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Nature Jun 2023Cancer alters the function of multiple organs beyond those targeted by metastasis. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks...
Cancer alters the function of multiple organs beyond those targeted by metastasis. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.
Topics: Animals; Mice; Cytochrome P-450 Enzyme System; Extracellular Vesicles; Fatty Acids; Fatty Liver; Liver; Pancreatic Neoplasms; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Liver Neoplasms; Humans; Inflammation; Palmitic Acid; Kupffer Cells; Oxidative Phosphorylation; rab27 GTP-Binding Proteins
PubMed: 37225988
DOI: 10.1038/s41586-023-06114-4 -
Frontiers in Oncology 2021Boron neutron capture therapy (BNCT) is an emerging treatment modality aimed at improving the therapeutic ratio for traditionally difficult to treat tumors. BNCT... (Review)
Review
Boron neutron capture therapy (BNCT) is an emerging treatment modality aimed at improving the therapeutic ratio for traditionally difficult to treat tumors. BNCT utilizes boronated agents to preferentially deliver boron-10 to tumors, which, after undergoing irradiation with neutrons, yields litihium-7 and an alpha particle. The alpha particle has a short range, therefore preferentially affecting tumor tissues while sparing more distal normal tissues. To date, BNCT has been studied clinically in a variety of disease sites, including glioblastoma multiforme, meningioma, head and neck cancers, lung cancers, breast cancers, hepatocellular carcinoma, sarcomas, cutaneous malignancies, extramammary Paget's disease, recurrent cancers, pediatric cancers, and metastatic disease. We aim to provide an up-to-date and comprehensive review of the studies of each of these disease sites, as well as a review on the challenges facing adoption of BNCT.
PubMed: 33718149
DOI: 10.3389/fonc.2021.601820 -
International Journal of Molecular... Jul 2023Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as... (Review)
Review
Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as catalysts. Targeted alpha emitters are in current development for several potential oncologic indications. Herein, we review the three most prevalently studied conjugated/chelated alpha emitters (actinium, lead, and astatine) and focus on contemporary clinical trials in an effort to more fully appreciate the breadth of the current evaluation. Phase I trials targeting multiple diseases are now underway, and at least one phase III trial (in selected neuroendocrine cancers) is currently in the initial stages of recruitment. Combination trials are now also emerging as alpha emitters are integrated with other therapies in an effort to create solutions for those with advanced cancers. Despite the promise of targeted alpha therapies, many challenges remain. These challenges include the development of reliable supply chains, the need for a better understanding of the relationships between administered dose and absorbed dose in both tissue and tumor and how that predicts outcomes, and the incomplete understanding of potential long-term deleterious effects of the alpha emitters. Progress on multiple fronts is necessary to bring the potential of targeted alpha therapies into the clinic.
Topics: Humans; Male; Alpha Particles; Prostatic Neoplasms; Radiopharmaceuticals; Clinical Trials as Topic
PubMed: 37511386
DOI: 10.3390/ijms241411626 -
Journal of Nuclear Medicine : Official... May 2021Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen...
Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen (PSMA)-targeting β- and α-emitters have been introduced, with promising response rates. Here, we present the first-to our knowledge-clinical data for PSMA-targeted α-therapy (TAT) using Ac-PSMA imaging and therapy (I&T). Fourteen patients receiving Ac-PSMA-I&T were included in this retrospective analysis. Eleven of the 14 had prior second-line antiandrogen treatment with abiraterone or enzalutamide, prior chemotherapy, and prior Lu-PSMA treatment. Patients were treated at bimonthly intervals until progression or intolerable side effects. Prostate-specific antigen (PSA) was measured for response assessment. Hematologic and nonhematologic side effects were recorded according to the Common Terminology Criteria for Adverse Events, version 5.0. Thirty-four cycles of Ac-PSMA-I&T were applied (median dose, 7.8 MBq; range, 6.0-8.5), with 1 cycle in 3 patients, 2 cycles in 7 patients, 4 cycles in 3 patients, and 5 cycles in 1 patient. No acute toxicity was observed during hospitalization. Baseline PSA was 112 ng/mL (range, 20.5-818 ng/mL). The best PSA response after TAT (a PSA decline ≥ 50%) was observed in 7 patients, and a PSA decline of any amount was observed in 11 patients. Three patients had no PSA decline at any time. A subgroup analysis of 11 patients with prior Lu-PSMA treatment showed any PSA decline in 8 patients and a decline of at least 50% in 5 patients. After TAT, grade 3 anemia was observed in 3 of the 14 patients, with 2 of them presenting with grade 2 anemia already at baseline. Grade 3 leukopenia was observed in 1 patient. Eight patients with preexisting xerostomia after Lu-PSMA showed no worsening after TAT. Newly diagnosed grade 1 or 2 xerostomia after TAT was observed in 5 patients. One patient reported no xerostomia at all. Our first clinical data for TAT using Ac-PSMA-I&T showed a promising antitumor effect in advanced metastatic castration-resistant prostate cancer. These results are highly comparable to data on Ac-PSMA-617 TAT.
Topics: Actinium; Antigens, Surface; Beta Particles; Glutamate Carboxypeptidase II; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome
PubMed: 33008928
DOI: 10.2967/jnumed.120.251017 -
Toxics Aug 2023Radon is a carcinogenic factor, but the effects of the potential carcinogenicity of radon progeny on the human body during the prenatal period have not yet been...
Radon is a carcinogenic factor, but the effects of the potential carcinogenicity of radon progeny on the human body during the prenatal period have not yet been explored. Based on data regarding the half-lives of radon-222 and radon-220 and their progeny, this paper considers their potential effects on the human body in the prenatal period. Radon-220 represents a small fraction of the total radon concentration in the air, but the dose of radon-220 progeny may have a significant effect in the prenatal period, as the precursors of polonium-212 exhibit substantially longer half-lives than the corresponding precursors of polonium-214. Theoretically, it is possible that radon-220 decay products, particularly polonium-212, are the predominant emitters of alpha particles in the prenatal period. Studies aiming to establish a relationship between exposure to radon during pregnancy and the subsequently observed incidence of childhood neoplasms should consider this observation.
PubMed: 37624186
DOI: 10.3390/toxics11080681 -
Frontiers in Medicine 2022According to the 2021 World Health Organization Classification of Tumors of the Central Nervous System, glioblastoma (GB) is a primary brain tumor and presents with the... (Review)
Review
According to the 2021 World Health Organization Classification of Tumors of the Central Nervous System, glioblastoma (GB) is a primary brain tumor and presents with the worst prognosis. Due to its infiltrating characteristic, molecular heterogeneity, and only partly preserved function of the blood-brain barrier, the median overall survival time is short (9-15 months), regardless of comprehensive treatment including surgery, radiotherapy, and chemotherapy. Several novel treatment strategies are under investigation. Unfortunately, none of them produced successful results; 90% of patients have a recurrence of the disease within 6 months. Local administration of the drug could be a promising approach to delivering treatment with minimized side effects, due to the recurrence of 95% glioblastomas in a margin of 2 cm at the primary site. Several ligand-receptor systems have been evaluated, such as targeting tenascin, the extracellular matrix protein, or radiolabeled somatostatin analogs, as it is overexpressed with the SSTR-2 receptor system in around 80% of gliomas. Moreover, this study revealed that the NK-1 receptor is overexpressed in GB, suggesting that substance P (SP) may serve as a ligand. A variety of radioisotopes, beta- (I, Y, or Lu) and alpha emitters (Bi, Ac, or At), with different physical properties were tested for treatment. Alpha particles have many advantages over beta radiation such as short range with higher linear energy transfer. According to that characteristic, it is extremely dose delivered to the targeted cells, while reducing harm to nearby healthy tissue. Additionally, the biological effect of alpha radiation is independent of the cell cycle phase, cell oxygenation and O-6-methylguanine-DNA methyltransferase () gene promoter methylation status. In this article, we summarize the experience with local treatment of primary and secondary GBs with locally used radioisotopes such as [Bi]Bi-DOTA-SP or [Ac]Ac-DOTA-SP.
PubMed: 36590948
DOI: 10.3389/fmed.2022.1085245 -
Cancers Aug 2021Prostate cancer (PCa) causes significant morbidity and mortality in men globally. While localized PCa may be managed with curative intent by surgery and/or radiation... (Review)
Review
Prostate cancer (PCa) causes significant morbidity and mortality in men globally. While localized PCa may be managed with curative intent by surgery and/or radiation therapy, the management of advanced hormone resistant metastatic disease (mCRPC) is more challenging. Theranostics is a principle based on the ability to use an organ specific ligand and label it to both a diagnostic and a therapeutic agent. The overexpression of prostate specific membrane antigen (PSMA) on prostate cancer cells creates a unique opportunity for development of targeted radionuclide therapy. The use of both beta and alpha emitting particles has shown great success. Several clinical trials have been initiated assessing the efficacy and safety profile of these radionuclide agents. The results are encouraging with PSMA directed radioligand therapy performing well in patients who have exhausted all other standard treatment options. Future studies need to assess the timing of introduction of these radionuclide therapies in the management schema of mCRPC. Drugs or therapies are not without side effects and targeted radionuclide therapies presents a new set of toxicities including xerostomia and myelosuppression. New therapeutic strategies are being explored to improve outcomes while keeping toxicities to a minimum. This review aims to look at the various PSMA labelled tracers that form part of the theragnostic approach and subsequently delve into the progress made in the area of radionuclide therapy.
PubMed: 34359805
DOI: 10.3390/cancers13153904