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 April 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 [email protected].
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Blood
Das Not Enough in CBF AML
Stone RM
In this issue of Blood, although their study is “negative,” Döhner et al are to be congratulated for their prospective clinical trial in chemotherapy-fit adults with core-binding factor acute myeloid leukemia (CBF AML) comparing standard induction therapy to standard induction chemotherapy plus the putative KIT (multikinase) inhibitor dasatinib.
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Blood
How I Approach Clinical Ethics Consultation in Hematology
Marron JM, Semler LR, Abel GA
Caring for individuals with hematologic disorders is increasingly complex, and with medical complexity often comes ethical complexity. Prognostic uncertainty, stakeholder conflicts, and myriad other ethical challenges can contribute to situations that may benefit from ethics support. Through the presentation of 3 vignettes focusing on ethical dilemmas arising from hematology cases, we review the 4 phases of clinical ethics consultation: consult triage; ethics consult intake; stakeholder meeting(s) and additional data collection; and ethics analysis and recommendations. In tandem, we review some of the most common ethical framework/approaches used to inform hematology ethics consultation support services. We conclude that ethics consult services can be a valuable resource in providing care for patients with blood disorders and are a vital resource to enhance patient care, support clinicians, and ensure that difficult choices are navigated with clarity, compassion, and integrity.
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Blood
Ibrutinib: 10 Years and Counting
Brown JR
In this issue of Blood, Itsara et al report the 10-year follow-up of the treatment of chronic lymphocytic leukemia (CLL) with the first-in-class covalent Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, demonstrating a median progression-free survival (PFS) of 9 years in front line and 4.1 years in relapsed CLL. Unexpectedly 15.5% of patients achieved undetectable minimal residual disease (uMRD) at a median of 5 years. The study was enriched in patients with multihit TP53 aberration, whose survival outcomes were improved compared to historical data but were still shorter than those without the TP53 aberration.
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Cancer Cell
Vascular STING Activation Facilitates NK Cell Anti-Tumor Immunity in Small Cell Lung Cancer
Campisi M, Dryg I, Stornante C, Wolff J, Weirather J, Weaver N, Tarannum M, Gillanders I, Bers A, Bobilev E, Lineberry MS, Schol P, Chen M, Ota K, Park SR, Fahey CG, Thai TC, Li Y, Li Z, Li ZH, Padrick C, Ivanova E, Ha M, Yang S, Olszewski H, Kivlehan S, Lizotte P, Hagen K, Gjeci I, Haller W, Zasadil LM, El Zarif T, Knelson EH, Brea EJ, Odintsov I, Tuladhar B, Ngo K, Pfaff K, Freedman M, Hodi FS, Tolstorukov MY, Oser MG, Sheffer M, Mitsiades CS, Gokhale PC, Paweletz CP, Romee R, Rodig S, Barbie DA, Mahadevan NR
Small cell lung cancer (SCLC) typically displays a "cold" tumor microenvironment with a paucity of immune infiltrate. Neuroendocrine SCLC cells also profoundly repress MHC-I expression, rendering them vulnerable to NK cell-mediated cytotoxicity. Here, we confirm that neuroendocrine SCLC cells are sensitive to NK cell-mediated attack, yet the quantitative spatial profiling of the SCLC immune microenvironment in patient samples reveals that effector immune cells, including NK cells, are excluded from MHC-Ilow/neg SCLC regions. To study this biology, we develop dynamic single-cell RNA sequencing of microphysiological immune tumor environments (DynaMITE-seq) and integrate findings with spatial transcriptomics in patient tissue, unveiling the microvasculature as a major checkpoint restricting NK cell extravasation/recruitment. We demonstrate that the activation of vascular Stimulator of Interferon Genes (STING) signaling restores NK cell infiltration and killing of neuroendocrine SCLC, suggesting a strategy to overcome this key SCLC immunologic barrier and prime therapeutic response to DLL3-targeted CAR-NK cell therapy.
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Cancer Discovery
HER2 Heterogeneous Breast Cancer Models Reveal Novel Therapeutic Targets and Subclonal Dynamics During Evolution to Resistance to HER2-Targeted Therapies
Goyette MA, Graser C, Patmanidis A, Rojas Jimenez E, Kamat A, Yan P, Foidart P, Li Z, James A, Sicinski P, Michor F, Polyak K
Intratumor heterogeneity for HER2 in HER2-positive breast cancer is a driver of resistance to HER2-targeted therapies. The advancement of treatments for HER2 heterogeneous tumors has been hindered by the lack of preclinical models that accurately mimic the human disease. Here we describe human HER2 heterogeneous breast cancer models composed of ERBB2 amplified (HER2hi) and non-amplified (HER2lo) cell populations derived from the same tumor. Utilizing these models, together with cellular barcoding, we demonstrate subclonal cooperation between HER2hi and HER2lo subpopulations. Furthermore, HER2lo cells drive resistance to HER2-targeting antibody-drug conjugates (ADC) like T-DXd but are sensitive to HER2 kinase inhibitors. CRISPR screens in heterogeneous co-cultures identified sensitizers of HER2lo cells to T-DXd including ABCC1 and USP9X. USP9X inhibition enhances the lysosomal targeting of HER2, thereby potentiating ADC payload release and reducing tumor recurrence after T-DXd treatment. Our results elucidate the functional relevance of HER2 heterogeneity and propose improved therapies for these tumors.
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Cell Stem Cell
Endogenous Aldehydes: A Driver of Clonal Hematopoiesis from Within?
Hsu JI, Ebert BL
Detoxification of endogenous aldehydes is critical for preserving genomic integrity in hematopoietic stem cells. In this issue, Kamimae-Lanning et al.1 show that excess formaldehyde can drive clonal hematopoiesis through attrition of blood-forming progenitors, accelerating neutral drift in the absence of known genetic drivers of positive selection.
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Journal of Clinical Oncology
Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial
Lee EQ
PURPOSE: GBM AGILE (ClinicalTrials.gov identifier: NCT03970447) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm.
METHODS: Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped.
RESULTS: When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control.
CONCLUSION: GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.
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Journal of Clinical Oncology
Precision Oncology 2.0: Guiding Magic Bullets with Expression-Based Liquid Biopsy
Gulati GS, Choueiri TK, Freedman ML, Baca SC
In the early 20th century, Paul Ehrlich coined the term “magic bullet” to describe a therapy that could selectively eliminate disease without harming healthy tissues. A century later, Ehrlich's vision is being realized in oncology. A deeper understanding of the differences between tumor and normal tissue has fueled an explosion of therapies targeting oncogenic drivers and tumor-specific markers. The first wave of magic bullets was enabled by large-scale genetic profiling, which revealed dozens of druggable alterations and drove unprecedented growth in targeted therapies.
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JAMA
Treatment for Brain Metastases with Stereotactic Radiation vs Hippocampal-Avoidance Whole Brain Radiation: A Randomized Clinical Trial
Aizer AA, Shin KY, Catalano PJ, Ricca I, Johnson M, Benham G, Spicer B, Mann E, Nosker J, Parsons MW, Mendu ML, Shi DD, Lamba N, Haas-Kogan DA, Rahman R, Tanguturi S
IMPORTANCE: Brain metastases are common in patients with cancer, and radiation is often used for management. Among patients with more than 4 brain metastases, the effects of stereotactic radiation targeting only individual tumors, compared with whole brain radiation with hippocampal avoidance, which radiates both tumors and normal brain, remain unknown.
OBJECTIVE: To determine whether stereotactic radiation improves symptom severity and interference with daily functioning, compared with whole brain radiation with hippocampal avoidance.
DESIGN, SETTING, AND PARTICIPANTS: Phase 3, open-label, randomized clinical trial conducted at 4 United States-based centers. Eligible patients had 5 to 20 brain metastases and no prior brain-directed radiation. Enrollment occurred between April 11, 2017, and May 17, 2024 (final follow-up, March 18, 2025).
INTERVENTION: Stereotactic radiation, compared with whole brain radiation with hippocampal avoidance.
MAIN OUTCOMES AND MEASURES: Mean weighted patient-reported symptom severity and interference score change over 6 months postbaseline relative to baseline using the MD Anderson Symptom Inventory-Brain Tumor instrument (scale, 0-10; score change range, -10 to 10; -10 = best). A clinically meaningful Δ was defined as 0.98.
RESULTS: Of 196 randomized patients (mean age, 61 years; 129 [66%] female; 176 [90%] White; median number of brain metastases, 14 [IQR, 11-18]; 49 [25%] with prior neurosurgical resection), 83 (42%) completed the 6-month assessment. For the primary outcome, between baseline and postbaseline assessments through the 6-month follow-up, stereotactic radiation changed the weighted composite MD Anderson Symptom Inventory-Brain Tumor score from 2.69 to 2.37 (mean change, -0.32) and hippocampal-avoidance whole brain radiation changed the score from 2.29 to 3.03 (mean change, 0.74) (mean difference, -1.06 [95% CI, -1.54 to -0.58]; P < .001). Related grade 3-5 adverse events occurred in 12 patients (12%) in the stereotactic radiation group and 13 patients (13%) in the hippocampal-avoidance whole brain radiation group; grade 1-3 fatigue was most frequent (27 [28%] vs 43 [44%], respectively).
CONCLUSIONS AND RELEVANCE: In patients with 5 to 20 brain metastases, these findings support stereotactic radiation over hippocampal-avoidance whole brain radiation to improve symptoms and interference with daily functioning, key components of quality of life.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03075072.
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JAMA Oncology
Including Parents in Young Adult Cancer Care-A Paradigm Shift
Hanania JW
Young adults with cancer, between 18 and 39 years, represent a vulnerable patient group with distinct developmental and psychosocial needs. Young adults frequently face a unique set of developmental, psychosocial, and practical challenges that are different than those of older adults or pediatric patients. A cancer diagnosis for young adults occurs during a critical life phase focused on major milestones. The young adult’s cancer experience abruptly disrupts and interrupts major developmental milestones including identity, fertility and decisions about future fertility, education and work, connection and growth of peer relationships, dating and intimacy, as well as future life goals.
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Nature Communications
Daratumumab in High-Risk MGUS and Low-Risk Smoldering Myeloma: Results of the Phase II D-PRISM Study
Nadeem O, Aranha MP, Redd RA, Yee AJ, Magidson S, Lightbody ED, Wu T, Chabrun F, Alberge JB, Dutta AK, Perry J, Sturtevant A, Rahmat M, Tsuji J, Davie C, Ricciardi C, Arters F, Marto M, Bergeron A, Rosenblatt J, O'Donnell EK, Mouhieddine TH, Pantano L, Laubach JP, Richardson PG, Getz G, Trippa L, Sklavenitis-Pistofidis R, Ghobrial IM
Daratumumab is approved for patients with multiple myeloma (MM) and high-risk smoldering MM (HR-SMM). However, HR-SMM is often as genomically complex as MM, suggesting it may be too advanced for single-agent intervention. We report on a Phase II trial of single-agent daratumumab in patients with earlier-stage disease, including high-risk monoclonal gammopathy of undetermined significance and low-risk SMM, to test if earlier treatment can induce deep responses and prevent progression to MM (D-PRISM/NCT03236428, n = 41). As primary outcome, the rate of Very Good Partial Response or better is 17% (95% CI: 7-32), which is comparable to what was observed in HR-SMM and does not meet the study's primary endpoint. The overall response rate is 54%, with two patients developing MM and 51% biochemical progression. Grade 3 or higher toxicities include hypertension (7%), diarrhea (2%), flu-like symptoms (2%), and headache (2%). Genomic and immune variables associated with biochemical progression are identified in exploratory analyses leveraging whole-genome and single-cell RNA-sequencing. This study demonstrates that, although less effective than expected, daratumumab is safe and can induce deep responses in certain early-stage patients, highlighting the importance of adopting genomic and immune profiling to improve patient selection and maximize the benefit/risk ratio in trials of early intervention.
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Nature Communications
Experimental Assessment of AI-Based Interactome Mapping
Lambourne L, Yadav A, Wang Y, Desbuleux A, Kim DK, Laval F, Spirohn-Fitzgerald K, Cafarelli T, Kovács IA, Jailkhani N, Schlabach S, De Ridder D, Luck K, Botchkarev VV Jr, Debnath O, Bian W, Shen Y, Yang Z, Jacob Y, Rolland T, McClain GG, Coté AG, Gebbia M, Kishore N, Knapp JJ, Mellor JC, Cusick ME, Zhong Q, Hao T, Charloteaux B, Roth FP, Falter-Braun P, Hill DE, Calderwood MA, Twizere JC, Vidal M
Genotype-phenotype relationships are mediated through intricate networks of physical and functional interactions among macromolecules. Knowledge of the interactome is vital to understand and model genetics and cellular biology. Recent advances in accurately predicting tertiary protein structures using artificial intelligence (AI) approaches such as AlphaFold1 have revived the vision that the protein-protein interactome might be fully predictable through computational modeling of quaternary structures. Here we present a comprehensive experimental framework to systematically assess the impact of AI-driven interactome predictions for yeast2 and human3. We find that the quality of high-confidence predictions is on par with established experimental approaches. However, in proteome-wide screening, the tested AI approaches underperform in the discovery of strictly novel protein-protein interactions (PPIs) compared to experimental reference interactome maps. In particular, the yeast interactome map described here identifies >40-fold more novel PPIs than its AI counterpart. Strikingly, AlphaFold provides structural models for a substantial number of experimentally identified PPIs missed by the virtual screens. Our results suggest that, at this stage, the main contribution of AI predictions is to provide quaternary structure models for experimentally identified PPIs.
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Science
A SWI/SNF-Specific Ig-Like Domain, SWIFT, is a Transcription Factor Binding Platform
Jain SU, Williamson KE, Ying AW, Turner AM, Raval S, So K, Allison MJ, Sankar A, Sáme Guerra DD, Mashtalir N, Papanastasiou M, Paulo JA, Gygi SP, Kadoch C
Mammalian switch/sucrose nonfermenting (mSWI/SNF) chromatin remodeling complexes modulate DNA accessibility and gene expression; however, their genomic targeting mechanisms remain incompletely understood. Here, we identify SWIFT [SWI/SNF immunoglobulin fold (Ig-fold) for transcription factor interactions], a conserved transcription factor (TF) binding domain on the SMARCD subunits. SWIFT is necessary and sufficient for direct engagement with the transactivation domain of the PU.1 TF. A single amino acid mutation disrupts PU.1-mSWI/SNF binding, impairs complex targeting, and attenuates oncogenic transcription and proliferation in PU.1-dependent human cancer cells. Dominant expression of the SWIFT domain in isolation sequesters TFs from mSWI/SNF and poisons TF-"addicted" cancer cells. Finally, TFs across diverse families interact with SMARCD paralog-specific SWIFT domains. These results define a major mechanism of cell type- and disease-specific mSWI/SNF chromatin targeting and inform approaches toward therapeutic modulation.
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Breast Cancer Research and Treatment
The LIFT UP Study: Feasibility of Systematically Identifying and Addressing Resource Needs in Those with Metastatic Breast Cancer
Fadelu TA, Odai-Afotey A, Martin A, Skeffington M, Hughes M, Fullem R, Revette A, Nava-Coulter B, Perilla-Glen A, Rn SB, Kusmick R, Moore A, Buck S, Sendrick K, Sammons S, Tolaney SM, Lin NU, Freedman RA
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Clinical Cancer Research
ctDNA Dynamics and Recurrence Patterns after Organ-Sparing Trimodality Therapy for Bladder Cancer
Epstein IB, Odogiyon A, Berg S, Otani Y, Mantia C, Pompa IR, Mossanen M, Wan J, Saraf A, Preston M, Ravi A, Carvalho F, Clinton T, Roberts D, Peng L, McGregor B, Bellmunt J, Kamran SC, Efstathiou JA, Miyamoto DT, Mouw KW
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Clinical Lymphoma, Myeloma and Leukemia
Safety and Tolerability of CAR T-Cell Therapy in Patients with End-Stage Kidney Disease on Hemodialysis: A Case Series
Ahmed Z, Hamouche W, Chowdhury R, Gupta S, Sullivan D, Duffy C, Anderson KC, Laubach J, Jacobson C, Nadeem O
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Expert Opinion on Biological Therapy
A Review of the Clinical Efficacy of Monoclonal Antibody (mAb)-Based Therapies for Relapsed/Refractory Multiple Myeloma (RRMM)
Liu Y, Mo CC, Salman TJ, Hossain S, Midha S, Nadeem O, Nicholson T, Croteau J, Kazierad N, Mouhieddine TH, Theprungsirikul P, Laubach JP, Richardson PG
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International Journal of Radiation Oncology, Biology, Physics
Four-Year Feasibility and Safety Results of a Phase 1/2 Single-Arm Prospective Clinical Trial of Stereotactic Magnetic Resonance-Guided Adaptive Radiation Therapy for Metachronous Oligometastatic Abdominopelvic Lymph Node and Soft Tissue Metastases
Howard TP, Walburn T, Benham G, Chirmade S, Yang DD, McGregor BA, Pomerantz MM, Leeman JE, Han Z, Huynh MA
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JAMA Network Open
Multimodal Assessment of Biological Age Following Radiation Therapy Among Patients with Early-Stage NSCLC
Lee G, Haugg F, Bontempi D, He J, Bitterman DS, Pai S, Guthier C, Fitzgerald KJ, Kozono DE, Kann BH, Aerts HJWL, Mak RH
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Journal of Nuclear Medicine
LASER: A Phase 2 Trial of (177)Lu-PSMA-617 as Systemic Therapy for RCC
Hazut Krauthammer S, Xie W, LaBrecque N, Arsenault L, Kabarame L, Shah H, Berg S, McGregor B, Serzan M, Xu W, Viswanathan SR, Wei XX, Choueiri TK, Jacene H, Ravi P
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Nature Metabolism
Irisin Ameliorates Obesity and Insulin Resistance via Adipose Tissue IL-33 and Regulatory T Cells
A M, Wang G, Zammit NW, Roth L, Maierhaba Y, Bogoslavski D, Cai C, Langston PK, Zhang Q, Spiegelman BM, Mathis D
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Nature Neuroscience
A Generalizable Foundation Model for Analysis of Human Brain MRI
Tak D, Garomsa BA, Zapaishchykova A, Chaunzwa TL, Climent Pardo JC, Ye Z, Zielke J, Ravipati Y, Pai S, Vajapeyam S, Mahootiha M, Smith C, Liu KX, Prabhu S, Arnaout O, Bandopadhayay P, Aerts HJ, Huang RY, Poussaint TY, Kann BH
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Neurology
Primary Motor Cortex Involvement and Its Association with Seizure Risk in Patients with Brain Metastases
Baselga-Garriga C, Purohit S, Lamba N, Catalano PJ, Haas-Kogan DA, Tobochnik S, Bubrick EJ, Marciscano AE, Khandekar MJ, Rahman RM, Tanguturi SK, Bi WL, Aizer AA
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