Biomarker Testing Journey Among Patients with Advanced Solid Tumors and Treatment Patterns by Homologous Recombination Repair Status: A Clinico-Genomic Database Study.

Introduction: Defects in the homologous recombination repair (HRR) pathway can include mutations in BRCA1 and BRCA2 (BRCAm) and other HRR genes (HRRm). These mutations are associated with a homologous recombination deficiency (HRD) phenotype. We evaluated testing journey and treatment patterns by BRCAm, HRRm, and HRD status in a real-world dataset.

Association Between Homologous Recombination Repair Biomarkers and Survival in Patients With Solid Tumors.

Purpose: Mutations in and/or (BRCAm), other homologous recombination repair genes (HRRm), and homologous recombination deficiency (HRD) lead to an accumulation of genomic alterations that can drive tumorigenesis. The prognostic impact of these HRR pathway defects on overall survival (OS) in patients not receiving poly (ADP-ribose) polymerase inhibitors (PARPi) or immunotherapy is unclear. We evaluated the association of HRR biomarkers with OS in patients with advanced solid tumors receiving therapy excluding PARPi and immunotherapy.

Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study.

Background: Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study.

Methods: DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries.

Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model.

Although highly effective, BCR-ABL1 tyrosine kinase inhibitors do not target chronic myeloid leukemia (CML) stem cells. Most patients relapse upon tyrosine kinase inhibitor therapy cessation. We reported previously that combined BCR-ABL1 and BCL-2 inhibition synergistically targets CML stem/progenitor cells.

Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.

Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer cells, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that induced methylated and silenced CpG island promoters driving a reporter gene (GFP) as well as endogenous TSGs in multiple cancer cell lines.

Mitochondrial Profiling of Acute Myeloid Leukemia in the Assessment of Response to Apoptosis Modulating Drugs.

BH3 profiling measures the propensity of transformed cells to undergo intrinsic apoptosis and is determined by exposing cells to BH3-mimicking peptides. We hypothesized that basal levels of prosurvival BCL-2 family proteins may modulate the predictive power of BH3 profiling and termed it mitochondrial profiling. We investigated the correlation between cell sensitivity to apoptogenic agents and mitochondrial profiling, using a panel of acute myeloid leukemias induced to undergo apoptosis by exposure to cytarabine, the BH3 mimetic ABT-199, the MDM2 inhibitor Nutlin-3a, or the CRM1 inhibitor KPT-330.

Prdm14 initiates lymphoblastic leukemia after expanding a population of cells resembling common lymphoid progenitors.

Understanding the heterogeneous genetic mechanisms of tumor initiation in lymphoid leukemias (LL) will lead to improvements in prognostic classification and treatment regimens. In previous studies of mouse leukemias, we showed that retroviral insertion at the ecotropic viral insertion site 32 locus leads to increased expression of Prdm14, a pluripotency gene implicated in the self-renewal capacity of embryonic stem cells and the early stages of breast cancer. Here, we show that PRDM14 is also overexpressed in ∼25% of human lymphoid neoplasms, with increased frequencies in T-cell acute LL and hyperdiploid precursor B-cell acute LL.

The zinc finger SET domain gene Prdm14 is overexpressed in lymphoblastic lymphomas with retroviral insertions at Evi32.

Background: AKXD recombinant inbred strains of mice have proven to be very useful in the identification of potential oncogenes and tumor suppressors involved in the development of lymphoid and myeloid malignancies. In these tumors, the hematopoietic insertion of an active AKV murine leukemia virus (MuLV) is associated with the onset of disease. Common sites of retroviral insertion (CIS) identify genes causally associated with the development or initiation of lymphoma.