Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma.

Background: Accumulation of malignant plasma cells in the bone marrow causes lytic bone lesions in 80% of multiple myeloma patients. Frequently fracturing, they are challenging to treat surgically. Myeloma cells surviving treatment in the presumably protective environment of bone lesions impede their healing by continued impact on bone turnover and can explain regular progression of patients without detectable minimal residual disease (MRD).

A single-cell transcriptomic map of the murine and human multiple myeloma immune microenvironment across disease stages.

Background: The long-term effectiveness of immunotherapies against Multiple Myeloma (MM) remains elusive, demonstrated by the inevitable relapse in patients. This underscores the urgent need for an in-depth analysis of the MM tumor-immune microenvironment (TME). Hereto, a representative immunocompetent MM mouse model can offer a valuable approach to study the dynamic changes within the MM-TME and to uncover potential resistance mechanisms hampering effective and durable therapeutic strategies in MM.

AXL as immune regulator and therapeutic target in Acute Myeloid Leukemia: from current progress to novel strategies.

Until recently, treatment options for patients diagnosed with Acute Myeloid Leukemia (AML) were limited and predominantly relied on various combinations, dosages, or schedules of traditional chemotherapeutic agents. Patients with advanced age, relapsed/refractory disease or comorbidities were often left without effective treatment options. Novel advances in the understanding of leukemogenesis at the molecular and genetic levels, alongside recent progress in drug development, have resulted in the emergence of novel therapeutic agents and strategies for AML patients.

Fueling CARs: metabolic strategies to enhance CAR T-cell therapy.

CAR T cells are widely applied for relapsed hematological cancer patients. With six approved cell therapies, for Multiple Myeloma and other B-cell malignancies, new insights emerge. Profound evidence shows that patients who fail CAR T-cell therapy have, aside from antigen escape, a more glycolytic and weakened metabolism in their CAR T cells, accompanied by a short lifespan.

Anti-Idiotypic VHHs and VHH-CAR-T Cells to Tackle Multiple Myeloma: Different Applications Call for Different Antigen-Binding Moieties.

CAR-T cell therapy is at the forefront of next-generation multiple myeloma (MM) management, with two B-cell maturation antigen (BCMA)-targeted products recently approved. However, these products are incapable of breaking the infamous pattern of patient relapse. Two contributing factors are the use of BCMA as a target molecule and the artificial scFv format that is responsible for antigen recognition.

Targeting mTOR signaling pathways in multiple myeloma: biology and implication for therapy.

Multiple Myeloma (MM), a cancer of terminally differentiated plasma cells, is the second most prevalent hematological malignancy and is incurable due to the inevitable development of drug resistance. Intense protein synthesis is a distinctive trait of MM cells, supporting the massive production of clonal immunoglobulins or free light chains. The mammalian target of rapamycin (mTOR) kinase is appreciated as a master regulator of vital cellular processes, including regulation of metabolism and protein synthesis, and can be found in two multiprotein complexes, mTORC1 and mTORC2.

AXL-specific single domain antibodies show diagnostic potential and anti-tumor activity in Acute Myeloid Leukemia.

AXL expression has been identified as a prognostic factor in acute myeloid leukemia (AML) and is detectable in approximately 50% of AML patients. In this study, we developed AXL-specific single domain antibodies (sdAbs), cross-reactive for both mouse and human AXL protein, to non-invasively image and treat AXL-expressing cancer cells. AXL-specific sdAbs were induced by immunizing an alpaca with mouse and human AXL proteins.

Scrutiny of chimeric antigen receptor activation by the extracellular domain: experience with single domain antibodies targeting multiple myeloma cells highlights the need for case-by-case optimization.

Introduction: Multiple myeloma (MM) remains incurable, despite the advent of chimeric antigen receptor (CAR)-T cell therapy. This unfulfilled potential can be attributed to two untackled issues: the lack of suitable CAR targets and formats. In relation to the former, the target should be highly expressed and reluctant to shedding; two characteristics that are attributed to the CS1-antigen.

RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma.

Background: Immunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of available compounds, strategies for appropriate choice of targets (combinations) are warranted. Simultaneously, risk assessment is advisable as patient's life expectancy varies between months and decades.

S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability in multiple myeloma.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy and is incurable because of the inevitable development of drug resistance. Methionine adenosyltransferase 2α (MAT2A) is the primary producer of the methyl donor S-adenosylmethionine (SAM) and several studies have documented MAT2A deregulation in different solid cancers. As the role of MAT2A in MM has not been investigated yet, the aim of this study was to clarify the potential role and underlying molecular mechanisms of MAT2A in MM, exploring new therapeutic options to overcome drug resistance.

Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment.

Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions.

Targeted α-Therapy Using Ac Radiolabeled Single-Domain Antibodies Induces Antigen-Specific Immune Responses and Instills Immunomodulation Both Systemically and at the Tumor Microenvironment.

Targeted radionuclide therapy (TRT) using targeting moieties labeled with α-particle-emitting radionuclides (α-TRT) is an intensely investigated treatment approach as the short range of α-particles allows effective treatment of local lesions and micrometastases. However, profound assessment of the immunomodulatory effect of α-TRT is lacking in literature. Using flow cytometry of tumors, splenocyte restimulation, and multiplex analysis of blood serum, we studied immunologic responses ensuing from TRT with an antihuman CD20 single-domain antibody radiolabeled with Ac in a human CD20 and ovalbumin expressing B16-melanoma model.

Metformin confers sensitisation to syrosingopine in multiple myeloma cells by metabolic blockage and inhibition of protein synthesis.

Multiple myeloma (MM) remains an incurable haematological malignancy despite substantial advances in therapy. Hypoxic bone marrow induces metabolic rewiring in MM cells contributing to survival and drug resistance. Therefore, targeting metabolic pathways may offer an alternative treatment option.

The prognostic value and therapeutic targeting of myeloid-derived suppressor cells in hematological cancers.

The success of immunotherapeutic approaches in hematological cancers is partially hampered by the presence of an immunosuppressive microenvironment. Myeloid-derived suppressor cells (MDSC) are key components of this suppressive environment and are frequently associated with tumor cell survival and drug resistance. Based on their morphology and phenotype, MDSC are commonly subdivided into polymorphonuclear MDSC (PMN-MDSC or G-MDSC) and monocytic MDSC (M-MDSC), both characterized by their immunosuppressive function.

Targeting the β -adrenergic receptor increases chemosensitivity in multiple myeloma by induction of apoptosis and modulating cancer cell metabolism.

While multi-drug combinations and continuous treatment have become standard for multiple myeloma, the disease remains incurable. Repurposing drugs that are currently used for other indications could provide a novel approach to improve the therapeutic efficacy of standard multiple myeloma treatments. Here, we assessed the anti-tumor effects of cardiac drugs called β-blockers as a single agent and in combination with commonly used anti-myeloma therapies.

Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?

Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although new treatment approaches combining immunomodulatory drugs, corticosteroids, proteasome inhibitors, alkylating agents, and monoclonal antibodies have significantly improved median life expectancy, MM remains incurable due to the development of DR, with the underlying mechanisms remaining largely ill-defined.

Metabolic cross-talk within the bone marrow milieu: focus on multiple myeloma.

Cancer cells are well-known for their capacity to adapt their metabolism to their increasing energy demands which is necessary for tumor progression. This is no different for Multiple Myeloma (MM), a hematological cancer which develops in the bone marrow (BM), whereby the malignant plasma cells accumulate and impair normal BM functions. It has become clear that the hypoxic BM environment contributes to metabolic rewiring of the MM cells, including changes in metabolite levels, increased/decreased activity of metabolic enzymes and metabolic shifts.

Radiotheranostic Agents in Hematological Malignancies.

Radioimmunotherapy (RIT) is a cancer treatment that combines radiation therapy with tumor-directed monoclonal antibodies (Abs). Although RIT had been introduced for the treatment of CD20 positive non-Hodgkin lymphoma decades ago, it never found a broad clinical application. In recent years, researchers have developed theranostic agents based on Ab fragments or small Ab mimetics such as peptides, affibodies or single-chain Abs with improved tumor-targeting capacities.

Emerging applications of nanobodies in cancer therapy.

Cancer is a heterogeneous disease, requiring treatment tailored to the unique phenotype of the patient's tumor. Monoclonal antibodies (mAbs) and variants thereof have enabled targeted therapies to selectively target cancer cells. Cancer cell-specific mAbs have been used for image-guided surgery and targeted delivery of radionuclides or toxic agents, improving classical treatment strategies.

System Xc inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance.

Multiple myeloma (MM) cells derive proliferative signals from the bone marrow (BM) microenvironment via exosomal crosstalk. Therapeutic strategies targeting this crosstalk are still lacking. Bortezomib resistance in MM cells is linked to elevated expression of xCT (the subunit of system Xc).

Pyrroline-5-Carboxylate Reductase 1: a novel target for sensitizing multiple myeloma cells to bortezomib by inhibition of PRAS40-mediated protein synthesis.

Background: Multiple myeloma (MM) remains an incurable cancer despite advances in therapy. Therefore, the search for new targets is still essential to uncover potential treatment strategies. Metabolic changes, induced by the hypoxic bone marrow, contribute to both MM cell survival and drug resistance.