Retinoblastoma

Leveraging RB-mediated senescence presents promising opportunities for cancer therapy, including novel approaches in tumor immunotherapy designed to enhance treatment efficacy. This review highlights recent advancements in the RB signaling pathway, focusing on its roles in cellular senescence and tumor suppression, and discusses its potential to improve tumor management and clinical outcomes.

In this small cohort of patients with retinoblastoma, non-RB1 variants did not appear to augment tumorigenesis or disease progression. Larger studies are required to determine associations between specific variants and development of SMN.

P1, N=26, Completed, The Hospital for Sick Children | Recruiting --> Completed | Trial completion date: Oct 2030 --> Oct 2024 | Trial primary completion date: Oct 2025 --> Oct 2024

This supports the notion that it may be safe to reduce the length of surveillance for new tumours in familial retinoblastoma from 7 years of age.

A player in this process is the retinoblastoma 1 (RB1) protein, whose phosphorylation prompts MCIDAS activation. Overall, this study identifies a role for actin-based mechanical inputs to the nucleus as controlling factors in cell differentiation.

P=N/A, N=100, Active, not recruiting, University of Washington

Affected children present at an early age and advanced stages of disease. This case highlights that FEVR can have a highly asymmetric and advanced presentation at an early age and must be distinguished from retinoblastoma in the differential diagnosis of leukocoria.

Notably, the system also shows an excellent in vivo safety profile. In conclusion, the CRISPR-ADAReader system represents a groundbreaking method for the detection and editing of RNA, offering a potent instrument for the customized and precise governance of cell behavior.

In this Review, I describe our current knowledge of genetic predisposition to childhood and adolescent cancers. Survival rates in children and adolescents with cancer and CPGs are often poor, necessitating better integration of genomic testing into clinical care to improve cancer prevention, surveillance and therapies.

In addition, we identified only three cases with two SMNs following RB diagnosis, with at least one of these being an EWS. This case broadens the clinical and genetic landscape of RB, demonstrates the importance of a multidisciplinary approach in these patients, and highlights genetic diagnosis as a mandatory feature for management.

Our retinoblastoma programme demonstrated continued improved outcomes in terms of early detection, treatment, RB mutation detection, and eye preservation, despite the different challenges posed by the economic crisis and pandemic.

CRX transcriptionally activates TCF7 to promote the proliferation of RPE and RB cells in vitro. CRX is a potential target for RPE-based regenerative medicine. The potential risk of this strategy, tumorigenic potential, should be considered.

Without a family history of cancer, a patient with retinoblastoma and BS presents two mutations in the germline on the RB1 gene; this results in very low levels of RB1 mRNA systemically, thereby increasing the patient´s risk of developing another type of cancer throughout his life.

P2, N=30, Not yet recruiting, Targeted Therapy Technologies, LLC

P=N/A, N=30, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Mar 2025 --> Nov 2024 | Trial primary completion date: Mar 2025 --> Nov 2024

In addition, knockdown of YAP1 or treatment with ferroptosis inducer erastin blocked the above effects caused by Bmal1 overexpression. Rbbp6-mediated Bmal1 ubiquitination suppressed YAP1 pathway, promoting ferroptosis in DITD. This study highlighted Rbbp6/Bmal1/YAP1 axis as a potential therapeutic target for mitigating DITD.

Rescue experiments confirmed the pivotal role of SIRT1 in USP49-mediated CBP resistance. Our findings delineate a novel molecular network involving USP49-mediated autophagy in promoting CBP resistance in RB, offering potential targets for therapeutic intervention to enhance treatment efficacy and improve outcomes for RB patients.

The median interval between initial retinoblastoma diagnosis and death in the 6 patients who died of their SPMN was 18.8 years (extremes 6.2 and 34.6 years) and between diagnosis of the SPMN and death was 1.2 years (extremes 0.25 and 4 years). Of the patients who had been treated with External Beam Radiotherapy (EBRT), 13 developed a SPMN within the previously irradiated field.

A next-generation sequencing (NGS) panel detected two intronic acceptor splice site variants in the RB1 gene. While the previous literature documents cases of retinocytoma with vitreous seeds, this is the first case to our knowledge of a sporadic multifocal retinocytoma with a large ON prelimiting membrane, subhyaloid seeds, and vitreous seeds associated with two intronic acceptor splice site variants in the RB1 gene and no other detectable mutations.

Mechanistically, inhibition of activin receptor-like kinase 1 signaling increased key restriction point mediators, and treatment with the CDK4/6 inhibitors palbociclib or ribociclib blocked increases in pRB1 and retinal AVMs in HHT mice. Endothelial cell-specific deletion of CDK6 was sufficient to protect HHT mice from AVM pathology. Thus, clinically approved CDK4/6 inhibitors might have the potential to be repurposed for HHT.

Finally, in vivo studies of DLBCL xenograft-bearing NSG mice achieved a dramatic tumor-burden reduction in response to targeted GAK inhibition. These results reveal a novel cell cycle kinase suitable for therapeutic exploitation in DLBCL patients and linked to the common, undruggable biomarker of RB loss of function.

35 novel (21 unique) genes across 12 disorders were identified: ADNP, AOC3, CDC42EP2, CHTOP, CNN1, DES, FOXF1, FXR1, HLTF, KCNMB1, MTF2, MYH11, PLN, PNPLA2, REST, SGCA, SORBS1, SYNPO2, TAGLN, WAPL, and ZMYM4. These genes are proffered as potential biomarkers or therapeutic targets for the corresponding rare diseases discussed.

Hypericin had more cytotoxic effect in Y79 cells compared with naringenin. Furthermore, hypericin and naringenin didn't have apoptotic synergistic effect in these cells. According to the real-time PCR results, hypericin induces apoptosis in Y79 cells by disrupt the ratio of Bax/Bcl-2.

P1, N=20, Not yet recruiting, Eye & ENT Hospital of Fudan University | Trial completion date: May 2027 --> Dec 2027 | Initiation date: May 2024 --> Dec 2024 | Trial primary completion date: May 2025 --> Jan 2025

Collectively, our findings suggest that the GCN2‒SLC7A11 axis regulates cell growth and survival upon arginine deprivation through coordinating autophagy, cell cycle arrest, and apoptosis in retinoblastoma cells. This work paves the way for the development of a novel treatment for retinoblastoma.

Finally, our results indicated that ANRIL overexpression facilitated Y79 cell proliferation and cisplatin-induced apoptosis. Our results indicated that ANRIL promoted the proliferation and cisplatin resistance of Y79 cells through activating autophagy by promoting TSC1/ULK2 ex- pression via acting as a miR-328-3p sponge.

SHAP analysis highlighted lower sphericity, higher flatness, and greater gray-level heterogeneity as predictive for MYCNampRB1+/+ status, yielding an AUC of 0.81 (SD 0.11). This study shows the potential of MRI-based radiomics to distinguish MYCNampRB1+/+ and RB1-/- retinoblastoma subtypes.

P3, N=60, Active, not recruiting, Children's Oncology Group | Trial completion date: Dec 2024 --> Dec 2025

Among these cases, some may exhibit characteristics of NEC. Unraveling the molecular mechanisms using CRC that harbors both PDC and NEC will be a task for future research.

We hypothesize that the activation of Dnmt3a, Rb1, and Ezh2 observed in ΔS/N cells may be a consequence of a stress response caused by the accumulation and malfunctioning of Rb1-interacting complexes for the epigenetic reprogramming of Pparγ2/Cebpa and prevention of adipogenesis in an inappropriate cellular context. The failure of ΔS/N cells to differentiate and express Pparγ2 and Cebpa in culture following the expression of the DN Rb1 mutant may indicate the creation of epigenetic memory for new reprogrammed epigenetic states of genes.

Moreover, we found that XAL1 is necessary for the H2O2-induced inhibition of primary root growth through the negative regulation of peroxidase and catalase activities. Furthermore, XAL1, in conjunction with RETINOBLASTOMA-RELATED (RBR), is essential for positively regulating the differentiation of columella stem cells and for participating in primary root growth inhibition in response to oxidative stress induced by H2O2 treatment.

In addition, in vitro and in vivo experiments demonstrated that SAM had an oncogenic effect on retinoblastoma. In this study, we verify in vitro and in vivo whether SAM inhibits the proliferation of retinoblastoma cell Y7, induces apoptosis and cell cycle arrest of Y79 cells by inhibiting the Wnt2/β-catenin pathway, and affects the morphology and structure of retinoblastoma cell Y79.

This approach offers a novel strategy for cervical cancer treatment through precise regulation of cancer signaling. Future research should concentrate on developing RNA-targeted interventions to improve cervical cancer treatment outcomes through increased therapeutic efficacy and specificity.

The number of CNVs detected in each tumor was between 1 and 7, depending on the age at diagnosis. The analysis of genomic alterations in retinoblastoma is useful to understand the severity of tumor progression and to apply appropriate treatments.

Rbbp6 overexpression similarly suppressed inflammatory activation of RAW264.7 cells, which was counteracted by Pla2g7 or Spi1 upregulation. In summary, this study demonstrates that the Pla2g7 loss and Spi1 upregulation participate in inflammatory responses in sepsis by elevating the Lp-PLA2 levels.

There were delayed but persistent DNA repair mechanisms in RB1+/- osteocytes, which were sufficient to maintain genomic integrity, thereby preventing or delaying the onset of tumors. This contrasts with our earlier observation of increased mineralization without corresponding gene expression changes, emphasizing the importance of high-throughput analysis over preselected gene set analysis in comprehending functional assay results.

The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions.

More importantly, downregulation of MDM4 decreased retinoblastoma 1 (Rb1) protein expression, which is a target of MDM4 and a regulator of E2F1 signaling. In summary, the current study revealed an SNRPB2/MDM4/Rb axis in promoting the progression of TNBC, providing novel insights and novel targets for combating TNBC.

Finally, HC-067047 increased the Akt signaling that was inhibited and responsible for the decreased survival rate of newborn cells following PISE. It is concluded that TRPV4 blockage inhibits stem cell proliferation in the hippocampal DG following PISE, likely through inhibiting ERK1/2 and p38 MAPK signaling to decrease cell cycle-related protein expression, and increases newborn cell survival rate likely through increasing phosphoinositide 3 kinase-Akt signaling.

Finally, in vitro and in vivo experiments confirmed that the expression level of ADRA2C may be associated with glioma cell migration, apoptosis, and invasion. ADRA2C exhibited to play a notable role in several cancer types, suggesting that ADRA2C could serve as a promising biomarker or target for cancer diagnosis, prognosis, and treatment, particularly for GBM.

These results suggest that patient phenotypes are associated with the inherent characteristics of germline RB1 variants. These findings indicate the potential application of genetic testing results in clinical practice.

P1, N=0, Withdrawn, Brown University | N=27 --> 0 | Trial completion date: Aug 2025 --> Aug 2024 | Recruiting --> Withdrawn