MECOM (MDS1 And EVI1 Complex Locus)

This proof-of-concept study opens the possibility to target one of the most incurable forms of AML with specific EVI1-CTBP inhibitors. This has important implications for other tumor types with aberrant expression of EVI1 and for cancers transformed by different CTBP-dependent oncogenic transcription factors.

Outcomes of 3q26.2/MECOM-rearranged CML are poor despite the availability of multiple BCR::ABL1 tyrosine kinase inhibitors (TKIs). Third-generation TKIs in combination with novel agents and possible allo-SCT could be considered given the poor outcomes and resistance to second-generation TKIs.

In conclusion, EVI1 & MEF2C were significantly expressed in AML cases. EVI1 & MEF2C overexpression were significantly associated with 11q23 rearrangements and t (9;22) and were indicators for poor outcome in adult AML patients; These results could be a step towards personalized therapy in those patients.

We have established a new risk prediction model using serum samples from T1 LUAD patients, enabling noninvasive identification of those with positive lymph node metastases.

This indicates a possible role of these TFs in the upregulation of (sialyl)Lewis antigens, particularly on GSL glycans, via FUT3/4 expression in colon-like cell lines. In conclusion, our study provides insights into the possible regulation of glycans in CRC and can serve as a guide for the development of diagnostic and therapeutic biomarkers.

This case report demonstrates the feasibility and role of combination pre-clinical high throughput screening to aid decision making in high-risk leukaemia. It also demonstrates the role a JAK1/2 inhibitor can have in the palliative setting in select patients with AML.

P1, N=32, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Aug 2024 --> Feb 2026 | Trial primary completion date: Feb 2024 --> Aug 2025

The ROC curve showed that the area under the curve of MECOM was 0.804 for LUAD and, of note, could reach 0.889 for advanced LUAD; specificity was up to 90%. MECOM may contribute to independently identifying LUAD patients, particularly in advanced stages.

ETV6-MECOM induces EMT-related properties by downregulating the transcriptional expression of E-cadherin and repressing its transactivation activity by binding to its core motif -1116TTAAAA-1111 in leukemia K562 cells. These findings could contribute to the development of a therapeutic target for patients with myeloid leukemia characterized by ETV6-MECOM.

GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.

P1, N=100, Recruiting, Jacqueline Garcia, MD | Trial completion date: Dec 2024 --> Feb 2026 | Trial primary completion date: Feb 2024 --> Feb 2025

P=N/A, N=24, Recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto | Not yet recruiting --> Recruiting | Trial completion date: Sep 2026 --> Dec 2026 | Initiation date: Sep 2023 --> Dec 2023 | Trial primary completion date: Sep 2026 --> Dec 2026

Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.

The logistics of proceeding to transplant might necessitate consolidation chemotherapy usually involving high dose cytarabine (HiDAC)...Infections included bacteremia from Klebsiella, E. Coli, Proteus, group B strep, vancomycin resistant E. Faecalis, and coagulase negative staph, pneumonia from Klebsiella, urinary tract infections from extended spectrum beta-lactamase resistant E. Coli, Klebsiella, and proteus mirabilis, fungal sinusitis, and Clostridium difficile colitis...HSCT is the sole curative option for high-risk AML patients, and the concept of bridging the period between induction and HSCT with HiDAC consolidation appears to offer no additional benefit compared to IDAC. Moreover, this approach prevents a subset of this population from being fit enough to receive HSCT.

We uncover a TF network involved in urothelial cell identity and BLCA. We identify novel candidate TFs involved in differentiation and cancer that provide opportunities for a better understanding of the underlying biology and therapeutic intervention.

The 16 common CNVs between cancers can be used to identify the target of pan-cancer drug design and targeted therapies. Additionally, 22 caner-specific CNVs can be used as unique diagnostic markers for each cancer type.

Appealing patterns of resistance emerged from genomic analysis: the “activating like� signature may help define a specific target among tyrosine kinase inhibitors, while “self-renewal like� patients may benefit from histone deacetylase inhibitors (as we previously published). HOXA genes overexpression open a novel therapeutic options for selected patients.

The patient recovered well after Allo-HSCT. Therefore, for patients with RUNX1-MECOM and RUNX1-RPL22 fusion genes, transplantation may be a good choice when chemotherapy is not effective.

In a heavily pre-treated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit.

High-resolution genome-wide evaluation not reliant on cell culture substantially expands the scope of detectable variants, for many of which determining the biologic and clinical implications will require larger scale prospective study. Importantly, application of OGM in the clinical setting is likely to result in clinically meaningful disease reclassification and restratification of risk, and in some cases may permit patients access to previously inaccessible targeted therapies (as in the instance of cytogenetically cryptic tyrosine kinase gene fusions).

Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study.

In this phase Ib dose escalation study, standard dose CPX-351 combined with 7 days of Ven was found to safe and tolerable in pts with rAML. The combination produced encouraging response rates in a poor risk population, including those with prior Ven treatment, allowing a significant proportion to undergo allo-SCT and extended survival. The RP2D is being studied in pts with newly diagnosed and less heavily pretreated AML.

Among 3 MDS with MECOM rearrangement, one patient received azacitidine with investigational drug (sabatolimab/placebo) and achieved complete hematologic response. Chemotherapy should be avoided in this subtype due to non-responsiveness, hypomethylating agent showed benefit and can be considered as a bridging treatment before stem cell transplantation. Novel therapy targeting MECOM gene should be further explored to improve outcomes in this AML subtype.

Salvage therapies for patients included re-induction with 7+3, FLAG-Ida, mitoxantrone-containing regimens, clofarabine-based protocols, or combination of hypomethylating agents with venetoclax. In summary, de novo AML inv(3)/t(3; 3) is a rare and aggressive subtype of AML conferring extremely poor prognosis. There appears to be an increase of incidence in females affecting a slightly younger demographic. Consistent with previous studies, the presence of chr 7 abnormalities was associated with even worse outcomes, which interestingly also drive EVI1 overexpression.

Through deep transcriptomic characterization combined with conventional diagnostics, this analysis uncovered novel mechanisms of VEN resistance while confirming established ones. The distinct gene expression patterns may help tailor targeted therapies, with patients showing the "activating-like" signature potentially benefiting from tyrosine kinase inhibitors and those with the "self-renewal like" signature possibly responding well to histone deacetylase inhibitors. Furthermore, HOXA gene overexpression presents an exciting therapeutic opportunity for selected patients.

The MyeChild 01 international phase III trial (NCT02724163) in children with de novo AML allocated patients up to 3 doses of gemtuzumab ozogamicin (GO 3mg/m2/dose) during the first course of induction chemotherapy (mitoxantrone 12 mg/m2/dose x4; cytarabine 100 mg/m2/dose x20). Two intensive courses of induction chemotherapy, including GO and mitoxantrone in course 1 and FLA-Ida in course 2, consolidated with allogeneic HSCT, appears to be an effective approach for most HR patients. 2 year estimated outcomes for HR patients compare favourably to recent trials of GO in pediatric AML, with particularly encouraging data for patients with KMT2A-r and FLT3-ITD.

1) Extensive genetic profiling indicated a substantial clonal evolution in the progression from CP to BP CML including loss of ASXL1 mutations, expansion of RUNX1 mutated clones, multiple CNA, and the frequent acquisition of a BCR rearrangement in BP with a transcriptomic phenotype resembling B-ALL. 2) A subset of CML cases in CP already showed a transcriptomic phenotype resembling acute leukemia indicating a rapid progression to BP. 3) The presence of a RUNX1 mutated subclone or a clonal BCR rearrangement seem to represent a warning signal in CML CP.

LINCS1000-CMap analysis, conducted with the RNA-Seq signature induced by lethal RUNX1 knockdown in AML cells with mutant (mt) RUNX1, was reported by us to reveal homoharringtonine (HHT or omacetaxine) and the anthelmintic fenbendazole (analog of mebendazole) as the top expression mimickers (EMs). These preclinical findings highlight the molecular features associated with progression of RUNX1-FPD to FPD-MM, including the newly established GMR-AML1 cell line. They also demonstrate that HHT or MB are effective against cellular models of FPD-MM versus RUNX1-FPD.

GT19715 but did not reduce total mouse BM CD45+ cells, suggesting favorable toxicity profiles of GT19715. In conclusion, TP53mut AML comprised highly enriched LSC populations compared to TP53wt AML and targeting of c-MYC protein is highly effective in TP53mut AML in vitro and in vivo with a therapeutic window between AML LSC and normal hematopoietic cells.

Interestingly, 7 patients (64%) were diagnosed while they were receiving lenalidomide after a median exposure to lenalidomide of 8.8 months (4.9 – 30.73)... The incidence of AML or MDS associated with lymphoid disease is low. Furthermore, the population is remarkably heterogeneous. The characteristics and the timing of onset of the disease account for different ontogenesis; a portion of the patient has a disease that harbors complex alterations, while the most frequent origin of AML and MDS can be researched in pre-existing or contemporary hematopoietic clones, that overall account for a whole bone-marrow disease.

Patients received intensive treatment (IT; 40% of patients, 41% of whom with the addition of venetoclax) or low intensity treatments (LIT; 60% of patients, 72% with venetoclax)... Although outcomes of patients with AML have improved, disease relapse remains a major obstacle with poor outcomes despite the availability of new salvage strategies. Highly effective induction and maintenance regimens are needed to reduce the risk of relapse.

This was consistent with previous reports that BET inhibitors (e.g., OTX015, mivebresib or ABBV-075 and JQ1) are effective against 3q26.2-r AML cell lines, patient-derived (PD) AML cells and PDX models...In follow-up experiments, XIAP/cIAPs inhibitors birinapant (10-1000 nM) or SM-164 (30-1000 nM), chosen based on the MIPE screen outcomes, induced significantly more dose-dependent apoptosis in 3q26.2-r versus the other AML cell lines...Treatment with the dual mTOR/PIK3CA inhibitor NVP-BGT226 (1-30 nM) or navitoclax or Bcl-xL-specific BH3 mimetic A-1155463 also exerted lethality and synergistically induced apoptosis with mivebresib in AML cells with inv3/t(3; 3)...Co-treatment with birinapant and tegavivint also synergistically induced apoptosis in 3q26.2-r AML cells...Additionally, compared to each drug or vehicle control, co-treatment with birinapant and the BETi OTX015 (30 mg/kg/day, by oral gavage) was more effective in reducing AML burden in the xenograft model. These findings demonstrate promising preclinical activity of IAP protein inhibition against the cellular models of AML with inv3/t(3; 3) with EVI1 overexpression, supporting the rationale to further evaluate in vivo efficacy of birinapant and/or BETi-based combinations against this AML sub-type.

Though <40% are cured after relapse in pAML, chemotherapy intensification is often not feasible, as toxicity causes ~10% mortality rate. Besides evaluating measurable residual disease, detecting unique driving events and concurrent molecular alterations impacts pAML management. Integration of genomic findings into clinical care for highrisk/refractory pAML patients, shows that ~14% can get targeted therapies.

Finally, we functionally validate that Arhgap5 and Mecom are tumor suppressor genes, providing possible therapeutic targets for CRC. Thus, we demonstrate the importance of the inactivation of senescence pathways in CRC development and progression in an inflammatory microenvironment, which can help progress toward precision medicine.