Welcome to Dana-Farber's Research News
December 1, 2025
This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from November 1 - 15.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing dfciresearchnews@dfci.harvard.edu.
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Blood Rivera J, Lannes R, Anderson KC, Munshi NC, Samur M Understanding the roles of myeloid cells in the tumor microenvironment (TME) has emerged as a promising strategy to identify novel targets to counteract the immunosuppressive barriers protecting multiple myeloma (MM). Neutrophils are a new cancer research focus due to their potential to reduce the efficacy of immune-based therapies. This study aimed to deepen understanding of neutrophil function in MM by analyzing freshly isolated myeloid cells from paired focal lesions (FLs) and bone marrow using single-cell RNA sequencing, immunofluorescence imaging, and functional assays. We describe 3 distinct CXCR2+ mature neutrophil subsets: TREM1+CD10+, RETN+LCN2+, and TNFAIP3+CXCL8+, each exhibiting unique phenotypes within the TME. Notably, the TREM1+CD10+ subset was highly prevalent, particularly in FLs, demonstrating potent immunosuppressive effects on T cells. This subset's gene signature was correlated with shorter overall survival (OS) in a large data set of patients with MM, underscoring its clinical significance. Targeted inhibition of neutrophil activity through CXCR2 blockade, alone or combined with standard anti-MM therapies, significantly reduced tumor burden, improving OS in preclinical MM models. These insights into neutrophil-mediated immunosuppression in MM provide valuable knowledge regarding mechanisms driving immune evasion, and reveal new therapeutic approaches to enhance the efficacy of MM treatment. |
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Blood Singh AK, Mejia L, Cancelas JA Hematopoietic stem cells (HSCs) exhibit a distinctive antioxidant profile during steady-state and stress hematopoiesis. HSCs and multipotential progenitors (MPPs) are metabolically coupled to bone marrow mesenchymal stromal cells through mitochondrial transfer, a process dependent on hematopoietic connexin 43 (Cx43) and low adenosine monophosphate-activated protein kinase (AMPK) activity. However, the mechanism by which Cx43 preserves mitochondrial functionality in HSCs remains elusive. Here, through integrated transcriptomic, proteomic, metabolomic, phenotypic, and functional analyses of HSCs and their isolated mitochondria, we identified that Cx43 is present on the inner and outer mitochondrial membranes of HSCs/MPPs, in which it primarily regulates mitochondrial metabolism and adenosine triphosphate synthesis by preserving the mitochondrial cristae, activation of mitochondrial AMPK, and 2-oxoglutarate dehydrogenase, a rate-liming enzyme in tricarboxylic acid cycle and electron transfer chain. During replicative stress, Cx43-deficient HSCs/MPPs fail to adapt metabolically and accumulate mitochondrial Ca2+, leading to increased mitochondrial AMPK activity, mitochondrial fission, mitophagy, and production of reactive oxygen species, thereby limiting HSC/MPP regeneration potential. Disruption of hyperfragmentation of mitochondria and mitophagy by Drp1 dominant-negative mutant (Drp1K38A) or restoration of mitochondrial function through ex vivo heteroplasmy prevents the harmful effects of Cx43 deficiency on mitochondrial metabolism and restore HSC activity in serial transplantation experiments. Re-expression analysis of Cx43 structure-function mutants indicates that Cx43 hemichannels are sufficient to reset HSC mitochondrial metabolism, dynamics, Ca2+ levels, and regeneration capacity. This report defines the cell-autonomous mechanism of action behind the role of Cx43 in HSC activity and opens a venue to translational applications in transplantation. |
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Cancer Cell Decoding the Spatial Dynamics of Tumor and Immune Cell Interactions in Solid Cancers Minogue E, Baldominos P, Hsu L, Haigis MC, Agudo J The spatial landscape of the tumor immune microenvironment (TIME) is under significant investigation as a driver of immunotherapy resistance in solid tumors. Most work centers on constituent immune cells within intra-tumoral niches, overlooking tumor cell phenotypes. Yet cancer cells shape their milieu by multiple modalities, including secreting and depleting metabolites. Here, we argue that integrating cancer cell phenotypic heterogeneity into spatial analyses is essential to reveal the mechanisms that generate TIME diversity and to better address resistance to immunotherapy. |
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Cancer Discovery Baldacci S, Brea EJ, Facchinetti F, Li Z, Ngo K, Malhotra S, Booker MA, Tolstorukov MY, Chakravarti S, Hinchey C, Mahadevan NR, Feng WW, Tsai JA, Hartley AV, Locquet MA, Saldanha A, Haller W, Zasadil LM, Zielinska M, Bui K, Tuladhar B, Lizotte PH, Ivanova EV, Sequist LV, Gokhale PC, Paweletz CP, Smith EL, Jänne PA, Barbie DA EGFR tyrosine kinase inhibitors have dramatically improved outcomes for patients with EGFR-mutated non-small cell lung cancer (NSCLC), but relapse frequently occurs because of drug-tolerant persister (DTP) cells that can evolve and develop diverse mechanisms of drug resistance. In samples from patients with EGFR-mutated NSCLC treated with EGFR tyrosine kinase inhibitors in the neoadjuvant setting, we observed enriched expression of the cell surface protein TROP2, a target of clinically active antibody-drug conjugates (ADC). We confirmed these findings across multiple EGFR-mutated NSCLC cell line and patient-derived xenograft models treated with osimertinib in vivo. Treatment with the TROP2 ADC sacituzumab govitecan at the time of osimertinib-induced minimal residual disease only modestly delayed tumor recurrence in vivo, whereas a single infusion of sacituzumab-based TROP2-directed chimeric antigen receptor (CAR) T cells significantly prolonged relapse-free survival, with evidence of cure. These data highlight the potential of engineering TROP2 CAR T-cell therapy to eliminate EGFR DTPs in patients. SIGNIFICANCE: We provide a rationale for targeting TROP2 in EGFR-mutated NSCLC DTPs. In contrast to TROP2 ADC therapy, targeting of TROP2 with CAR-T cells can eliminate osimertinib-induced DTPs in vivo, revealing the promise of developing novel TROP2-based CAR-T cells to promote durable response and prevent disease relapse in patients. |
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Cancer Discovery Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer Kotýnková K, Uzunbas GK, Tomono H, Andersen S, Denney D, Lewis TA, Kaplan B, Cherniack AD, Meyerson M, Greulich H Exon 20 insertions of HER2, encoded by ERBB2, and other activating HER2 mutations occur in 2-4% of lung adenocarcinomas, but there are only limited therapeutic options available for these patients. Sevabertinib (BAY 2927088) is a potent and reversible dual EGFR-HER2 inhibitor that is selective with respect to wild-type EGFR. Here, we report the preclinical activity of sevabertinib in lung cancer models harboring alterations of HER2, including exon 20 insertions, point mutations, and amplification of wild-type ERBB2. We furthermore demonstrate the activity of sevabertinib in a cancer cell line dependent on a fusion of NRG1, a ligand for the HER2 family member and heterodimerization partner, HER3. Finally, we report patient responses to sevabertinib from a Phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung cancer. |
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Journal of Clinical Oncology Inotuzumab Ozogamicin Then Blinatumomab for Older Adults with Newly Diagnosed B-Cell ALL: Alliance Study A041703 Cohort 1 Results Stone RM PURPOSE: Older patients with ALL receiving conventional chemotherapy have poor survival due to toxic death and relapse. We hypothesized that a chemotherapy-free, targeted regimen using the anti-CD22 antibody-calicheamicin conjugate inotuzumab ozogamicin followed by the bispecific anti-CD19/CD3 T-cell engager blinatumomab would reduce toxic death and yield high rates of prolonged remission and survival. METHODS: Eligible patients were age 60 years and older with untreated, Philadelphia chromosome (Ph)-negative, CD22-positive, B-cell ALL. Patients received up to two cycles of inotuzumab ozogamicin followed by four or five cycles of blinatumomab with intrathecal methotrexate CNS prophylaxis. The primary end point was 1-year event-free survival (EFS). RESULTS: The 33 eligible patients had a median age of 71 years (range, 60-84) and a median CD22 expression of 92% (range, 21%-100%). Eight (24%) had previous chemotherapy or radiation for other cancers, six for multiple myeloma. The composite complete remission rate was 85% after two cycles of inotuzumab ozogamicin and 97% by the end of two cycles of blinatumomab. At a median follow-up of 30 months, the 1-year EFS and overall survival were 75% (95% CI, 61 to 92) and 85% (95% CI, 73 to 98), respectively. EFS was shorter with lower CD22 expression or detectable measurable residual disease at any time point. CONCLUSION: Inotuzumab ozogamicin then blinatumomab without maintenance chemotherapy in older patients with untreated, Ph-negative, CD22-positive, B-cell ALL yields a high remission rate and excellent EFS. Given the lack of standard, safe, and effective therapies in this population, the regimen should be considered a standard treatment option. |
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Journal of Clinical Oncology Gillani R, Shulman DS, Klega K, Tanhaemami M, Ward A, Bainer V, Ricker C, DuBois SG, Church AJ, Crompton BD, Janeway KA PURPOSE: Identifying discrete subgroups associated with treatment response and resistance in localized Ewing sarcoma (EWS) remains a challenge. The primary objective of the Children's Oncology Group (COG) biology study AEWS18B1-Q was to molecularly characterize patients with localized EWS on prospective modern-day trials. PATIENTS AND METHODS: We analyzed clinical and molecular features from patients with localized EWS enrolled on frontline COG trials. All patients had available formalin-fixed paraffin-embedded (FFPE) tissue, frozen tissue, or whole-genome-amplified material. Sequencing was performed for identification of canonical fusions, recurrent copy number alterations (CNAs), and alterations in TP53 and STAG2. Available tissue was analyzed for loss of STAG2 protein expression. Molecular features were evaluated for their association with cumulative incidence of relapse in univariate and multivariable analyses. RESULTS: Three hundred fifty-one patients had sufficient tissue, which in most cases was extracted from two FFPE slides. EWS canonical fusions were identified in 282 patients (80.3%). Pathogenic mutations in TP53 and STAG2 were identified in 5.1% and 7.6% of patients, respectively. A total of 63.1% of patients were found to have recurrent CNAs. In univariate analysis, there was an increased cumulative incidence of relapse in patients with TP53 mutation (5-year cumulative incidence of relapse 43%, 95% CI [17% to 67%] v 22%, 95% CI [17% to 27%]; Gray's test P = .039), STAG2 mutation (53%, 95% CI [29% to 73%] v 21%, 95% CI [16% to 26%]; P < .001), and recurrent CNAs (30%, 95% CI [22% to 37%] v 16%, 95% CI [9% to 24%]; P = .005). In a multivariable analysis, STAG2 mutation was the only molecular biomarker that remained prognostic. CONCLUSION: This is a prospective validation of the molecular prognostic features of patients with localized EWS receiving standard-of-care therapy on therapeutic clinical trials. Building on previous work, patients with STAG2 mutations were at high risk of relapse. |
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Journal of Clinical Oncology Drutchas A It was the kind of day that almost seemed made up a clear, cerulean sky with sunlight bouncing off the gold dome of the State House. The contrast between this view and the drab hospital walls as I walked into my patient's room was jarring. My patient, whom I will call Suresh, sat in a recliner by the window. His lymphoma had relapsed, and palliative care was consulted to help with symptom management. The first thing I remember is that despite the havoc cancer had wreaked – sunken temples and a hospital gown slipping off his chest – Suresh had a warm, peaceful quality about him. |
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Journal of the National Cancer Institute Tarantino P, O'Meara T, Morganti S, Waks AG, Lin NU, Tolaney SM, Sammons S BACKGROUND: Most patients with metastatic breast cancer (MBC) are eligible for treatment with trastuzumab deruxtecan (T-DXd). No data are available to guide treatment after exposure to T-DXd. METHODS: We utilized a nationwide electronic health record-derived, deidentified database to review data of patients with MBC who initiated T-DXd between December 2019 and December 2023 and who received an additional line of treatment after T-DXd. Tumors were categorized as HER2-positive if ever positive before T-DXd, and HER2-negative if never HER2-positive before T-DXd. We compared real-world progression-free survival (rwPFS) and overall survival for post-T-DXd treatments using the Kaplan-Meier method and the log-rank test. RESULTS: We identified 793 patients receiving a post-T-DXd treatment. Post-T-DXd treatment outcomes differed significantly by MBC subtype: median rwPFS was 4.6?months for HER2-positive, 3.4?months for hormone receptor- (HR)-positive/HER2-negative, and 2.8?months for triple-negative MBC (P?<?.001). Outcomes with post-T-DXd treatments also varied significantly according to treatment regimen (P?<?.001). Among patients with HER2-positive MBC, median rwPFS ranged from 6.7?months with endocrine treatment regimens to 2.6?months with sacituzumab govitecan (SG). Among patients with HR-positive/HER2-negative MBC, rwPFS ranged from 5.9?months with eribulin to 2.6?months with SG. Among patients with triple-negative MBC, poor outcomes (rwPFS ?3?months) were observed with most treatment regimens, including SG (3?months), eribulin (2?months), and multiagent chemotherapy (2.5?months). CONCLUSIONS: Outcomes of post-T-DXd treatments differ significantly by MBC subtype and type of regimen administered. The use of SG immediately after T-DXd was associated with relatively short rwPFS across subtypes, highlighting some degree of cross-resistance with T-DXd. TRIAL REGISTRATION: N/A. |
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Journal of the National Cancer Institute Leeman JE, Shin KY, Droznin A, Catalano P, Cagney DN, Singer L, Oniyangi RD, Zhai K, Benham G, Chirmade S, Campbell J, Boyle S, Saranteas A, Williams CL, Huynh E, Han Z, Sudhyadhom A, Hu YH, Ferguson D, Singhrao K, Hsu SH, Bredfeldt J, Martin NE, Mancias JD, Mamon HJ, Van Dams R, Venkatachalam V, Tanguturi SK, Huynh MA, Fitzgerald KJ, Elhalawani H, Bitterman DS, Schoenfeld JD, Nguyen P, Haas-Kogan DA, Mak R BACKGROUND: Master clinical trial protocol structures offer administrative, procedural, and statistical advantages but have not been applied in assessing new radiotherapy devices. Herein, we report on a pooled analysis from a first-of-kind master trial evaluating stereotactic MRI-guided adaptive radiotherapy (SMART). METHODS: Subjects were enrolled in a prospective master protocol evaluating SMART for multiple oncologic indications. CTCAE v5 toxicities, patient-reported outcome measures (PROMs), and treatment efficiency metrics were assessed across the entire cohort and in anatomic subsets. RESULTS: One hundred and ninety three subjects were enrolled into 20 sub-protocols for different SMART indications. Data were analyzed from the first 161 subjects. The median time from subprotocol amendment submission to activation was 70.5?days (range: 63-93). All completed phase I sub-protocols (n?=?9) met the primary endpoints of safety and feasibility. The risk of grade 3+ toxicity was 1.9% (95% CI 0.4% to 5.3%), 7.1% (95% CI 0.9% to 23.5%), 1.8% (95% CI 0.05% to 9.6%) and 0% (95% CI 0.0% to 4.7%) in the overall cohort and thoracic, abdominal and pelvic subsets, respectively. PROMs (PROMIS-10) during and after SMART were unchanged from baseline in all subsets. SMART delivery efficiency improved over the study period (first vs. final 3?months: 78.5 vs. 48.2?minutes, P?<?.001). Adaptive planning performed for 771 fractions resulted in clinically significant plan improvements in 93.0% of fractions (52.7% for organ-at-risk sparing, 20.5% for target coverage, and 19.8% for both). CONCLUSIONS: SMART is feasible and safe for multiple thoracic, abdominal and pelvic radiotherapy indications. The master protocol platform offers an adaptable approach for assessment of new oncologic treatment technologies applicable to multiple indications. CLINICAL TRIAL: NCT04115254. |
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Lancet Oncology Kann BH, Huang RY Artificial intelligence (AI) has the potential to enable more precise, efficient, and reproducible interpretation of medical imaging data to improve patient care in paediatric neuro-oncology. Paediatric brain tumours present distinct histopathological, molecular, and clinical challenges that require tailored AI solutions. Recent advances have led to paediatric-specific AI tools for tumour segmentation, treatment response evaluation, recurrence prediction, toxicity assessment, and integrative multimodal analysis. These innovations have the potential to improve diagnostic accuracy, streamline workflows, and inform personalised treatment strategies. However, clinical implementation remains hindered by challenges related to data heterogeneity, model generalisability, and integration into clinical practice. In this Policy Review, we highlight key developments, challenges, and priority areas for imaging-based AI for paediatric neuro-oncology. Our goal is to provide oncology practitioners with a focused overview of current capabilities, unmet needs, and future directions at the intersection of AI and paediatric neuro-oncology. |
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Lancet Oncology Di Federico A, Pecci F, Wang X, Ricciuti B BACKGROUND: Immune checkpoint inhibitors targeting PD-L1 or PD-1 as monotherapy or combined with CTLA-4 inhibitors or chemotherapy (or both) are the standard of care for patients with advanced non-small-cell lung cancer (NSCLC). However, it remains unclear which patients benefit from the addition of CTLA-4 inhibitors. We aimed to evaluate whether dual checkpoint blockade with CTLA-4 and PD-L1 or PD-1 inhibitors provides similar efficacy to PD-L1 or PD-1 inhibitor monotherapy, or whether these strategies produce distinct outcomes across NSCLC subpopulations. METHODS: We conducted a search of PubMed, MEDLINE, and Embase for randomised phase 3 trials published from database inception to Nov 21, 2024, that investigated PD-L1 or PD-1 inhibitors, with or without CTLA-4 inhibitors, in patients with advanced NSCLC. We focused on studies reporting Kaplan-Meier survival data at 5 years or biomarker analyses based on PD-L1, KRAS, and STK11 mutational status. Individual patient data were extracted from Kaplan-Meier curves with WebPlotDigitizer version 5 and reconstructed with the IPDfromKM method. The primary endpoint of the study was 5-year overall survival in the overall population and in subpopulations based on PD-L1 tumour proportion score (TPS), tumour histology, and mutational status (mutant vs wild-type) of KRAS and STK11. This study was registered with PROSPERO, CRD420251081707. FINDINGS: The initial search yielded 1026 results, and six randomised clinical trials met the eligibility criteria and were included. Among the 2881 patients eligible for analysis (838 [29·1%] female and 2043 [70·9%] male), 1282 received dual CTLA-4 and PD-L1 or PD-1 blockade and 1599 received single PD-L1 or PD-1 blockade. Patients treated with dual CTLA-4 and PD-L1 or PD-1 blockade had similar median overall survival compared with those treated with single PD-L1 or PD-1 inhibition (16·1 months [95% CI 15·0-17·8] vs 16·9 months [15·5-18·3]; HR 0·95 [95% CI 0·87-1·03], p=0·19). Median overall survival was significantly longer with dual CTLA-4 and PD-L1 or PD-1 blockade among patients with PD-L1 TPS less than 1% versus those treated with single PD-L1 or PD-1 inhibition (15·5 months [95% CI 13·6-18·5] vs 14·5 months [13·4-15·9]; HR 0·85 [95% CI 0·74-0·98], p=0·021), with 5-year overall survival rates of 16·6% (95% CI 13·4-20·6) versus 9·3% (7·0-12·3), respectively. Median overall survival in patients with tumours harbouring STK11 mutations was also significantly longer with dual CTLA-4 and PD-L1 or PD-1 blockade compared with single PD-L1 or PD-1 inhibition (13·9 months [95% CI 9·8-20·8] vs 7·8 months [6·4-12·9]; HR 0·67 [95% CI 0·49-0·91], p=0·012). However, no significant differences in overall survival were found between treatment groups by tumour histology (squamous vs non-squamous NSCLC) or by KRAS mutational status. INTERPRETATION: Compared with single PD-L1 or PD-1 inhibition, dual immune checkpoint blockade with CTLA-4 and PD-L1 or PD-1 inhibitors was associated with improved overall survival in patients with advanced NSCLC and PD-L1 TPS less than 1% and in those with STK11 mutations, but not in the overall population. Prospective validation of these results in clinical trials is warranted. FUNDING: NextGenerationUE. |
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Nature Covariation MS Uncovers a Protein that Controls Cysteine Catabolism Xiao H, Ordonez M, Fink EC, Covington TA, Woldemichael HB, Jain MS, Wei SM, Burger N, Sharif MA, Wang Y, Petrocelli JJ, Blackmore K, Smythers AL, Zhang B, Gilbert M, Cheong H, Khetarpal SA, Smith A, Bogoslavski D, Lei Y, Vaites LP, Donovan KA, Huttlin EL, Mills EL, Fischer ES, Chouchani ET The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes. |
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Nature Chemical Biology Mutant p53 Protein Accumulation is Selectively Targetable by Proximity-Inducing Drugs Sadagopan A, Carson M, Zamurs EJ, Garaffo N, Chang HJ, Schreiber SL, Meyerson M, Gibson WJ TP53 mutant cancers are associated with approximately half of cancer deaths. The most common mechanism of p53 inactivation involves missense mutations. Such mutations in TP53 result in a robust upregulation of the p53 protein. Here, we demonstrate an induced proximity approach to selectively kill TP53 mutant cells. This approach uses the increased abundance of p53 protein in TP53 mutant cancer cells to concentrate toxic molecules in these cells. We demonstrate this approach with a molecule that binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboring TP53Y220C mutations. The resulting bifunctional molecule promotes formation of a p53Y220C-PLK1 ternary complex, mislocalizes PLK1, inhibits PLK1 activity, elicits selective G2/M arrest and induces apoptosis in TP53Y220C cells while sparing wild-type TP53 cells. These data exemplify a potentially generalizable framework for targeting TP53 missense mutations by leveraging mutant p53 protein abundance to induce cell death, independent of p53's transcriptional activity. |
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Nature Communications Modeling and Addressing On-Target/Off-Tumor Toxicity of Claudin 18.2 Targeted Immunotherapies Carstens EJ, Takahashi K, De Vizio M, Morgado M, Nikkhoi SK, Mangipudi A, Nguyen CH, Weltzin T, Klempner SJ, Ramasubramanian A, Nowak JA, Aguirre AJ, Smith EL Successfully extending immunotherapies to solid tumors involves addressing several key challenges, importantly the "antigen dilemma", the expression of a solid tumor target antigen on the normal tissue of tumor origin. Claudin 18.2 (CLDN18.2) has emerged as an important target for upper gastrointestinal (GI) cancer therapies (such as Zolbetuximab, a naked antibody, recently approved; or CT041, a second-generation chimeric antigen receptor (CAR) T cell therapy with promising clinical data). However, GI toxicities are reported from clinical use of both Zolbetuximab and CT041. Here, we describe clinical Zolbetuximab treatment associated cases of gastric erosive lesions. We also demonstrate and characterize on-target/off-tumor gastric toxicity targeting CLDN18.2 in a preclinical mouse model of CT041-scFv derived CAR T cell therapy. By developing CLDN18.2 fully-human VH-only single domain CARs, we demonstrate that on-target/off-tumor toxicity inversely correlates with affinity of the binder, and that a lower affinity CAR may widen the therapeutic window for CLDN18.2 by decreasing on-target/off-tumor toxicity while preserving efficacy. |
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Nature Genetics St Laurent JD, Xu GD, Ying AW, Patil A, Paulo JA, Cervantes KS, Feng WW, Sankar A, Samé Guerra DD, Qi J, Neel DS, Hornick JL, Kolin DL, Gygi SP, Kadoch C The mammalian (m)SWI/SNF family of chromatin remodelers govern cell type-specific chromatin accessibility and gene expression and assemble as three distinct complexes: canonical BRG1-associated or BRM-associated factor (cBAF), poly(bromo)-associated BAF (PBAF) and noncanonical BAF (ncBAF). ARID1A and ARID1B are paralog subunits that specifically nucleate the assembly of cBAF complexes and are frequently co-mutated in highly aggressive dedifferentiated or undifferentiated endometrial carcinomas (DDEC/UECs). Here in cellular models and primary human tumors, we find that ARID1A and/or ARID1B (ARID1A/B) deficiency-mediated cBAF loss results in increased ncBAF and PBAF biochemical abundance and chromatin-level functions to maintain the DDEC oncogenic state. Furthermore, treatment with clinical-grade SMARCA4 and/or SMARCA2 ATPase inhibitors markedly attenuates DDEC cell proliferation and tumor growth in vivo and synergizes with carboplatin-based chemotherapy to extend survival. These findings reveal the oncogenic contributions of shifted mSWI/SNF family complex stoichiometry and resulting gene-regulatory dysregulation and suggest therapeutic utility of mSWI/SNF small molecule inhibitors in DDEC/UECs and other cBAF-disrupted cancer types. |
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New England Journal of Medicine Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer Tolaney SM BACKGROUND: Patients with previously untreated, locally advanced, unresectable or metastatic triple-negative breast cancer who are not candidates for inhibitors of programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) have limited treatment options. METHODS: In this international, phase 3, open-label, randomized trial, we enrolled patients with previously untreated, advanced triple-negative breast cancer who were not candidates for PD-1 or PD-L1 inhibitors owing to previous use or coexisting conditions. Patients had either PD-L1-negative tumors with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages divided by the total number of viable tumor cells, multiplied by 100) of less than 10 or PD-L1-positive tumors with a CPS of 10 or higher and were assigned in a 1:1 ratio to receive sacituzumab govitecan or chemotherapy (paclitaxel, nanoparticle albumin-bound paclitaxel, or gemcitabine plus carboplatin). The primary end point was progression-free survival, assessed by blinded independent central review. Secondary end points included overall survival, objective response, the duration of response, and safety. RESULTS: Among 558 patients, median progression-free survival was 9.7 months (95% confidence interval [CI], 8.1 to 11.1) with sacituzumab govitecan and 6.9 months (95% CI, 5.6 to 8.2) with chemotherapy (stratified hazard ratio for disease progression or death, 0.62; 95% CI, 0.50 to 0.77; P<0.001). An objective response was confirmed in 48% of patients (95% CI, 42 to 54) who received sacituzumab govitecan and 46% (95% CI, 40 to 52) who received chemotherapy; the median response duration was 12.2 months (95% CI, 9.7 to 13.8) and 7.2 months (95% CI, 5.7 to 8.4), respectively. Adverse events of grade 3 or higher occurred in 66% of patients who received sacituzumab govitecan (most frequently neutropenia [in 43%], diarrhea [in 9%], and leukopenia [in 7%]) and in 62% of patients who received chemotherapy (most frequently neutropenia [in 41%], anemia [in 16%], and leukopenia [in 13%]). The incidence of adverse events that led to discontinuation of sacituzumab govitecan or at least one chemotherapy drug was 4% and 12%, respectively. CONCLUSIONS: Sacituzumab govitecan led to significantly longer progression-free survival than chemotherapy among patients with advanced triple-negative breast cancer who were not candidates for treatment with PD-1 or PD-L1 inhibitors. The incidence of adverse events of grade 3 or higher with sacituzumab govitecan was similar to that with chemotherapy, but adverse events were common. (Funded by Gilead Sciences; ASCENT-03 ClinicalTrials.gov number, NCT05382299.). |
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Proceedings of the National Academy of Sciences of the U.S.A. Li Y, Qiu X, Sandusky Z, Tagliaferri K, Li R, Zhang T, Liu S, Yan P, Lu F, Xiao T, Goldman S, Polyak K, Liu XS, Long HW, Adelman K, Rosenbluth JM, Brown M The mechanisms underlying sustained proliferation and aberrant cellular plasticity that drive early breast tumorigenesis remain unclear. Using CRISPR knockout (KO) screens, we systematically characterized the regulators of cellular fitness in the normal mammary epithelium. We found that loss of METTL3 stimulates mammary epithelial proliferation and reprograms gene expression in an m6A methyltransferase-dependent manner. Single-cell analysis in normal breast organoids revealed that METTL3 ablation causes disruption of the mammary cellular hierarchy through increased aberrant luminal differentiation. Mechanistically, METTL3 loss reduces RNA m6A modification of transcribed transposable elements leading to their increased expression and upregulation of interferon-STAT signaling. This inflammatory response leads to cross talk between STAT and GATA3 transcription factors, resulting in transcriptional activation of luminal genes in the mammary epithelium. These findings identify a cell-intrinsic epigenetic loop contributing to mammary epithelial differentiation and highlight a potential role of loss of METTL3-dependent m6A modification during neoplastic transformation. |
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American Journal of Kidney Diseases Chewcharat A, Wang M, Gupta S, Singh H, Chowdhury RB |
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Annals of Surgical Oncology Hans M, Tamaskar AS, Recko A, Bychkovsky BL, Pace LE, King TA, Park KU |
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Blood Advances Krasnow N, Maurer K, Song C, Rhoades J, Xiong K, Crnjac A, Blewett T, Gao L, Jacene H, Merryman R, Gohil SH, Duffy C, Guerrero LI, Dela Cruz J, McDonough M, Wolff JO, Redd R, Makrigiorgos GM, Neuberg DS, Rodig SJ, Armand P, Jacobson C, Adalsteinsson VA, Wu CJ |
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Blood Cancer Journal Aguirre LE, Stone RM, DeAngelo DJ |
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BMJ Supportive and Palliative Care Beaussant Y, Sager Z, Kristan I, Ljuslin M, Mazzola E, Nigam K, Rinaldi AD, Schaefer KG, Sholevar R, Summer L, Tulsky JA |
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Brachytherapy Al Balushi MM, Perkins TM, Shin KY, Buzurovic IM, Talbot SG, Goldberg JE, O'Farrell DA, King MT, Mamon HJ, Devlin PM |
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Breast Cancer Research and Treatment Lloyd K, Ogayo ER, Mayer EL, Freedman RA, King TA, Mittendorf EA, Kantor O |
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Breast Cancer Research and Treatment Gonzalo-Encabo P, Giobbie-Hurder A, Mayer EL, Partridge AH, Poorvu PD, Waks AG, Tanasijevic AM, Dieli-Conwright CM, Ligibel JA |
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British Journal of Pharmacology Ligandability Assessment of Interferonopathy-Associated Proteins Using Chemoproteomics Jones LH |
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Cancer Nagy MR, Puopolo O, Alston E, Challa S, Ceca E, Li Y, Cherniack AD, Lazo de la Vega L, Meyerson M, Church AJ, Janeway K |
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