T-cell redirecting bispecific antibody treatment in multiple myeloma: current knowledge and future strategies for sustained T-cell engagement.

Introduction: T-cell redirecting bispecific antibodies (BsAbs), targeting B-cell maturation antigen (BCMA) or G-protein - coupled receptor class C group 5 member D (GPRC5D), are efficacious new agents for the treatment of patients with relapsed or refractory MM.

Areas Covered: This review discusses the pharmacokinetic properties, efficacy, and safety profile of T-cell redirecting BsAbs in MM, with a special focus on their optimal dosing schedule, resistance mechanisms and future strategies to enhance efficacy, reduce toxicity, and maximize duration of response.

Expert Opinion: To further improve the efficacy of BsAbs, ongoing studies are investigating whether combination therapy can enhance depth and duration of response.

Hyperthermia as a Potential Cornerstone of Effective Multimodality Treatment with Radiotherapy, Cisplatin and PARP Inhibitor in -Mutated Cancer Cells.

Mutations in the isocitrate dehydrogenase 1 (IDH1MUT) gene occur in various types of malignancies, including ~60% of chondrosarcomas, ~30% of intrahepatic cholangiocarcinomas and >80% of low-grade gliomas. IDH1MUT are causal in the development and progression of these types of cancer due to neomorphic production of the oncometabolite D-2-hydroxyglutarate (D-2HG). Intracellular accumulation of D-2HG has been implicated in suppressing homologous recombination and renders IDH1MUT cancer cells sensitive to DNA-repair-inhibiting agents, such as poly-(adenosine 5′-diphosphate−ribose) polymerase inhibitors (PARPi).

IDH1/2 Mutations in Cancer Stem Cells and Their Implications for Differentiation Therapy.

Isocitrate dehydrogenase 1 and 2 (IDH1/2) are enzymes recurrently mutated in various types of cancer, including glioma, cholangiocarcinoma, chondrosarcoma, and acute myeloid leukemia. Mutant IDH1/2 induce a block in differentiation and thereby contribute to the stemness and oncogenesis of their cells of origin. Recently, small-molecule inhibitors of mutant IDH1/2 have been Food and Drug Administration-approved for the treatment of -mutated acute myeloid leukemia.

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow.

Energy production by means of ATP synthesis in cancer cells has been investigated frequently as a potential therapeutic target in this century. Both (an)aerobic glycolysis and oxidative phosphorylation (OXPHOS) have been studied. Here, we review recent literature on energy production in glioblastoma stem cells (GSCs) and leukemic stem cells (LSCs) versus their normal counterparts, neural stem cells (NSCs) and hematopoietic stem cells (HSCs), respectively.

A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with -Mutated Solid Tumors.

Background: Mutations in isocitrate dehydrogenase 1 () occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid -mutated tumors produce the oncometabolite -2-hydroxyglutarate (-2HG) and are more vulnerable to disruption of their metabolism.

Methods: Patients with -mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine.

Energy Metabolism in Wild-Type and -Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?

Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS).

A Phase II Study Demonstrates No Feasibility of Adjuvant Treatment with Six Cycles of S-1 and Oxaliplatin in Resectable Esophageal Adenocarcinoma, with ERCC1 as Biomarker for Response to SOX.

We assessed the feasibility of adjuvant S-1 and oxaliplatin following neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Patients treated with nCRT (paclitaxel, carboplatin) and esophagectomy received six 21-day cycles with oxaliplatin (130 mg/m) on day 1 and S-1 (25 mg/m twice daily) on days 1-14. The primary endpoint was feasibility, defined as ≥50% completing treatment.

Immunohistochemical Detection of Neural Stem Cells and Glioblastoma Stem Cells in the Subventricular Zone of Glioblastoma Patients.

Glioblastoma usually recurs after therapy consisting of surgery, radiotherapy, and chemotherapy. Recurrence is at least partly caused by glioblastoma stem cells (GSCs) that are maintained in intratumoral hypoxic peri-arteriolar microenvironments, or niches, in a slowly dividing state that renders GSCs resistant to radiotherapy and chemotherapy. Because the subventricular zone (SVZ) is a major niche for neural stem cells (NSCs) in the brain, we investigated whether GSCs are present in the SVZ at distance from the glioblastoma tumor.

2D and 3D assays to quantify the invasive behavior of glioblastoma stem cells in response to SDF-1α.

Invasion is a hallmark of cancer and therefore invasion assays are important tools in cancer research. We aimed to describe 2D transwell assays and 3D spheroid assays to quantitatively determine the invasive behavior of glioblastoma stem cells in response to the chemoattractant SDF-1α. Matrigel was used as a matrix in both assays.

Development and validation of an LC-MS/MS method for simultaneous quantification of co-administered trastuzumab and pertuzumab.

Given the increasing use of combination therapy with multiple monoclonal antibodies (mAbs), there is a clinical need for multiplexing assays. For the frequently co-administered anti-human epidermal growth factor receptor 2 (HER2) mAbs trastuzumab and pertuzumab, we developed a high-throughput and robust hybrid ligand-binding liquid chromatography-mass spectrometry (LC-MS)/MS quantitative assay. Nanomolar concentrations of trastuzumab and pertuzumab were determined in 10 µL serum samples after extraction by affinity purification through protein A beads, followed by on-bead reduction, alkylation, and trypsin digestion.

CXCR4 Antagonists as Stem Cell Mobilizers and Therapy Sensitizers for Acute Myeloid Leukemia and Glioblastoma?

Glioblastoma is the most aggressive and malignant primary brain tumor in adults and has a poor patient survival of only 20 months after diagnosis. This poor patient survival is at least partly caused by glioblastoma stem cells (GSCs), which are slowly-dividing and therefore therapy-resistant. GSCs are localized in protective hypoxic peri-arteriolar niches where these aforementioned stemness properties are maintained.

Phase II Feasibility and Biomarker Study of Neoadjuvant Trastuzumab and Pertuzumab With Chemoradiotherapy for Resectable Human Epidermal Growth Factor Receptor 2-Positive Esophageal Adenocarcinoma: TRAP Study.

Purpose: Approximately 15% to 43% of esophageal adenocarcinomas (EACs) are human epidermal growth factor receptor 2 (HER2) positive. Because dual-agent HER2 blockade demonstrated a survival benefit in breast cancer, we conducted a phase II feasibility study of trastuzumab and pertuzumab added to neoadjuvant chemoradiotherapy (nCRT) in patients with EAC.

Patients And Methods: Patients with resectable HER2-positive EAC received standard nCRT with carboplatin and paclitaxel and 41.

Study protocol of a phase II clinical trial of oral metformin for the intravesical treatment of non-muscle invasive bladder cancer.

Background: Non-muscle-invasive bladder cancer (NMIBC) is the most common neoplasm of the urinary tract and requires life-long invasive surveillance to detect disease recurrence. Currently, there are no effective oral therapies that delay disease recurrence or progression. We recently demonstrated that in mice, metformin accumulates unchanged in the urine.

Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies.

Glioblastoma is the most aggressive primary brain tumor. Slowly dividing and therapy-resistant glioblastoma stem cells (GSCs) reside in protective peri-arteriolar niches and are held responsible for glioblastoma recurrence. Recently, we showed similarities between GSC niches and hematopoietic stem cell (HSC) niches in bone marrow.

A simple approach to generate gene-expression profiles from subsets of cancer genomics data.

In biomedical research, large-scale profiling of gene expression has become routine and offers a valuable means to evaluate changes in onset and progression of diseases, in particular cancer. An overwhelming amount of cancer genomics data has become publicly available, and the complexity of these data makes it a challenge to perform data exploration, integration and analysis, in particular for scientists lacking a background in computational programming or informatics. Many web interface tools make these large datasets accessible but are limited to process large datasets.

Comparison of different methodologies and cryostat versus paraffin sections for chromogenic immunohistochemistry.

Immunohistochemistry (IHC) specifically localizes proteins in cells and tissues, but methodologies vary widely. Therefore, we performed a methodological IHC optimization and validation study. First, we compared advantages and disadvantages of cryostat sections versus paraffin sections.

Correction: Wild-type and mutated IDH1/2 enzymes and therapy responses.

The originally published version of this article contained an error in Figure 2. On the IDH1/2 mutated arrow, it incorrectly read 'NADP ->NADPH' instead of the correct 'NADPH ->NADP'. This has now been corrected in the PDF and HTML versions of the article.

Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress.

Diffuse gliomas often carry point mutations in isocitrate dehydrogenase ( IDH1), resulting in metabolic stress. Although IDH gliomas are difficult to culture in vitro, they thrive in the brain via diffuse infiltration, suggesting brain-specific tumor-stroma interactions that can compensate for IDH-1 deficits. To elucidate the metabolic adjustments in clinical IDH gliomas that contribute to their malignancy, we applied a recently developed method of targeted quantitative RNA next-generation sequencing to 66 clinical gliomas and relevant orthotopic glioma xenografts, with and without the endogenous IDH-1 mutation.

Metabolic Mapping: Quantitative Enzyme Cytochemistry and Histochemistry to Determine the Activity of Dehydrogenases in Cells and Tissues.

Altered cellular metabolism is a hallmark of many diseases, including cancer, cardiovascular diseases and infection. The metabolic motor units of cells are enzymes and their activity is heavily regulated at many levels, including the transcriptional, mRNA stability, translational, post-translational and functional level. This complex regulation means that conventional quantitative or imaging assays, such as quantitative mRNA experiments, Western Blots and immunohistochemistry, yield incomplete information regarding the ultimate activity of enzymes, their function and/or their subcellular localization.

IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity.

Isocitrate dehydrogenase ( IDH1)-1 is mutated in various types of human cancer, and the presence of this mutation is associated with improved responses to irradiation and chemotherapy in solid tumor cells. Mutated IDH1 (IDH1) enzymes consume NADPH to produce d-2-hydroxyglutarate (d-2HG) resulting in the decreased reducing power needed for detoxification of reactive oxygen species (ROS), for example. The objective of the current study was to investigate the mechanism behind the chemosensitivity of the widely used anticancer agent cisplatin in IDH1 cancer cells.

The hypoxic peri-arteriolar glioma stem cell niche, an integrated concept of five types of niches in human glioblastoma.

Glioblastoma is the most lethal primary brain tumor and poor survival of glioblastoma patients is attributed to the presence of glioma stem cells (GSCs). These therapy-resistant, quiescent and pluripotent cells reside in GSC niches, which are specific microenvironments that protect GSCs against radiotherapy and chemotherapy. We previously showed the existence of hypoxic peri-arteriolar GSC niches in glioblastoma tumor samples.

Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation.

Introduction: Chondrosarcoma is a malignant cartilage-forming bone tumour in which mutations in IDH1 and IDH2 frequently occur. Previous studies suggest an increased dependency on glutaminolysis in IDH1/2 mutant cells, which resulted in clinical trials with the drugs CB-839, metformin and chloroquine. In this study, the preclinical rationale for using these drugs as a treatment for chondrosarcoma was evaluated.