Welcome to Dana-Farber's Research News
September 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 August 16 - August 31.
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 Davids MS ZUMA-8 evaluated the safety of brexucabtagene autoleucel (brexu-cel), a CD19-directed autologous chimeric antigen receptor (CAR) T-cell immunotherapy, for patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Patients with ?2 prior lines of therapy (including a Bruton tyrosine kinase inhibitor) underwent leukapheresis, optional bridging therapy, and conditioning chemotherapy (fludarabine/cyclophosphamide) before infusion of 1 × 106 (cohort 1) or 2 × 106 (cohort 2) anti-CD19 CAR T cells per kg. Patients in cohort 3 (low tumor burden), and cohort 4A (postibrutinib) received 1 × 106 cells per kg. Fifteen patients, median age of 63 years (range, 52-79), were treated in cohorts 1 (n = 6), 2 (n = 3), 3 (n = 3), and 4A (n = 3). Median follow-up was 24.3 months. One dose-limiting toxicity was observed in cohort 3 (grade 4 cytokine release syndrome). Grade ?3 neurologic events occurred in 3 patients (20%). Seven of 15 patients responded (overall response rate, 47%; complete response [CR], 7%), including all 3 patients in cohort 3 (1 with CR). CAR T-cell expansion occurred in 4 patients (27%), with an apparent weak inverse correlation with absolute lymphocyte count before apheresis. Brexu-cel had no new safety signals in R/R CLL. CAR T-cell expansion and responses occurred in patients with low tumor burden. This trial was registered at www.clinicaltrials.gov as #NCT03624036. |
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JAMA Oncology Ligibel JA, Delahanty LM, Frank E, Mayer EL, Partridge AH IMPORTANCE: Obesity is associated with a higher risk of recurrence, mortality, comorbidities, treatment-related adverse effects, and poor quality of life in patients with breast cancer. Scalable interventions are needed to promote weight loss in this population. OBJECTIVE: To evaluate the impact of a remotely delivered weight loss intervention (WLI) on weight change at 1 year in patients with breast cancer and obesity and to explore factors associated with weight change. DESIGN, SETTING, AND PARTICIPANTS: The Breast Cancer Weight Loss trial is a phase 3, randomized clinical trial evaluating the impact of a telephone-based WLI on invasive disease-free survival and other outcomes in women with obesity and early breast cancer at 637 sites across the US and Canada. Participants were enrolled to the study between August 2016 and February 2021. Participants included women with stage II to III, ERBB2-negative breast cancer and a body mass index (BMI) of 27 or higher. INTERVENTIONS: Participants were randomized to a 2-year, telephone-based WLI plus health education or health education alone control group. MAIN OUTCOME AND MEASURES: The primary end point for this prespecified secondary analysis was weight change at 1 year. Weight was measured at baseline and 1 year, and changes in weight were compared between groups. Weight change was evaluated with a linear mixed-effects model including treatment group, weight over time, a time-by-group interaction, menopausal status, race and ethnicity, and hormone receptor status. RESULTS: A total of 3180 women with breast cancer and BMI of 27 and higher were included in the study; 1591 were randomized to the WLI and 1589 to the control group. At baseline, the mean (SD) age of participants was 53.4 (10.6), and the mean (SD) BMI was 34.4 (5.6). The racial and ethnic breakdown included 406 (12.8%) Black, 231 (7.3%) Hispanic or Latino, 2906 (91.4%) non-Hispanic, and 2555 (80.3%) White participants. WLI participants lost a mean of 4.3 kg (95% CI 3.9-4.6 kg), or 4.7% (95% CI, 4.3%-5.0%) of baseline body weight at 1 year vs control participants, who gained 0.9 kg (95% CI, 0.5-1.3 kg), or 1.0% (95% CI 0.1%-1.4%) of baseline body weight (P?<?.001). Participants randomized to WLI experienced significant weight loss (vs control group participants) across demographic and tumor factors. WLI effect differed significantly by menopausal status, with postmenopausal participants having greater weight loss than premenopausal participants, and by race and ethnicity, with Black and Hispanic participants having less weight loss compared to other races and ethnicities. CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, a telephone-based WLI induced significant weight loss in patients with breast cancer with overweight and obesity across demographic and treatment factors. Further follow-up of the Breast Cancer Weight Loss trial will evaluate whether the WLI improves disease outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02750826. |
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Molecular Cell Chang RB, Toyoda HC, Hobbs SJ, Richmond-Buccola D, Burger N, Chouchani ET, Kranzusch PJ Cyclic oligonucleotide-based anti-phage signaling systems (CBASSs) are bacterial anti-phage defense operons that use nucleotide signals to control immune activation. Here, we biochemically screen 57 diverse E. coli and Bacillus phages for the ability to disrupt CBASS immunity and discover anti-CBASS 4 (Acb4) from the Bacillus phage SPO1 as the founding member of a large family of >1,300 immune evasion proteins. A 2.1 Å crystal structure of Acb4 in complex with 3'3'-cyclic guanosine monophosphate (GMP)-AMP (3'3'-cGAMP) reveals a tetrameric assembly that functions as a sponge to sequester CBASS signals and inhibit immune activation. We demonstrate that Acb4 alone is sufficient to disrupt CBASS activation in vitro and enable immune evasion in vivo. Analyzing phages that infect diverse bacteria, we explain how Acb4 selectively targets nucleotide signals in host defense and avoids disruption of cellular homeostasis. Together, our results reveal principles of immune evasion protein evolution and explain a major mechanism phages use to inhibit host immunity. |
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Molecular Cell Expanding the Druggable Zinc-Finger Proteome Defines Properties of Drug-Induced Degradation S?abicki M, Park J, Nowak RP, Roy Burman SS, Pellman J, Zou C, Carreiro J, Rastogi S, Goldstein A, Nagiec MM, Donovan KA, Che J, Hunkeler M, Hsu CL, Lakshminarayan M, Shu C, Zon RL, Kozicka Z, Park PMC, Tsai JM, Yoon H, Jones LH, Sperling AS, Fischer ES, Ebert BL Glutarimide analogs, such as thalidomide, redirect the E3 ubiquitin ligase CRL4CRBN to induce degradation of certain zinc finger (ZF) proteins. Although the core structural motif recognized by CRBN has been characterized, it does not fully explain substrate specificity. To explore the role of residues adjacent to this core motif, we constructed a comprehensive ZF reporter library of 9,097 reporters derived from 1,655 human ZF proteins and conducted a library-on-library screen with 29 glutarimide analogs to identify compounds that collectively degrade 38 ZF reporters. Cryo-electron microscopy and crystal structures of ZFs in complex with CRBN revealed the importance of interactions beyond the core ZF degron. We used systematic mutagenesis of ZFs and CRBN to identify modes of neosubstrate recruitment requiring distinct amino acids. Finally, we found subtle chemical variations in glutarimide analogs that alter target scope and selectivity, thus providing a roadmap for their rational design. |
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Nature Targeting G1-S-Checkpoint-Compromised Cancers with Cyclin A/B RxL Inhibitors Singh S, Laimon YN, Durmaz YT, Sarkar A, Ngo K, Savla V, Li Y, Abu-Remaileh M, Li X, Locquet MA, Tuladhar B, Doench JG, Vendrell I, Fischer R, Kessler B, Gokhale PC, Signoretti S, Spektor A, Oser MG Small-cell lung cancers (SCLCs) contain near-universal loss-of-function mutations in RB1 and TP53, compromising the G1-S checkpoint and leading to dysregulated E2F activity1. Other cancers similarly disrupt the G1-S checkpoint through loss of CDKN2A or amplification of cyclin D or cyclin E, also resulting in excessive E2F activity2,3. Although E2F activation is essential for cell cycle progression, hyperactivation promotes apoptosis4-9, presenting a therapeutic vulnerability. Cyclin proteins use a conserved hydrophobic patch to bind to substrates bearing short linear RxL motifs10-13. Cyclin A represses E2F through an RxL-dependent interaction10,14, which, when disrupted, hyperactivates E2F15. However, this substrate interface has remained difficult to target. Here we developed cell-permeable, orally bioavailable macrocyclic peptides that inhibit RxL-mediated interactions of cyclins with their substrates. Dual inhibitors of cyclin A and cyclin B RxL motifs (cyclin A/Bi) selectively kill SCLC cells and other cancer cells with high E2F activity. Genetic screens revealed that cyclin A/Bi induces apoptosis through cyclin B- and CDK2-dependent spindle assembly checkpoint activation. Mechanistically, cyclin A/Bi hyperactivates E2F and cyclin B by blocking cyclin A-E2F and cyclin B-MYT1 RxL interactions. Notably, cyclin A/Bi promoted the formation of neomorphic cyclin B-CDK2 complexes, which drive spindle assembly checkpoint activation and mitotic cell death. Finally, orally administered cyclin A/Bi showed robust anti-tumour activity in chemotherapy-resistant SCLC patient-derived xenografts. These findings reveal gain-of-function mechanisms through which cyclin A/Bi triggers apoptosis and support their development for E2F-driven cancers. |
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Nature Communications Modeling Integration Site Data for Safety Assessment with MELISSA Ceoldo G, Klatt D, Brendel C, Pellin D Gene and cell therapies pose safety concerns due to potential insertional mutagenesis by viral vectors. We introduce MELISSA, a regression-based statistical framework for analyzing Integration Site (IS) data to assess insertional mutagenesis risk, by estimating and comparing gene-specific integration rates and their impact on clone fitness. We characterized the IS profile of a lentiviral vector on Mesenchymal Stem Cells (MSCs) and compared it with that of Hematopoietic Stem and Progenitor Cells (HSPCs). We applied MELISSA to published IS data from patients enrolled in gene therapy clinical trials, successfully identifying both known and novel genes that drive changes in clone growth through vector integration. MELISSA offers a quantitative tool to bridge the gap between IS data and safety and efficacy evaluation, facilitating the generation of comprehensive data packages supporting Investigational New Drug (IND) and Biologics License (BLA) applications and the development of safe and effective gene and cell therapies. |
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Nature Communications Structural Basis of VCP-VCPIP1-p47 Ternary Complex in Golgi Maintenance Shah B, Hunkeler M, Bratt A, Yue H, Jaen Maisonet I, Fischer ES, Buhrlage SJ VCP/p97 regulates a wide range of cellular processes, including post-mitotic Golgi reassembly. In this context, VCP is assisted by p47, an adapter protein, and VCPIP1, a deubiquitylase (DUB). However, how they organize into a functional ternary complex to promote Golgi assembly remains unknown. Here, we use cryo-EM to characterize both VCP-VCPIP1 and VCP-VCPIP1-p47 complexes. We show that VCPIP1 engages VCP through two interfaces: one involving the N-domain of VCP and the UBX domain of VCPIP1, and the other involving the VCP D2 domains and a region of VCPIP1 we refer to as VCPID. The p47 UBX domain competitively binds to the VCP N-domain, while not affecting VCPID binding. We show that VCPID is critical for VCP-mediated enhancement of DUB activity and proper Golgi assembly. The ternary structure along with biochemical and cellular data provides new insights into the complex interplay of VCP with its co-factors. |
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Nature Genetics Tamoxifen Induces PI3K Activation in Uterine Cancer Kübler K, Nardone A, Anand S, Hermida-Prado F, Akhshi T, Feiglin A, Feit AS, Cohen Feit G, Pun M, Kuang Y, Cha J, Miller M, Gibson WJ, Paweletz CP, Van Allen EM, Nguyen QD, Leshchiner I, Stewart C, Matulonis UA, Getz G, Jeselsohn R Mutagenic processes and clonal selection contribute to the development of therapy-associated secondary neoplasms, a known complication of cancer treatment. The association between tamoxifen therapy and secondary uterine cancers is uncommon but well established; however, the genetic mechanisms underlying tamoxifen-driven tumorigenesis remain unclear. We find that oncogenic PIK3CA mutations, common in spontaneously arising estrogen-associated de novo uterine cancer, are significantly less frequent in tamoxifen-associated tumors. In vivo, tamoxifen-induced estrogen receptor stimulation activates phosphoinositide 3-kinase (PI3K) signaling in normal mouse uterine tissue, potentially eliminating the selective benefit of PI3K-activating mutations in tamoxifen-associated uterine cancer. Together, we present a unique pathway of therapy-associated carcinogenesis in which tamoxifen-induced activation of the PI3K pathway acts as a non-genetic driver event, contributing to the multistep model of uterine carcinogenesis. While this PI3K mechanism is specific to tamoxifen-associated uterine cancer, the concept of treatment-induced signaling events may have broader applicability to other routes of tumorigenesis. |
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New England Journal of Medicine Menopausal Symptom Management in Breast Cancer Survivors - A Promising New Option Partridge AH Among women with a history of early breast cancer treated with endocrine therapy (tamoxifen or aromatase inhibitors), vasomotor symptoms are common, occurring in up to 90% of this population, and often severe. These symptoms are attributable to mainstay treatments used to reduce disease recurrence and improve survival. Two such treatments are chemotherapy, which causes temporary or permanent ovarian suppression and is associated with precipitously low levels of estradiol in premenopausal women, and endocrine therapy, which is used to decrease or block estrogen in breast cancer survivors of all ages. Menopausal symptoms not only affect quality of life among survivors of breast cancer but also may have indirect adverse effects on disease-free and overall survival, especially if the symptoms lead to nonadherence to risk-reducing endocrine therapy. In a large cross-sectional study involving breast cancer survivors, half the participants reported nonadherence to endocrine therapy; nonadherence was significantly more likely among participants reporting more-severe vasomotor symptoms than those with less-severe symptoms, which suggests that improved symptom management is a vital issue in breast cancer care. |
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Science Translational Medicine Tavakolpour S, Nili A, Munaretto LA, Huang CK, Rakhshandehroo T, Kim Z, Knight AE, Farid AS, Alasharee MA, Allen H, Uslu S, Moravej H, Cong M, Berland L, Simkova E, Shahbazian H, Rowley JE, Mantri SR, Noe MH, Ward A, Tsokos GC, Rashidian M Pemphigus vulgaris is a B cell-mediated autoimmune disease characterized by autoantibodies targeting desmoglein-3 (Dsg3), a critical adhesion molecule in epithelial tissues. Current treatments rely on broad immunosuppression, highlighting the need for more targeted therapeutic approaches in pemphigus vulgaris and other autoantibody-driven disorders. We engineered a therapeutic fusion protein consisting of the pathogenic domains of Dsg3 linked to either human immunoglobulin G1 (IgG1) or mouse IgG2a (Dsg3-Fc). In vitro, Dsg3-Fc selectively eliminated Dsg3-autoreactive B cells. In vivo, Dsg3-Fc effectively depleted human B cells expressing patient-derived anti-Dsg3 B cell receptors, even in the presence of circulating autoantibodies. Moreover, Dsg3-Fc inhibited both disease initiation and progression in a polyclonal, active pemphigus vulgaris model in immunocompetent mice. In addition, Dsg3-Fc rapidly neutralized pathogenic autoantibodies without inducing systemic toxicity. These findings demonstrate that targeting pathogenic B cells and neutralizing autoantibodies through autoantigen-Fc fusion proteins may represent a promising therapeutic strategy for pemphigus vulgaris and potentially other autoantibody-mediated diseases without the need for global immunosuppression. |
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American Journal of Kidney Disease Chewcharat A, Wang M, Gupta S, Singh H, Chowdhury RB |
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Annals of Surgical Oncology Rosenberg SM, Schreiber KL, Hughes KS, Frank ES, Darai S, Lanahan C, Partridge AH |
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Blood Advances Little JS, Medina Pena A, Kim EB, Yee AJ, Nadeem O, Midha S, Sperling AS, Munshi NC, Raje N, Frigault MJ, Cirstea DD, Hammond SP |
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Blood Cancer Journal Ryan CE, Ahn IE, Sekar A, Parry EM, Davids MS |
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BMC Cancer Association Between Polygenic Risk and Survival in Breast Cancer Patients Kurant DE, Groha S, Ding Y, German C, Wang W, Granka JM, Holmes MV, Shringarpure SS, Gusev AS |
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Brachytherapy Al Balushi MM, Perkins TM, Shin KY, Buzurovic IM, Talbot SG, Goldberg JE, O'Farrell DA, King MT, Mamon HJ, Devlin PM |
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Breast Artificial Intelligence as Treatment Support in Breast Cancer: Current Perspectives Corti C, Tolaney SM, Tarantino P, Leone JP |
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Cancer Research Epigenetic De-repression of PROX1 Promotes Neuroendocrine Prostate Cancer Progression Venkadakrishnan VB, Presser A, Voss NCE, Neiswender J, Brenan L, Sosa KP, Weng K, Vazquez F, Beltran H |
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Cell Reports Integrative Genomic Identification of Therapeutic Targets for Pancreatic Cancer Guo JA, Gong D, Evans K, Takahashi K, Shiau C, Wu WW, Chugh S, Kapner KS, Dilly J, Chen P, Smith EL, Mancias JD, Vazquez F, Singh H, Hwang WL, Aguirre AJ |
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Cell Reports Medicine Genomic Landscape and Immunological Profile of Glioblastoma in East Asian Patients Zhong S, Dubois F, Deng D, Bergholz JS, Shao Y, Liu J, Liu L, Chen S, Beroukhim R, Zhao JJ |
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Clinical Cancer Research Ren Y, Jeselsohn R, Burstein HJ, DeMeo M, Tolaney SM, Regan MM, Mayer EL |
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Clinical Cancer Research Pecci F, Gariazzo E, Garbo E, Aldea M, Santo V, Paoloni F, Rossato de Almeida G, Wang X, Rotow J, Awad MM, Janne PA, Ricciuti B |
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Clinical Trials Incorporating Data from Multiple Ongoing Trials for Bayesian Two-Stage Phase II Single-Arm Studies Trippa L |
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Critical Reviews in Oncology/Hematology Targeting Cancer Metabolism: Therapeutic Potential of the Fatty Acid Synthase (FASN) Inhibitors Loda M |
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Developmental Cell Loss of NOTCH2 Creates a TRIM28-Dependent Vulnerability in Small Cell Lung Cancer Hong D, Becker JS, Booker MA, Masuzawa K, Devos Z, Wang T, Saito S, Liu Q, Li Y, Li Z, Knelson EH, Thai T, Duplaquet L, Laimon YN, Roberti De Oliveira G, Signoretti S, Doench JG, Barbie DA, Tolystorukov MY, Qi J, Bernstein BE, Oser MG |
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ESMO Open Adjuvant Capecitabine in Patients with Triple-Negative Breast Cancer After Neoadjuvant Chemotherapy Jin Q, Hughes ME, Vincuilla J, Parker T, Tarantino P, Mittendorf EA, King TA, Tolaney SM, Tayob N, Lin NU, Garrido-Castro AC |
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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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JAMA Otolaryngology – Head and Neck Surgery Margalit DN |
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Journal of Cancer Survivorship Myers SP, Morton CR, Bain PA, Minami CA, Mittendorf EA, King TA |
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Journal of Physical Activity and Health Christopher CN, Dieli-Conwright CM, Lee IM |
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Nature Reviews Urology Finding a Brush When You Expect a Broom: A Novel Model of Paediatric Wilms Tumour Evolution Mullen EA |
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NPJ Breast Cancer Brantley KD, Kirkner GJ, Hughes ME, Varella L, Suggs G, Cunningham OM, Ravikumar S, Snow C, Tolaney SM, Sammons S, Partridge AH, Lin NU |
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Pediatric Blood and Cancer Rosenbaum ARP, Ream M, Yi-Frazier JP, Rosenberg AR |
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Pediatrics Supporting Parents of Infants with Chronic Critical Illness in the Transition from NICU to Home Deming RS, Porter AS, Wojcik MH, Wolfe J, Snaman JM |
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Science Bulletin Dahal A, Uppaluri R, Schoenfeld JD |
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Transplantation and Cellular Therapy Schaefer DA, Keane EP, Larizza IS, Boardman AC, Rosenberg J, Mate-Kole M, Waldman LP, Amonoo HL |