AbstractEwing’s sarcoma (EWS) is an aggressive bone and soft-tissue cancer, characterized by a hallmark fusion oncoprotein comprising the amino terminus of a FET gene and the carboxy terminus of an ETS gene, most commonly (85%), the EWSR1-FLI1 t (11,22) fusion.TK-216 is a first-in-class EWSR1-FLI1 inhibitor currently in phase II clinical trials for EWS. Although TK-216 was designed to target the fusion protein interaction directly, it has demonstrated limited efficacy as a monotherapy. Thus, more effective TK-216 combination therapies are needed. We have used genome wide Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Knockout screening in EWS cells treated with TK-216 to identify novel synthetic lethality. We have identified 97 genes whose deletion potentially enhances the action of TK-216 in EWS cells. We have also identified several druggable targets, such as USP9X and the oxidative phosphorylation (OXPHOS) pathway as synthetic lethal interactions for TK-216. USP9X is known to deubiquitinate and stabilize the EWS-FLI1 fusion protein. USP9X and EWS-FLI1 protein expression levels were found to be positively correlated in EWS clinical specimens. USP9X siRNA-mediated gene silencing reduced EWS cell viability. Most importantly, USP9X siRNA-mediated gene silencing sensitized EWS cells to TK-216 treatment. In addition, inhibition of USP9X with a small-molecule inhibitor WP1130, led to significant cell death in EWS alone and in combination with TK-216 with wide therapeutic indices. The molecular mechanism of synergy and in vivo efficacy of the novel TK-216 combination will be determined in our study for future clinical translation.Citation Format: Daenikka Ravindrarajah, Sukriti Krishan, Kayleen Simpson, Twishi Gulati, Belamy B. Cheung, Glenn M. Marshall. Using genome-wide CRISPR screening to develop novel combination therapies for high-risk Ewing’s sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1080.

2024-03-22·Cancer Research

Abstract 4599: A novel small molecule inhibitor targeting MYC oncogenic signaling as an enhancer of HDAC inhibitors for the treatment of high-risk medulloblastoma

作者: Wang, Qian ; Marshall, Glenn M. ; Cheung, Belamy B. ; Gadde, Satyanarayana ; Ng, Sin Wi

AbstractBackground: Medulloblastoma (MB) is the most prevalent malignant childhood brain tumour. Although prognosis has improved over time, 95% of children with high-risk or relapsed MB eventually succumb to the disease. A key driver gene in high-risk MB is the c-MYC oncogene, for which there are currently no approved inhibitors. Histone deacetylases (HDACs) are transcriptional repressors that are dysregulated in many cancers, making them an attractive therapeutic target. Although several HDAC inhibitors have been FDA-approved for cancer treatment, they have been associated with high toxicity and limited efficacy as single agents. Therefore, simultaneously targeting c-MYC and HDACs may result in synergistic effects that could overcome drug resistance in high-risk MB.Methods and Results: We previously reported a novel pyrido-benzimidazole analogue, SE486-11, which enhanced the therapeutic effect of HDAC inhibitors in MYCN-driven cancers. We recently developed analogues (UNSW-SC compounds) with more potent activity (IC50: 0.017 to 3.70 µM). Here, we showed that these compounds significantly reduced cell viability and induced apoptosis in MB cells. MYC status was a key determinant of sensitivity of UNSW-SC compounds, with more than 3-fold higher cytotoxicity in high MYC compared to low MYC MB cells. The lead compound, UNSW-SC-22, was shown to reduce MYC protein expression and was found to be highly synergistic in enhancing the efficacy of HDAC inhibitors in MB cells. Most importantly, we demonstrated that UNSW-SC-22 was able to freely cross the blood brain barrier, reaching a concentration of 10.8 μM, with a half-life of 1.22 hours. UNSW-SC-22 directly bound to c-MYC and MYCN proteins at low micromolar equilibrium dissociation constant (KD) values which was demonstrated by surface plasmon resonance assay. In a MYCN-driven MB mouse model, we found that UNSW-SC-22 as a single agent at 90 mg/kg decreased tumor growth and prolonged survival. Through RNA-sequencing, we identified 512 differentially expressed genes after in vitro treatment with UNSW-SC-22. Importantly, GSEA analysis revealed MYC targets and cell cycle pathways as highly downregulated pathways, and upregulation in the p53 pathway. Several genes, such as MELK and USP1 were validated as down-stream targets of UNSW-SC-22. As UNSW-SC-22 is a first-in-class anticancer drug, which we are currently testing extensively in other MYC-driven MB mice models.Conclusion: Collectively, our data strongly suggest that c-Myc and MYCN are the molecular targets of UNSW-SC compounds, and these compounds have strong potential to serve as specific targeted therapy to treat subgroup 3 and 4 of MB patients with c-Myc and MYCN overexpression and amplification.Citation Format: Sin Wi Ng, Satyanarayana Gadde, Qian Wang, Belamy B. Cheung, Glenn M. Marshall. A novel small molecule inhibitor targeting MYC oncogenic signaling as an enhancer of HDAC inhibitors for the treatment of high-risk medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4599.

2024-03-22·Cancer Research

Abstract 2673: Copper chelation overcomes the immunosuppressive neuroblastoma microenvironment to potentiate anti-GD2 antibody therapy

作者: Murray, Jayne ; Salerno, Antonella ; Tedla, Nicodemus ; Haber, Michelle ; Trahair, Toby N. ; Luciani, Fabio ; Rouaen, Jourdin R. ; Vittorio, Orazio ; Shai-Hee, Tyler

AbstractNeuroblastoma is the most frequent extra-cranial pediatric cancer with high-risk disease possessing a dismal five-year survival rate <50%. Antibody-based therapies targeting the surface disialoganglioside GD2 have shown promising anti-tumor activity in patients however efficacy is strongly hampered by immunosuppressive mechanisms present in the tumor microenvironment. Neuroblastomas typically feature low mutational burdens, limited major histocompatibility complex class I expression, increased immune checkpoint markers, sparse immune infiltration, and soluble mediators which drastically limit anti-tumor immunity. Given the emerging link between elevated copper levels and tumoral immune evasion, we explored copper chelation as a therapeutic strategy using the agents tetraethylenepentamine (TEPA) and the clinically approved analogue triethylenetetramine (TETA). Using the immunocompetent TH-MYCN model, we performed single-cell RNA sequencing supported by OPAL multiplex immunohistochemistry and cytokine profiling of resected tumors to assess cellular and molecular changes occurring after one week of TEPA treatment. Therapy was observed to successfully deplete intratumoral copper and reinvigorate anti-tumor immunity with increased infiltration and activity of pro-inflammatory immune cells, and was specifically found to induce egress and N1-polarisation of neutrophils. Further mechanistic studies in vitro revealed the sequestration of copper by neuroblastoma cells attenuated neutrophil function, which could be successfully reversed upon TEPA treatment. Findings propose a novel mechanism of immune evasion, highlighting copper chelation as a therapeutic strategy to counteract immunosuppression. Using the TH-MYCN model, TEPA was employed as a priming agent to effectively potentiate anti-GD2 antibody therapy and achieve durable tumor control. Importantly, this was associated with increased Fc-receptor-bearing natural killer and myeloid cells, which elicit tumor clearance via antibody-dependent cellular cytotoxicity. Currently indicated for the treatment of copper overload disorder Wilson’s disease, TETA was evaluated for potential repurposing as a novel immunomodulatory agent. Using the syngeneic NXS2 model, TETA exhibited an exceptional safety profile and combination therapy achieved durable tumor control with no relapses occurring after treatment cessation. This result was similarly associated with the infiltration of pro-inflammatory immune cells, including N1 neutrophils. Collectively, this study credentials copper chelation as a non-toxic strategy to disrupt the immunosuppressive tumor microenvironment and reinvigorate anti-tumour immunity. Findings provide crucial translational evidence for repurposing TETA to potentiate anti-GD2 antibody therapy and improve neuroblastoma patient responses.Citation Format: Jourdin R. Rouaen, Antonella Salerno, Fabio Luciani, Jayne Murray, Tyler Shai-Hee, Nicodemus Tedla, Michelle Haber, Toby N. Trahair, Orazio Vittorio. Copper chelation overcomes the immunosuppressive neuroblastoma microenvironment to potentiate anti-GD2 antibody therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2673.

项与 Children's Cancer Institute Australia 相关的新闻（医药）

2024-06-28

·drugs

Precision-Guided Treatment Improves Outcomes for High-Risk Pediatric Cancer

FRIDAY, June 28, 2024 -- Precision-guided treatment improves outcomes for children with high-risk cancer, according to a study published online June 6 in Nature Medicine . Loretta M.S. Lau, M.B.B.S., Ph.D., from the Children's Cancer Institute at the University of New South Wales Sydney, and colleagues reported data from 384 patients with high-risk pediatric cancer with at least 18 months of follow-up on the ZERO Childhood Cancer Precision Medicine Program PRecISion Medicine for Children with Cancer trial to examine which patients will benefit most from PGT. Overall, 67 and 29 percent of children received PGT recommendations and received a recommended treatment, respectively. The researchers found that the objective response rate was 36 percent with PGT, and two-year progression-free survival was improved with PGT versus standard of care or targeted agents not guided by other molecular findings (26 percent versus 12 and 5.2 percent, respectively). Based on tier 1 evidence, the greatest clinical benefit was seen for PGT targeting fusions or commenced before disease progression. "This study demonstrates that children with high-risk cancers benefit from PGT identified by comprehensive molecular profiling," the authors write. "Treatment strategies should focus on the identification of drivers and early treatment of patients with highly targetable molecular drivers." Several authors disclosed ties to the pharmaceutical industry. Abstract/Full Text Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

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