VDR

MONROE TOWNSHIP, N.J. & OXFORD, England--( BUSINESS WIRE )--Blue Earth Diagnostics, a Bracco company and recognized leader in the development and commercialization of innovative PET radiopharmaceuticals, today announced additional results from its Phase 3 LIGHTHOUSE trial that evaluated the diagnostic performance and safety of 18 F-rhPSMA-7.3 in newly diagnosed prostate cancer. 18 F-rhPSMA-7.3 is an investigational high affinity radiohybrid (rh) Prostate-Specific Membrane Antigen-targeted PET imaging agent. The results were reported in a presentation at the 2023 ASCO Genitourinary Cancers Symposium (ASCO GU), held February 16 -18, in San Francisco, Calif. “ Up to 25% of patients with primary prostate cancer may have detectable regional pelvic lymph node metastases, which are correlated with a risk for recurrence and associated overall survival,” said Brian F. Chapin, MD, Associate Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, and Coordinating Investigator of the LIGHTHOUSE study. “ Effective staging in primary disease − determining its presence and whether it may have metastasized − is critical in establishing optimal clinical management strategies. Pelvic lymph node dissection (PLND), or pelvic lymphadenectomy, is considered the gold standard in assessing pelvic node lesions, but its use is limited to the planned surgical area. Conventional imaging techniques such as CT and MRI are limited in the information they may provide. An ideal staging technique for detecting metastatic prostate cancer should include both pelvic nodes as well as more distant soft tissue and skeletal findings. The LIGHTHOUSE study looked at unfavorable intermediate, high and very high risk patients who were scheduled for radical prostatectomy plus PLND prior to 18 F-rhPSMA-7.3 PET. Results were encouraging and showed that between 9% - 13% (28 and 42/314, respectively), across the readers, of patients for whom conventional imaging was negative, actually had distant (M1) metastatic lesions that were visible on 18 F-rhPSMA-7.3 PET. Thus, 18 F-rhPSMA-7.3 PET provided clinically valuable information prior to surgery that would likely result in management changes for these patients.” “ We are pleased to share these results from the Phase 3 LIGHTHOUSE study with the clinical community at ASCO GU 2023, as they are included in our New Drug Application for 18 F-rhPSMA-7.3 PET imaging, which is currently under review by the U.S. Food and Drug Administration,” said David E. Gauden, D.Phil., Chief Executive Officer of Blue Earth Diagnostics. “ 18 F-rhPSMA-7.3 represents a new class of PSMA-targeted PET radiopharmaceuticals based on novel radiohybrid technology PSMA technology, which offers potential theranostic utility in both diagnostic PET imaging and therapy. Early studies with 18 F-rhPSMA-7.3 potentially show a high binding affinity for PSMA, and biodistribution data suggest the potential for low bladder activity. We believe that these attributes will make it a valuable diagnostic tool that is radiolabeled with 18 F for high image quality and readily available patient access.” The findings presented at ASCO GU 2023 included assessment of the Verified Detection Rate (VDR) of distant metastatic (M1) lesions by 18 F-rhPSMA-7.3 PET imaging. VDR was the proportion of patients with M1 lesions identified by blinded image evaluation and also subsequently confirmed as True Positive (TP) by biopsy (used in ~15% of M1 positive cases) or follow-up conventional imaging (used in ~85% of M1 positive cases). Findings were based on individual read results from 3 blinded, independent PET readers. Men with treatment-naïve, unfavorable intermediate to very high-risk prostate cancer who were scheduled to undergo radical prostatectomy and PLND underwent PET imaging after administration of 18 F-rhPSMA-7.3. Onsite readers interpreted the images before submission for blinded interpretation and evaluation by the central readers. Of the 335 men analyzed (median [range] PSA, 8.89 [1.15-120] ng/mL), 16-28% (53-93) had M1 lesions across the 3 readers. In total, 10-15% (35-49) had verified M1 lesions. By region, verified M1 lesions were most common in bone, ranging from 6.0-11% across readers. Similar data were shown among a subgroup who had negative baseline conventional imaging. In these 314 patients, the VDR ranged from 9-13% across readers, with bone showing the highest regional VDR, ranging from 5-9%. The LIGHTHOUSE Phase 3 clinical trial ( NC04186819 ) was a prospective, Phase 3, multi-center, single-arm, imaging study conducted in the United States and Europe to evaluate the safety and diagnostic performance of 18 F-rhPSMA-7.3 PET in men with newly diagnosed prostate cancer. Results for the co-primary endpoints of efficacy and safety for the LIGHTHOUSE trial were previously presented at the 23 rd Annual Scientific Meeting in Urologic Oncology (SUO) in December 2022. 1 The most recent findings, which reflect an analysis of additional LIGHTHOUSE study endpoints, “ Detection of true positive M1 lesions by 18 F-rhPSMA-7.3 PET in newly diagnosed prostate cancer: Results from the phase 3 prospective LIGHTHOUSE study,” were presented at ASCO GU 2023 on February 16, 2023, by Brian F. Chapin, MD, Associate Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, on behalf of Bridget F. Koontz, MD, Duke University Medical Center (at the time of the study), for the LIGHTHOUSE Study Group. Full session details and the abstract are available in the ASCO GU 2023 online program here . About Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA) rhPSMA compounds consist of a radiohybrid (“rh”) Prostate-Specific Membrane Antigen-targeted receptor ligand which attaches to and is internalized by prostate cancer cells and they may be radiolabeled with 18 F for PET imaging, or with isotopes such as 177 Lu or 225 Ac for therapeutic use – creating a true theranostic technology. They may play an important role in patient management in the future, and offer the potential for precision medicine for men with prostate cancer. Radiohybrid technology and rhPSMA originated from the Technical University of Munich, Germany. Blue Earth Diagnostics acquired exclusive, worldwide rights to rhPSMA diagnostic imaging technology from Scintomics GmbH in 2018, and therapeutic rights in 2020, and has sublicensed the therapeutic application to its sister company Blue Earth Therapeutics. Blue Earth Diagnostics has completed two Phase 3 clinical studies evaluating the safety and diagnostic performance of 18 F-rhPSMA-7.3 PET imaging in prostate cancer: (“SPOTLIGHT,” NCT04186845 ), in men with recurrent disease and (“LIGHTHOUSE,” NCT04186819 ), in men with newly diagnosed prostate cancer. Currently, rhPSMA compounds are investigational and have not received regulatory approval. About Blue Earth Diagnostics Blue Earth Diagnostics, an indirect subsidiary of Bracco Imaging S.p.A., is a growing international molecular imaging company focused on delivering innovative, well-differentiated diagnostic solutions that inform patient care. Formed in 2014, the Company’s success is driven by its management expertise and supported by a demonstrated track record of rapid development and commercialization of positron emission tomography (PET) radiopharmaceuticals. Blue Earth Diagnostics’ expanding oncology portfolio encompasses a variety of disease states, including prostate cancer and neuro-oncology. Blue Earth Diagnostics is committed to the timely development and commercialization of precision radiopharmaceuticals for potential use in imaging and therapy. For more information, please visit: www.blueearthdiagnostics.com . About Bracco Imaging Bracco Imaging S.p.A., part of the Bracco Group, is a world-leading diagnostic imaging provider. Headquartered in Milan, Italy, Bracco Imaging develops, manufactures and markets diagnostic imaging agents and solutions. It offers a product and solution portfolio for all key diagnostic imaging modalities: X-ray imaging (including Computed Tomography-CT, Interventional Radiology, and Cardiac Catheterization), Magnetic Resonance Imaging (MRI), Contrast Enhanced Ultrasound (CEUS), and Nuclear Medicine through radioactive tracers and novel PET imaging agents to inform clinical management and guide care for cancer patients in areas of unmet medical need. Our continually evolving portfolio is completed by a range of medical devices, advanced administration systems and dose-management software. In 2019 Bracco Imaging enriched its product portfolio by expanding the range of oncology nuclear imaging solutions in the urology segment and other specialties with the acquisition of Blue Earth Diagnostics. In 2021, Bracco Imaging established Blue Earth Therapeutics as a separate, cutting-edge biotechnology vehicle to develop radiopharmaceutical therapies. Visit: www.braccoimaging.com . 1 Chapin BF, LIGHTHOUSE Study Group. 134: Diagnostic performance and safety of 18 F-rhPSMA-7.3 PET in patients with newly diagnosed prostate cancer: Results from a phase 3, prospective, multicenter study (LIGHTHOUSE). SUO Annual Meeting. Orlando, FL: https://suo-abstracts.secure-platform.com/a/gallery/rounds/15/details/2390 , 2022.

Millions of people across the globe regularly consume arsenic-contaminated water. Exposure to arsenic has previously been associated with the development of various cancers including skin cancer. Research on the underlying molecular mechanisms regulating arsenic-mediated carcinogenesis remains sparse. Using in vitro studies, researchers demonstrate how calcitriol, or activated vitamin D3, inhibits arsenic-mediated carcinogenesis in certain types of skin cells known as 'keratinocytes.' Millions of people across the globe regularly consume arsenic-contaminated water. Exposure to arsenic has previously been associated with the development of various cancers including skin cancer. Research on the underlying molecular mechanisms regulating arsenic-mediated carcinogenesis remains sparse. Using in vitro studies, researchers from Japan demonstrate how calcitriol, or activated vitamin D3, inhibits arsenic-mediated carcinogenesis in certain types of skin cells known as "keratinocytes." According to recent estimates, over 140 million people from 50 countries regularly get exposed to arsenic through drinking water. The exposure level significantly exceeds the guideline value (10 μg/L) stipulated by the World Health Organization. It is an established fact that chronic arsenic exposure from drinking water causes a variety of cancers including skin cancer. Unfortunately, there is a general paucity of data on the underlying biological mechanisms that regulate arsenic-mediated carcinogenesis. Moreover, methods for the prevention and treatment of arsenic-mediated carcinogenesis have remained elusive thus far. Researchers at the Shibaura Institute of Technology (SIT) and Nagoya University have recently been able to identify the underlying biological mechanisms of carcinogenesis inhibition. Using in vitro studies, the research team has been able to demonstrate how calcitriol, or activated vitamin D3, inhibits arsenic-mediated carcinogenesis in certain types of skin cells known as "keratinocytes." These cells are primarily found in the epidermis, the outermost layer of the skin. It is a scientifically established fact that certain signaling molecules -- kinase proteins (e.g., MEK or "AKT") that control the fate of various biological processes -- are strongly associated with tumor development. Professor Ichiro Yajima from the Unit of Molecular and Cellular Toxicology, Department of Bioscience and Engineering, SIT, who led the research team, says, "Our in vitro study in human nontumorigenic HaCaT skin keratinocytes showed that calcitriol, which is also known as activated vitamin D3 or 1,25-dihydroxy-vitamin D3, inhibited arsenic-mediated anchorage-independent growth with downregulations of cancer-related activation of several signaling pathways, including MEK, ERK1/2, and AKT, as well as activity of cell cycle." To elucidate the relationship between arsenic uptake and calcitriol treatment, the researchers measured arsenic levels in HaCaT cells -- long-lived, spontaneously immortalized human epidermal keratinocytes -- treated with calcitriol using an inductively coupled plasma-mass spectrophotometer. Quite interestingly, arsenic levels in HaCaT cells cultured with arsenic significantly decreased when these cells were treated with increasing doses of calcitriol. The findings from their study have been published in the American Journal of Cancer Research. Dr. Masashi Kato, who serves as a Professor at the Department of Occupational and Environmental Health, Nagoya University, Japan, and is a collaborator on the study, adds, "Calcitriol significantly repressed arsenic uptake in HaCaT cells with the regulation of expressions of aquaporin genes (AQP7, 9, and 10), which were modified by arsenic exposure. Vitamin D receptor expression was significantly increased by arsenic exposure whereas calcitriol had no effect on the expression of the receptor." The researchers then sought to understand whether calcitriol had an inhibitory effect on arsenic-induced tumorigenesis in cells other than skin keratinocytes. To this end, they performed anchorage-independent growth assays using a human normal lung epithelial cell line called "Beas-2b." The results of these assays were equally astonishing: arsenic-mediated anchorage-independent growth of Beas-2b cells treated with calcitriol was suppressed by 21.4-70.0%, suggesting that calcitriol's potential to suppress arsenic-induced tumorigenesis is not restricted to keratinocytes. Prof. Yajima muses, "These results suggest that calcitriol suppresses arsenic-induced tumorigenesis not only in keratinocytes, but also in other target cells including lung epithelial cells. Furthermore, the expression pattern of aquaporin genes involved in arsenic uptake, a critical step in arsenic-induced carcinogenesis, is significantly altered by calcitriol treatment. We therefore believe that activated vitamin D3, or calcitriol, may contribute to the prevention and therapy for arsenic-mediated diseases including cancer." Environmental toxins such as arsenic contribute significantly to the development of life-threatening diseases such as cancer. However, it may take years, even decades, for cancer to develop from drinking arsenic-contaminated water. The current research clearly indicates that calcitriol could be used as a test compound for validating the safety and efficacy of activated vitamin D3 and/or its analogs in preventing or treating arsenic-triggered cancer. Taking vitamin D3 beforehand in arsenic-contaminated areas may reduce the risk of cancer development 5 or 10 years later and help people maintain good health for a long time. This is certainly welcome news for millions of people forced to survive on polluted water worldwide.

A new study could lead to ongoing health monitoring of astronauts to assess possible health risks and prevent disease progression. Astronauts are at higher risk for developing mutations -- possibly linked to spaceflight -- that can increase the risk of developing cancer and heart disease during their lifetimes, according to a first-of-its kind study from the Icahn School of Medicine at Mount Sinai. A team of researchers collected blood samples from National Aeronautics and Space Administration (NASA) astronauts who flew space shuttle missions between 1998 and 2001. They discovered DNA mutations, known as somatic mutations, in the blood-forming system (hematopoietic stem cells) in all 14 astronauts studied. Their findings, published in the August issue of Nature Communications Biology, suggest that spaceflight could be associated with these mutations and emphasize the importance of ongoing blood screening of astronauts throughout their careers and during their retirement to monitor their health. Somatic mutations are mutations that occur after a person is conceived and in cells other than sperm or egg cells, meaning they cannot be passed on to offspring. The mutations identified in this study were characterized by the overrepresentation of blood cells derived from a single clone, a process called clonal hematopoiesis (CH). Such mutations are frequently caused by environmental factors, such as exposure to ultraviolet radiation or certain chemicals, and may be a result of cancer chemo- or radiotherapy. There are few signs or symptoms associated with CH; most patients are identified after genetic testing of their blood for other diseases. Although CH is not necessarily an indicator of disease, it is associated with a higher risk for cardiovascular disease and blood cancer. "Astronauts work in an extreme environment where many factors can result in somatic mutations, most importantly space radiation, which means there is a risk that these mutations could develop into clonal hematopoiesis. Given the growing interest in both commercial spaceflights and deep space exploration, and the potential health risks of exposure to various harmful factors that are associated with repeated or long-duration exploration space missions, such as a trip to Mars, we decided to explore, retrospectively, somatic mutation in the cohort of 14 astronauts," said the study's lead author David Goukassian, MD, Professor of Medicine (Cardiology) with the Cardiovascular Research Institute at Icahn Mount Sinai. The study subjects were astronauts who flew relatively short (median 12 days) space shuttle missions between 1998 and 2001. Their median age was approximately 42 years old; roughly 85 percent were male, and six of the 14 were on their first mission. The researchers collected whole blood samples from the astronauts 10 days before their flight and on the day of landing, and white blood cells only three days after landing. The samples were stored at -80ºC for approximately 20 years. Using DNA sequencing followed by extensive bioinformatics analyses, researchers identified 34 mutations in 17 CH-driver genes. The most frequent mutations occurred in TP53, a gene that produces a tumor-suppressing protein, and DNMT3A, one of the most frequently mutated genes in acute myeloid leukemia. However, the frequency of the somatic mutations in the genes that the researchers assessed was less than two percent, the technical threshold for somatic mutations in hematopoietic stem cells to be considered clonal hematopoiesis of indeterminate potential (CHIP). CHIP is more common in older individuals and is associated with increased risk of developing cardiovascular disease and both hematologic and solid cancer. "Although the clonal hematopoiesis we observed was of a relatively small size, the fact that we observed these mutations was surprising given the relatively young age and health of these astronauts. The presence of these mutations does not necessarily mean that the astronauts will develop cardiovascular disease or cancer, but there is the risk that, over time, this could happen through ongoing and prolonged exposure to the extreme environment of deep space," Dr. Goukassian said. "Through this study, we have shown that we can determine the individual susceptibility of astronauts to develop disease related to their work without any implications that can affect their ability to do their work. Indeed, our studies demonstrate the importance of early and ongoing screening to assess that susceptibility. Our recommendation is that NASA, and its medical team, screen astronauts for somatic mutations and possible clonal expansion, or regression, every three to five years, and, not less importantly, well into their retirement years when somatic mutations may expand clonally and become CHIP." The team's research follows previous studies that used the same samples to identify predictive biomarkers in exosomes -- small lipid-layered microscopic vesicles of nucleic acids, proteins, lipids, and metabolites that form within the cells of the human body and are subsequently released into the blood circulation, hence carrying the information from their cells of origin that reflects their intercellular condition. This feature of exosomes may qualify them as great biomarkers of health and/or disease, as well as transfer information from one cell to another at great distance in the body. When they treated human heart cells with exosomes derived from astronauts, the researchers found that the exosomes affected the biology of the vitamin D receptor, which plays a key role in bone, heart, and skeletal muscle health. They also assessed the impact of space flight on mitochondrial DNA -- the genome of small organelles that supply energy to cells. In that study, the team found that the amount of cell-free mitochondrial DNA circulating in the blood of astronauts was two to 350 times higher than normal, which may lead to oxidative damage and inflammation elsewhere in the body. "Through these studies, we have demonstrated the potential to assess the health risk of space flight among astronauts. What is important now is to conduct longitudinal retrospective and well-controlled prospective studies involving a large number of astronauts to see how that risk evolves based on continued exposure and then compare that data against their clinical symptoms, imaging, and lab results. That will enable us to make informed predictions as to which individuals are more likely to develop disease based on the phenomena we are seeing and open the door to individualized precision medicine approaches to early intervention and prevention," said Dr. Goukassian.