مختارات المحررين، يونيو 2026: الوقاية من سرطان القولون والمستقيم، واستهداف التداخل العصبي لوقف تكرار الورم الأرومي الدبقي، والمزيد

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This June, the whole world has gathered for the most exciting event of the summer: Editors’ Picks from the journals of the American Association for Cancer Research (AACR). There may be a soccer match or two happening as well, but that’s nothing compared with the researchers who have scored big with discoveries and advances in cancer research. The findings from this month’s highlighted studies include identifying patients with multiple myeloma who may benefit from debulking chemotherapy prior to receiving teclistamab (Tecvayli), discovering a key messenger in the cross-talk between glioblastoma cells and neurons that could be targeted to impede recurrence, assessing the potential of a shared neoantigen vaccine to prevent colorectal cancer in individuals with Lynch syndrome, and revealing considerable improvements in five-year relative survival rates of childhood and adolescent cancer patients between 1975 and 2020. Read the full abstracts of all the featured studies below and follow the links for the full text of each article, freely available for a limited time. Journal: Blood Cancer Discovery Debulking Chemotherapy Can Overcome Primary Resistance to Teclistamab in Relapsed/Refractory Multiple Myeloma Bispecific antibodies have revolutionized the treatment of multiple myeloma;

however, primary treatment failure occurs in 30% to 40% of patients. In this study, we analyzed correlates of response to teclistamab and strategies to overcome primary resistance. Across two independent cohorts (n = 90), we developed the high risk of primary resistance (Hi-MM) variable, defined by extramedullary disease, plasma cell leukemia, bone marrow plasmacytosis ≥50%, or transfusion within 30 days, as a composite correlate of nonresponse. Patients without Hi-MM had overall response rates of 84% to 96% (vs. 20%–40% with Hi-MM) and significantly superior progression-free survival (P < 0.001) and overall survival (P < 0.001). Debulking chemotherapy was utilized in 19 patients;

79% then responded to teclistamab, including 100% who no longer had Hi-MM. All four patients who were primary refractory to a BCMA bispecific immediately prior to debulking then achieved deep responses to teclistamab. In conclusion, simple clinical parameters correlate with response to teclistamab, whereas debulking chemotherapy can overcome Hi-MM and successfully bridge patients to teclistamab or salvage nonresponders. Significance: A clinically assessable composite variable, Hi-MM, identifies patients who may benefit from debulking chemotherapy prior to teclistamab. By treating patients at a time of low disease burden or using debulking chemotherapy for those with a high risk of resistance, nearly all patients can benefit from the deep and durable remissions induced by teclistamab. Learn more about multiple myeloma: Glioblastoma-Secreted C1QL1 Orchestrates Tumor Microtube Expansion and Neural Synaptic Pruning to Drive Malignant Synapse Formation and Recurrence Glioblastoma (GBM) cells form neuron-to-glioma malignant synapses on neurite-like tumor microtubes (TM), driving infiltrative growth and recurrence. The mechanisms underlying coordinated cross-talk among GBM cells and with neurons to favor malignant over normal synapses remain largely unknown. Here, we demonstrate that glioma-secreted C1QL1 is a key messenger for glioma–neuron and glioma–glioma cross-talk to drive TM expansion and malignant synapse formation. C1QL1 binds to its receptor BAI3 on neighboring neurons and GBM cells, activating RAC1-mediated cytoskeleton rearrangement to prune normal synapses and outgrow TMs, promoting malignant synapse and glioma network formation. Targeted treatment with a non–GEF-targeting, first-in-class RAC1 inhibitor rescues C1QL1-mediated synaptic pruning, inhibiting TMs and malignant synapses to impede glioma recurrence. Our findings elucidate how cross-talk among GBM cells and neurons allows infiltrating GBM cells to sculpt and integrate into the existing neural network, highlighting a therapeutic strategy against GBM recurrence through simultaneous inhibition of TMs and glioma-induced synaptic pruning. Significance: Our study identifies C1QL1 as a key messenger secreted by infiltrating glioma cells, orchestrating glioma–glioma and glioma–neuron cross-talk to induce TM expansion and neural synaptic pruning, driving malignant synapse formation and recurrence through a C1QL1–BAI3–RAC1 axis. Targeting RAC1 with a non–GEF-targeting RAC1 inhibitor could impede glioma recurrence and improve survival. The article was featured on the cover of the June issue, which also included a related commentary. Journal: Cancer Epidemiology, Biomarkers & Prevention Trends in Long-Term Excess Mortality Risk and Survival among Childhood and Adolescent Cancer Survivors in the United States Background: Childhood and adolescent cancer survivors represent a growing population whose outcomes reflect both advances in therapy and late effects of treatment. We quantified trends in long-term excess mortality risk and survival using standardized mortality ratios (SMR) and relative survival, respectively. Methods: Using the Surveillance, Epidemiology, and End Results data, we assessed 5-year relative survival and 5-year relative survival, conditional on surviving 5 years, by period of diagnosis (1975–1979 vs. 2016–2020, and 1975–1979 vs. 2011–2015, respectively). Trends were quantified by year at diagnosis using the joinpoint survival model. SMRs were estimated by 5-year time-since-diagnosis intervals and calendar-year diagnosis periods. Results: Between 1975 and 2020, there were improvements in 5-year relative survival, with acute myeloid leukemia (AML) and non–Hodgkin lymphoma (NHL) having the greatest survival gains. For osteosarcoma, central nervous system tumors, and Wilms tumor, 5-year relative survival plateaued in recent decades. Five-year relative survival, conditional on surviving 5 years, was >90% for survivors diagnosed between 2011 and 2015 for all cancer sites analyzed. Overall, SMRs declined with increasing time since diagnosis. Excess mortality risk also decreased over calendar-year diagnosis periods, particularly during the first 5 years since diagnosis, for cancers such as lymphoid leukemia, AML, Hodgkin lymphoma, and NHL. Conclusions: Overall, we observed considerable improvements in 5-year relative survival and declines in excess mortality risk over time. Impact: These findings reflect advances in treatment and survivorship care. Long-term follow-up and continued research efforts are needed to understand long-term mortality risks within an evolving treatment landscape and to achieve further progress. A related commentary was published in the June issue. Learn about the long-term health risks experienced by survivors of pediatric cancer: Pediatric Cancer’s Aftershocks: The Challenges for Survivors Beyond Childhood Journal: Cancer Immunology Research Targeted TNF Potentiates the Activity of Bispecific T-cell Engagers in Solid Tumors by Turning Cold Tumors Hot Colorectal cancer remains a major global health burden and an area of urgent unmet medical need. Immunotherapy has shown limited success in colorectal cancer as most patients present with an immune-excluded, “cold” tumor microenvironment (TME). In this study, we report a dual-modality approach to treating colorectal cancer by combining the tumor necrosis factor (TNF)–based fusion protein directed to the extradomain B (EDB) of fibronectin, L19-TNF, which induces localized intratumoral inflammation and facilitates T-cell infiltration, with a CD3-based bispecific T-cell engager (TCE) targeting carcinoembryonic antigen (CEA), which mediates antigen-specific cytotoxicity. Together, these agents aim to remodel the TME, convert “cold” tumors into inflamed “hot” lesions, and broaden the therapeutic reach of immunotherapy in colorectal cancer. Immunohistochemistry confirmed coexpression of CEA and EDB across microsatellite-stable and -instable tumors. In vitro, L19-TNF in combination with a CEAxCD3 TCE significantly enhanced tumor cell killing and CD8+ T-cell proliferation. In vivo, the combination induced complete tumor regression in most animals, prolonged survival, and conferred durable protection against tumor rechallenge. Furthermore, mechanistic analyses revealed enhanced TCE extravasation, upregulated intercellular adhesion molecule 1 expression, and increased CD8+ T-cell infiltration, indicating vascular modulation and remodeling of the TME toward an inflamed “hot” phenotype. These findings confirm that targeted delivery of TNF to the TME can effectively enhance the activity of immunotherapeutic agents, such as T cell–redirecting therapies, in challenging tumor settings. Journal: Cancer Prevention Research Mutations Targeted by Nous-209 Immunotherapy Occur Early in Lynch Syndrome Carriers’ Precancer Lesions with Microsatellite Instability This study provides a molecular characterization of precancerous colorectal lesions in Lynch syndrome (LS) carriers to assess the preventive potential of Nous-209 immunotherapy against colorectal cancer development. A total of 50 adenomas and 12 advanced adenomas (AA) were collected from 26 LS carriers with pathogenic variants in either MLH1 or MSH2. Molecular analyses included assessment of mismatch repair (MMR) status, microsatellite instability (MSI), and detection of mutations targeted by Nous-209. We found that 83% of AAs and 58% of adenomas were MMR-deficient (dMMR). Notably, although all dMMR AA were MSI-high (MSI-H), only 66% of dMMR adenomas showed MSI-H. The presence of Nous-209 mutations correlated strongly with MSI status, with mutation counts ranging from 15 to 57 in dMMR/MSI-H lesions. dMMR adenomas classified as MSI-low carried a limited number of mutations (6–19), whereas microsatellite-stable lesions harbored very few (0–2) Nous-209 mutations, regardless of MMR proficiency. These findings confirm the molecular heterogeneity of precancerous lesions and support the potential of Nous-209 immunotherapy to prevent MSI colorectal cancer in LS by targeting the adenoma–carcinoma sequence at the time of MSI acquisition. Prevention Relevance: Our study shows that MSI and neoantigen accumulation emerge during the evolution of precancerous lesions in LS. These findings support the clinical evaluation of Nous-209, a shared neoantigen vaccine, as an immunoprevention strategy for MSI-driven colorectal carcinogenesis, with important implications for cancer prevention research. Learn about the clinical efficacy of Nous-209 for the prevention of colorectal cancer: Stopping Cancer Before It Starts in Lynch Syndrome Journal: Cancer Research (June 1 Issue) Dynamic Reprogramming of PDGFRA-Expressing Stromal Cells Facilitates WNT-Driven Transformation by Promoting a Fetal-Like State in the Intestinal Epithelium Stromal fibroblasts of the mesenchyme regulate critical signaling gradients along the crypt–villus axis in the intestine and provide a niche that supports intestinal stem cells. In this study, we reported that PDGFRA-expressing fibroblasts secrete ligands that promote a fetal-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Data from a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing of mesenchymal cell populations revealed a dynamic reprogramming of PDGFRA+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFβ signaling is notably induced in PDGFRA+ fibroblasts in the presence of oncogenic epithelium, and TGFβ was essential to sustain the fetal-like growth of organoids ex vivo. Reduction of CDX2 in β-catenin mutant intestinal epithelium elevated the fetal-like transcriptome and accelerated WNT-dependent oncogenic transformation in vivo. These results demonstrate that PDGFRA+ fibroblasts are activated during WNT-driven oncogenesis to promote a fetal-like state in the epithelium that precedes and facilitates tumor formation.