Welcome to Dana-Farber's Research News
December 15, 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 16 - 30.
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 Hemophagocytic Lymphohistiocytosis in Adults Hsu JI, Nikiforow S, Berliner N Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder characterized by unchecked immune activation and hyperinflammation, resulting in end-organ tissue damage and high mortality rates in untreated patients. Since the first description of this condition in 1939, our understanding of HLH has continued to deepen, with increasing appreciation of the differences and similarities between primary (familial) HLH and secondary (acquired) HLH. While primary HLH presents in the early years of life on the backdrop of inherited genetic mutations affecting cytotoxic immune cell function, secondary HLH more commonly presents in adults and is a heterogenous disorder with various potential triggers ranging from infections to malignancy, autoimmune disease, immunodeficiency, and medications. Yet, they converge in a common pathway of widespread systemic inflammation, which clinically manifests with fevers, organomegaly, cytopenias, laboratory derangements, and rapid development of multiorgan failure. As such, early recognition and intervention is critical to prevent irreversible organ damage and death in both primary and secondary HLH. In this review, we focus our attention on adult secondary HLH and explore the latest updates on the pathophysiology, precipitants, clinical presentation, diagnosis and management of this life-threatening condition. Note that primary HLH is reviewed separately as a companion article in this review series. |
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Cancer Discovery Bergholz JS, Jiang T, Wang W, Ji R, Li Y, He X, Jing Q, Johnson JL, Yaron-Barir TM, Cantley LC, Roberts TM, Zhao JJ Loss of tumor suppressor PTEN drives cancer progression and therapeutic resistance, yet no targeted therapies exist for PTEN-deficient tumors. Here, we identify a critical druggable mechanism where PTEN-loss induces PI3K? phosphorylation for tumorigenesis. Using BioID interactome, we uncovered phosphorylation-dependent PI3K?-EPHA2 interaction in PTEN-null cells, driven by p-PI3K?Y962. PTEN functions as a tyrosine phosphatase that normally dephosphorylates p-PI3K?Y962. In PTEN-deficient contexts, enhanced p-PI3K?Y962 forms a complex with EPHA2 and SRC, where both kinases contribute to PI3K? phosphorylation, activating oncogenic pERK/c-MYC and pAKT pathways. We developed a selective p-PI3K?Y962 antibody detecting p-PI3K?Y962 in PTEN-deficient tumors across preclinical models and clinical tumor specimens. Disrupting p-PI3K?Y962 suppressed tumor growth in multiple PTEN-null models. Dasatinib, an FDA-approved SRC/EPHA2 inhibitor, effectively reduced p-PI3K?Y962 and inhibited tumor progression in PTEN-null but not PTEN-WT tumors. These findings establish p-PI3K?Y962 as a druggable target and biomarker for developing targeted therapy in PTEN-deficient cancers beyond conventional PI3K kinase inhibition. |
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Cell Inhibition of Oligomeric BAX by an Anti-Apoptotic Dimer Newman CE, Gygi MA, DeAngelo TM, Camara CM, Mintseris J, Yu E, Harvey EP, Hauseman ZJ, Godes M, Gehtman J, Cathcart AM, Gygi SP, Bird GH, Walensky LD BAX is a pro-apoptotic BCL-2 protein that resides in the cytosol as a monomer until triggered by cellular stress to form an oligomer that permeabilizes mitochondria and induces apoptosis. The paradigm for apoptotic blockade involves heterodimeric interactions between pro- and anti-apoptotic monomers. Here, we find that full-length BCL-w forms a distinctive, symmetric dimer (BCL-wD) that dissociates oligomeric BAX (BAXO), inhibits mitochondrial translocation, promotes retrotranslocation, blocks membrane-porating activity, and influences apoptosis induction of cells. Structure-function analyses revealed discrete conformational changes upon BCL-w dimerization and reciprocal structural impacts upon BCL-wD and BAXO interaction. Small-angle X-ray scattering (SAXS) analysis demonstrated that BAXO disrupts membranes by inducing negative Gaussian curvature, which is reversed by positive Gaussian curvature exerted by BCL-wD. Systematic truncation and mutagenesis dissected the core features of BCL-wD activity-dimerization, BAXO engagement, and membrane interaction. Our studies reveal a downstream layer of apoptotic control mediated by protein and membrane interactions of higher-order BCL-2 family multimers. |
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JAMA Wong JMW, Kao PC, London WB, Grace RF IMPORTANCE: Eltrombopag, a thrombopoietin receptor agonist, is approved by the US Food and Drug Administration for children with chronic immune thrombocytopenia. Efficacy of eltrombopag during the newly diagnosed phase of pediatric immune thrombocytopenia is unknown. OBJECTIVE: To determine if the proportion of patients with a platelet response is significantly greater in patients with newly diagnosed immune thrombocytopenia treated with eltrombopag than in those treated with standard therapy (first-line treatments). DESIGN, SETTING, AND PARTICIPANTS: This phase 3, randomized clinical trial enrolled patients (aged 1-<18 years) with newly diagnosed primary immune thrombocytopenia (platelet count <30?×?109/L who required pharmacological treatment but did not have severe bleeding or need a rapid increase in platelet count) from May 7, 2019, to January 25, 2024, at 23 centers participating in the Pediatric ITP Consortium of North America. Final follow-up occurred on February 26, 2025. INTERVENTIONS: Eltrombopag was administered orally based on a standard dosing schedule (n?=?78) vs standard therapy (investigator choice of glucocorticoids, intravenous immunoglobulin, or anti-D immunoglobulin) (n?=?40). MAIN OUTCOMES AND MEASURES: The primary outcome was a sustained platelet response defined as 3 or more of 4 platelet counts greater than 50?×?109/L during weeks 6 to 12 without rescue treatment. The secondary outcomes included bleeding scores, change in health-related quality of life, and serious adverse events. RESULTS: Of 118 pediatric patients (median age, 8 years [IQR, 4-12 years]; 49% were male), 63% experienced an initial treatment failure after observation or medical therapy. Enrollment ended after a planned interim analysis met a prespecified threshold for efficacy. Of 71 patients in the eltrombopag group, 46 (65% [95% CI, 54%-76%]) had a sustained platelet response compared with 13 of 37 patients (35% [95% CI, 20%-51%]) in the standard therapy group (between-group difference, 30% [95% CI, 11%-49%]; P?=?.002), which crossed the monitoring boundary for efficacy. Overall, there was no between-group difference in the number and type of adverse events. CONCLUSIONS AND RELEVANCE: In pediatric patients with newly diagnosed immune thrombocytopenia requiring pharmacological treatment, eltrombopag resulted in a higher rate of sustained platelet response compared with standard therapy. Eltrombopag may be an effective option for pediatric patients with newly diagnosed immune thrombocytopenia with nonsevere bleeding who warrant medical intervention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03939637. |
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Journal of Clinical Oncology Jacobson CA Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Here, we report updated clinical outcomes from ZUMA-5 in 159 enrolled patients with R/R indolent non-Hodgkin lymphoma (iNHL; 127 with FL and 31 with marginal zone lymphoma) after a median follow-up of 64.6 months. Patients underwent leukapheresis and received lymphodepleting chemotherapy and axi-cel (2 × 106 CAR T cells/kg). The overall response rate was 90% (75% complete response rate). The median duration of response was 60.4 months, and the median progression-free survival (PFS) was 62.2 months; median time to next treatment and overall survival were not reached (NR). At data cutoff, 55% of patients were alive without requiring subsequent anticancer therapy. Median lymphoma-specific PFS in patients with FL was NR; 34% had progression or death due to lymphoma or study treatment. Notably, after 30 months postinfusion, progression or lymphoma-related deaths were rare. Late-onset toxicities were infrequent and largely unrelated to axi-cel. Durable response and prolonged survival in FL were associated with robust early CAR T-cell expansion and naïve product phenotype. These findings confirm sustained responses and manageable safety with axi-cel in the long term among patients with R/R iNHL and its potential as a curative therapy in FL. |
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Journal of Clinical Oncology If Exercise Were a Pill, We’d All Prescribe It to Patients With Cancer. But It’s Not Ligibel JA Exercise improves quality and quantity of life in patients with cancer. Decades of research shows that exercise reduces side effects of cancer treatment and improves quality of life in patients during and after cancer treatment, leading the American Society of Clinical Oncology and other groups to recommend exercise for patients with cancer. The Challenge trial (ClinicalTrials.gov identifier: NCT00819208) fills a critical gap by demonstrating that exercise after diagnosis improves disease-free and overall survival. The CHALLENGE trial randomly assigned 889 patients with Stage II to III colon cancer who were free of disease after completing adjuvant chemotherapy to a 3-year supervised aerobic exercise intervention or usual care. Patients randomly assigned to the exercise intervention experienced a 28% improvement in disease-free survival, with a reduction both in the incidence of distant metastatic disease and in second primary cancers and, even more strikingly, a 37% improvement in overall survival. |
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Journal of the National Cancer Institute FaceAge as a Biomarker for Prognosis and Treatment Stratification in 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, 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 estimating biological age from facial photographs, has shown potential as a biomarker for cancer prognosis. This study investigates 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 cancer patients aged ?60 treated with radiation therapy between 2008-2023 were analyzed. FaceAge estimates were compared with chronological age across different diagnoses/clinical contexts, and survival analyses were performed. All tests were two-sided. RESULTS: FaceAge was older than chronological age in 65% (median FaceAge 74 versus age 70). Younger patients, female sex, diagnoses with worse prognosis, and treated for palliative intent had higher likelihood of FaceAge-Age ?10?years. Patients with FaceAge-Age ?10?years had significantly worse survival while those with FaceAge-Age ?-5?years had better survival. On multivariate analysis, FaceAge-Age ?10?years predicted higher mortality risk (HR 1.26, P<.001) and early mortality at 30?days (OR 1.38, P=.004) and 60?days (OR 1.33, P<.001), whereas FaceAge-Age ?-5?years predicted lower mortality risk (HR 0.90, P<.001). CONCLUSIONS: Patients with more advanced cancers tend to have significantly older FaceAge compared with 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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Nature Communications Fu J, Waks AG, Pimenta E, Titchen B, Bi K, Camp S, Pappa T, Keenan T, Shannon E, Vigneau S, Bemus M, Nag A, Thorner AR, Park J, DiLullo M, Wrabel E, Jeselsohn R, Mittendorf EA, Abravanel DL, Tolaney SM, Van Allen EM The efficacy of immune checkpoint inhibitors combined with chemotherapy varies among breast cancer subtypes and is particularly less effective in hormone receptor-positive (HR?+?) breast cancers. Here, we analyze pre-, on-, and post-treatment biopsies from 20 female patients with stage II-III HR+ breast cancer who participated in a clinical trial of neoadjuvant chemo-immunotherapy with nab-paclitaxel and pembrolizumab. Through single-nucleus RNA and ATAC sequencing of these tumor biopsies, we identified gene expression metaprograms (MPs) associated with differential therapy responses. Here we show that favorable responders exhibit increased activity in pathways related to tumor state transition, T cell effector functions, and pro-inflammatory macrophage states. Unfavorable responders demonstrate increased tumor estrogen signaling and immunosuppressive tumor-immune interactions. In this work, we highlight the interplay between tumor and microenvironmental cells in treatment naïve and exposed HR+ breast cancers and reveal that pivotal shifts in tumor cell, macrophage, and T cell states may mediate response to chemo-immunotherapy. |
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Nature Communications Waks AG, Fu J, Chu X, Binboga Kurt B, Li T, Kuntz TM, Shen Y, Yang D, Meli K, Reardon B, Park J, Partridge A, Abravanel D, Jeselsohn R, Wrabel E, Alberti J, DiLullo M, Chen S, Mohammed-Abreu A, Morgan XC, Krop IE, Tayob N, Van Allen EM, Mittendorf EA, Tolaney SM Patients with hormone receptor-positive (HR?+?)/HER2- breast cancer may benefit from neoadjuvant immune checkpoint inhibitor (ICI) plus chemotherapy. The effect of chemotherapy or ICI run-in before combination therapy in this population is unexplored. In this randomized pilot trial, patients with HR?+?/HER2- breast cancer received two weeks of neoadjuvant nab-paclitaxel or pembrolizumab, with baseline and post-run-in tumor biopsy, followed by combined nab-paclitaxel/pembrolizumab. The primary endpoint was PD-L1 expression change between biopsies. Tumor whole exome/RNA sequencing were performed. Of 29 patients, 72% were node-positive. Residual cancer burden (RCB) 0-1 rate was 28% (inclusive of patients receiving additional neoadjuvant adriamycin/cyclophosphamide). No significant change in PD-L1 expression occurred following nab-paclitaxel or pembrolizumab run-in, thus the primary endpoint was not met. Other secondary outcome measures included overall response rate of 80% to the neoadjuvant regimen, and 3-year event-free survival of 86% (95% CI 69-100%); there were no unexpected safety signals. In exploratory biomarker analyses, higher baseline PD-L1 expression and inflammatory gene signatures were associated with favorable response (RCB 0-1); higher expression of estrogen response genes, with unfavorable response (RCB 2-3). Clinical Trial Number: NCT02999477. |
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Nature Communications Wiggers CRM, Cho EY, Ozdemir M, Hegel J, Frede J, Warlitz F, Heavican-Foral TB, Koch V, Bledsoe JR, Pikman Y, Harris MH, Place AE, Lohr JG, Knoechel B Changes in the immune microenvironment are frequent in cancers occurring in adult patients, yet our understanding of the pediatric cancer immune microenvironment and its clinical relevance is limited. We investigate the immune microenvironment in pediatric T cell acute lymphoblastic leukemia (T-ALL), using single-cell CITE-seq and immune repertoire analyses. We identify a T-ALL subgroup characterized by a remodeled immune microenvironment, which is associated with adverse clinical outcome in minimal residual disease low patients. This adverse immune landscape is dominated by the presence of a population of non-malignant CD4-CD8-TCR?? T cells that interact with CXCL16 expressing non-classical monocytes. Leukemia cell intrinsic transcriptional rewiring in these patients is associated with activation of Rap1 signaling. Inhibiting Rap1 signaling results in increased sensitivity to the BCL2/BCL-XL inhibitor navitoclax. Our study provides insights into the immune microenvironment of pediatric hematologic malignancies, forming the basis for identifying potential (immuno) therapeutic targets and risk stratification for treatment. |
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Nature Medicine Targeting of HIF2-Driven Cachexia in Kidney Cancer Abu-Remaileh M, Stransky LA, Shirole NH, Jiang Q, Saad E, Machaalani M, Vigeant SM, Woldemichael H, Xu C, Enomoto K, Choueiri TK, Carr SA, Udeshi ND, Kaelin WG Jr Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC), is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show that PTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increased PTHLH expression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in patients with ccRCC, including in some who did not exhibit objective tumor shrinkage. Our findings support prospective clinical studies to determine whether HIF2 inhibitors can be leveraged not only for tumor control, but also for the treatment of cancer-associated cachexia in renal cell carcinoma. |
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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, Jones M, Xiao T, 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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Annals of Surgical Oncology Axillary Management and Outcomes After Neoadjuvant Endocrine Therapy in the Randomized PELOPS Trial Weiss A, Jin Q, Tayob N, Wrabel E, DeMeo M, Carter J, Constantine M, Faggen M, Block C, Mittendorf EA, Jeselsohn R, Metzger Filho O, King TA |
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Blood Advances Rapid Loss of Viability in Acute Myeloid Leukemia Cells Upon Telomerase Inactivation Aquilanti EA, Kageler L, Bozinov V, Meyerson ML |
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Breast Cancer Research and Treatment Ream M, Rosenbaum AR, Yi-Frazier JP, Junkins CC, Rosenberg AR |
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British Journal of Haematology Repurposing Pacritinib to Target MYD88-Mutated Waldenström Macroglobulinaemia Liu S, Kofides A, Liu X, Hatcher JM, Sun H, Tsakmaklis N, Guijosa A, Guerrera ML, Pizzarella D, Peachey AL, Patterson CJ, Hunter ZR, Meid K, Castillo JJ, Sarosiek SR, Treon SP |
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Cancer Research BESTDR Enables Bayesian Quantification of Mechanism-Specific Drug Responses McDonald TO, Bruno S, Michor F |
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Cell Reports Medicine A Triple-Action PROTAC for Wild-Type p53 Cancer Therapy Bird GH, Adhikary U, Schmidt MJ, Godes M, Tesar B, Camara CM, Paulo JA, Vidlak JF, DeAngelo TM, Marquez M, Gokhale P, Li R, Ho Sui SJ, Gygi SP, Walensky LD |
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Clinical Cancer Research Perez KJ, Horick N, Baginska J, Giobbie-Hurder A, Gomez Diaz I, Nau AN, Dryg ID, Pfaff K, Rodig SJ, Hodi FS, Redston M, Bird A, Holovatska M, Abrams T, Patel A, Rubinson DA, Schlechter BL, Kulke MH, Chan JA |
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HemaSphere Redd RA, Pullarkat P, Crombie JL, Abramson JS, Armand P, Qualls DA |
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Journal of Adolescent and Young Adult Oncology Venkataraman V, Revette A, Nava-Coulter B, George S, Shulman DS, Greenzang KA |
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Journal of Virology Anang S, Zhang S, Ennis A, Nguyen HT, Sodroski JG |
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Journal of the American Chemical Society Rewiring the Fusion Oncoprotein EWSR1::FLI1 in Ewing Sarcoma with Bivalent Small Molecules Bond MJ, DiGiovanni G, Howard B, Alexe G, Ross K, Stegmaier K |
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Leukemia and Lymphoma Soluble BCMA: A Window into Tumor Burden Monitoring in Waldenström Macroglobulinemia? Guijosa A, Castillo JJ |
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Pediatric Blood and Cancer McCormick KG, Modest AM, Recklitis CJ, Greenzang KA |
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Transplantation and Cellular Therapy Ullrich C |