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Azacytidine is used as standard treatment for myelodysplastic syndrome (MDS) but, although it induces responses, remissions are rare and not durable. In patients with MDS, malignant cells rely on glutamine for survival and exhibit elevated levels of glutaminase, an essential enzyme for glutamine metabolism. Our results from preclinical and clinical studies demonstrate the effectiveness of combining the glutaminase inhibitor telaglenastat with azacytidine in advanced MDS.
Despite the promise of chimeric antigen receptor (CAR) T cell therapy, predicting patient response is challenging. Single-cell multiomics of myeloma treated with B cell maturation antigen (BCMA)-targeted CAR T cells now reveal that poor clinical response is associated with an immunosuppressive environment and CAR T cells transition to exhausted phenotypes, indicating a mechanism for reduced persistence.
Hata and colleagues discuss the complexity and clinical importance of cancer persister cells, as well as existing methods for studying and eliminating them, expanding on challenges and opportunities in this area of research.
In the ongoing search for innovative treatments to combat refractory and relapsed cancer, new preclinical work in multiple myeloma shows that increasing binding avidity by targeting two antigens in one T cell-engaging trispecific antibody boosts anti-tumor activity and reduces the likelihood of tumor escape relative to current antibody-based therapies.
The anti-apoptotic protein MCL1 is a therapeutic target in cancer, but long-term MCL1 inhibition has been found to increase the risk of cardiotoxicity. We developed BRD-810 as a potent and selective MCL1 inhibitor that induces cancer cell death in vivo within a few hours. As BRD-810 was designed to be rapidly cleared, it targets cancer cells while minimizing the risk for cardiotoxicity.
The clinical utility of immune checkpoint inhibitors is limited by immune-related adverse events (irAEs); understanding the mechanisms of irAE development is thus crucial. A study reports that IL-17A-expressing CD4+ T cells were elevated at irAE onset and provides proof of concept for using IL-17A blockade to improve irAEs in two patients.
Early trials of immune checkpoint inhibitors (ICIs) in multiple myeloma (MM) showed increased mortality, halting their development. A study now reports promising results and distinct changes in the immune microenvironment after TIGIT and LAG3 blockade in heavily pre-treated patients with MM, marking a potential revival for ICIs in MM therapy.
An integrative single-cell analysis of the human colorectum reveals tumor-associated cellular alterations and regulatory pathways. Patient stratification based on cellular composition of the tumor microenvironment suggests distinct immune evasion mechanisms in colorectal cancer.
Resistance of cancers to immune checkpoint blockades is frequently observed. Pancreatic cancer cells are now shown to create a tumor microenvironment that protects them from immunotherapy by overexpression of cytidine deaminase. This leads to increased production of uridine diphosphate that attracts immunosuppressive macrophages.
Precision medicine holds immense promise for treating individuals with cancer. A new study unveils MTX-531 â a drug that can inhibit two signaling proteins, EGFR and PI3K â which was developed through innovative computational drug design and offers new hope for more-effective and better-tolerated cancer treatments.
Recent advancements in targeted immune checkpoint blockade (ICB) therapy have reshaped cancer treatment paradigms. However, many patients do not respond, highlighting the need for robust biomarkers. A study now introduces an approach using multi-omics data and machine learning to improve patient selection for ICB therapy, offering more effective treatment.
Combining SOS1 inhibitors with KRAS inhibitors improved the depth and durability of response in lung and colorectal cancer models. Restoration of response was observed in preclinical models rendered resistant to KRAS inhibitors. These results highlight the potential of SOS1 inhibitors to broaden the response to KRAS inhibitors in the clinic.
Fong and colleagues provide a Review on γδ T cells as mediators of anti-tumor immunity, discuss their role in the tumor microenvironment and reflect on therapeutic approaches to exploit γδ T cells.
Our non-randomized single-center clinical trial demonstrates the safety, cost-saving and time-saving potential of artificial intelligence (AI) assistance in the detection of breast cancer metastases in sentinel lymph nodes. AI assistance shows important benefits for pathologists and the laboratory workflow, which are needed as cancer incidence and diagnostics continue to rise.
The mainly hematologic expression profile of phosphatidylinositol-3-kinase-γ (PI3Kγ) makes it an attractive therapeutic target. Recent work from three independent groups shows that inhibiting PI3Kγ impairs the metabolism and growth of acute myeloid leukemia cells â a finding that justifies further mechanistic and clinical exploration.
Cancer dependency maps have accelerated the discovery of essential genes and potential drug targets. Here we used machine learning to build translational dependency maps of patientsâ tumors and normal tissue biopsies, which identified oncogenes and synthetic lethalities that are predictive of drug responses and patientsâ outcomes.
Current prostate cancer risk predictors are not able to fully capture a patientâs risk of recurrence at the time of diagnosis. Evolutionary metrics of tumor diversity, based on low-cost sequencing and digital pathology, might provide a new dimension of information to close the gap between prediction and outcome.
Rebecca and colleagues discuss the complex biology of metastatic melanoma, as well as determinants of resistance to therapy and existing and promising therapy strategies.
Prives and colleagues comprehensively discuss the current knowledge on cancer-related mutations of p53 and the impact they have on anticancer immunity.
Acute myeloid leukemia (AML) is an aggressive hematological cancer with limited treatment options. A study now provides compelling data and develops a therapeutic approach of targeting AML with a prolyl hydroxylase inhibitor, a strategy based on the sensitivity of myeloid cells to modulation of the transcription factor HIF.
