MYC amplification

Aurora kinase inhibitors such as alisertib can destabilize MYC-family oncoproteins and have demonstrated compelling anti-tumor efficacy. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC- driven SCLC. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC- and/or N-MYC.

MYC amplifications had a prognostic influence on survival, whereas ARID1A gene mutations were correlated with microvascular invasion. These may serve as prognostic biomarkers and should be validated in large, independent cohort.

sWGS and targeted sequencing identified therapeutic opportunities in 75% of p53abn EC patients. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn ECs.

We identified MYC amplification and ERBB3 as possible predictors of disease metastases and recurrence. Additional research regarding targetable MYC and ERBB3 therapies are warranted.

These results highlight the value of preclinical tumoroid models in understanding the pathogenesis of rare cancers and developing treatments. LCNEC showed a high success rate in tumoroid establishment, indicating its potential application in personalized medicine.

The combination of CDK4/6i and A80.2HCl result in marked regression in tumor growth in vivo. Altogether, these results reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the utilization of the MYC degrading molecule A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i.

We confirmed the previously reported associations with MYC and TP63 in the prognostically relevant subgroups of ACC-I and II, respectively, and report immunologic differences among these subtypes. Survival outcomes are comparatively worse in ACC-I regardless of treatment type.

Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery.

Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC.

Therefore, relevant clinicoradiologic information and ancillary work up, including immunohistochemistry and molecular studies, may be helpful for the accurate classification. Our tumor further raises awareness of this rare event, expands the spectrum of its clinical presentation, and explores the molecular features.

Our prelimary data suggest that sAS discloses an immunosuppressive environment; therefore, compared to pAS, sAS might be a better candidate to immunotherapy.

There is a great genomic variability in each intrinsic subtype of advanced BC, with apparently no genomic pattern correlating with each phenotype. Although a transcriptomic test (Prosigna) can help in the classification of the tumors, NGS sequencing with an extended panel allows identifying genetic variants that might benefit the patient with a targeted therapy i a significant percentage of cases.

Results showed 8 active compounds, targeting MB reported targets and several are currently approved or in clinical trials for pediatric patients with PBTs, including MB. Moreover, hits were combined to avoid tumor resistance, identifying 3 synergistic pairs, one of which is currently under clinical study for recurrent MB and other PBTs.

Additional risk factors comprised elevated serum AST, LDH or ALP, decreased Hb, genetic markers like RB1 and PTEN loss, PIK3CB and MYC amplification, as well as numerous PC treatments either acting directly or indirectly through inducing liver injury. Further research regarding predictive factors, early detection strategies, and targeted therapies for PCLM are critical for improving patient outcomes.

These preclinical findings highlight the promise of marinopyrrole MP1 as a novel MYC inhibition approach for MYC-amplified MB.

Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRASi and represents a promising therapeutic target for combination strategies with KRASi in the treatment of KRAS-mutant cancers.

No abstract available

P1, N=30, Completed, Prelude Therapeutics | Active, not recruiting --> Completed

As part of a nationwide cancer genome screening project, J-SCRUM GI SCREEN database provides comprehensive genomic information for Asian population (Japan). The prevalence of key actionable gene alterations in each tumor type was highly comparable between J-SCRUM GI-SCREEN and TCGA data.

The combination of HER2 amplification and PD-L1 expression in Chinese patients with GC could stratify the total populations into several subgroups with distinctive genomic and immune landscapes, which should be considered when making personalized treatment decisions.

Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels.

Orally administered CDDD11-8 also inhibited growth of mammary intraductal TNBC xenograft tumours with no overt toxicity in vivo (mice) or ex vivo (human breast tissues). In conclusion, our studies indicate that CDK9 is a viable therapeutic target in TNBC and that CDDD11-8, a novel selective CDK9 inhibitor, has efficacy in TNBC without apparent toxicity to normal tissues.

Finally, we detail strategies for metabolite identification and data analysis. For complete details on the use and execution of this protocol, please refer to Gwynne et al..

MYC defines a biologically distinct subset of PCa patients and is characterized with multiple proxies of advanced disease. These data suggest that MYC may be prognostic; independent cohorts are needed to validate these findings.

Interestingly, in lung cancer, KRAS mutations are less common in both smokers and non-smokers with AFR ancestry, whereas the association of TP53 mutations with AFR ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates. Our study highlights the need to increase representation of patients with AFR ancestry in drug development and biomarker discovery.

The NOTCH3 sole variant was an independent and favorable prognostic factor for left-sided CRC (p < 0.01). The prognostic significance of gene alterations differed between left-sided CRC and right-sided CC.

We identify that combining YBX1 inhibition sensitizes to both gemcitabine and vincristine in vitro and in vivo. We are currently evaluating this YBX1 inhibitor in an “anchor-probe” screen combining with all currently FDA approved drugs. Our findings impart an alluring prospect of targeting YBX1 in combination with chemotherapy, and possibly other compounds could improve patients’ outcomes.

Our study identifies the combination of entinostat with olaparib as a new potential therapeutic approach for MYC-driven Group 3 MB.

10 patients were platinum sensitive and 10 patients were platinum resistant. The histological type was identified as High grade serous carcinoma at 90% and endometrioid carcinoma at 10%. LOH score increased in 15 patients (88%).

MET-amplified, ALK + NSCLC often presents with high-level and heterogeneous amplification in tissue, seldom overlaps with ALK mutations, and frequently co-occurs with alterations associated with aggressive tumor biology.

Genetic aberrations classified as high-risk by the ELN recommendations such as mutations in ASXL1 and RUNX1 were not associated with a significantly worse response rate. On the contrary and as expected, mutations in TP53 showed the worst response rate.

Targeting pediatric brain tumors with an anti-B7H3 CAR-NK cell therapy may provide a safe and effective treatment for patients who have extremely limited therapeutic options. As B7-H3 is a tumor associated antigen found to be overexpressed in a large variety of tumor types, this strategy may also be useful for treatment of other B7-H3 expressing cancers.

Enrollment commenced in January 2022 in the United States and in May 2023 in Europe.

Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression.

In addition, the Committee has data analyses and a clinical trial under way to evaluate approaches to local management of the primary tumor and metastatic sites. Given the rarity of bone sarcomas, we have prioritized international interactions and are in the process of forming an international data-sharing consortium to facilitate refinement of risk stratification and study of rare disease subtypes.

In EWS we observed a predominant pattern of emergence of new biological and/or actionable variants over time with emergence of new STAG2 or TP53 mutations occurring in 26% of patients, confirming the importance of these genes in resistant disease. In OS, we observed mixed patterns of change including persistence, emergence and disappearance of variants, suggesting the previously described unstable genome in OS impacts key oncogenes and potentially targetable genes. Given the observed patterns of genomic change in OS and EWS, there may be utility to repeat sequencing of relapsed tumor biopsies.

Enrollment commenced in January 2022 in the United States and in May 2023 in Europe.

MT-1 is a bivalent BD inhibitor that is 100-fold more potent than the first-in-class BD inhibitor JQ1...The treatment of 3D cell cultures derived from three unique clinically annotated heavily pretreated patient-derived PC xenografts (PDX) mice models with increasing doses of MT-1 demonstrated the lowest IC in tumors with c-Myc amplification and clinically resistant to Docetaxel, Cabazitaxel, Abiraterone, and Enzalutamide. An intraperitoneal injection of either MT-1 or in combination with 3jc48-3, an inhibitor of obligate heterodimerization with MYC-associated protein X (MAX), in mice implanted with orthotopic PC PDX, decreased tumor growth. This is the first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation.

At present, she has finished four cycles of the regimen and remained in complete remission. Venetoclax plus azacitidine could be an effective regimen for the poor prognosis of AML with dmin through MYC amplification.