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CAR T cell therapies have made great strides in the clinic; however, multiple hurdles limit the efficacy of this approach for solid tumors. A new study has developed an optimized, dual-targeting CAR T cell that overcomes several of these challenges by enhancing T cell persistence and reducing therapy escape due to antigen loss.
Pseudouridine is the most abundant RNA modification, but its biological role remains poorly understood. A study now finds dysregulated pseudouridine synthase PUS7 in glioblastoma and demonstrates that pharmacological inhibition of PUS7 leads to reduced tumorigenesis, which underpins the therapeutic potential of targeting epitranscriptomic regulators in cancer.
Combining radiation and immune checkpoint blockade is a promising treatment strategy, yet the mechanisms and optimal dosing strategies are not well known. A new study finds that a specific radiation dose can activate secretory club cells to promote the anti-tumor effects of radiotherapy combined with immunotherapy in NSCLC.
Ding and colleagues discuss the era of pan-cancer analysis, covering the fundamental insights gained, unique opportunities and challenges, and the future of such approaches in the basic and clinical space.
Drug resistance may pre-exist or arise during therapy, but how precisely cancer treatment itself influences these processes is a major gap in the understanding of therapy resistance in cancer. A study of acute lymphocytic leukemia now provides direct evidence of thiopurine-induced mutations in the gene encoding the tumor suppressor p53 that result in multi-drug-resistant relapse.
Melenhorst and colleagues review the current status of chimeric antigen receptor T cell therapies, focusing on the rapid progress achieved in this area of immunotherapy, but also the challenges to be overcome.
Immuno-oncology approaches have shown little efficacy against high-grade glioma, a devastating manifestation of brain cancer. A new study now finds a metabolic vulnerability in IDH1-mutant glioma that can be targeted to reprogram tumor-infiltrating macrophages and create a tumor microenvironment that is more responsive to immune-checkpoint therapy.
Institutional clinical data repositories provide a depth and consistency of data elements that is difficult to match even with data pooled from diverse sources. A study now demonstrates how real-world data and clinical encounters can be captured in an integrated ‘data story’ to enable continuous learning and hypothesis generation in oncology.
Prostate cancer is largely unresponsive to immunotherapy. A new study finds elevated expression of the chemokine IL-8, or its mouse homolog Cxcl15, in prostate cancer after castration, which leads to the recruitment of immunosuppressive myeloid cells. Blocking tumor infiltration with these cells could improve the response to immune-checkpoint inhibition and androgen-deprivation therapy.
Pasha and Turner review recent insights into the role of intratumoral heterogeneity in therapeutic resistance in metastatic breast cancer and discuss forward-looking strategies to overcome this hurdle.
Despite substantial advances in understanding of the molecular features of gliomas, the therapeutic options for these aggressive tumors remain scarce. Rich, Mitchell and colleagues provide their views about a phase 1 clinical trial testing the safety and efficacy of vaccines against cancer expressing mutant metabolic enzyme IDH1 in patients with high-grade glioma.
FTO, an m6A RNA demethylase, is known mainly as an oncoprotein in various cancer types. FTO is now shown to act as a cancer suppressor in a subset of epithelial tumors through an interplay between epithelial-to-mesenchymal transition and Wnt signaling.
The DNA polymerase Polθ is synthetic lethal with homologous-recombination deficiency, but a lack of specific targeting compounds has limited its therapeutic potential. Two studies now describe first-in-class inhibitors of Polθ with in vivo efficacy and thus provide alternative therapeutic approaches to PARP inhibitors for cancers deficient in homologous recombination.
Scatiltri and colleagues review the paradigms of targeting PI3K in solid tumors in the clinic, including the progress so far in developing effective inhibitors as well as clinical limitations due to toxicity and therapeutic resistance.
Mutations in genes encoding epigenetic modifiers are frequent in acute myelogenous leukemia (AML) and have been proposed to cause AML via activation of oncogenes and repression of tumor suppressors. Two studies now identify unexpected oncogenic mechanisms and therapeutic vulnerabilities in AML arising from mutations in genes encoding the epigenetic regulators DNMT3A and ASXL1.
Two recent studies demonstrate how autophagy, in both tumor cells and host tissues, regulates anti-tumor T cell responses. These works add to accumulating evidence that inhibitors of autophagy could be used in combination with immunotherapy in certain cancer types.
Cancer cells need to adapt their metabolic state to different microenvironments, particularly during metastatic spread, when they are exposed to the circulatory system as well as the distant organ. Two studies now show that upregulation of fatty acid synthesis is required for the formation of breast cancer metastasis in the lipid-poor environment of the brain.
Small-molecule kinase inhibitors have made major advances in cancer therapy, but their efficacy remains limited by intrinsic and acquired resistance. The expression and thermostability of the kinase CDK6 are now shown to mediate intrinsic resistance to CDK4/6 inhibitors and degraders across cancer types.
Passaro and colleagues discuss recent advances in treating EGFR-mutant lung cancer, including methods for detecting disease and tracking therapy response, developments in understanding of resistance mechanisms and ongoing clinical trials to circumvent therapeutic resistance to EGFR targeting.