Cancer Biotherapy and Radiopharmaceuticals最新文献

Introduction: Integrin antagonist complex (IAC), a novel αvβ3 integrin antagonist peptidomimetic, has emerged as a promising agent for molecular imaging of tumor angiogenesis. This study evaluates the biodistribution and clinical efficacy of [⁶⁸Ga]Ga-DOTAGA-IAC PET/CT in detecting radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC), comparing its diagnostic performance with [¹⁸F]F-FDG PET/CT. Materials and Methods: In this prospective pilot study, RAIR-DTC patients underwent whole-body imaging with [¹⁸F] F-FDG PET/CT, followed by [⁶⁸Ga]Ga-DOTAGA-IAC PET/CT. Biodistribution patterns of [⁶⁸Ga]Ga-DOTAGA-IAC were assessed. Lesions with abnormal, nonphysiologic tracer uptake (showing activity exceeding mediastinal blood pool) were considered positive for disease. Imaging findings were compared between the two modalities, and quantitative metrics, including SUV_max, metabolic tumor volume, and total lesion glycolysis, were analyzed statistically. Results: Among 30 patients with RAIR-DTC, [⁶⁸Ga]Ga-DOTAGA-IAC PET/CT revealed predominant physiological tracer uptake in the kidneys. [¹⁸F]F-FDG PET/CT identified 97 lesions, predominantly nodal (73.2%), while [⁶⁸Ga]Ga-DOTAGA-IAC PET/CT detected 34 lesions, 50% of which were nodal. Few patients exhibited multiple lesions with varying uptake grades, with 20% showing coexisting higher-grade lesions (grade II or above) on [⁶⁸Ga]Ga-DOTAGA-IAC PET/CT. Conclusion: Angiogenesis imaging using [⁶⁸Ga]Ga-DOTAGA-IAC PET/CT demonstrates limited sensitivity for lesion detection in patients with RAIR-DTC compared with [¹⁸F]F-FDG PET/CT. However, the potential of [⁶⁸Ga]Ga-DOTAGA-IAC as a diagnostic tool for other cancers has been used in other cancers with positive imaging characteristics warranting further exploration.

[¹⁷⁷Lu]Lu-DOTATATE is a newly trending acceptable therapy in recurrent/residual meningioma with good safety. However, recognizing any possible side effects in this special population would be helpful for better management and individualization of this useful treatment. Although the seizure has been previously reported in a few cases after [¹⁷⁷Lu]Lu-DOTATATE therapy in recurrent meningioma, the acute onset of seizure in these patients, early after therapeutic radioligand administration, is not reported to the best of our knowledge. This report presents a case with the progression of residual meningioma after previous surgery in 2016 who developed with generalized tonic-clonic seizure, a few hours after administration of 200 mCi [¹⁷⁷Lu]Lu-DOTATATE. The patient was taking prophylactic doses of the lacosamide, although no previous history of seizure was reported.

Background: Vascular endothelial growth factor receptor-3 (VEGFR-3) plays an indispensable role in lymphangiogenesis. Previous findings suggest that blocking the VEGFR-3 signaling pathway can inhibit lymph node metastasis effectively, thus reducing the incidence of distant metastasis. The development of new VEGFR-3-targeting drugs for early detection and effective treatments is, therefore, urgently required. Methods: In vitro biopanning of a phage-displayed peptide library was used to identify specific peptides binding to the extracellular domain of VEGFR-3. We obtained a novel VEGFR-3-targeting peptide, TMVP1 (LARGR). Our combined immunofluorescence and radiolabeling studies revealed that FITC-TMVP1 and ^99mTc-labeled TMVP1 specifically accumulated in VEGFR-3-positive lymphatic vessels of tumors after intravenous administration in tumor xenograft models in vivo. To enhance the therapeutic efficacy of anticancer drugs, TMVP1 was fused to a proapoptotic peptide, _D(KLAKLAK)². Results: The fusion peptide strongly inhibited tumor lymphangiogenesis in vitro and in vivo and specifically suppressed lung metastasis in a 4T1 breast cancer xenograft model. The accumulation of the TMVP1 in lymphatic vessels was specific. Conclusions: Our results suggest that TMVP1 is a potential therapeutic strategy for developing new diagnostic tracers or alternative anticancer agents for tumor lymphangiogenesis and lymphatic metastasis.

Background: Circular RNA (circRNA) plays a regulatory role in the malignancy of papillary thyroid cancer (PTC). However, the role of a novel circRNA, hsa_circ_0118578, in PTC is not yet fully understood. This report focuses on unveiling hsa_circ_0118578's effect on PTC cell malignancy and reveals its mechanism in PTC progression. Methods: Levels of hsa_circ_0118578 in PTC were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The functional roles of hsa_circ_0118578 in PTC cell malignancy were evaluated through Transwell, 5-ethynyl-2'-deoxyuridine (EdU), and wound healing assays. A xenograft model in nude mice was used to examine the effects of hsa_circ_0118578's in vivo. The interaction between eukaryotic translation initiation factor 4A3 (EIF4A3) and hsa_circ_0118578 was confirmed using RNA-binding protein immunoprecipitation, qRT-PCR, and western blotting. Results: The hsa_circ_0118578 with high expression in PTC tissues was associated with higher tumor node metastasis stage, lymph node metastasis, as well as poor differentiation. Cell functional assays demonstrated that silencing hsa_circ_0118578 inhibited PTC cell proliferation, invasion, and migration. In the xenograft assay, tumorigenicity of PTC cells in vivo was reduced following hsa_circ_0118578 suppression. Additionally, EIF4A3, as an RNA-binding protein, was shown to interact with hsa_circ_0118578 to stabilize its expression in PTC cells. Conclusions: Upregulated hsa_circ_0118578 in PTC interacts with EIF4A3 to exert oncogenic effects by enhancing hsa_circ_0118578 stability, contributing to PTC development. These findings shed light on the oncogenic role of hsa_circ_0118578 in PTC and suggest it as a potential therapeutic target.

Objective: [⁶⁸Ga]Ga-DOTA-FGFR1-peptide is a novel positron emission tomography (PET) radiotracer targeting fibroblast growth factor receptor 1 (FGFR1). This study evaluated the safety, biodistribution, radiation dosimetry, and imaging potential of [⁶⁸Ga]Ga-DOTA-FGFR1-peptide. Methods: The FGFR1-targeting peptide DOTA-(PEG2)-KAEWKSLGEEAWHSK was synthesized by manual solid-phase peptide synthesis with high-performance liquid chromatography purification, and labeled with ⁶⁸Ga with DOTA as chelating agent. We recruited 14 participants and calculated the radiation dose of 4 of these pathologically confirmed nontumor subjects using OLINDA/EXM 2.2.0 software. At the same time, the imaging potential in 10 of these lung cancer patients was evaluated. Results: The biodistribution of [⁶⁸Ga]Ga-DOTA-FGFR1-peptide in 4 subjects showed the highest uptake in the bladder and kidney. Dosimetry analysis indicated that the bladder wall received the highest effective dose (3.73E-02 mSv/MBq), followed by the lungs (2.36E-03 mSv/MBq) and red bone marrow (2.09E-03 mSv/MBq). No normal organs were found to have excess specific absorbed doses. The average systemic effective dose was 4.97E-02 mSv/MBq. The primary and metastatic tumor lesions were clearly visible on PET/computed tomography (CT) images in 10 patients. Conclusion: Our results indicate that [⁶⁸Ga]Ga-DOTA-FGFR1-peptide has a good dosimetry profile and can be used safely in humans, and it has significant potential value for clinical PET/CT imaging.

Background: Hepatocellular carcinoma (HCC) is a highly aggressive cancer. This study elucidates the role of Glyoxylate reductase/hydroxypyruvate reductase (GRHPR) in HCC proliferation and metastasis, along with its molecular mechanism, and identifies miRNAs targeting GRHPR. Materials and Methods: Expression levels of GRHPR and miR-138-5p were assessed using real-time fluorescent quantitative polymerase chain reaction and Western blot techniques. Bioinformatic analysis was employed to identify miRNAs targeting GRHPR, and the results were confirmed via dual-luciferase reporter assays. HCC cell lines overexpressing GRHPR were established to investigate its roles in cell proliferation, migration, and invasion. The biological function of miR-138-5p targeting GRHPR in HCC cells was also evaluated. Furthermore, a xenograft mouse model was utilized to examine the in vivo functions of GRHPR. Results: GRHPR expression was downregulated in HCC, whereas miR-138-5p was upregulated. Overexpression of GRHPR suppressed HCC cell proliferation, migration, and invasion. Conversely, inhibition of GRHPR by miR-138-5p promoted HCC cell proliferation and invasive properties. MiR-138-5p was found to regulate Phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) phosphorylation levels by inhibiting GRHPR expression. Conclusion: This study highlights GRHPR's role as a tumor suppressor in HCC, with its function being regulated by miR-138-5p.

There is an unmet need to recognize and address the psychosocial and spiritual support of the rapidly growing population of cancer survivors living with advanced metastatic disease which is essentially incurable. Palliative chemotherapy may do more harm than good. The role of the physician in the provision of a supportive, compassionate relationship of mutual trust is critical in the exploration of spirituality and the meaning of life for each individual patient. The objective must be to enhance quality of life rather than prolong it at any cost. Nuclear physicians are now equipped to offer effective control of advanced metastatic cancer of prostate and neuroendocrine neoplasms without clinically evident toxicity. They also now have the potential to practice phronesis, and in so doing, to significantly ameliorate the quality of life of patients afflicted with these specific advanced cancers. During the time of prolonged symptom-free survival, these patients may be encouraged to find life's meaning and a peaceful acceptance of their inevitable demise.

Background: Prostate specific membrane antigen (PSMA)-targeted radioligand therapies represent a highly effective treatment for metastatic prostate cancer. However, high and sustain uptake of PSMA-ligands in the salivary glands led to dose limiting dry mouth (xerostomia), especially with α-emitters. The expression of PSMA and histologic analysis couldn't directly explain the toxicity, suggesting a potential off-target mediator for uptake. In this study, we searched for possible off-target non-PSMA protein(s) in the salivary glands. Methods: A machine-learning based quantitative structure activity relationship (QSAR) model was built for seeking the possible off-target(s). The resulting target candidates from the model prediction were subjected to further analysis for salivary protein expression and structural homology at key regions required for PSMA-ligand binding. Furthermore, cellular binding assays were performed utilizing multiple cell lines with high expression of the candidate proteins and low expression of PSMA. Finally, PSMA knockout (PSMA-/-) mice were scanned by small animal PET/MR using [⁶⁸Ga]Ga-PSMA-11 for in-vivo validation. Results: The screening of the trained QSAR model did not yield a solid off-target protein, which was corroborated in part by cellular binding assays. Imaging using PSMA-/- mice further demonstrated markedly reduced PSMA-radioligand uptake in the salivary glands. Conclusion: Uptake of the PSMA-targeted radioligands in the salivary glands remains primarily PSMA-mediated. Further investigations are needed to illustrate a seemingly different process of uptake and retention in the salivary glands than that in prostate cancer.

Background: Long noncoding RNAs (lncRNAs) contribute to the initiation and progression of gastric cancer (GC). This study examined the potential role of lncRNA colorectal neoplasia differentially expressed (CRNDE) in modulating the expression of migration and invasion enhancer 1 (MIEN1) through the suppression of miR-136-5p in GC. Methods: The biological roles of CRNDE, miR-136-5p, and MIEN1 in GC were assessed both in laboratory settings and through the examination of clinical samples. Results: CRNDE was found to be significantly increased in GC tissues, and this upregulation was associated with an unfavorable prognosis of GC patients. In vitro experiments showed that inhibiting cell growth and migration, along with promoting apoptosis in GC cells, could be achieved by either disabling CRNDE or MIEN1, or by increasing the expression of miR-136-5p. MIEN1 is a specific recipient of miR-136-5p, and the anticancer effects of miR-136-5p can be counteracted by the increased expression of MIEN1. Through the examination of clinical specimens, it has been observed that there is a significant positive correlation between the expression of MIEN1 and CRNDE. In contrast, miR-136-5p expression in GC tissues shows a negative correlation. Conclusion: A previously unexplored therapeutic target for GC involves the CRNDE/miR-136-5p/MIEN1 signal transduction cascade.

Background: Breast cancer is a leading cause of cancer-related deaths in women worldwide, posing a significant threat to female health. Therefore, it is crucial to search for new therapeutic targets and prognostic biomarkers for breast cancer patients. Method: Bioinformatics analysis, quantitative real-time PCR (qRT-PCR), and fluorescence in situ hybridization (FISH) were employed to investigate the expression of hsa_circ_002144 in breast cancer. Transwell assay, Western blotting, and cell viability assay were utilized to assess the impact of hsa_circ_002144 on the proliferation, migration, and invasion of breast cancer cells. Additionally, a mouse model was established to validate its functionality. Flow cytometry, WB analysis, enzyme-linked immunosorbent assay (ELISA), qRT-PCR, exosomes isolation, and co-culture system were employed to elucidate the molecular mechanism underlying macrophage polarization. Result: we have discovered for the first time that hsa_circ_002144 is highly expressed in breast cancer. It affected tumor growth and metastasis and could influence macrophage polarization through the glycolytic pathway. Conclusion: This finding provides a new direction for breast cancer treatment and prognosis assessment.