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 June 16 through June 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 [email protected].
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Blood
PI3Kγ in Leukemia: Class IB PI3 Kinase Reemerges as a Cancer-Intrinsic Target
Luo Q, Fortune AL, Lane AA
Phosphoinositide 3-kinase gamma (PI3Kγ), the only class IB PI3 kinase, is a cell-extrinsic immunotherapy target in solid tumors. PI3Kγ inhibition reprograms immunosuppressive myeloid cells to acquire immunostimulatory phenotypes, which promote antitumor cytotoxic T-cell activity. Although PI3Kγ inhibition has no direct effect on solid tumor cells, several new studies have nominated PI3Kγ as a cell-intrinsic target in various leukemias, particularly acute myeloid leukemia. Intrinsic dependency on PI3Kγ is present at baseline in leukemias with specific pathological characteristics, is inducible by extrinsic inflammation in others, and may also be acquired with resistance to certain therapies. The discovery of leukemia PI3Kγ dependency has generated enthusiasm for immediate clinical trial evaluation of inhibitor monotherapy and combinations. Parallel laboratory evaluation is needed to develop an improved understanding of leukemia disease features associated with clinical inhibitor sensitivity that might suggest biomarker-directed patient enrichment strategies. In this review, we discuss recent progress credentialing PI3Kγ as a bona fide target in leukemia. We also highlight open questions, including a need to understand the mechanism of acquired resistance to PI3Kγ inhibition, how to optimally prioritize combination therapies to enhance PI3Kγ inhibitor utility, and how cell-extrinsic effects of PI3Kγ inhibition in the leukemia microenvironment might also contribute to clinical activity.
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JAMA
The Role of Affirming Language
Rosenberg AR
Fourteen countries explicitly criminalize the gender identity and/or expression of transgender people, and the national state of emergency for LGBTQIA+ US residents declared by the Human Rights Campaign in 2023 is intensifying. As of April 2025, 851 antitransgender bills have been introduced across 49 states, 64 have passed in 21 states with 51 signed into law, and another 742 are currently under deliberation. Since 2021, this is a 495% increase in the number of antitransgender bills being considered, making 2025 the sixth consecutive record-breaking year for antitransgender legislation introduced in the US. This Viewpoint provides clinicians with tools to support transgender patients given the evolving antitransgender policies.
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JAMA Oncology
Navigating Selective Dose Intensification in EGFR-Variant Non-Small Cell Lung Cancer
Marks JA
The prospective ACHIEVE study by Fan et al1 explores selective dose intensification for patients with EGFR-variant non–small cell lung cancer (NSCLC). In addition to demonstrating safety and efficacy with this approach, the study draws attention to the strategy behind dose selection in the era of targeted therapy and may support revisiting long-held practices.
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Journal of Clinical Oncology
Patritumab Deruxtecan (HER3-DXd; MK-1022) in Non-Small Cell Lung Cancer After Platinum-Based Chemotherapy and Immunotherapy
Jänne PA
PURPOSE: Patritumab deruxtecan (HER3-DXd; MK-1022) is an investigational HER3-directed antibody-drug conjugate composed of a human immunoglobulin G1 monoclonal antibody to HER3 (patritumab) covalently linked via a stable tetrapeptide-based cleavable linker to a topoisomerase I inhibitor payload that has shown durable antitumor activity in previously treated patients with
EGFR-mutated advanced non-small cell lung cancer (NSCLC). We extend these observations to patients with advanced NSCLC with other/no identified driver genomic alterations.
METHODS: Patients with advanced squamous or nonsquamous NSCLC without a common EGFR-activating mutation whose disease had progressed on previous therapies including platinum-based chemotherapy, immune checkpoint inhibitors, and targeted therapy (for patients with known actionable genomic alterations) received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks. The primary end point was confirmed objective response rate (cORR).
RESULTS: Forty-seven patients were treated with HER3-DXd (median treatment duration, 4.2 [range, 0.7-19.8] months). The cORR was 27.7% (95% CI, 15.6% to 42.6%), and the median duration of response was 8.1 (95% CI, 4.2 to not evaluable) months. The median progression-free survival was 5.5 (95% CI, 4.0 to 11.2) months, and the median overall survival was 15.2 (95% CI, 10.8 to 17.7) months. Similar efficacy was observed in patients with NSCLC harboring identified driver genomic alterations and in those without such genomic features. The rate of study drug discontinuation associated with treatment-emergent adverse events (TEAEs) was 12.8%. Study drug-related grade ≥3 TEAEs occurred in 51.1% of patients and were serious in 12.8% (none were associated with death). Adjudicated treatment-related interstitial lung disease occurred in five patients (10.6%; all grade 1 or 2).
CONCLUSION: The previously reported efficacy and safety of HER3-DXd in heavily pretreated patients with EGFR-mutated NSCLC are also observed in those with other NSCLC subtypes and warrant further clinical evaluation.
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New England Journal of Medicine
Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer
Uppaluri R, Haddad RI
BACKGROUND: The benefit of the addition of perioperative pembrolizumab to standard care with surgery and adjuvant therapy for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) is unclear.
METHODS: In this phase 3, open-label trial, we randomly assigned participants with locally advanced HNSCC in a 1:1 ratio to receive 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab (both at a dose of 200 mg every 3 weeks) in addition to standard care (pembrolizumab group) or standard care alone (control group). Standard care was surgery and adjuvant radiotherapy with or without concomitant cisplatin. The primary end point was event-free survival, sequentially assessed in participants whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS) of 10 or more (CPS-10 population), participants whose tumors expressed PD-L1 with a CPS of 1 or more (CPS-1 population), and all the participants. A higher CPS indicates a higher proportion of cells that express PD-L1.
RESULTS: A total of 363 participants (234 with a CPS of ≥10 and 347 with a CPS of ≥1) were assigned to the pembrolizumab group and 351 (231 with a CPS of ≥10 and 335 with a CPS of ≥1) to the control group. Surgery was completed in approximately 88% of the participants in each group. At the first interim analysis, the median follow-up was 38.3 months. Event-free survival at 36 months was 59.8% in the pembrolizumab group and 45.9% in the control group (hazard ratio for progression, recurrence, or death, 0.66; 95% confidence interval [CI], 0.49 to 0.88; two-sided P = 0.004) in the CPS-10 population; 58.2% and 44.9%, respectively (hazard ratio, 0.70; 95% CI, 0.55 to 0.89; two-sided P = 0.003), in the CPS-1 population; and 57.6% and 46.4%, respectively (hazard ratio, 0.73; 95% CI, 0.58 to 0.92; two-sided P = 0.008), in the total population. Grade 3 or higher treatment-related adverse events occurred in 44.6% of the participants in the pembrolizumab group and in 42.9% of those in the control group, including death in 1.1% and 0.3%, respectively. Potentially immune-mediated adverse events of grade 3 or higher occurred in 10.0% of the participants in the pembrolizumab group.
CONCLUSIONS: The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced HNSCC. Neoadjuvant pembrolizumab did not affect the likelihood of surgical completion. No new safety signals were identified. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-689 ClinicalTrials.gov number, NCT03765918.).
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Science
CTC1-STN1-TEN1 Controls DNA Break Repair Pathway Choice Via DNA End Resection Blockade
Swift ML, Chowdhury D
Antagonistic activities of the 53BP1 axis and the tumor suppressor BRCA1-BARD1 determine whether DNA double-strand breaks (DSBs) are repaired by end joining or homologous recombination. We show that the CTC1-STN1-TEN1 (CST) complex, a central 53BP1 axis component, suppresses DNA end resection by EXO1 and the BLM-DNA2 helicase-nuclease complex but acts by distinct mechanisms in restricting these entities. Whereas BRCA1-BARD1 alleviates the CST-imposed EXO1 blockade, it has little effect on BLM-DNA2 restriction. CST mutants impaired for DNA binding or BLM-EXO1 interaction exhibit a hyper-resection phenotype and render BRCA1-deficient cells resistant to poly(ADP-ribose) polymerase (PARP) inhibitors. Our findings mechanistically define the crucial role of CST in DNA DSB repair pathway choice and have implications for understanding cancer therapy resistance stemming from dysfunction of the 53BP1 axis.
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Abdominal Radiology
Biliary Tract Neoplasms from Common to Rare: Diagnosis, Assessment, and Management
El Khoury T, Schawkat K, Koch M, Cahill B, Clancy TE, Jajoo K, Mancias J, Singh H, Wolpin BM, Rosenthal MH
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Blood Advances
Invasive Fungal Disease is Rare in Patients with Relapsed/Refractory Multiple Myeloma Treated with BCMA CAR T-Cell Therapy
Little JS, Medina Pena A, Kim EB, Yee AJ, Nadeem O, Midha S, Sperling AS, Munshi NC, Raje NS, Frigault MJ, Cirstea DD, Hammond SP
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Cell Reports Medicine
Cell States and Neighborhoods in Distinct Clinical Stages of Primary and Metastatic Esophageal Adenocarcinoma
Yates J, Mathey-Andrews C, Park J, Garza A, Gagné A, Hoffman S, Bi K, Titchen B, Remland J, Carnes M, Shannon E, Camp S, Balamurali S, Cavale SK, Li Z, Raghawan AK, Boland G, Aguirre AJ, Sethi NS, Van Allen EM
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JCI Insight
Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a Target for Antibody-Drug Conjugate Therapy
Shigeta K, Daimon T, Hongo H, Ku SY, Ozawa H, Haratake N, Fushimi A, Nakashoji A, Bhattacharya A, Takamori S, Kono M, Rokugo M, Beltran H, Kufe DW
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JCI Insight
Imlunestrant a Next-Generation Oral SERD Overcomes ESR1 Mutant Resistance in Estrogen Receptor-Positive Breast Cancer
Sherman S, Sandusky ZM, Russo D, Nardone A, Friel D, Hermida-Prado F, Heraud C, Kuziel G, Verma A, Gaglia G, Kabraji S, Nguyen QD, Santagata S, Fanning SW, Jeselsohn R
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Leukemia
Mutations and Translocations Associated with Venetoclax Resistance in Chronic Lymphocytic Leukemia
Mashima K, Kuang Y, Fernandes SM, Xu S, Hanna B, Shupe S, Mikhaleva M, Santos RA, Predko P, Fardoun R, Bidgoli A, Martindale SP, Naeem A, Davids MS, Paweletz C, Brown JR
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