This twice-monthly newsletter highlights recently published research in which Dana-Farber faculty are listed as first or senior authors. The information is sourced from PubMed, and this issue covers papers published October 1-15.
If you are a Dana-Farber faculty member and believe your paper is missing from Research News, please contact us at [email protected].
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Blood
Genomic Determinants of Response and Resistance to Pirtobrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia
Brown JR
Pirtobrutinib, a non-covalent, reversible Bruton tyrosine kinase inhibitor (BTKi), demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), resistant to covalent BTKi (cBTKi). Genomic correlations with response and resistance to pirtobrutinib were analyzed in elapsed/refractory (R/R) CLL patients pretreated with cBTKi and enrolled in the phase 1/2 BRUIN trial. DNA sequencing was performed on PBMCs at baseline, on treatment, and at progressive disease (PD). Common alterations at baseline included mutations in BTK (43%), TP53 (38%), SF3B1 (25%), NOTCH1 (23%), ATM (19%), XPO1 (11%), PLCG2 (9%), BCL2 (8%) and 17p deletion (28%). Common baseline BTK mutations included C481S (85%), C481R (10%), C481F (6%) and C481Y (4%). At PD, 60/88 patients (68%) acquired ≥1 mutation, including 44% with acquired BTK mutations and 24% with other acquired mutations. A total of 55 acquired BTK mutations were detected in 39 patients, including gatekeeper mutations (T474I/F/S/L/Y/P, 26%), kinase-impaired L528W (16%), C481F/R/Y (5%), V416L (2%), and A428D (1%) and others proximal to the ATP-binding pocket, D539G/H/A (1%) and Y545N (1%). Decrease or complete clearance of BTK C481x was observed at PD in 36/43 patients (84%). Using a more sensitive assay, 37% (18/49) of acquired BTK mutations were detected at baseline at low allele frequency. Using the highly sensitive assay at progression, a similar frequency of acquired BTK mutations (39%) was detected, and all patients had detectable acquired mutations. This study highlights the complex clonal dynamics of BTK mutations in R/R CLL patients undergoing pirtobrutinib treatment, and the extent of resistance without an obvious genomic driver. NCT03740529.
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JAMA Oncology
Duffy Null-Associated Absolute Neutrophil Counts and Cancer Clinical Trial Eligibility
Merz LE, Wang Y, Cronin A, Sharon E, Walsh TP, Lathan CS, Hantel A
Non-Hispanic Black (hereafter, Black) individuals are underrepresented in cancer trials, partly due to restrictive laboratory-based eligibility criteria.1 Duffy is an erythrocyte antigen and the null phenotype is a nonpathologic variant associated with 40% lower absolute neutrophil counts (ANCs).2 While 66% of Black and less than 1% of non-Hispanic White (hereafter, White) US residents have this phenotype,3 ANC-related trial criteria do not account for this variation.4 This study evaluated how ANC-related criteria contribute to racial and ethnic disparities in ineligibility, modeling these disparities by Duffy status.
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JAMA Oncology
Impact of a Weight Loss Intervention on 1-Year Weight Change in Women with Stage II/III Breast Cancer: Secondary Analysis of the Breast Cancer Weight Loss (BWEL) Trial
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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Journal of the National Cancer Institute
Frequency and Clinical Features of Germline Pathogenic Variants in Sarcoma: A Case-Control Study
Rodriguez-Hernandez A, Horiguchi M, Bychkovsky BL, Buehler RM, George S, Merriam P, Garber JE, Rana HQ
BACKGROUND: Germline multi-gene panel testing (MGPT) is not yet integrated into standard care for patients with sarcoma. This study aimed to assess the frequency and distribution of germline pathogenic variants (gPVs) in patients with sarcoma compared to cancer-free controls and identify differences between patients with and without gPVs.
METHODS: This retrospective cohort included 488 sarcoma patients, and 2,440 cancer-free controls matched 1:5 by age, sex, and ethnicity. MGPT was performed between 2016 and 2024 at a single germline testing laboratory. The frequency of gPVs in selected genes was compared using Fisher's exact test, with odds ratios (ORs) and 95% confidence intervals (CIs). Additionally, within the case-only cohort, clinical characteristics were evaluated to assess associations with the presence of gPVs in any gene.
RESULTS: Among 488 patients with sarcoma, 67.8% (n = 331) were female, with a median age at sarcoma diagnosis of 47 years (range 0.5-87.5). Cases had a higher frequency of gPVs compared to controls (26.2% vs. 10.5%; OR 3.05, p < .001). We observed a higher frequency of gPVs in TP53, BRCA2, CHEK2, NF1, SDHA, BRIP1, POT1, RB1, and CDH1 among patients with sarcoma compared to controls. Age at sarcoma diagnosis did not differ between groups.
CONCLUSIONS: This study confirms the high detection rate of gPVs in patients with sarcoma and describes several associated genes. These findings indicate that age at sarcoma diagnosis may not reliably predict gPVs. Expanding germline testing for patients with sarcoma would enhance personalized treatment strategies and familial risk assessment.
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Journal of Clinical Oncology
Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B)
Jänne PA
PURPOSE: WU-KONG1B (ClinicalTrials.gov identifier: NCT03974022) is a multinational phase II, dose-randomized study to assess the antitumor efficacy of sunvozertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins).
METHODS: Eligible patients with advanced-stage EGFR exon20ins NSCLC were randomly assigned by 1:1 ratio to receive sunvozertinib 200 mg or 300 mg once daily (200 and 300 mg-rand cohorts). After predefined interim analysis, additional patients were enrolled and treated with the 300 mg dose once daily. The primary end point was blinded independent review committee (IRC)-assessed confirmed objective response rate (cORR), and the key secondary end point was duration of response (DoR).
RESULTS: Among 85, 89, and 107 efficacy-evaluable patients in 200 mg-rand, 300 mg-rand, and 300 mg-all (including randomly assigned and nonrandomized patients) cohorts, the cORRs were 45.9% (97.5% CI, 33.6% to 58.5%), 47.2% (97.5% CI, 35.1% to 59.5%), and 45.8% (97.5% CI, 34.8% to 57.0%), respectively, per IRC assessment. The predefined null hypothesis was rejected with statistical significance (P < .0001). Comparing 300 and 200 mg-rand cohorts, higher cORRs were observed in patients with baseline brain metastasis (52.4% v 28.6%) and previous amivantamab treatment (41.7% v 25%), as well as longer DoR (13.8 v 11.1 months). At 200 and 300 mg once daily, the most common treatment-related adverse events with grade ≥3 included diarrhea (2.2% v 18%), blood creatine phosphokinase increased (6.6% v 12.6%), and anemia (4.4% v 6.3%).
CONCLUSION: Sunvozertinib is efficacious at both 200 and 300 mg once daily in treating platinum-pretreated patients with advanced EGFR exon20ins NSCLC. The treatment-related adverse events of sunvozertinib were consistent with an EGFR tyrosine kinase inhibitor, with a more favorable safety profile at 200 mg than 300 mg once daily.
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Journal of the National Cancer Institute
Prognostic Value of Visually and Computationally-Assessed Tumor-Infiltrating Lymphocytes in Early-Stage Triple-Negative Breast Cancer (TBCRC-030)
Nader-Marta G, Chu X, Kurt BB, DeMeo M, Tung NM, Schnitt SJ, Tayob N, Mayer EL
BACKGROUND: Tumor-infiltrating lymphocytes (TILs), assessed by visual examination (VE), are prognostic and predictive in early-stage triple-negative breast cancer (TNBC). Computational assessment (CA) may provide a complementary approach. We evaluated the prognostic value of TILs by VE and CA.
METHODS: TBCRC 030 was a randomized phase II trial enrolling patients with BRCA1/2-proficient stage I-III TNBC to receive preoperative cisplatin or paclitaxel. The primary endpoint was pathologic response at surgery. TILs were visually scored on digitized pre-treatment biopsies per International TILs Working Group recommendations. CA used the 4D QPOR platform to generate TILs, immune heterogeneity index (IHI), and a combined immune/cell cycle biomarker (CmbI). Predictive performance for residual cancer burden (RCB) 0/1 was assessed using ROC curves and odds ratios (ORs) with 95% CIs; all statistical tests were two-sided.
RESULTS: Of 139 response-evaluable patients, 121 had matched VE and CA data (59 cisplatin, 62 paclitaxel). Median VE TILs were higher in responders (40.0% vs. 10.0%, p = .002) and predicted response (OR 1.86, 95% CI 1.24-2.87, AUC 0.69, 95% CI 0.57-0.80). CA CmbI differed by response group and predicted RCB 0/1 (OR 3.20, 1.05-11.07; AUC 0.62, 0.51-0.73). CA TILs and IHI were not predictive. VE TILs and CA CmbI predicted response to paclitaxel (OR 2.91, 1.56-6.14; OR 9.17, 2.01-66.39, respectively), but not to cisplatin.
CONCLUSION: VE TILs and CA CmbI were each associated with response to NAC in TNBC in the overall cohort and the paclitaxel arm. CA CmbI did not outperform visual assessment. Further validation is needed before clinical implementation of computational approaches.
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Journal of Clinical Oncology
Randomized Phase II Trial of Pazopanib Versus Placebo in Patients with Advanced Extrapancreatic Neuroendocrine Tumors (Alliance A021202)
Meyerhardt JA
PURPOSE: Patients with advanced, well-differentiated extrapancreatic neuroendocrine tumors (epNETs) have limited systemic treatment options. Pazopanib, an oral multikinase inhibitor with activity against vascular
endothelial growth factor receptor (VEGFR)-2 and -3, PDGFR-alpha and-beta, and c-Kit, was tested for efficacy in epNET.
PATIENTS AND METHODS: We conducted a multicenter, randomized, double-blind, phase II study of pazopanib (800 mg once daily) versus placebo in low- to intermediate-grade epNET with radiologic progressive disease (PD) within 12 months of study entry. Previous somatostatin analog (SSA) was required for midgut tumors, and concurrent SSA was allowed. The primary end point was progression-free survival (PFS) by blinded independent central review. Unblinding and crossover were allowed if PD was confirmed by central review.
RESULTS: One hundred seventy-one patients (97 pazopanib and 74 placebo) were randomly assigned between September 2013 and October 2015. The majority had a midgut primary site (75%) and previous SSA treatment (93%). About half (49%) of the patients had functional tumors. The median follow-up was 61 months (95% CI, 60 to 63). Median PFS was 11.8 versus 7.6 months in pazopanib versus placebo, respectively (hazard ratio, 0.54 [95% CI, 0.37 to 0.79]; P < .001); 49 placebo patients crossed over to pazopanib. There was no significant difference in overall survival between the treatment arms. Rates of grade 3 or greater adverse events (regardless of attribution) were higher in pazopanib versus placebo (84% v 47%; P < .001), as were grade 5 death events (8% v 0%, P = .017).
CONCLUSION: Pazopanib compared with placebo significantly improves PFS in patients with progressive epNET, confirming that the VEGF signaling pathway is a valid target for therapy in epNET. However, after integrating the associated risks relative to the benefits, further development of pazopanib in this clinical context is not planned.
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Journal of Clinical Oncology
Second Mitochondrial Activator of Caspases Mimetics Accelerate Progression of Locally Advanced Head and Neck Cancer
Dougan M, Dougan SK
Resistance to apoptosis is a hallmark of cancer. Multiple nodes in the apoptosis pathway have been targeted for cancer therapy, including the inhibitor of apoptosis proteins (IAPs). In the Original Report by Bourhis et al1 that accompanies this article, a phase III trial of the IAP inhibitor xevinapant combined with chemoradiation for locally advanced squamous cell carcinoma of the head and neck (SCCHN) showed poorer outcomes in the experimental arm, necessitating a reassessment of the role of IAPs in human cancer.
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Journal of Clinical Oncology
Xevinapant or Placebo Plus Platinum-Based Chemoradiotherapy in Unresected Locally Advanced Squamous Cell Carcinoma of the Head and Neck (TrilynX): A Randomized, Phase III Study
Haddad R, Schoenfeld JD
PURPOSE: TrilynX was a randomized, double-blind, phase III study evaluating the addition of xevinapant (an inhibitor of apoptosis proteins inhibitor) or placebo to chemoradiotherapy (CRT) in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
METHODS: Patients with unresected LA SCCHN (oropharynx [p16-negative only], hypopharynx, or larynx) were randomly assigned 1:1 to six cycles of oral xevinapant 200 mg/day or matched placebo (once daily on Days 1-14 of a 21-day cycle) plus CRT for the first three cycles (cisplatin [100 mg/m2 once on Day 2 of every cycle] plus intensity-modulated radiotherapy [70 Gy; 35 fractions of 2 Gy/day, 5 days/week]). The primary end point was event-free survival (EFS) assessed by the blinded independent review committee. Progression-free survival, overall survival (OS), and safety were secondary end points.
RESULTS: Between September 20, 2020, and February 27, 2023, 730 patients were randomly assigned to xevinapant plus CRT (n = 364) or placebo plus CRT (n = 366). The median (95% CI) EFS was 19.4 months (14.5 to not estimable) with xevinapant and 33.1 months (21.0 to not estimable) with placebo (hazard ratio [HR], 1.33 [95% CI, 1.05 to 1.67]; P = .9919). OS was worse in the xevinapant arm (HR, 1.39 [95% CI, 1.04 to 1.86]). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 320 (87.9%; xevinapant) and 286 (80.3%; placebo) patients; anemia (78 [21.4%] v 51 [14.3%]) and neutropenia (71 [19.5%] v 69 [19.4%]) were the most common. Serious TEAEs occurred in 194 (53.3%; xevinapant) and 129 (36.2%; placebo) patients. TEAEs leading to death occurred in 22 (6.0%; xevinapant) and 13 (3.7%; placebo) patients.
CONCLUSION: Xevinapant plus CRT did not improve EFS (EFS was shorter with xevinapant v placebo) and demonstrated an unfavorable safety profile versus placebo plus CRT in patients with unresected LA SCCHN.
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Lancet Oncology
First-Line Immunotherapy with or without Chemotherapy Versus BRAF Plus MEK Inhibitors in BRAF(V600E)-Mutated Metastatic Non-Small-Cell Lung Cancer (FRONT-BRAF): A Multicentre, Retrospective Cohort Study
Di Federico A, Hambelton GM, Alessi JV, Pecci F, Wang X, Awad MM, Dagogo-Jack I, Johnson BE, Ricciuti B
BACKGROUND: Patients with BRAFV600E (ie, Val600Glu)-mutated non-small-cell lung cancer (NSCLC) can be treated with BRAF and mitogen-activated protein kinase (MEK) inhibitors, or with immune checkpoint inhibitors (ICIs) with or without chemotherapy. We aimed to investigate which initial systemic treatment should be prioritised in this population.
METHODS: In this retrospective cohort study conducted across 17 centres in the USA, Italy, France, and Brazil, clinicopathological data were collected from participants aged 18 years and older with stage IV, treatment-naive, metastatic BRAFV600E-mutated NSCLC and with an Eastern Cooperative Oncology Group performance status of 0-3, who started first-line treatment with ICIs with or without chemotherapy (PD-1 or PD-L1 inhibitors with or without platinum-based chemotherapy) or BRAF and MEK inhibitors (dabrafenib and trametinib or encorafenib and binimetinib) between Jan 2, 2015, and July 11, 2024. The primary endpoint was overall survival with first-line ICIs with or without chemotherapy versus with BRAF and MEK inhibitors.
FINDINGS: 284 participants were identified for this study, of whom 88 (31%) received ICIs with or without chemotherapy and 196 (69%) received BRAF and MEK inhibitors. The median age of participants was 68 years (IQR 61-74), and 148 (52%) participants were female and 136 (48%) male. Participants in the ICIs with or without chemotherapy group had a higher history of smoking (73 [83%] vs 118 [60%]; p=0·0002) and a higher PD-L1 expression (≥50% in 58 [66%] vs 76 [39%], 1-49% in 16 [18%] vs 67 [34%], and <1% in eight [9%] vs 31 [16%]; p=0·0003) than those in the BRAF and MEK inhibitor group. At a median follow-up time of 45·0 months (95% CI 39·0-55·7), ICIs with or without chemotherapy were associated with improved median overall survival compared with BRAF and MEK inhibitors (40·9 months [95% CI 33·3-not reached] vs 25·2 months [19·9-31·1]; hazard ratio [HR] 0·69 [0·49-0·98], p=0·039). In subgroup analyses, ICIs with or without chemotherapy, compared with BRAF and MEK inhibitors, were associated with longer median overall survival in participants with a history of smoking (HR 0·60 [0·40-0·90], p=0·013), with a PD-L1 tumour proportion score of ≥1% or higher (HR 0·66 [0·45-0·98], p=0·039), aged 70 years or older (HR 0·54 [0·31-0·94], p=0·029), with TP53 co-mutations (HR 0·46 [0·27-0·79], p=0·0048), and without brain metastases (HR 0·66 [0·45-0·99], p=0·045). With BRAF and MEK inhibitors, frequencies of adverse events of any grade and of grade 3 and higher were similar whether administered as first-line therapy or as second-line therapy following ICIs with or without chemotherapy.
INTERPRETATION: First-line ICIs with or without chemotherapy were associated with improved overall survival compared with BRAF and MEK inhibitors in participants with metastatic BRAFV600E-mutated NSCLC, particularly among specific subpopulations. These findings, although suggesting potential clinical relevance, remain exploratory and require confirmation from prospective studies.
FUNDING: NextGenerationEU.
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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, 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
Selective HLA Knockdown and PD-L1 Expression Prevent Allogeneic CAR-NK Cell Rejection and Enhance Safety and Anti-Tumor Responses in Xenograft Mice
Liu F, Tarannum M, Deng X, Nguyen M, Dinh K, Yang S, Ali AK, Choueiri TK, Ritz J, Romee R
Allogeneic cellular immunotherapy exhibits promising efficacy for cancer treatment, but donor cell rejection remains a major barrier. Here, we systematically evaluate human leukocyte antigens (HLA) and immune checkpoints PD-L1, HLA-E, and CD47 in the rejection of allogeneic NK cells and identify CD8+ T cells as the dominant cell type mediating allorejection. We demonstrate that a single gene construct that combines an shRNA that selectively interferes with HLA class I but not HLA-E expression, a chimeric antigen receptor (CAR), and PD-L1 or single-chain HLA-E (SCE) enables the one-step construction of allogeneic CAR-NK cells that evade host-mediated rejection both in vitro and in a xenograft mouse model. Furthermore, CAR-NK cells overexpressing PD-L1 or SCE effectively kill tumor cells through the upregulation of cytotoxic genes and reduced exhaustion and exhibit a favorable safety profile due to the decreased production of inflammatory cytokines involved in cytokine release syndrome. Thus, our approach represents a promising strategy in enabling "off-the-shelf" allogeneic cellular immunotherapies.
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Nature Genetics
Rapid Epigenomic Classification of Acute Leukemia
Steinicke TL, Benfatto S, Capilla-Guerra MR, Monteleone AB, Young JH, Shankar S, Michaels PD, Tsai HK, Good JD, Kreso A, van Galen P, Schliemann C, Chen EC, Griffin GK, Hovestadt V
Acute leukemia requires precise molecular classification and urgent treatment. However, standard-of-care diagnostic tests are time-intensive and do not capture the full spectrum of acute leukemia heterogeneity. Here, we developed a framework to classify acute leukemia using genome-wide DNA methylation profiling. We first assembled a comprehensive reference cohort (n = 2,540 samples) and defined 38 methylation classes. Methylation-based classification matched standard-pathology lineage classification in most cases and revealed heterogeneity in addition to that captured by genetic categories. Using this reference, we developed a neural network (MARLIN; methylation- and AI-guided rapid leukemia subtype inference) for acute leukemia classification from sparse DNA methylation profiles. In retrospective cohorts profiled by nanopore sequencing, high-confidence predictions were concordant with conventional diagnoses in 25 out of 26 cases. Real-time MARLIN classification in patients with suspected acute leukemia provided accurate predictions in five out of five cases, which were typically generated within 2 h of sample receipt. In summary, we present a framework for rapid acute leukemia classification that complements and enhances standard-of-care diagnostics.
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Proceedings of the National Academy of Sciences of the U.S.A.
Small-Molecule Allosteric Activator of Ubiquitin-Specific Protease 7 (USP7)
Jaen Maisonet I, Sharafi M, Salazar-Chaparro A, Bratt AS, Varca AC, Shah B, Darnowski M, Chung M, Teh WP, Che J, Buhrlage SJ
Ubiquitin-specific protease 7 (USP7) is a deubiquitylase essential for cell homeostasis, DNA repair, and regulation of both tumor suppressors and oncogenes. Recently, haploinsufficiency of USP7 has been associated with Hao-Fountain syndrome (HAFOUS), a rare neurodevelopmental disorder. Although a range of USP7 inhibitors have been developed over the last decade, in the context of HAFOUS, USP7 activators may represent a more relevant approach. To address this challenge, we report the identification and characterization of a small-molecule activator of USP7 called MS-8. Structural and functional studies show that MS-8 allosterically activates USP7, mimicking the endogenous autoactivation mechanism of the enzyme. We observed that MS-8 engages and activates mutant USP7 in a cellular context, impacting downstream proteins. Taken together, our study provides validation of the USP7 activator that paves the way toward activation-driven USP7 pharmacology.
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Blood Advances
Long-Term Follow-Up of Venetoclax Monotherapy in Previously Treated Patients with Waldenström Macroglobulinemia
Castillo JJ, Guijosa A, Flynn CA, Meid K, Budano N, Nguyen J, Tsakmaklis N, Hunter ZR, Patterson CJ, Treon SP, Sarosiek S
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Cell Reports Medicine
Pan-Cancer Spatial Characterization of Key Immune Biomarkers in the Tumor Microenvironment
Lindsay JR, Altreuter J, Alessi JV, Weirather JL, Giobbie-Hurder A, Dryg I, Hoebel K, Sharma B, Felt K, Hodi FS, Lindeman N, Sholl LM, Cerami E, Nowak JA, Awad MM, Rodig SJ, Lotter W
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Clinical Cancer Research
Elraglusib, a Glycogen Synthase Kinase-3β (GSK-3β) Inhibitor, Plus Chemotherapy with or without Immunotherapy in Patients with Recurrent, Metastatic Salivary Gland Carcinoma
Hanna GJ, Scarfo N, Shin KY, O'Neill A, Bedard V, Dennis MJ, Sehgal K, Jo VY, Wong K, Haddad RI
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EMBO Reports
p300/CBP is an Essential Driver of Pathogenic Enhancer Activity and Gene Expression in Ewing Sarcoma
Godfrey LC, Regalado B, Schweber SR, Hatton C, Wenge DV, Wen Y, Boileau M, Wessels M, Qi J, Ott CJ, Stegmaier K, Rivera MN, Armstrong SA
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Journal of Cardiac Failure
Implementing HeartPal: Design and Early Results of a Specialized Care Delivery Model for Advancing Palliative Care in Advanced Heart Disease Populations
Jain N, Santo EC, Lehto HR, Schaefer KG, Manning KA, Landzberg MJ, Warraich HJ, Givertz MM, Mehra MR, Tulsky JA, Desai AS
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Journal of Clinical Medicine
Preliminary Efficacy/Feasibility Study of a Breast Cancer-Related Lymphedema Prospective Screening and Early Intervention Program at the Dana-Farber Brigham Cancer Center
Myers SP, Jasper JM, Higgins T, Serig A, Faust AC, Tappan LJ, Nakhlis F, Taylor EM, Agarwal S, Mittendorf EA, King TA
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Leukemia
Combining MCL-1 Inhibition and CD37-Directed Chimeric Antigen Receptor T Cells as an Effective Strategy to Target T-Cell Lymphoma
Heavican-Foral TB, Korell F, Scarfò I, Wiggers CRM, B AT, Eisenbies Z, Powers F, Hegel J, Liu J, Kulp S, Silva H, Wu G, Letai A, Stegmaier K, Lohr JG, Weinstock DM, Maus MV, Knoechel B
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Leukemia
Rare Germline Variant in NFATC4 Associated with Familial CLL
Itchaki G, Bai H, Tiao G, Improgo R, Oppenheimer BE, Kasar S, Tesar B, Fernandes SM, Pochet N, Machado JH, Thrash EM, Freedman AS, Getz G, Brown JR
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Nature Cardiovascular Research
Cardiac Adaptation to Endurance Exercise Training Requires Suppression of GDF15 Via PGC-1α
Khetarpal SA, Li H, Vitale T, Rhee J, Challa S, Castro C, Pabel S, Sun Y, Liu J, Bogoslavski D, Vargas-Castillo A, Smythers AL, Blackmore KA, Grauvogel L, Mittenbühler MJ, Khandekar MJ, Curtin C, Narvaez-Paliza JM, Wang C, Houstis NE, Sprenger HG, Jurgens SJ, Biddinger KJ, Kuznetsov A, Freeman R, Ellinor PT, Nahrendorf M, Paulo JA, Gygi SP, Dumesic PA, Asnani A, Aragam KG, Puigserver P, Roh JD, Spiegelman BM
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Neuro-Oncology
Clinical, Molecular, and Radiological Predictors of Prognosis in Newly Diagnosed Astrocytoma, IDH-Mutant, WHO Grade 4
Lasica AB, Lan Z, Miller JJ, Jiao A, Pan I, Aker L, Prabhakar P, Japo J, Russ A, Westergaard C, Aquilanti E, Chukwueke U, Gonzalez Castro LN, Lee EQ, Nayak L, Beroukhim R, Batchelor TT, Cahill DP, Nakhate V, Lanman T, Pablo Ospina J, Stec N, Patel RV, Meredith DM, Bi WL, Reardon DA, Ligon KL, Huang RY, Wen PY, Youssef G
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Oncologist
Domains of Prognostic Awareness, Quality of Life, and Psychological Distress in Patients with Advanced Cancer
Amonoo HL, Keane EP, Greer JA, Lindenberger EC, Ufere NN, Temel JS, Park ER, Jackson V, El-Jawahri A
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Oral Oncology
Financial Instability, Insurance, and Transportation Influence Timely Head and Neck Cancer Care in the United States: Patient and Healthcare Worker Perspectives
Batool S, Hansen EE, Sethi RKV, Rettig EM, Goguen LA, Annino DJ, Uppaluri R, Faden DL, Ortega G, Dohan D, Reich AJ, Bergmark RW
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Stem Cell Reports
Satellite Glial Contact Enhances Differentiation and Maturation of Human iPSC-Derived Sensory Neurons
LeBlang CJ, Pazyra-Murphy MF, Silagi ES, Dasgupta S, Tsolias M, Miller T, Petrova V, Zhen S, Woolf CJ, Tasdemir-Yilmaz O, Segal RA
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