with poor patient prognosis. In this study, the potential role of EphA2 in this clinically relevant phenomenon is investigated as metastasis of breast cancer to bone is a major cause of morbidity and mortality in patients. It was found that the EphA2 function in breast cancer cells promotes osteoclast activation and the development of osteolytic bone disease. Blocking EphA2 function molecularly and pharmacologically in breast tumors reduced the number and size of bone lesions and the degree of osteolytic disease in intratibial and intracardiac mouse models, which correlated with a significant decrease in the number of osteoclasts at the tumor–bone interface. EphA2 loss of function in tumor cells impaired osteoclast progenitor differentiation in coculture, which is mediated, at least in …

Background Despite a 2009 recommendation from the AMA that disaster medicine and public health response training should be implemented in medical schools, anywhere from 31% to 47% of medical education programs lack a formalized disaster medicine curriculum. A need for disaster medicine response training for University of Alabama medical students in an appropriately socially distanced format was identified during the COVID‐19 pandemic. Methods Our emergency medicine faculty in collaboration with the Federal Emergency Management Agency Center for Disaster Preparedness (FEMA CDP) created and implemented a novel virtual disaster medicine and pandemic response course for third‐year medical students at the University of Alabama at Birmingham (UAB). The course was administered via a teleconferencing platform (Zoom, Zoom Video Communications, Inc.) in spring 2020 to more than …

Ergothioneine (ERGO) is a rare amino acid mostly found in fungi, including mushrooms, with recognized antioxidant activity to protect tissues from damage by reactive oxygen species (ROS) components. Prior to this publication, the biodistribution of ERGO has been performed solely in vitro using extracted tissues. The aim of this study was to develop a feasible chemistry for the synthesis of an ERGO PET radioligand, [11C]ERGO, to facilitate in vivo study. The radioligand probe was synthesized with identical structure to ERGO by employing an orthogonal protection/deprotection approach. [11C]methylation of the precursor was performed via [11C]CH3OTf to provide [11C]ERGO radioligand. The [11C]ERGO was isolated by RP-HPLC with a molar activity of 690 TBq/mmol. To demonstrate the biodistribution of the radioligand, we administered approximately 37 MBq/0.1 mL in 5XFAD mice, a mouse model of Alzheimer …

A novel detection concept for high-energy gamma rays for medical applications has been tested using the coincident detection of the Cherenkov photons from Compton-electrons in an optically transparent radiator material. Such detection capability would facilitate imaging of the distribution of certain targeted alpha-emitter therapies and also could be applicable in range verification for proton therapy, which are both connected to prompt gamma emission. To prove the concept, a demonstrator experiment at energies below the MeV scale was conducted: measurements with a 22 Na gamma source emitting two 511-keV photons were performed and the Cherenkov light from Compton and photo electrons in UV transparent polymethyl metacrylate (PMMA) was detected in coincidence. Using a silicon photomultiplier (SiPM) array and fast FPGA-based read-out electronics, efficiency in the order of 0.1 % was …

Wolfgang A. Weber and Johannes Czernin Scientific discoveries published in The Journal of Nuclear Medicine over the past 60 years have shaped the practice of medicine and form the foundation for the future of nuclear medicine, molecular imaging, and theranostics. Nuclear medicine now provides diagnostic, prognostic, predictive, and intermediate endpoint biomarkers in oncology, cardiology, neurology, and infectious and inflammatory disorders. Whole-body target expression can be quantified and used for predicting therapy response. Treatment-induced metabolic changes serve as early prognosticators of therapy effectiveness. At the same time, technologic advances such as total-body and hybrid PET/MR imaging are revolutionizing the diagnostic capabilities of PET systems. Artificial intelligence (AI), machine learning, and radiomics have become trendy buzzwords, but their true value for clinical decision …

630Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Targeted therapies such as epidermal growth factor receptor (EGFR) neutralizing monoclonal antibodies (ie. cetuximab and panitumumab) are approved for patients with advanced wild-type (WT) RAS CRC with a reported response rate of 10-23%. However, drug resistance is common and limits treatment options. Alterations in glutamine (Gln) metabolism have been shown to play a critical role in cancer cell growth and survival. Recently, drugs targeting glutaminolysis have been developed for the treatment of a variety of cancers. Preclinically, we have demonstrated that combination of EGFR inhibition and blockade of Gln metabolism results in improved cytoreduction of CRC cells in vitro and in vivo. This data formed the basis of the therapeutic combination used in the current clinical trial. However, there …

Rationale Lymphangioleiomyomatosis (LAM) cells have high utilization for glutamine due to downstream effects of the activated mTOR signaling pathway. We hypothesized that 11C-labeled glutamine (11C-GLN) PET/CT will show uptake within the lungs or other associated lesions of LAM patients and that treatment with mTOR inhibitor will reduce this uptake. Thus, 11C-GLN PET/CT may serve as a biomarker for LAM activity and response to treatment. Methods Female subjects greater than 18 years of age with sporadic or tuberous sclerosis complex associated LAM not currently treated with an mTOR inhibitor were recruited from the Vanderbilt University Medical Center LAM clinic to undergo 11C-GLN PET/CT imaging prior to start of mTOR inhibitor therapy and 8 weeks following initiation of treatment. A comparison cohort of patients with colorectal cancer without lung metastases undergoing 11C-GLN PET/CT at …

A coincident detection of Cherenkov photons from electrons in the MeV range in PMMA has been performed with the prospect of an application in medical imaging techniques like a Compton Camera or TOF-PET. Using a 8 × 8 SiPM-array a timing resolution of 242 ps has been achieved. A spatial sensitivity for an electron source location from accumulated coincident light signals could be shown. Counting the number of detected photons was enabled. The results obtained are in good agreement with theoretical calculations taking fundamental detector and set-up properties into account. These measurements constitute an important step towards the feasibility of the electron detection in a Compton Camera.