Dana-Farber Research News 06.01.2026
Welcome to Dana-Farber's Research News
June 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 May 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 Bone Marrow Stem Cell Connexins: Misconceptions and New Insights Singh AK, Rallis KS, Cancelas JA Hematopoietic regeneration requires coordinated activation of hematopoietic stem and progenitor cells (HSPCs) and adaptive remodeling of the bone marrow (BM) microenvironment to meet extreme metabolic and oxidative demands imposed by cytotoxic injury, transplantation, and inflammation. While soluble factors and cytokine signaling are central to this process, emerging evidence identifies direct intercellular communication as a critical regulatory layer in stress hematopoiesis. Connexins, particularly Connexin-43 (Cx43), form an evolutionarily conserved communication network that integrates metabolic coupling, redox buffering, and organelle dynamics across hematopoietic and stromal compartments. Beyond canonical gap junction channel activity, connexins exert non-junctional, compartment-specific functions through cytoplasmic, nuclear, and mitochondrial pools that regulate signaling scaffolds, transcriptional programs, cytoskeletal organization, mitochondrial dynamics, calcium homeostasis, and bioenergetics. In HSPCs, mitochondrial Cx43 functions as a metabolic checkpoint that preserves regenerative capacity by supporting oxidative phosphorylation, limiting chronic AMPK activation, maintaining fusion-fission balance, and preventing mitochondrial Ca²? overload. In parallel, Cx43 enables mitochondrial transfer from donor HSPCs to stromal niche cells, restoring stromal metabolic competence and promoting effective niche repair and engraftment. Dysregulation of connexin networks contributes to marrow failure, clonal evolution, leukemic niche remodeling, and chemoresistance, highlighting their context-dependent roles in health and disease. This review synthesizes advances in connexin biology in hematopoiesis, reframes connexins as integrators of metabolic and regenerative signaling rather than passive conduits, and defines emerging translational opportunities. Isoform- and compartment-specific targeting of connexin pathways offers a therapeutic strategy to enhance hematopoietic recovery, preserve long-term stem cell function, and disrupt pathological niche support in hematologic malignancies. |
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Blood Sun H, Sklavenitis-Pistofidis R, Liu S, Liu X, Tsakmaklis N, Hatcher JM, Guerrera ML, Kofides A, Ramirez-Gamero A, Peachey AL, Li S, Keskin DB, Chea V, Kim N, Lyu H, Lu W, Livak KJ, Meid K, Guijosa A, Flynn CA, Pizzarella D, Patterson CJ, Branagan AR, Wu CJ, Ghobrial IM, Sarosiek SR, Castillo JJ, Hunter ZR, Treon SP To elucidate the molecular basis underlying differential responses and resistance to ibrutinib in Waldenström macroglobulinemia (WM), we conducted a prospective phase 2 trial of ibrutinib monotherapy in treatment-naïve patients. A total of 74 sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multiomics. BM cells were segregated primarily into B-cell/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B cells/plasma cells identified 3 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 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 combination strategy. In parallel, GZMB+ CD8+ effector-memory T cells expanded after treatment in patients with progressive disease and coexisted with tumor evolution. These cells exhibited persistently impaired cytotoxic programs (eg, GNLY), a dedifferentiated memory-like state, elevated PDCD1 expression, and reduced T-cell receptor diversity. Together, this study provides, to our knowledge, 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. This trial was registered at www.ClinicalTrials.gov as NCT02604511. |
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Blood Proteasome Subunit PSMD1 is a Key Therapeutic Target in Multiple Myeloma Du T, Fang T, Pillai S, Ray A, Wang M, Wan X, Wen K, Liu Y, Xu J, Musa MA, Liu X, Fulciniti M, Munshi NC, Garbicz F, Carrasco RD, Yao Y, 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 small interfering RNA (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 affecting 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 Bridging Clinical Gaps in Personalized Cancer Neoantigen Vaccines Khaddour K, Ott PA Personalized cancer neoantigen vaccines (PCV) represent an individualized form of immunotherapy. Neoantigens encoded by individual tumor mutations offer precise targets for robust, tumor-specific immunity. Next-generation sequencing and advanced bioinformatics have facilitated personalized neoantigen discovery, while progress in vaccine platforms has enabled optimization of delivery technologies and generated a versatile and scalable framework for neoantigen vaccine therapy, allowing therapeutic administration across diverse clinical settings. The integration of neoantigen vaccines with other treatment modalities requires careful consideration of timing, sequencing, and synergistic potential. In this review, we synthesize emerging data highlighting tumor indications suitable to investigate PCVs, define optimal clinical settings for vaccine administration, and discuss combinatorial regimens to enhance efficacy, as well as the timing and sequencing in multimodal treatment, aiming to address key translational opportunities and challenges essential to deploying neoantigen vaccines broadly in the clinic. |
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Cancer Cell Dendritic Cell Redundancy Enables Priming of Anti-Tumor CD4(+) T Cells in Pancreatic Cancer Kureshi CTS, Walsh MJ, Kureshi R, Cardot-Ruffino V, Agardy DA, Ali LR, Qiang L, Shen J, Zuo C, Lenehan PJ, Wang SJ, Chang E, Remland J, Brais L, Clancy TE, Cleary JM, Hornick JL, Huffman BM, Mancias JD, Molina G, Fairweather M, Nowak JA, Perez KJ, Rubinson DA, Slater S, van Dams R, Wang J, Wolpin BM, Zhao L, Singh H, Dougan M, Dougan SK Pancreatic ductal adenocarcinoma (PDAC) is resistant to current immunotherapies and lacks effective anti-tumor CD8+ T cells, which is potentially due to insufficient cross-presentation by cDC1s. Here, we combine a STING agonist with anti-CTLA-4 and anti-PD-1 to achieve durable remissions and immunologic memory in multiple mouse models of poorly immunogenic PDAC. We find that tumor control does not depend on CD8+ T cells or tumor cell MHC expression but instead requires IFN?-producing CD4+ T cells (Th1s) that are primed by dendritic cells in lymph nodes. The triple combination immunotherapy induces an accumulation of activated cDC2s carrying tumor antigen into tumor-draining lymph nodes; cDC2s are required for orthotopic tumor clearance. Intratumoral CD4+ T cells and cDC2s remain present in treatment-naive and chemotherapy-exposed human PDAC. In chemotherapy-exposed patients' blood, cDC2s outnumber cDC1s by 10-fold. Therefore, therapeutic targeting of the cDC2-CD4+ T cell-IFN? axis could be efficacious in PDAC. |
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Cancer Cell Whole-Genome Doubling Drives Immune Evasion by Silencing Antigen Presentation Foidart P, Li Z, Cai X, Seehawer M, Tawawalla A, Baldominos P, Parvin S, Nishida J, Rojas-Jimenez E, Bui TM, Diciaccio B, Goyette MA, Scales T, Yan P, Qiu X, Li R, Jiang Y, Xie Y, Huang XY, Stevens LE, Cejas P, Letai AG, Long HW, Agudo J, Polyak K Whole-genome doubling (WGD) is a common yet poorly understood event associated with poor clinical outcomes. Here, we characterize mechanisms by which WGD drives tumor evolution, utilizing mouse mammary tumor models of WGD established through cell fusion. We find that WGD increases transcriptomic and epigenetic heterogeneity and identify the YM155 BIRC5 inhibitor as a compound specifically suppressing WGD+ tumors. WGD triggers immune evasion by escaping CD8+ T cell responses, rendering WGD+ tumors more sensitive to anti-PD-L1. Through single-cell profiling, we discover that WGD+ cancer cells exhibit reduced antigen presentation and response to IFN?, attributed to the epigenetic silencing of MHCI transcriptional regulators via elevated histone H3 lysine 27 trimethylation. Further investigations reveal decreased KDM6 activity and increased succinate levels in WGD+ tumors. PRC2 inhibition preferentially suppresses WGD+ tumor growth, enhances antigen presentation, and CD8+ T cell infiltration. Our results underscore metabolic and epigenetic alterations as critical drivers of WGD-associated immune escape. |
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Cell Biodiversity and Biogeography of the Multi-Kingdom Cancer Microbiome Dohlman AB, Jiang K, Shumate A, Lee I, Yakubu AR, Huttenhower C, Meyerson M Microorganisms represent an important component of the tumor microenvironment, but conflicting reports have left the extent of microbial prevalence across cancer types unclear, necessitating more robust methods for characterizing tumor-associated microbiomes. We built and benchmarked a host-subtraction and classification pipeline to identify microbiota in whole-genome sequencing data and applied it to 16,369 high-depth tumor whole genomes from the UK 100,000 Genomes Project. After decontamination, microbial signatures were indistinguishable from the background in most cancer types. However, in orodigestive tumors, we detected multi-kingdom polymicrobial communities, including bacteria, fungi, viruses, archaea, and, in some cases, Trichomonas, a protozoan parasite. These communities varied by tumor site and subtype, with increased microbial colonization of microsatellite-instable and polymerase ? (POLE)/polymerase ? (POLD1)-mutated tumors, supported by a correlation between microbial load and tumor mutation burden observed across orodigestive cancers. This analysis helps to resolve pan-cancer microbial structure and links the tumor microbiome to host phenotype and tumor genomic context. |
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Cell Lyu P, Agarwal G, Guo CJ, Sychla A, Bourgeois W, Ye T, Weng C, Antoszewski M, Joubran S, Caulier A, Poeschla M, Armstrong SA, Rouskin S, Sankaran VG The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We found that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9, which we named HOXA opposite-strand transcript, stem-cell regulator, antisense mid-cluster between loci (HOTSCRAMBL). The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9, in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA-dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression. |
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Journal of Clinical Oncology Hanna GJ PURPOSE: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis, particularly those with human papillomavirus (HPV)-negative disease, in which elevated epidermal growth factor receptor and transforming growth factor-? impair tumor penetration of immune cells and lessen immunotherapy responses. METHODS: We present results from an expansion cohort of a first-in-human phase I/Ib trial (ClinicalTrials.gov identifier: NCT04429542) evaluating first-line treatment with ficerafusp alfa 1,500 mg once every week in combination with pembrolizumab 200 mg once every 3 weeks administered intravenously in patients with R/M HNSCC overexpressing PD-L1 (combined positive score ?1). The primary end point was safety. Secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). RESULTS: Between February 2022 and April 2023, 42 patients received ?1 dose of study drug and 39 were included in the efficacy-evaluable set (?1 postbaseline scan). The median follow-up was 26.3 months. Nineteen of 42 patients (45%) had a grade 3 treatment-related adverse event (TRAE), and one (2%) had a grade 4 TRAE. The most common grade ?3 TRAEs were anemia (14%) and acneiform dermatitis (12%). In efficacy-evaluable patients with HPV-negative (n = 28) or HPV-positive (n = 11) tumors, confirmed ORRs were 54% (complete response in 21%) and 27%, respectively. In the HPV-negative subgroup, median DOR was 21.7 months (95% CI, 6.0 to not estimable [NE]), median PFS was 9.9 months (95% CI, 4.4 to 22.7), and median OS was 21.3 months (95% CI, 9.9 to NE). CONCLUSION: Ficerafusp alfa plus pembrolizumab demonstrated favorable safety and tolerability with promising antitumor activity in the first-line treatment of R/M HNSCC, particularly in those with HPV-negative tumors. |
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Journal of Clinical Oncology Xie W, Manning DK, Van Allen E, Kochupurakkal B, Shapiro GI PURPOSE: Radium-223 is an ?-emitting radiopharmaceutical that improves survival in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data suggest synergy between poly(ADP-ribose) polymerase (PARP) inhibition and radiation. After phase I dose-finding, we conducted a randomized phase II trial to assess efficacy and safety of this combination versus radium-223. PATIENTS AND METHODS: Men with mCRPC and ?2 bone metastases (BM) were randomly assigned 1:1 to olaparib (200 mg twice daily) plus radium-223 (55 kBq/kg intravenous once every 4 weeks × 6 doses) or radium-223. Crossover was allowed at progression. The primary end point was investigator-assessed radiographic progression-free survival (rPFS). RESULTS: A total of 120 patients were randomly assigned. Most had prior androgen receptor pathway inhibitor exposure (96%), 52% had received docetaxel, 47% had >20 BM, and 90% received bone-protecting agents. The combination significantly improved rPFS (median 8.9 v 4.7 months; hazard ratio [HR], 0.50 [one-sided 90% CI, 0.35 to 0.70]; one-sided P = .0042). The benefit was most pronounced in patients without prior docetaxel (13.7 v 5.7 months; HR, 0.24 [90% CI, 0.15 to 0.40]) and those with ?20 BM (13.4 v 4.2 months; HR, 0.21 [90% CI, 0.13 to 0.33]). The 1-year cumulative incidence of symptomatic skeletal-related events was lower with the combination (12.7% v 22.9%). Median overall survival was similar (20.2 v 21.1 months). Grade ?3 treatment-related adverse events occurred in 56% versus 33% (combination v radium-223), primarily hematologic, including lymphopenia (31% v 9.1%), anemia (22% v 16%), and thrombocytopenia (6.8% v 3.6%). CONCLUSION: Olaparib plus radium-223 significantly prolonged rPFS compared with radium-223 in men with mCRPC and BM. Despite increased hematologic toxicity, the regimen was manageable and supports further exploration of DNA damage-targeted strategies in this population. |
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Journal of Clinical Oncology Sentana-Lledo D, Morgans AK Vasomotor symptoms (VMS), including hot flashes, plague many patients with prostate cancer receiving androgen deprivation therapy (ADT). A majority of patients report VMS to be the most bothersome ADT-related symptom, which can ultimately affect adherence to a cornerstone of systemic therapy in prostate cancer. Perhaps due to decades with a lack of precise understanding of the biologic mechanism underlying VMS, a paucity of readily available efficacious treatment options, and a general disinterest by patients in taking more medications, the search for effective therapies against VMS for the prostate cancer population has lagged behind that of other patient groups. |
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Journal of the National Cancer Institute FaceAge as a Biomarker for Prognosis and Treatment Stratification in a Large-Scale Oncology Cohort Lee G, Haugg F, Bontempi D, He J, Zalay O, Bitterman DS, Catalano P, Prudente V, Pai S, Guthier C, Kann BH, De Aerts HJWL, Mak RH BACKGROUND: Humans age at different rates, and facial characteristics may yield insight into biological age and physiologic health. FaceAge, a deep learning system designed to estimate biological age based on facial photographs, has shown potential as a biomarker for cancer prognosis. This study investigated the prognostic value of extreme discordance between FaceAge and chronological age (FaceAge?-?Age) in predicting survival and early mortality across a large clinical dataset of 28 cancer types. METHODS: Data from 24?556 patients with cancer aged 60 years or older treated with radiation therapy between 2008 and 2023 were analyzed. FaceAge estimates were compared with chronological age across different diagnoses/clinical contexts, and survival analyses were performed. All tests were 2-sided. RESULTS: The FaceAge estimate was older than the chronological age in 65% of participants (median FaceAge?=?74 years vs chronological age?=?70 years). Younger patients, female patients, patients with diagnoses associated with worse prognosis, and patients receiving treatment with palliative intent had a higher likelihood of FaceAge?-?Age ?10 years. Patients with FaceAge?-?Age ?10 years had statistically significantly worse survival, while patients with FaceAge?-?Age ??5 years had better survival. On multivariate analysis, FaceAge?-?Age ?10 years predicted higher mortality risk (hazard ratio?=?1.26; P?<?.001) and early mortality at 30?days (odds ratio?=?1.38, P?=?.004) and 60?days (odds ratio?=?1.33, P?<?.001), whereas FaceAge?-?Age ??5 years predicted lower mortality risk (hazard ratio?=?0.90; P?=?.002). CONCLUSIONS: Patients with more advanced cancers tend to have statistically significantly older FaceAge than chronological age, and extreme discordance between FaceAge and chronological age is a novel, independent predictor of survival and early mortality. These findings support further development of facial health assessments for clinical prognostication models and personalized treatment decision making. |
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Molecular Cell Aconitase 2 the Rescue: A Safeguard Against Excess Mitochondrial Citrate Vander Heiden MG The tricarboxylic acid (TCA) cycle is a metabolic pathway that enables nutrient oxidation to support ATP production and biosynthetic precursor generation. Carbon flow through the TCA cycle is regulated to meet cell bioenergetic and biosynthetic demands in different physiological contexts. However, dysfunction at different TCA-cycle enzymatic steps causes tissue-specific phenotypes with wide-ranging disease severities in humans, illustrating that when and why specific nodes of the TCA cycle are essential in health and disease is incompletely understood. |
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Nature A Glucocorticoid-FAS Axis Controls Immune Evasion During Metastatic Seeding Cassandras M, Sanchez X, Hsu L, Huang Y, Getzler AJ, Ganguly D, Baldominos P, Codinachs I, Chuong J, Martin EE, Smith BE, Marina E, Spasic M, Qin X, Parsons HA, Mayer EL, Sarosiek KA, Dougan SK, Mittendorf EA, McAllister SS, Hsu YC, Agudo J Metastasis is the major cause of death for patients with triple-negative breast cancer and other solid malignancies. Metastases arise from cancer cells that disseminate from the original tumour, survive systemic immune surveillance and colonize new organs1. Little is known about how initial disseminated tumour cells (DTCs) overcome anti-tumour immunity after seeding a new organ. Here we use a visible antigen in a model of triple-negative breast cancer with cognate CD8+ T cells to study the mechanisms of immune evasion in early metastatic seeding. Analysis of surviving DTCs revealed glucocorticoid receptor (GR) activation as a key driver of resistance to both CD8+ T cells and natural killer cells. Niche profiling using an optimized labelling tool identified FAS-FASL as a key pan-cytotoxic pathway against DTCs, which is repressed by GR activation. Pharmacological inhibition of GR in combination with immunotherapy reduced metastatic burden and expanded lifespan in mice. Thus, we identified a mechanism of immune evasion that operates specifically in DTCs, illustrating the unique immune-cancer interactions at this stage in the metastatic cascade. Our findings suggest that there are therapeutic opportunities to eliminate DTCs, separately from treatments aimed at primary tumours, and GR inhibition is one promising target. |
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Nature Biotechnology The Promises and Challenges of Neoantigen Cancer Vaccines Ott PA Transformational advances in genomic sequencing capabilities, vastly improved HLA class I epitope prediction algorithms and powerful delivery platforms have facilitated the clinical development of vaccines targeting neoantigens encoded by tumor mutations. Early clinical trials indicate that vaccination against neoantigens can induce robust and durable T cell immunity that may persist for decades. mRNA vaccines, originally developed for cancer applications, have demonstrated considerable promise due to their efficacy and scalable production, as evidenced during the SARS-CoV-2 pandemic. However, the optimal cancer vaccine platform and delivery strategy is not yet known, as current approaches have not been compared head-to-head and substantial technological advances to improve immunogenicity and potentially clinical efficacy are achievable. For example, lipid-based formulations, while necessary for the effective delivery of mRNA vaccines, may also improve the immunogenicity of peptides and other delivery strategies. Here we review the current state of neoantigen vaccines in the clinic and highlight emerging opportunities for advancement in the field. |
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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 Chemical Biology Algov I, Liang F, Zhou X Dysregulated extracellular proteolytic activity is a prominent hallmark of cancer and can thus be exploited for tumor detection and therapeutic development. However, the discovery of tumor-responsive probes has been hindered by the lack of methods to directly screen proteolytic events in specific tissue samples. Here we report PSurf, a platform that enables the identification of tissue-specific protease sensors with tissue specimens. Through differential selection of tumor-specific sequences over healthy tissue, PSurf identifies context-specific tumor-activated probes that precisely distinguish metastatic lesions in lung tissue slices. Using these substrates, we engineered nanobody-targeted biosensors that release urinary reporters upon tumor-specific cleavage in vivo, enabling precise non-invasive tumor detection in a mouse lung metastasis model. PSurf provides a foundation for developing conditionally activated agents through tissue-specific activity mapping and probe discovery. |
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Nature Communications Bourgeois W, Rice HE, Wenge DV, Yue H, Regalado BD, Wan G, Schroeder JC, Sommerschield A, Hatton C, Safer JF, Iqbal S, Perry JA, Fischer ES, Doench JG, Cutler JA, Armstrong SA Menin inhibitors have entered clinical trials for histone lysine methyltransferase 2?A (KMT2A)-rearranged and nucleophosmin 1 (NPM1)-mutant acute leukemias and are demonstrating promising activity. CRISPR base editor screening previously predicted several MEN1 (menin) mutations that have arisen in patients receiving SNDX-5613 and confer resistance. The extent to which MEN1 mutations will impact each menin inhibitor is mostly unknown. Here we show that CRISPR base editor screens can be leveraged to profile the MEN1 mutations that may impact five different menin inhibitors in clinical trials. We identify shared (M327I/V/T, G331D) and inhibitor-specific (C334R, E368K/V, V372A) resistance mutations. Co-crystal structures of menin bound to each menin inhibitor suggest resistance mechanisms related to how each inhibitor engages the KMT2A binding pocket of menin. Orthogonal in vitro and in vivo MEN1 mutation generation under therapeutic pressure suggest the MEN1 mutations identified with CRISPR base editor screening are likely to arise and impact all menin inhibitors. |
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Nature Communications PTPN2 Inhibition Unleashes Response to STING Agonism in Head and Neck Squamous Cell Cancer Li Z, Fu C, Sehgal K, Egloff AM, Thai TC, Monge OA, Chuong CL, Senent Y, Lineberry MS, Eschle BK, Haratani K, Ivanova EV, Campisi M, Mahadevan NR, Quadarella JD, Gedeon PC, Schoenfeld JD, Kono M, Fahey CG, Chayawatto C, Ngo K, Paweletz CP, Gokhale PC, Manguso RT, Uppaluri R, Barbie DA cGAS-STING signaling can promote antitumor immunity, and tumor cell STING is suppressed in a variety of cancer subtypes that resist immune checkpoint blockade. Although STING agonists have failed clinical trials, precision approaches targeting restoration of tumor cell STING expression have yet to be explored. Here, we report that head and neck squamous cell cancer (HNSCC) exhibits a mechanism of STING suppression related to upregulation of protein tyrosine phosphatase non-receptor (PTPN) type 2 (PTPN2) that is also evident in other cancers. PTPN2 inhibition (PTPN2i) increases HNSCC tumor cell STING by restoring IFN?-STAT1-mediated induction of STING mRNA. This restores sensitivity to STING agonism and natural killer cell activation, suppressing tumor growth in an immune cell-dependent manner in anti-PD-1 refractory syngeneic HNSCC mouse tumor models in female mice. Together, these findings demonstrate that PTPN2i can unleash STING agonist response, providing a rationale for the evaluation of this therapeutic combination in HNSCC and potentially other cancer types. |
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Nature Communications Hanna GJ, Gupta TR, Trippa L, Rettig EM, Margalit DN, Tishler RB, Pashtan I, Kim E, Droznin A, Gunasti L, Maddox R, Minken J, Mukundan D, Sehgal K, Dennis MJ, O'Connor T, Qian JM, Boyd GH, Saraf A, Massiel Gil D, Sethi RK, Annino DJ, Goguen LA, Guenette JP, Bakhtiar M, Jo VY, Wong K, Uppaluri R, Haddad RI, Schoenfeld JD Circulating tumor DNA (ctDNA) has an expanding role in oncology. It is unknown whether on-treatment ctDNA can be used to personalize radiation dose. This phase 2 exploratory clinical trial enrolled 102 patients with human papillomavirus (HPV)-positive oropharyngeal carcinoma (OPC). Intermediate-risk patients (T4 disease or >10 pack-year smokers with pre-treatment HPV ctDNA scores >200) were reclassified as low-risk if HPV ctDNA cleared by >95% mid-treatment. All clinically low-risk and reclassified patients received de-intensified (chemo)radiation. The primary outcome was progression-free survival (PFS) among de-escalated patients; secondary outcomes included tolerability, distant metastatic-free, and overall survival. Eighty-nine patients received de-escalated treatment (60 low-risk, 29 reclassified). Two-year PFS among de-escalated patients was 93% (95%CI, 87-99). Post-hoc analyses suggested that intermediate-risk patients reclassified as low-risk and treated with de-escalation had distinct HPV ctDNA dynamics and favorable outcomes. HPV ctDNA is an emerging biomarker that might improve risk stratification for patients with intermediate-risk HPV-positive OPC. Registration number: NCT04900623. |
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Nature Communications Cheng X, Zhang Y, Qian C, Holdridge E, Ananda G, Jiang T, Ni J, Xie S, Gu H, Ji R, Ivanova EV, Nucci MR, Wang Z, Chen K, Kochupurakkal B, Freeman GJ, Shapiro GI, Liu J, Konstantinopoulos PA, Matulonis U, Zhao JJ Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we develop a clinically relevant, immunocompetent serous-like mouse model incorporating oncogenic PIK3CA mutation, Trp53 loss, and MYC overexpression. Using this model together with human EC cell lines, patient-derived organoids (PDOs), xenografts, and patient datasets, we investigate mechanisms underlying resistance to PI3K?-targeted therapy. Single-cell profiling reveals that FGFR1/2 upregulation associates with intrinsic resistance, whereas FGFR3 characterizes acquired resistance. Dual FGFR and PI3K? inhibition produces superior tumor control compared with either agent alone. Mechanistically, FGFR signaling promotes immune evasion by downregulating MHC-I/HLA-mediated antigen presentation and enriching M2-type tumor-associated macrophages. FGFR inhibition reverses these changes and synergizes with anti-PD-1 therapy to enhance antitumor immune responses and establish durable immune memory. Collectively, these findings identify FGFR signaling as a key driver of therapeutic resistance and immune escape in SEC and support FGFR-targeted combination strategies. |
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New England Journal of Medicine Daraxonrasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer Wolpin BM BACKGROUND: Current therapies for patients with pancreatic ductal adenocarcinoma (PDAC) provide modest benefit. Activating RAS mutations occur in more than 90% of PDAC tumors. Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate-bound mutant and wild-type RAS. METHODS: In this phase 1-2 study, we evaluated daraxonrasib in patients with advanced solid tumors with activating RAS mutations. Patients received 10 to 400 mg of daraxonrasib orally once daily; 300 mg was selected as the phase 3 dose. The primary end point was safety. Pharmacokinetics and antitumor activity were secondary end points. This report focuses on the 168 study patients with previously treated RAS-mutated PDAC. RESULTS: Among the 168 patients with PDAC who received daraxonrasib at a dose of 300 mg or less, treatment-related adverse events of any grade were reported in 96%; such events of grade 3 or higher were reported in 30%. Treatment-related adverse events that occurred in at least 10% of the patients included rash, diarrhea, nausea, stomatitis or mucositis, vomiting, and fatigue. In a subgroup of 26 patients with RAS G12 mutations who were treated with second-line daraxonrasib at a dose of 300 mg, an objective response to therapy was reported in 35% (95% confidence interval [CI], 17 to 56). The median duration of response was 8.2 months (95% CI, 3.8 to not evaluable), with median values of 8.5 months for progression-free survival and 13.1 months for overall survival. Among the 38 patients with RAS G12, G13, or Q61 mutations, 29% (95% CI, 15 to 46) had an objective response. The median duration of response was 8.2 months (95% CI, 3.8 to 8.8), with median values of 8.1 months for progression-free survival and 15.6 months for overall survival. CONCLUSIONS: Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.). |
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Advances in Radiation Oncology Neibart SS, Chen YH, Droznin A, Huynh MA, Guthier C, Martin N, Mancias JD, Lam MB, Shiloh R, Peng L, Ng K, Surana R, Enzinger PC, Meyerhardt JA, Mamon HJ |
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American Journal of Hematology DeAngelo DJ |
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American Journal of Hematology Plasmablastic Lymphoma: 2026 Update on Diagnosis, Risk Stratification, and Management Castillo JJ |
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American Journal of Hematology Guijosa A, Tsakamaklis N, Kobs M, Kofides A, Budano N, Nguyen J, Eurell A, Meid K, Guerrera ML, Hunter ZR, Treon SP, Sarosiek S, Castillo JJ |
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Annals of Surgical Oncology Receipt of Combined Axillary Dissection and Nodal Irradiation Varies by Age Mittendorf EA, King TA, Kantor O |
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Bioinformatics FuFiHLA: A Tool for Full-Field HLA Typing from Long-Read Data Hu J, Qin Q, Li H, Zhou Y |
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Blood Cancer Discovery Laying the Foundation for Clinically Actionable Genomic Subtyping in Diffuse Large B-cell Lymphoma Shipp MA |
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Cancer Drug Development Trajectory of Anticancer Drugs After Initial Pediatric-Eligible Trials Martin SD, Pitafi D, Bourgeois F, DuBois SG |
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Cancer Science Nakazawa N, Ugai S, Kondo A, Matsuda K, Zhang X, Chan AT, Ogino S, Ugai T |
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Clinical Breast Cancer Age and Sex in Breast Cancer: Moving Beyond a One-Size-Fits-All Approach Leone JP |
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Clinical Cancer Research Immune Spatial Organization Predicts Distant Metastasis Risk in Aggressive Localized Prostate Cancer Yang DD, Abdelnaser A, Haas AJ, Wala J, Barney AA, Saad E, Crowdis JP, Ricker CA, Awad S, Park J, King MT, Nguyen PL, Choueiri TK, Einstein DJ, Balk SP, Tewari AK, Salari K, Taplin ME, Wu CL, Van Allen EM |
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Clinical Cancer Research Michaud D, Tolaney SM, McAllister SS, Guerriero JL, Sammons S |
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Clinical Lymphoma, Myeloma, and Leukemia Raje NS, Munshi NC |
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European Journal of Haematology Wei LJ, Richardson PG |
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Expert Opinion on Investigational Drugs Liu Y, Mo C, Midha S, Hartley-Brown M, Nadeem O, Nicholson T, Salman TJ, Laubach J, Richardson PG |
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Genes and Development Wang Y, Manokaran C, Zou Y, Chen J, Gu H, Liu D, Zhao JJ, Roberts TM |
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International Journal of Radiation Oncology, Biology, Physics Droznin AD, Tiwari P, Chen YH, Margalit DN, Tishler RB, Hanna GJ, Mak RH, Fitzgerald KJ, Sehgal K, Li S, Gunasti L, Kim E, Minken J, Baginska J, Nau A, Diaz IG, Shim B, Janes JT 3rd, Uppaluri R, Haddad RI, Livak KJ, Schoenfeld JD |
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International Journal of Radiation Oncology, Biology, Physics Einstein DJ, Regan MM |
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JAMA Network Open Extended Endocrine Therapy and Survival for Breast Cancer Subtypes in Premenopausal Patients Valenza C, Zheng Y, Kirkner GJ, Dibble KE, Regan MM, Partridge AH |
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JAMA Network Open Stage IV Breast Cancer Incidence and Survival, 2010-2021 Tayob N, Regan MM, Hassett MJ, Lin NU, Tolaney SM, Leone JP |
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JCO Oncology Practice Cancer Screening, Diagnosis, and Treatment for Vulnerable Patients Incarcerated in US Prisons Manz CR, Nava-Coulter B, Voligny E, Wright AA |
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JNCI Cancer Spectrum Freedman RA, Revette A, Nava-Coulter B, Piantadosi S, George S |
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Journal of Developmental and Behavioral Pediatrics Challenging Case: Navigating End-of-Life in Neuro-Inclusive Cancer Care Hanania JW, Levin M, Miran DM, Ramirez KJ, Rhee JY, Svoboda LA |
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Journal of Geriatric Oncology Thompson LL, Shah SB, Gregg AT, Yoon J, Florissi C, Amin PM, Lipson S, Jiang S, Saeed N, Saraf A, Guthier C, Warrington A, Jimenez R, Mak RH |
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Journal of Pain and Symptom Management Opportunities for Palliative Care in Long-Term Acute Care: A Concurrent Mixed-Methods Study Walker KH, Lambert V, Liu A, Rubin EB, Chua IS, Ufere NN, Reich AJ, Tulsky JA, Lakin JR |
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Journal of Palliative Medicine Cronin A, Stal J, Uno H, Fisher L, Lakin JR, Mack JW |
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Journal of Thrombosis and Thrombolysis Sylvester KW, Kanaan DM, Lupi KE, Connors JM |
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Nature Microbiology Ragucci AE, Antine SP, Leviss EM, Mooney SE, Garcia JM, Lee ASY, Kranzusch PJ |
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Oncogene The Impact of K-Ras Gly12 Mutants on Homeostasis and Tumorigenesis in the Colonic Epithelium Yang MH, Sheth S, Shui B, Grabski IN, Park SS, Irizarri R, Haigis KM |
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Pain Management Nursing Symptom Networks in Postsurgical Cancer Pain Across Recovery Stages Zhao J, Schreiber KL, DeForge SM, Wilson J PhD, Chai P, Edwards R, Azizoddin DR |
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Pediatric Blood and Cancer Frazier AL |
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Pediatric Blood and Cancer Chevalier LL, Bober SL |
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Prostate Surveillance Versus Treatment for Favorable Intermediate-Risk Prostate Cancer and Mortality-Risk Sayan M, Qian Z, Dall CP, Cole AP, Leeman JE, King MT, Nguyen PL, D'Amico AV |
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