Dana-Farber Research News 10.15.2026
Welcome to Dana-Farber's Research News
October 15, 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 September 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 PKMYT1 is a Targetable Vulnerability in Del(17p) High-Risk Multiple Myeloma Schavgoulidze A, Cui J, Mayoral JE, Favasuli V, Talluri S, Shammas M, Anderson KC, Aktas-Samur A, Samur MK, Munshi NC, Fulciniti M Deletion of chromosome 17p [del(17p)] is among the most adverse cytogenetic abnormalities in multiple myeloma (MM). By integrating RNA sequencing data from cells of patients with MM with genetic dependency data from MM cell lines, we identified protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the WEE family, as a potential therapeutic target in MM cells harboring del(17p). Genetic suppression or pharmacological inhibition of PKMYT1 activity with the selective inhibitor RP-6306 triggered accumulation of DNA damage, micronucleus formation, and mitotic catastrophe, resulting in preferential cell death in del(17p) MM cells while largely sparing del(17p)- MM cells and healthy cells. RP-6306 also reduced tumor burden and extended survival in vivo in both xenograft and TP53-deficient syngeneic models. Collectively, our findings nominate PKMYT1 as an actionable target and support PKMYT1 inhibition as a biomarker-driven therapeutic strategy for patients with del(17p) or TP53-deficient MM. |
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Blood Venetoclax plus Inotuzumab Ozogamicin for Relapsed and Refractory Acute Lymphoblastic Leukemia Luskin MR, Keating JH, Frost BF, Jaeckle SL, Shimony S, Flamand Y, Garcia JS, Stone RM, Booker M, Weizer CM, Ryan JA, Lee J, Galinsky IA, Shah SI, Smith E, Kulkarni A, Tolstorukov M, Chen EC, Winer ES, Letai A, Murakami MA, DeAngelo DJ In relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), responses to the CD22 antibody-drug conjugate inotuzumab ozogamicin (INO) are frequent but short-lived. Based on preclinical evidence of synergy, we conducted a phase 1 trial of the BCL-2 inhibitor venetoclax (VEN) plus standard-dose INO for adults with R/R CD22+ ALL/LBL. Twenty-three patients enrolled (15 ALL, 8 LBL): three at dose level 1 (DL1; VEN 200 mg/day), six at DL2 (VEN 400 mg/day), and fourteen in an expansion cohort (VEN 400 mg/day). The recommended dose was VEN 400 mg/day for 21 days per cycle. No dose-limiting toxicities or early mortality occurred. Patients received a median of 2 cycles (range 1-5). The most common grade 3 adverse events were thrombocytopenia (43.5%) and neutropenia (39.1%). Four patients (17.4%) developed sinusoidal obstructive syndrome. Of 22 evaluable patients, 21 (95.5%) achieved complete remission, including 19 after one cycle. Measurable residual disease (MRD) cleared in 16/18 (88.9%) by flow cytometry (<10-4) and 14/19 (73.7%) by next-generation sequencing (<10-6). Fourteen (63.6%) patients proceeded to HSCT. With a median follow-up of 25.3 months (95% CI 19.0-32.4), two-year disease-free (DFS) and overall survival (OS) were 48% (95% CI 24-72%); median DFS was 22.1 months (95% CI 10.4-NA), and median OS was not reached. MRD-positivity was associated with lower baseline BCL-2 dependence. Correlates of progression included acquired MCL-1 dependence, CD22 antigen escape, drug efflux gene ABCB1 expression, and oncogenic mutations. In summary, VEN+INO is safe and effective for R/R B-ALL/LBL, producing frequent and durable MRD-negative remissions. NCT05016947. |
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Cancer Discovery Spatially Confined IL-12 Programs CAR-NK Through mTORC1 to Coordinate Antitumor Immune Networks Tarannum M, Dinh K, Nguyen M, Campisi M, Maia A, Liu F, Yang S, Birch GC, Bobilev E, Gillanders I, Sheffer M, Gupta S, Wang J, Ganapathy S, Michaud DE, Dalton GN, Chugh S, Nguyen QD, Paweletz CP, Gokhale PC, Guerriero JL, Choueiri TK, Barbie DA, Aguirre AJ, Porter RL, Matulonis UA, Koreth J, Wu CJ, Soiffer RJ, Ritz J, Chen J, Romee R Solid tumors evade immunotherapy because of immunosuppressive microenvironments that limit immune cell persistence and function. Although interleukin-12 (IL-12) potently activates antitumor immunity, its clinical use has been constrained by systemic toxicity. Here we engineered a CAR natural killer (NK) cell platform that integrated IL-12 signaling to enhance antitumor immunity. IL-12 signaling synergized with CAR activation to sustain mTORC1 activity through convergent Ras-ERK and PI3K pathways, promoting metabolic fitness, autonomous expansion, and sustained effector function. IL-12 also activated bystander NK cells, T cells, and macrophages to remodel the tumor microenvironment. To improve safety, IL-12 was tethered to a collagen-binding A3-domain, restricting its activity to the extracellular matrix and limiting systemic exposure. In ovarian and pancreatic cancer models, matrix-anchored IL-12 CAR NK cells expanded without exogenous cytokines and achieved durable tumor control. These findings suggest that mTORC1-mediated integration of CAR and cytokine signaling can enhance immune fitness and overcome immunosuppressive tumor microenvironments. |
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Cell Qiang L, Hoffman MT, Parent B, Hambitzer F, Peprah F, Kureshi CTS, Lim BS, Chang E, Walsh MJ, Tello JG, Atajanova T, Perkins C, Kureshi R, Molina-Aponte Y, Dougan JM, Zuo C, 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, Singh H, Aguirre AJ, Dougan M, Dougan SK Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies, for which reinvigoration of CD8 T cells through immune checkpoint blockade is insufficient to induce long-term, durable remissions. Direct KRAS inhibitors (KRASi) have shown clinical promise, although acquired resistance is common. We modeled KRASi response and relapse in mice and demonstrated that, unlike chemotherapy or combinations with checkpoint blockade, an interleukin (IL)-21 cytokine mimic (21h10) induced long-term, durable remissions. Its efficacy depends on T helper 1 (Th1)-polarized CD4 T cells, but not on CD8 T cells or tumor cell expression of major histocompatibility complex class I (MHC class I). Specifically, CD4 T cells primed by type 2 conventional dendritic cells (cDC2s) produce interferon ? (IFN-?), which promotes macrophage-mediated phagocytosis of tumor cells. Ex vivo treatment of human PDAC specimens with 21h10 induces IFN-? production by infiltrating T cells. Thus, IL-21-elicited CD4 T cells exert antitumor activity in mice and potentially in humans, converting transient responses to KRAS inhibition into durable remissions. |
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Cell Stem Cell Klatt D, Mucci A, Liu B, Peschers M, Schiroli G, Manis J, Armant M, Scadden DT, Pellin D, Williams DA, Brendel C Ex vivo hematopoietic stem cell (HSC) gene therapy is effective for non-malignant blood disorders including sickle cell disease (SCD), but requires hospitalization, ex vivo cell manipulation, and conditioning. Direct in vivo gene delivery could remove these barriers and widen access. Here, we explore phagocytosis-shielded lentiviral and alpha-retroviral vectors pseudotyped with the baboon endogenous retrovirus glycoprotein variant BaEVRLess for in vivo HSC gene transfer. Vector injection into mobilized humanized mice yielded up to 8.8% gene marking in hCD45+ cells, which chemoselection enriched to 70% of hCD45+ cells and 54% of HSCs. Barcode analysis showed polyclonal reconstitution in over 90% of mice, which remained stable in secondary recipients. For SCD, we targeted BCL11A and ZNF410 selectively in erythroid cells using miRNA-embedded shRNAs to derepress gamma-globin, reaching therapeutically relevant levels of 61.5% of beta-like globins. In summary, BaEVRLess-pseudotyped lentiviral vectors enable clinically relevant in vivo gene transfer and fetal globin induction for SCD. |
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Journal of Clinical Oncology Pollard JA, Place A PURPOSE: The Children's Oncology Group phase III clinical trial AAML1831 (ClinicalTrials.gov identifier: NCT04293562) evaluated liposomal daunorubicin and cytarabine (CPX-351) versus standard daunorubicin/cytarabine (DA) induction therapy in children and young adults with newly diagnosed AML. We hypothesized that CPX-351 given during induction 1 and 2 would improve outcomes compared with DA. PATIENTS AND METHODS: Patients (21 years and younger) were randomly assigned to two cycles of DA induction (arm A = DA) or CPX-351 (arm B = CPX-351). All patients also received gemtuzumab ozogamicin in induction 1. Postinduction chemotherapy was according to risk assignment made at the end of induction 1 (EOI1). Those with high-risk (HR) AML received consolidation with allogeneic hematopoietic stem-cell transplantation (HSCT), whereas low-risk (LR) patients received chemotherapy alone. Protocol-specified interim analysis monitored efficacy and futility of CPX-351 induction with respect to the primary end point, event-free survival (EFS) from study entry. Disease-free survival (DFS) was calculated to determine the impact of EOI1 risk assignment. RESULTS: Seven hundred twenty-one eligible patients with FLT3 wild-type AML were randomly assigned to DA (n = 358) or CPX-351 (n = 363). Interim analysis determined that the futility monitoring rule was crossed because of inferior EFS in the CPX-351 arm and the random assignment was stopped. The two-year EFS from study entry was 62.2% for DA versus 51.2% for CPX-351 (P = .011). DFS for patients with HR AML was comparable for both arms. However, DFS was significantly lower and cumulative incidence of relapse (CIR) was higher for LR patients assigned to CPX-351 versus DA (2-year DFS from EOI1: DA: 73.8% v CPX-351 57.5% [P = .001]; 2-year CIR Arm DA: 23.6% v CPX-351: 39.9% [P = .001]). CONCLUSION: CPX-351 was inferior to DA induction in the AAML1831 trial with differential EFS largely driven by events in LR patients. |
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Journal of the National Cancer Institute Zhang GQ, Ma C, Yang VB, Nowak JA, Twombly T, Zhao M, Takashima Y, Ogino S, Goldberg JE, Meyerhardt JA BACKGROUND: Postoperative circulating tumor DNA (ctDNA) is a highly prognostic marker of residual disease among patients with stage III colon cancer, and physical activity has been associated with improved survival after curative resection. Whether physical activity predicts outcomes according to postoperative ctDNA status remains unknown. METHODS: We conducted a post hoc analysis of CALGB/SWOG 80702, a phase III study evaluating adjuvant celecoxib vs. placebo and 3 vs. 6 months of chemotherapy. Total physical activity volume was assessed using validated and quantified in metabolic equivalent task hours per week (MET-h/week). ctDNA status was determined using a clinically validated, tumor-informed assay (SignateraTM, Natera, Inc.). RESULTS: Among 763 patients (median follow-up 6.0 years), 32.3% were inactive (<3.0 MET-h/week), 24.4% were highly active (?18.0), and 17.8% were ctDNA-positive. Among patients who were ctDNA-negative, moderate (adjusted hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.37-0.91) and high physical activity (HR 0.49, 95% CI 0.27-0.86) were associated with improved disease-free survival (DFS) compared to inactivity, with similar trends in overall survival (OS). Physical activity was not associated with DFS/OS in the ctDNA-positive subcohort (P?>?0.05 for all), though interactions were not statistically significant. Among patients who were physically active (?9.0 MET-h/week) and received adjuvant celecoxib, improved DFS was observed in both ctDNA-negative (HR 0.41, 95% CI 0.22-0.77) and ctDNA-positive (Ref: inactive, placebo; HR 0.29, 95% CI 0.15-0.57) subgroups. CONCLUSIONS: Greater physical activity was associated with improved DFS among patients who were ctDNA-negative. Physical activity and adjuvant celecoxib was associated with favorable survival outcomes regardless of ctDNA status. |
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Lancet Precision Prevention and Early Detection: Framework for a New Clinical Cancer Control Pathway Rebbeck TR Stage at diagnosis remains the strongest determinant of cancer survival, yet only 13% of cancers are detected through guideline-based screening, and 20-50% first present in an emergency department. Precision prevention and early detection (PPED) tailors cancer control by asking who is at elevated risk of developing cancer, what preventive intervention is appropriate, when should intervention be applied and at what intensity, and how and where preventive services should be delivered. De-escalation of preventive interventions in low-risk individuals is as important as preventive care escalation in high-risk individuals. The hereditary cancer syndromes demonstrate that this logic works when cancer risk is sufficiently enriched. Although the science must continue to mature, the health-system infrastructure and workforce required to sustain longitudinal prevention planning are a defining cancer control challenge in the next decade. |
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Nature GPCR Antagonism via Rewiring of Receptor Trafficking and Degradation Rhee K, Shue L, Adachi A, Osei-Owusu J, Zhou D, Cheng A, Xu YR, Baluapuri A, Harvey EP, Adelman K, Skiba MA, Huh JR, Kruse AC, Zhou X G-protein-coupled receptors (GPCRs) represent one of the most important yet incompletely addressed classes of therapeutic targets. Here we report a strategy for functional GPCR antagonism through bispecific antibody-mediated endocytosis and lysosomal degradation. GPCR-TfR1 targeting chimeras (GTACs) achieve potent and selective downregulation of multiple GPCRs, including BILF1, RXFP1 and CCR6-viral, cancer and immune targets that have been difficult to drug. GTACs lead to complete inhibition of receptor signalling, including constitutive signalling, with more than one to two orders of magnitude greater potency than conventional antibody antagonists. Using protein engineering and multicolour live-cell imaging, we establish a context-dependent degrader design and explain the cellular mechanisms, with broad relevance for degrader technology. The GTAC platform establishes induced endocytosis and rewiring protein trafficking as a model for therapeutic GPCR modulation. |
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Nature Human Genetics Implicates a BACH2-NRF2 Axis in Fetal Haemoglobin Activation Guo CJ, Arora UP, Cheng X, Xu W, Cato LD, Li R, Lu HY, Lee AJ, Yu F, Agarwal G, Lyu P, Ye T, Antoszewski M, Wissmann M, Nilsson B, Sankaran VG Human genetic studies have identified key regulators of fetal haemoglobin (HbF) expression, including BCL11A, resulting in therapeutic advances. Yet the mechanisms by which HbF expression is activated remain incompletely understood. Here we conduct a large multi-ancestry genome-wide association study of HbF levels in 28,279 individuals that identifies 91 conditionally independent associations across 12 genomic regions. In one previously uncharacterized associated region, the high-HbF-linked causal variant rs1010474-C reduces BACH2 expression and elevates HbF levels. Direct perturbation or inhibition of BACH2 likewise increases HbF expression. Mechanistically, BACH2 restrains activation of the HbF-encoding ?-globin genes, while loss of BACH2 enhances NRF2 chromatin occupancy and promotes the formation of activation foci at the ?-globin genes. Although BACH2 and NRF2 binding motifs in the ?-globin promoters overlap, they can be selectively edited to activate or repress ?-globin, respectively, and do so independently of BCL11A. These findings illustrate how human genetic variation continues to advance our understanding of therapeutically relevant regulatory mechanisms underlying HbF expression. |
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Nature Medicine Some Answers, More Questions for Multi-Cancer Early Detection Tests Marinac CR, Rebbeck TR, O'Donnell EK In current practice, only about 13% of cancers are detected by guideline-based screening programs. Although these programs reduce mortality rates for some cancers, most cases and deaths are attributed to cancer types without recommended screening strategies. Current cancer screening approaches are largely organ-specific, and uptake is variable. These challenges have led to interest in blood-based multicancer early detection (MCED) tests as a complementary approach to existing screening strategies. Three contemporaneous publications, two in this issue of Nature Medicine and one in the New England Journal of Medicine, report results from the PATHFINDER 2 and NHS-Galleri trials, both evaluating the Galleri test, together providing some of the most substantial evidence so far on the implementation and clinical utility of MCED testing. |
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Proceedings of the National Academy of Sciences of the U.S.A. Positive Selection Screen Identifies Natural Product ?-Catenin Inactivators Boudreau MW, Corbett SC, Yu W, Jiang Q, Splaine J, Pfaff JL, Yu D, Chandler BC, Abeja DM, Donovan KA, Che J, Lampson BL, Szajner P, Smith JA, Koduri V, Kaelin WG Jr Many genetically validated targets in cancer, including the transcription factor ?-catenin (?-cat), have historically been viewed as undruggable. Cell-based phenotypic screening of chemical compounds can reveal unanticipated biological and pharmacological principles. Natural products are powerful probes because of their superior structural diversity, drug-like properties, and biological activities as compared to unoptimized synthetic compounds. We screened 326,304 natural product mixtures (40,744 extracts and 285,560 fractions derived from them) using mammalian cells expressing an oncogenic version of ?-cat fused to a suicide protein. Multiple fractions degraded the ?-cat fusion protein or drove it into a compartment where both fusion partners were apparently inactive. The active natural product from one of the latter specifically activates novel, but not classical, protein kinase Cs and thereby relocates ?-cat to juxtamembrane vacuolar structures. These findings suggest a path for inactivating oncogenic ?-cat and underscore the power of screening natural product collections with robust phenotypic assays. |
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Science Germline EGFR T790M Mutation and Lung Cancer Risk LoPiccolo J, Koeller DR, Yatzus H, Williamson VG, Avila JA, Liautaud RB, Fields ND, Collins RL, Garber JE, Christiani DC, Gusev A, Jänne PA Most lung cancers are tobacco related, with genetic factors influencing smoking behavior identified through genome-wide association studies. However, inherited risk in familial and non-smoking-related lung cancers, including risk in carriers of EGFR T790M, remains poorly understood. Here, in more than 3.3 million individuals, the EGFR T790M germline variant is significantly associated with lung cancer risk, with no increased risk for 17 other cancers and no interaction with polygenic risk. This risk exceeds that conferred by smoking and is several-fold higher in never-smokers. Global geographic and ancestry analyses show higher T790M prevalence in the US than in British- and Irish-descendant populations, reflecting a Southern Appalachian founder event about 200 to 225 years ago, increasing regional prevalence and affecting those of British, Irish, and African descent. Recognition of high-risk carriers may inform targeted genetic testing and screening strategies. |
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Cell Reports Atomistic TCR-pMHC Interactions Bias CD8 Memory Fate within a Single Antigen-Specific Repertoire Akitsu A, Mallis RJ, Booker MA, Duke-Cohan JS, Brazin KN, Parkins AN, Aryal S, Cinella V, Lee JJ, Uberoy KI, Koenig JK, Biddle M, Messier CM, Lizotte PH, Tolstorukov MY, Reinherz EL |
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Critical Care Explorations Upham EJ, Gouda SR, Lindvall C, DeCourcey DD |
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Expert Opinion on Pharmacotherapy Current and New Approaches to the Treatment Landscape for Adults with Waldenström Macroglobulinemia Edwards CV, Castillo JJ, Mouhieddine TH, Sarosiek SR |
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Immunity Cancers Modulate Processing and Presentation of p53 Neoantigens to Evade T Cell Detection Haratani K, Reinhold B, Duke-Cohan JS, Fahey CG, Mallis RJ, Gusev A, Kehl KL, Luo J, Hennessey CJ, Blasco RB, Thai TC, Gibbons GM, Kivlehan S, Lizotte P, Paweletz CP, Aguirre AJ, Ligon KL, Chiarle R, Barbie DA, Reinherz EL |
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International Journal of Cancer Alcindor T |
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iScience Pervasive Tissue Specificity of Driver Genes Revealed by Mutational Analysis of 265 Cancer Types Chen J, Collins RL, Haigis KM |
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JNCI Cancer Spectrum Timing and Prognosis of Brain Metastasis Development in Breast Cancer by Subtype Rashid NS, Lamba N, Ricca I, Johnson M, Catalano PJ, Tanguturi SK, Rahman R, Haas-Kogan DA, Sammons SL, Lin NU, Aizer AA |
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Journal of Cell Biology Components of an ESCRT-Independent Nuclear Envelope Assembly Pathway Sydir EM, Farra MH, Paulo JA, Swarup S, Harper JW, Lee IJ, Pellman D |
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Journal of Pain and Symptom Management GOC Conversations About LVAD Deactivation in Destination Therapy and Bridge-to-Candidacy Decedents Santo EC, Lehto HR, Peng Y, O'Shea LK, Coakley L, Reich AJ, Bernacki RE |
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Journal of Pain and Symptom Management Cubbison C, Kematick B, Bacon M, Scullion B, Lally K |
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Journal of the American Academy of Dermatology Mortelliti C, Neff H, Solomon B, Murchison K, Stevens J, Ran NA, Ruiz E, Silk AW |
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Journal of the National Comprehensive Cancer Network Targeting KRAS-Mutant Lung Cancers Garbo E, Hoe HJ, Luo J, Shaw AT, Ricciuti B |
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Nature Reviews Molecular Cell Biology Mechanisms and Disease Relevance of DNA Break Repair Pathway Choice Swift ML, Chowdhury D |
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Neuro-Oncology Glioma and Ependymoma Through the Lens of Brain Development, Stem Cells, and Plasticity Lo Cascio C, Filbin MG |
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Science Advances De Silva P, Fitzgerald S, Cazaubiel J, Qian K, Hofree M, Lin JR, Pelletier R, Lopez Leon M, Ho PVM, Takashima Y, Matsuda K, Ugai T, Ford-Roshon D, Bala P, Hacohen N, Ng K, Nowak JA, Ogino S, Sorger PK, Giannakis M |
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Transplantation and Cellular Therapy Kelly CA, Bona K |
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Transplant Infectious Disease Hannaford A, Swank Z, van Haren SD, Izaguirre N, Syphurs C, Lan Z, Yates B, Kanwal U, Valentine G, Woehl E, Regan D, Levine H, Tong A, Shehata M, Oladipupo F, Sedney C, Ryff K, Thomas S, Diray-Arce J, Li X, Dufresne KA, Parisi LA, Eustace A, Walt DR, Levy O, Kelkar A, Soiffer RJ, Ho VT, Baden LR, Issa NC, Woolley AE, Sherman AC |