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Purpose: Although treatment planning and individualized dose application for emerging prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) are generally recommended, it is still difficult to implement in practice at the moment. In this study, we aimed to prove the concept of pretherapeutic prediction of dosimetry based on imaging and laboratory measurements before the RLT treatment. Methods: Twenty-three patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA I&T RLT were included retrospectively. They had available pre-therapy 68 Ga-PSMA-HEBD-CC PET/CT and at least 3 planar and 1 SPECT/CT imaging for dosimetry. Overall, 43 cycles of 177Lu-PSMA I&T RLT were applied. Organ-based standard uptake values (SUVs) were obtained from pre-therapy PET/CT scans. Patient dosimetry was calculated for the kidney, liver, spleen, and salivary glands using Hermes Hybrid Dosimetry 4.0 from the planar and SPECT/CT images. Machine learning methods were explored for dose prediction from organ SUVs and laboratory measurements. The uncertainty of these dose predictions was compared with the population-based dosimetry estimates. Mean absolute percentage error (MAPE) was used to assess the prediction uncertainty of estimated dosimetry. Results: An optimal machine learning method achieved a dosimetry prediction MAPE of 15.8 ± 13.2% for the kidney, 29.6% ± 13.7% for the liver, 23.8% ± 13.1% for the salivary glands, and 32.1 ± 31.4% for the spleen. In contrast, the prediction based on literature population mean has significantly larger MAPE (p < 0.01), 25.5 ± 17.3% for the kidney, 139.1% ± 111.5% for the liver, 67.0 ± 58.3% for the salivary glands, and 54.1 ± 215.3% for the spleen. Conclusion: The preliminary results confirmed the feasibility of pretherapeutic estimation of treatment dosimetry and its added value to empirical population-based estimation. The exploration of dose prediction may support the implementation of treatment planning for RLT. [ABSTRACT FROM AUTHOR]

The helix–loop–helix protein Id-1 has been suggested to play a positive role in cell proliferation and tumorigenesis of many types of human cancers. However, little is known about the molecular mechanism involved in the function of Id-1. In this study, using four stable Id-1 transfectant clones, we investigated the involvement of MAPK signaling pathway in the Id-1 induced serum independent prostate cancer cell growth. Our results demonstrated that both transient and stable ectopic Id-1 expression in prostate cancer LNCaP cells led to activation of the Raf/MEK1/2 signaling pathway. In addition, inhibition of MEK1/2 phosphorylation by one of its inhibitors, PD098059, resulted in the decreased cell cycle S phase fraction and cell growth rate, suggesting that activation of MAPK signaling pathway is essential for Id-1 induced prostate cancer cell proliferation. Furthermore, treatment with antisense oligonucleotide complementary to Id-1 mRNA in PC-3 and DU145 cells resulted in a decreased Id-1 expression which was accompanied by decreased Egr-1 protein. Our results suggest for the first time that the function of Id-1 is associated with MAPK signaling pathway activation and indicate a possible novel mechanism in which Id-1 regulates prostate cancer cell growth and tumorigenesis.Oncogene (2002) 21, 8498–8505. doi:10.1038/sj.onc.1206007 [ABSTRACT FROM AUTHOR]

Cripto-1 (CR-1) is a member of the epidermal growth factor-Cripto-1/FRL1/Cryptic gene family that plays a key role in the various malignant cancers. However, the role of CR-1 in prostate carcinoma (PCa) remains limited. The expression of CR-1 was down-regulated by small interfering RNA (siRNA). Western blot measured the expression levels of CR-1 and some related proteins. We performed Cell Counting Kit-8, 5-ethynyl-2-deoxyuridine (EdU) incorporation assay and flow cytometry to detect the cellular proliferation and cycle. The transwell assay was used to observe cellular migration and invasion. The ability of angiogenesis was evaluated by tube formation assay. Our results showed that CR-1 knockdown markedly inhibited cell proliferation and induced cycle arrest in G1 phase, as p21 and p27 were up-regulated, whereas cyclin D1 and cyclin E1 were diminished. Moreover, silencing of CR-1 dramatically inhibited cell migration and invasion, repressed matrix metalloproteinases, and disturbed epithelial-mesenchymal transition. CR-1 siRNA suppressed the secreted level of vascular endothelial growth factor, and reduced protein level of Vascular endothelial growth factor receptor 2. We further found that decreased CR-1 expression inhibited FAK/Src/PI3K and Wnt/β-catenin signalling in PCa cells. These results suggested CR-1 might be served as an effective therapeutic target in PCa. [ABSTRACT FROM AUTHOR]

Zbtb7a has previously been described as a powerful proto-oncogene. Here we unexpectedly demonstrate that Zbtb7a has a critical oncosuppressive role in the prostate. Prostate-specific inactivation of Zbtb7a leads to a marked acceleration of Pten loss-driven prostate tumorigenesis through bypass of Pten loss-induced cellular senescence (PICS). We show that ZBTB7A physically interacts with SOX9 and functionally antagonizes its transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long noncoding RNA precursor for an RB-targeting microRNA. Inactivation of Zbtb7a in vivo leads to Rb downregulation, PICS bypass and invasive prostate cancer. Notably, we found that ZBTB7A is genetically lost, as well as downregulated at both the mRNA and protein levels, in a subset of human advanced prostate cancers. Thus, we identify ZBTB7A as a context-dependent cancer gene that can act as an oncogene in some contexts but also has oncosuppressive-like activity in PTEN-null tumors. [ABSTRACT FROM AUTHOR]