Welcome to Dana-Farber's Research News
March 1, 2026
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 February 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 Sorial MN, Jacobsen E, Jain S We assessed the overall survival (OS) impact of time to relapse (TTR) in multinational cohorts with independent observational and randomized validation. Patients with nMTCL with frontline complete response were assigned to TTR12 (?12 months) or without TTR12 based on time to progression or next therapy. OS analyses included modified landmark (m-LM), standard landmark (s-LM), and time-dependent Cox (td-Cox), adjusting for age, histology, and prognostic index for T-cell lymphoma (PIT) score. Across 452 patients, 165 (36.5%) had TTR12, 181 (40%) relapsed at ?12 months, and 106 (23.5%) remained relapse-free. TTR12 conferred worse OS using m-LM (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.58-2.90; P< .001), s-LM (HR, 1.92; 95% CI, 1.39-2.66; P< .001); and td-Cox (HR, 5.81; 95% CI, 2.94-11.46; P< .001). Results were consistent in the independent validation cohorts. TTR12 consistently conferred worse OS irrespective of frontline stem cell transplantation or PIT score, in peripheral T-cell lymphoma, not otherwise specified (m-LM: HR, 2.32; 95% CI, 1.51-3.55; P< .001; s-LM: HR, 2.10; 95% CI, 1.33-3.31; P = .001), anaplastic large cell lymphoma (m-LM: HR, 3.34; 95% CI, 1.18-9.50; P = .023; s-LM: HR, 2.96; 95% CI, 1.02-8.81; P = .046), and angioimmunoblastic T-cell/T follicular helper cell lymphoma (m-LM only: HR, 1.92; 95% CI, 1.15-3.21; P = .013). Second-line novel therapies improved OS (second-line start to death) vs chemotherapy in TTR12 only (HR, 0.60; 95% CI, 0.37-0.97; P = .038; without TTR12: HR, 0.82; 95% CI, 0.51-1.32; P = .407). TTR12 serves as a prognostic and potential OS surrogate marker, supporting stratification of new risk groups and need for their differential treatment. |
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Blood Sun H, Sklavenitis Pistofidis R, Liu S, Liu X, Tsakmaklis N, Hatcher JM, Guerrera ML, Kofides A, Ramirez-Gamero AF, Peachey A, Li S, Keskin D, Chea V, Kim N, Lyu H, Lu W, Livak KJ, Meid KE, Guijosa A, Flynn C, Pizzarella D, Patterson CJ, Branagan AR, Wu CJ, Ghobrial IM, Sarosiek S, Castillo JJ, Hunter ZR, Treon SP To elucidate the molecular basis underlying differential response and resistance to ibrutinib in Waldenström's macroglobulinemia (WM), we conducted a prospective phase II trial (ClinicalTrials.gov; NCT02604511) of ibrutinib monotherapy in treatment-naïve patients. Seventy-four sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multi-omics. BM cells segregated primarily into B/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B/plasma cells identified three distinct evolutionary patterns: "evolution" (early clone contraction with late clone expansion and increasing genomic complexity), "devolution" (early clone expansion with late clone contraction and genomic simplification), and "no-evolution" (stable clonal architecture). The "evolution" pattern was strongly associated with disease progression, whereas "devolution" correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström's Ibrutinib Prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combinatorial strategy. In parallel, GZMB? CD8? effector-memory (TEM) cells expanded post-treatment in progressing patients and co-existed with tumor "evolution". These cells exhibited persistently impaired cytotoxic programs (e.g., GNLY), a de-differentiated memory-like state, elevated PDCD1 expression, and reduced TCR diversity. Together, this study provides the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM; introduces the WIP score as a predictive biomarker for treatment response; and identifies actionable tumor-intrinsic and immune mechanisms driving resistance. |
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Blood Hantel A, Wang Y, Cronin A, Walsh TP, Gallagher E, Luskin MR, Lathan CS, Uno H, DeAngelo DJ, Abel GA Clinical trial eligibility criteria select a target population and reduce anticipated risks for participants but may unnecessarily limit participation both overall and differently across demographic groups. We previously abstracted eligibility criteria for 190 phase 2/3 acute myeloid leukemia (AML) trials and used US Food and Drug Administration and professional society guidance on modernizing criteria to develop alternative, safety-based eligibility criteria for each trial. In this analysis, these trial- and safety-based eligibility criteria sets were applied to a retrospective cohort of 2226 newly diagnosed patients across 8 hospitals to assess the impact on eligibility. Eligibility proportions increased from a median of 47.9% with trial-based criteria to 84.2% with safety-based criteria (median difference, 30.0%; P< .001); excluding age criteria, the increase was 11.5% (P< .001). Non-Hispanic (NH) Asian, NH Black, NH White, and Hispanic patients were eligible for median proportions of 41.1%, 44.0%, 47.9%, and 50.0%, respectively, with trial-based criteria, increasing by 27.9% to 31.6% when using safety-based criteria (within-group changes, all P< .001; between-group changes, all P> .05). Excluding age criteria, increases were between 10.0% and 11.9%. Moving from trial- to safety-based criteria decreased the proportion of trials with significant eligibility differences between NH White and NH Asian (-11.1%), NH Black (-4.2%), and Hispanic (-12.1%) patients. Criteria significantly associated with increased eligibility and decreased between-group differences in eligibility were coronary artery disease, congestive heart failure, aspartate transaminase level, upper age limits, and previous malignancy. These data suggest that modernization of eligibility for AML trials to focus on safety-based criteria can improve both overall enrollment and population representation. |
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Blood Proteasome Subunit PSMD1 is a Key Therapeutic Target in Multiple Myeloma Du T, Fang T, Pillai SC, Ray A, Wang M, Wan X, Wen K, Liu Y, Xu J, Musa MA, Liu X, Fulciniti M, Munshi NC, Garbicz F, Carrasco RD, Zhang Z, Song Y, Anderson KC We found that PSMD1, a key subunit of the 19S proteasome regulatory particle, was overexpressed and correlated with poor prognosis in multiple myeloma (MM). Genetic depletion of PSMD1 decreased cancer cell viability, induced polyubiquitinated protein accumulation, and promoted apoptosis. Proteomic analysis revealed the activation of immune-related pathways, suggesting the potential for immune modulation. Targeting PSMD1 with siRNA, delivered via lipid nanoparticles (LNPs), reduced tumor growth in MM cell lines and primary patient samples while sparing normal cells. It also overcame proteasome inhibitor resistance and the protective effects of the bone marrow milieu. In MM xenograft mouse models, PSMD1 siRNA LNPs significantly reduced tumor growth and prolonged survival. In addition, PSMD1 depletion had similar effects on other types of cancer cell lines. These findings position PSMD1 as a critical target in cancer therapy, with broad implications for overcoming drug resistance, improving therapeutic outcomes, and potentially impacting immune responses across various cancers. These findings provide a foundation for the clinical development of PSMD1-targeted therapies in myeloma and other malignancies |
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Cancer Cell Targeting STING to Generate Therapeutic Anti-Tumor Immunity Fahey CG, Cordova AF, Gedeon PC, Barbie DA The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway bridges cytosolic DNA sensing with type I interferon activation in cancer. Despite promising preclinical results, generating clinically meaningful anti-tumor immunity with STING agonists has faced substantial challenges, highlighting gaps in model systems and the biologic complexity of STING signaling. In the tumor microenvironment (TME), STING activation elicits highly context- and cell type-dependent outcomes, with divergent effects on tumor cells, myeloid cells, T cells, and other cell types. Furthermore, the downstream induction of type I interferon and other cytokines in the TME can have both pro- and anti-tumorigenic consequences, with emerging interferon-independent functions of STING signaling adding further complexity. In this review, we chart the diverse impact of STING activation across the TME and discuss how recent insights can inform the design of next-generation therapeutic strategies that more effectively harness STING-driven innate immunity to promote durable anti-tumor activity in humans. |
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Cancer Cell The Cellular Orchestra of CAR-T Success Samur MK, Munshi NC In this issue of Cancer Cell, Rade et al. report a longitudinal single-cell atlas of multiple myeloma patients receiving BCMA-directed chimeric antigen receptor (CAR) T cell therapy (ide-cel or cilta-cel) and identify features linked to long-term responses, including CD4+ T cell-driven cytotoxicity, memory-biased T cell states, reduced exhaustion, and microenvironment effects. |
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Cell Meylan M, Tian Y, Wu L, Ling AL, Barlow GL, Nguyen LD, Pyrdol J, Marx S, Westphal L, Michel J, Gonzalez Castro LN, Dumont S, Santos A, Suvà ML, Chiocca EA, Wucherpfennig KW A recent first-in-human clinical trial demonstrated that survival in glioblastoma (GBM) patients following rQNestin34.5v.2 oncolytic virus treatment was associated with immune activation signatures. This study was registered at ClinicalTrials.gov (NCT03152318). Here, we provide in situ evidence of ongoing T cell-mediated cytotoxicity against tumor cells at late time points following single treatment, with deep and persistent T cell infiltration into tumor regions. Shorter distances between cleaved caspase-3+ tumor cells and granzyme B+ T cells were associated with longer progression-free survival following treatment. Pre-existing tumor-infiltrating T cells expanded locally upon treatment, correlating with longer overall patient survival. T cells with an early activation program closely interacted with tumor cells and were strongly enriched upon treatment. Viral remnants were restricted to necrotic regions, while T cells infiltrated deeply into live tumor regions. These data demonstrate that single oncolytic virus treatment can expand pre-existing T cell clones and trigger persistent T cell-mediated immunity against GBM. |
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JAMA Patel AK, Sethi NS, Park H IMPORTANCE: Globally, 968?350 new cases and 659?853 deaths from gastric cancer were reported in 2022. In the US, 30?300 new cases and 10?780 deaths were estimated in 2025. OBSERVATIONS: Gastric cancer is more common in men, and the median age at diagnosis is 68 years. Most gastric cancers (>90%) are adenocarcinomas. Worldwide, 85% of cases arise from the stomach body or antrum and 15% from the cardia. In the US, more than 90% of patients diagnosed with gastric cancer present with symptoms such as weight loss and abdominal pain. At presentation, approximately 13% have localized disease (limited to the stomach), 15% to 25% have locally advanced disease, defined as a tumor that has spread to regional lymph nodes, and 35% to 65% have metastatic disease. Helicobacter pylori infection is a treatable risk factor associated with 90% of gastric body and antrum cancers globally. Additional modifiable risk factors include smoking, alcohol, obesity, and salt intake. In countries with high incidence such as Japan and Korea, routine endoscopic screening beginning at age 40 years is associated with improved survival. Diagnosis is made by endoscopic biopsy. Patients with localized gastric cancer are treated with surgical resection and have a 5-year relative survival rate of 75% with treatment. Patients with more advanced-stage disease should receive gastrectomy, perioperative chemotherapy with 5-fluorouracil, oxaliplatin, and docetaxel and immunotherapy (durvalumab). Metastatic or unresectable disease may be treated with chemotherapy, immunotherapy, and/or targeted therapy depending on biomarkers, including programmed cell death ligand 1 (PD-L1), human epidermal growth factor receptor 2 (ERBB2; formerly HER2 or HER2/neu), and claudin-18, isoform 2 (CLDN18.2). For PD-L1-expressing gastric cancer, adding immune checkpoint inhibitors, such as nivolumab and pembrolizumab, is associated with an additional 3 months of survival when compared with chemotherapy alone. For gastric cancers overexpressing the ERBB2 or CLDN18.2 proteins, the addition of trastuzumab or zolbetuximab, respectively, is associated with an additional 3 to 4 months' survival. Early supportive care focusing on symptom management and on nutritional and psychosocial support is associated with 3 months of survival benefit. Less than 10% of patients with metastatic gastric cancer survive more than 5 years. CONCLUSIONS AND RELEVANCE: Approximately 30?300 new cases of gastric cancer are diagnosed annually in the US. Localized gastric cancer is treated with gastrectomy, and locally advanced disease is treated with surgery and chemoimmunotherapy. For patients with unresectable or metastatic gastric cancer, chemotherapy with immune checkpoint inhibitors and targeted therapies such as trastuzumab or zolbetuximab improves survival by several months. |
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JAMA Oncology Rakaee M, Nassar AH, Bou Farhat E, Adib E, Gusev A, Ricciuti B, Sholl LM, Kwiatkowski DJ IMPORTANCE: Artificial intelligence (AI) models are emerging as rapid, low-cost tools for predicting targetable genomic alterations directly from routine pathology slides. Although these approaches could accelerate treatment decisions in lung cancer, little is known about whether their performance is consistent across diverse patient populations and tissue contexts. OBJECTIVE: To evaluate the performance and generalizability of 2 open-source AI pathology models for predicting EGFR mutation status in lung adenocarcinoma (LUAD) across independent cohorts and ancestral subgroups. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included patients with LUAD from 2 cohorts: Dana-Farber Cancer Institute (DFCI) from June 2013 to November 2023, and a European-based trial (TNM-I) from August 2016 to February 2022. All patients had paired next-generation sequencing data and hematoxylin-eosin-stained whole-slide images. In the DFCI cohort, genetic ancestry was inferred using germline genotype data. Data analyses were performed from July 2025 to September 2025. MAIN OUTCOMES: The primary outcome was model performance for predicting EGFR mutation status, measured as the area under the receiver operating characteristic curve (AUC), evaluated overall and across ancestry subgroups and sample types. RESULTS: Overall, 2098 patients with LUAD were included (mean [SD] age, 66.6 [10.3] years; 1315 female individuals [63%] and 783 male individuals [37%]). In the DFCI cohort (n?=?1759; 54 African, 101 American, 95 Asian, 1465 European), EGFR mutations were detected in 432 patients (25%). One AI-pathology model achieved an AUC of 0.83 (95% CI, 0.81-0.85) compared with 0.68 (95% CI, 0.65-0.70) for the other model. In the TNM-I cohort (n?=?339), EGFR mutations were detected in 50 patients (15%), with AUCs of 0.81 (95% CI, 0.74-0.88) and 0.75 (95% CI, 0.68-0.83), respectively. In ancestry-stratified analyses of the DFCI cohort, AUCs for the higher-performing model were 0.84 (95% CI, 0.81-0.86) in patients of European ancestry, 0.85 (95% CI, 0.72-0.94) in African ancestry, and 0.68 (95% CI, 0.55-0.78) in Asian ancestry. In sample type analyses, performance declined in pleural (AUC, 0.66; 95% CI, 0.56-0.76) compared with lung specimens (AUC, 0.86; 95% CI, 0.83-0.88). AI-guided triage analyses showed a potential 57% reduction in rapid EGFR testing, while maintaining sensitivity of 0.84 and specificity of 0.99. CONCLUSIONS: This cohort study found that AI-based pathology tools may serve as preliminary adjuncts for EGFR prediction in lung cancer, though performance differences by ancestry warrant careful interpretation. |
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Journal of Clinical Oncology Ye Z, Mojahed-Yazdi R, Zapaishchykova A, Tak D, Mahootiha M, Pardo JCC, Zielke J, Zha Y, Guthier C, Tishler RB, Margalit DN, Schoenfeld JD, Haddad RI, Uppaluri R, Aerts HJWL, Hoebers F, Kann BH PURPOSE: Extranodal extension (ENE) is a biomarker in oropharyngeal carcinoma (OPC) but can only be diagnosed via surgical pathology. We applied an automated artificial intelligence (AI) imaging platform integrating lymph node autosegmentation with ENE prediction to determine the prognostic value of the number of predicted ENE nodes. MATERIALS AND METHODS: We conducted a multisite, retrospective study of 1,733 OPC patients with pretreatment computed tomography who underwent definitive radiation therapy across three institutions. Malignant lymph nodes were segmented using a validated deep learning auto-segmentation model, and segmented lymph nodes were sequentially processed with a validated ENE prediction model to calculate number of nodes with AI-predicted ENE (AI-ENE) per patient. We evaluated associations of AI-ENE with disease outcomes using site-stratified, multivariable Cox regression, adjusting for human papillomavirus (HPV) status, smoking pack-years, tumor and nodal stage, age, and sex. We evaluated risk-stratification improvement when incorporating AI-ENE into the Radiation Therapy Oncology Group (RTOG)-0129 risk groupings and derived American Joint Committee on Cancer (AJCC) 8th edition staging with Uno C-indices and decision curve analyses. RESULTS: Overall, median AI-ENE node number was 1 (range, 0-6). AI-ENE node number was independently associated with poorer distant control (DC; hazard ratio [HR], 1.44 [95% CI, 1.23 to 1.69]; P < .001) and overall survival (OS; HR, 1.30 [95% CI, 1.16 to 1.46]; P < .001). Increasing AI-ENE node number was incrementally associated with worse outcome, particularly DC (P < .001). C-indices improved in the external data set when incorporating AI-ENE into RTOG-0129 groupings (OS: 0.70 v 0.65; DC: 0.65 v 0.57) and AJCC-8 stage (OS: 0.75 v 0.70; DC: 0.72 v 0.67; P < .001 for each). The largest improvements were observed among HPV-negative patients (C-index: +15% for OS, +14% for DC). CONCLUSION: Automated, AI-ENE node number is a novel risk factor for OPC that may better inform pretreatment risk stratification and decision-making. |
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Journal of Clinical Oncology Aktas Samur A, Talluri S, Rivera J, Fan Y, Dakiki Korucu B, Fulciniti M, Anderson KC, Sperling A, Parmigiani G, Munshi NC, Samur MK PURPOSE: The diagnosis of smoldering multiple myeloma (SMM) primarily relies on clinical features such as plasma cell involvement, immunoglobulin protein levels, and end-organ damage. However, as early intervention becomes a priority, the role of genomic features in differentiating risk is gaining attention. METHODS: This study analyzed next-generation sequencing data from 224 precursor condition samples with 51 patients having paired SMM and multiple myeloma (MM) and 1,779 samples from newly diagnosed MM to identify genomic features linked to progression in SMM and those with a low-risk nonprogressor precursor condition. RESULTS: Our findings from paired samples revealed no significant differences in somatic alterations and clonal structures between SMM and MM samples from the same patient. This indicates that plasma cells in progressor SMM are genomically pre-equipped with changes that define myeloma. Over 80% of driver mutations were present at both time points, and more than 66% of progressor samples showed only minor clonal changes. We further compared genomic changes between nonprogressor and progressor SMM. Nonprogressor plasma cells showed significantly lower mutational load and the absence of copy number alterations on chromosome 8. They reduced focal genomic loss compared with progressor plasma cells. A scoring system using genomic features predictively identified patients with low-risk SMM unlikely to progress, validated on 101 additional independent samples, and additive clinical value of genomic classification was further shown in combination with 20/2/20. CONCLUSION: In summary, the genomic distinctions now suggest that a proportion of SMMs with progressor phenotype are akin to MM, whereas nonprogressor SMM has monoclonal gammopathy of undetermined significance-like characteristics. The results should influence further investigation in larger studies to inform future diagnostic criteria and trial designs. |
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Nature Efficient Near-Telomere-to-Telomere Assembly of Nanopore Simplex Reads Qu H, Park PJ, Li H Telomere-to-telomere (T2T) assembly is the ultimate goal for de novo genome assembly. Existing algorithms1,2 capable of near-T2T assembly all require Oxford Nanopore Technologies (ONT) ultra-long reads, which are costly and experimentally challenging to obtain and are thus often unavailable for samples without established cell lines3. Here we introduce hifiasm (ONT), an algorithm that can produce near-T2T assemblies from standard ONT simplex reads, eliminating the need for ultra-long sequencing. Compared with existing methods, hifiasm (ONT) reduces computational demands by an order of magnitude and reconstructs more chromosomes from telomere to telomere on the same datasets. This advance substantially broadens the feasibility of T2T assembly for applications previously limited by the high cost and experimental requirement of ultra-long reads. |
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Nature Biotechnology Sensitive Detection of Cancer Antigens Enabled by User-Defined Peptide Libraries Manakongtreecheep K, Ctortecka C, Correa-Medero LO, Zhu T, Lippincott I, Lawrence GM, Howard A, Hernandez GM, Forman C, Duggan EC, Wilbrink MA, Verzani EK, Afeyan AB, Li J, Oliveira G, Keskin DB, Ott PA, Clauser KR, Bakalar M, Sarkizova S, Hacohen N, Carr SA, Abelin JG, Wu CJ Human leukocyte antigen (HLA)-bound tumor peptides can be routinely isolated from cancer samples and identified using mass spectrometry (MS). However, MS approaches can be stochastic or rely on spectral libraries, which are not customarily available for individual-specific peptides, thus limiting the ability to discover novel peptides. Here, we introduce Pepyrus, which generates user-defined, individual-specific or disease-specific peptide libraries in Escherichia coli to improve the sensitivity and confidence of MS peptide identification, including lowly abundant neoantigens. Using Pepyrus-generated peptide libraries paired with an HLA-specific data-independent acquisition strategy, we recover >75% of the expected sequences per single injection for libraries of >10,000 peptides and identify 0.1?fmol of spiked-in peptides in a complex background. We apply Pepyrus to create personalized libraries, facilitating identification of clinically relevant HLA peptides, including several novel peptides from cell lines derived from persons with melanoma and renal cell carcinoma. Pepyrus enables identification of rare HLA-bound peptides and provides the ability to generate large training datasets to improve spectra, retention time and ion mobility prediction tools. |
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Proceedings of the National Academy of Sciences of the U.S.A. Rojas-Jimenez E, Bui TM, Yan P, Li Z, Seehawer M, Nishida J, Foidart P, Freeman GJ, Polyak K Estrogen receptor (ER) positive breast cancer is the most prevalent subtype, commonly responsive to endocrine therapies. Immune checkpoint inhibitors (ICIs) have limited efficacy in ER-positive disease, highlighting the need for the development of combination immunotherapies for these patients. We previously established that nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats mimic immune evasive mechanisms and the heterogeneity of ICI response observed in patients. We identified a "luminal growing" gene signature in ER-positive tumors, which correlated with tumor growth and immune-related differences. Here, we evaluated targeting candidates from this signature KMT5B/C and IKBKE using inhibitors A-196 and IKBKEi respectively, alongside anti-estrogen (fulvestrant) and a TGF? blocking antibody (NIS793), both individually and in combination with ?PD-L1, within this rat model. Fulvestrant emerged as the most effective treatment, inducing regression of most existing tumors and reducing on-treatment tumor burden when combined with ?PD-L1. A-196, while ineffective as a monotherapy, demonstrated enhanced response when combined with ?PD-L1. Comprehensive tumor profiling through polychromatic flow cytometry and single-cell RNA sequencing revealed that A-196 induced a luminal-to-basal shift in tumor epithelial cells, enhancing antigen presentation, whereas epithelial-to-mesenchymal transition was linked to fulvestrant resistance. Our findings underscore the value of the rat mammary tumor model for preclinical studies in ER-positive breast cancer and advocate for the further validation and potential clinical development of KMT5B/C inhibitors to enhance the efficacy and broaden the applicability of ICI therapy in cancer patients. |
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Proceedings of the National Academy of Sciences of the U.S.A. Traphagen NA, Wheeler E, Li R, Akhshi T, Ravindranathan R, Alfieri C, Lu F, Ahmed B, Tewari AK, Balk SP, Long H, D'Andrea AD, Qiu X, Brown M Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors as a potential treatment for castration-resistant prostate cancer. This combination treatment is based on the premise that AR directly regulates expression of DNA repair genes, leading to synergy between PARP and AR inhibition. Despite some promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)-proficient tumors. To investigate this discrepancy between preclinical and clinical results, we profiled the effects of PARP inhibition in prostate cancer models in the presence or absence of AR inhibition. Surprisingly, AR inhibition impaired response to PARP inhibitors in castration-sensitive cells and had no effect on response in castration-resistant cells. AR inhibition also did not regulate DNA repair in either the castration-resistant or castration-sensitive setting. Instead, we find that cell cycle progression is required for response to PARP inhibition in homologous recombination-proficient prostate cancer. |
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Proceedings of the National Academy of Sciences of the U.S.A. Mutations and Structural Variants Arising During Double-Strand Break Repair Dalin S, Webster S, Zhang S, Cui T, Beroukhim R Double-strand break (DSB) repair is highly mutagenic compared to normal replication. In budding yeast, repair of an HO (homothallism) endonuclease-induced DSB at the mating-type ? locus (MAT?) can be repaired by using an ectopic heterochromatic HMR::Kl-URA3 donor, producing MAT::Kl-URA3. Among MAT::Kl-Ura3- mutations arising during repair, 50% are base-pair substitutions. 30% are 1-bp indels in short homonucleotide runs, with -1 strongly favored over +1, whereas during replication, spontaneous -1 and +1 events are equal. Microhomology-bounded, repair-associated intragenic deletions (IDs) are recovered 12 times more frequently than tandem duplications (TDs). These data suggest a picture of the structure of the repair replication fork: IDs and TDs occur within the open structure of a migrating D-loop, where the 3' end of a partly copied new DNA strand can dissociate and anneal with a single-stranded region of microhomology either within ~80 bp ahead or ~40 bp behind the 3' end. Approximately ~10% of repair-associated mutations are interchromosomal template switches (ICTS), even though the Kluyveromyces lactis URA3 sequence in HMR is only 72% identical (homeologous) with Saccharomyces cerevisiae ura3-52. ICTS events begin and end at regions of short (~7.5 bp) microhomology; however, ICTS events are constrained to the middle of the copied sequence. Whereas microhomology usage in intragenic deletions is not influenced by adjacent homeology, we show that extensive pairing of adjacent homeology plays a critical role in ICTS. Thus, although by convention, structural variants are characterized by the precise base pairs at their junction, microhomology-mediated template switching actually requires alignment of extensive adjacent homeology. |
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Annals of Thoracic Surgery Segmentectomy vs Lobectomy for Occult N1 in Non-Small Cell Lung Cancer: Is Less More? Abdallat M, Leo RT, Sugarbaker EA, McAllister M, Xie Y, Mazzola E, Silvestri M, Bueno R, Jaklitsch M, Ugalde P, Swanson SJ, Wiener DC |
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Blood Advances Shimony S, Murdock HM, Keating JH, Tsai HK, Sasi A, Reilly CR, Neuberg DS, Stone RM, Lindsley RC |
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Blood Neoplasia Merryman RW, Redd RA, Olszewski H, Welsh E, Pfaff K, Lee H, McDonough M, Ahn IE, Brown JR, Crombie JL, Davids MS, Fisher DC, Jacobsen ED, Jacobson CA, Kim AI, Odejide OO, Parry EM, Ryan CE, Shipp MA, Armand P, Rodig S, Abramson JS, LaCasce AS |
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Breast Valenza C, Partridge AH, Regan MM |
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Cancer Lin M, Shusterman S, Ioakeim-Ioannidou M, Yock TI, Catalano PJ, Elhalawani H, Huang MS, Friedmann AM, Diller LR, Marcus KJ, MacDonald SM, Haas-Kogan DA, DuBois SG, Liu KX |
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Cell Chemical Biology Metabolic Control of Innate Immune Activation in TET2-Mutant Clonal Hematopoiesis Kim PG, Hergott CB, Miller AP, Deik A, Boileau M, Bullock K, Pierce KA, Choy AH, Shin W, McConkey M, Loke J, Ryback BA, Trinh MN, Rutter JC, Yue H, Yoon H, Park P, Roy Burman SS, Vander Heiden MG, Fischer ES, Armstrong SA, Clish C, Ebert BL |
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Cell Chemical Biology Systematic Cysteine Scanning Identifies a Druggable Pocket in Oncogenic KRAS van Tienen LM, Bayoumi S, Muneeruddin K, Leymarie N, Shekhar M, Mueller M, Li R, Chilukuri H, Kornfilt DJP, Atack TC, Kesar D, Bian Y, Shaw KL, Sellers WR |
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Cell Reports Abou Alaiwi S, Adib E, Zhang Z, Spisak S, Cordeiro P, El Zarif T, Sztupinszki ZM, Nassar AH, Seo JH, Campbell R, Steinharter JA, Pomerantz M, Signoretti S, Szallasi Z, Gusev A, Baca SC, Choueiri TK, Freedman ML |
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Clinical Cancer Research Lynce F, Graham N, Kochupurakkal BS, Nguyen H, Bychkovsky B, Poorvu PD, Attaya V, Davis R, DiLullo M, D'Andrea AD, Garber JE, Paweletz CP, Tayob N, Shapiro GI, Tolaney SM |
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Clinical Cancer Research Perez KJ, Horick N, Baginksa J, Giobbie-Hurder A, Gomez Diaz I, Nau AN, Dryg ID, Pfaff K, Rodig SJ, Hodi FS, Redston M, Bird A, Hovalanska M, Abrams T, Patel A, Rubinson DA, Schlechter BL, Chan JA |
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Contemporary Clinical Trials Onyeaka HK, Mate-Kole MN, Acheampong IA, Song MT, Amonoo HL |
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European Journal of Nuclear Medicine and Molecular Imaging Borges N, Liu M, Cheng SC, Könik A, Ritzer J, Wolanski A, Ng TSC, Choudhury AD, Taplin ME, Ravi P, Jacene H |
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European Urology Nguyen PL, Einstein DJ, Bubley GJ, Shin KY, Kibel AS, Taplin ME |
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International Journal of Radiation Oncology, Biology, Physics Harris TC, Jacobson M, Ferguson D, Hu YH, Myronakis M, Etemadpour R, Berbeco RI |
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JAMIA Open MedSlice: Fine-Tuned Large Language Models for Secure Clinical Note Sectioning Davis J, Sounack T, Sciacca K, Brain JM, Durieux BN, Agaronnik ND, Lindvall C |
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JCO Oncology Practice Raman HS, Abel GA, Lindvall C, Odejide OO |
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JCO Oncology Practice Agaronnik ND, Davis J, Manz CR, Tulsky JA, Lindvall C |
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JCO Oncology Practice Rosenberg AR, Comiskey L, Junkins CC, Yi-Frazier JP |
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JCO Clinical Cancer Informatics Validation of Claims-Based Algorithms to Classify Thoracic Radiation Therapy Courses Neibart SS, Lin N, Hogan J, Moningi S, Kann BH, Mak RH, Lam M |
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Journal of Affective Disorders Positive Psychological Well-Being and Psychological Distress in Higher Education Students Lam JA, Seo V, Overhage LN, Keane EP, Granoff MD, Amonoo HL |
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