Cell
Anti-LAG-3 Boosts CD8 T Cell Effector Function
Kureshi CT, Dougan M, Dougan SK
LAG-3 is the third immune checkpoint pathway successfully targeted for cancer therapy. Although ineffective as a monotherapy, combination of LAG-3 and PD-1 blockade improves survival from advanced melanoma. In this issue of Cell, two studies in mice and a human clinical trial provide insights on LAG-3 in immune regulation.
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Cancer Cell
Mammalian SWI/SNF Complex Activity Regulates POU2F3 and Constitutes a Targetable Dependency in Small Cell Lung Cancer
Duplaquet L, So K, Ying AW, Li X, Xu GD, Li Y, Qiu X, Li R, Singh S, Liu Q, Qi J, Heiling HM, Mazzola E, Lee Y, Doench JG, Long HW, Kadoch C, Oser MG
Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ?12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.
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Cancer Discovery
Activating Point Mutations in the MET Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors
Pecci F, Nakazawa S, Ricciuti B, Alessi JV, Barrichello A, Vaz VR, Lamberti G, Di Federico A, Gandhi MM, Gazgalis D, Feng WW, Jiang J, Baldacci S, Locquet MA, Gottlieb FH, Lee E, Haradon D, Smokovich A, Voligny E, Nguyen T, Wang X, Bahcall M, Heist RS, Iqbal S, Che J, Jänne PA, Awad MM
Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ?0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.
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JAMA Oncology
Breast Cancer Index in Premenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer
Regan MM
IMPORTANCE: Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking.
OBJECTIVE: To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022.
MAIN OUTCOMES AND MEASURES: Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses.
RESULTS: Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction?=?.006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction?=?.11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n?=?1110; P?=?.004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively.
CONCLUSIONS AND RELEVANCE: In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.
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JAMA Oncology
Hypofractionated vs Conventionally Fractionated Postmastectomy Radiation After Implant-Based Reconstruction: A Randomized Clinical Trial
Wong JS, Uno H, Tramontano AC, Fisher L, Pellegrini CV, Abel GA, Burstein HJ, Chun YS, King TA, Bellon JR, Recht A, Soto DE, Shiloh RY, Taghian AG, Warren LE, Punglia RS
IMPORTANCE: Postmastectomy radiation therapy (PMRT) improves local-regional disease control and patient survival. Hypofractionation (HF) regimens have comparable efficacy and complication rates with improved quality of life compared with conventional fractionation (CF) schedules. However, the use of HF after mastectomy in patients undergoing breast reconstruction has not been prospectively examined.
OBJECTIVE: To compare HF and CF PMRT outcomes after implant-based reconstruction.
DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial assessed patients 18 years or older undergoing mastectomy and immediate expander or implant reconstruction for breast cancer (Tis, TX, or T1-3) and unilateral PMRT from March 8, 2018, to November 3, 2021 (median [range] follow-up, 40.4 [15.4-63.0] months), at 16 US cancer centers or hospitals. Analyses were conducted between September and December 2023.
INTERVENTIONS: Patients were randomized 1:1 to HF or CF PMRT. Chest wall doses were 4256 cGy for 16 fractions for HF and 5000 cGy for 25 fractions for CF. Chest wall toxic effects were defined as a grade 3 or higher adverse event.
MAIN OUTCOMES AND MEASURES: The primary outcome was the change in physical well-being (PWB) domain of the Functional Assessment of Cancer Therapy-Breast (FACT-B) quality-of-life assessment tool at 6 months after starting PMRT, controlling for age. Secondary outcomes included toxic effects and cancer recurrence.
RESULTS: Of 400 women (201 in the CF arm and 199 in the HF arm; median [range] age, 47 [23-79] years), 330 patients had PWB scores at baseline and at 6 months. There was no difference in the change in PWB between the study arms (estimate, 0.13; 95% CI, -0.86 to 1.11; P?=?.80), but there was a significant interaction between age group and study arm (P?=?.03 for interaction). Patients younger than 45 years had higher 6-month absolute PWB scores if treated with HF rather than CF regimens (23.6 [95% CI, 22.7-24.6] vs 22.0 [95% CI, 20.7-23.3]; P?=?.047) and reported being less bothered by adverse effects (mean [SD], 3.0 [0.9] in the HF arm and 2.6 [1.2] in the CF arm; P?=?.02) or nausea (mean [SD], 3.8 [0.4] in the HF arm and 3.6 [0.8] in the CF arm; P?=?.04). In the as-treated cohort, there were 23 distant (11 in the HF arm and 12 in the CF arm) and 2 local-regional (1 in the HF arm and 1 in the CF arm) recurrences. Chest wall toxic effects occurred in 39 patients (20 in the HF arm and 19 in the CF arm) at a median (IQR) of 7.2 (1.8-12.9) months. Fractionation was not associated with chest wall toxic effects on multivariate analysis (HF arm: hazard ratio, 1.02; 95% CI, 0.52-2.00; P?=?.95). Fewer patients undergoing HF vs CF regimens had a treatment break (5 [2.7%] vs 15 [7.7%]; P?=?.03) or required unpaid time off from work (17 [8.5%] vs 34 [16.9%]; P?=?.02).
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the HF regimen did not significantly improve change in PWB compared with the CF regimen. These data add to the increasing experience with HF PMRT in patients with implant-based reconstruction.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03422003.
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JAMA Oncology
When Best Care Takes a Back Seat to the Bottom Line
Leeman JE, Han Z, Haas-Kogan DA
Within the last decade, an elegant radiotherapy system was developed that incorporated a low-field magnetic resonance imaging (MRI) scanner together with a linear accelerator (MR-linac) for cancer treatment. This technologic synergy, which was produced by ViewRay, proved to be transformative, as for the first time since the advent of radiotherapy, real-time MRI-guided radiotherapy (MRgRT) allowed the physician to visualize the tumor and surrounding anatomy while the patient was actively receiving radiotherapy. The result was a paradigm shift in the precision of radiotherapy, providing much greater confidence and unprecedented accuracy, particularly for tumors in sensitive or mobile locations. The MRgRT system was adopted by more than 60 centers, including the Dana-Farber Brigham Cancer Center, where we began using this technology in 2019.
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Journal of Clinical Oncology
Circulating Tumor DNA Assay Detects Merkel Cell Carcinoma Recurrence, Disease Progression, and Minimal Residual Disease: Surveillance and Prognostic Implications
Thakuria M, Silk AW, Kim EY
PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a 40% recurrence rate, lacking effective prognostic biomarkers and surveillance methods. This prospective, multicenter, observational study aimed to evaluate circulating tumor DNA (ctDNA) as a biomarker for detecting MCC recurrence.
METHODS: Plasma samples, clinical data, and imaging results were collected from 319 patients. A tumor-informed ctDNA assay was used for analysis. Patients were divided into discovery (167 patients) and validation (152 patients) cohorts. Diagnostic performance, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed.
RESULTS: ctDNA showed high sensitivity, 95% (discovery; 95% CI, 87 to 99) and 94% (validation; 95% CI, 85 to 98), for detecting disease at enrollment, with corresponding specificities of 90% (95% CI, 82 to 95) and 86% (95% CI, 77 to 93). A positive ctDNA during surveillance indicated increased recurrence risk, with hazard ratios (HRs) of 6.8 (discovery; 95% CI, 2.9 to 16) and 20 (validation; 95% CI, 8.3 to 50). The PPV for clinical recurrence at 1 year after a positive ctDNA test was 69% (discovery; 95% CI, 32 to 91) and 94% (validation; 95% CI, 71 to 100), respectively. The NPV at 135 days after a negative ctDNA test was 94% (discovery; 95% CI, 90 to 97) and 93% (validation; 95% CI, 89 to 97), respectively. Patients positive for ctDNA within 4 months after treatment had higher rates of recurrence, with 1-year rates of 74% versus 21% (adjusted HR, 7.4 [95% CI, 2.7 to 20]).
CONCLUSION: ctDNA testing exhibited high prognostic accuracy in detecting MCC recurrence, suggesting its potential to reduce frequent surveillance imaging. ctDNA also identifies high-risk patients who need more frequent imaging and may be best suited for adjuvant therapy trials.
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Journal of Clinical Oncology
Overcoming Systemic Barriers to Make Patient-Partnered Research a Reality
Venkataraman V, Salmi L, Claus EB, Diehl D, Janeway KA, Mack JW, George S
Direct participant engagement in research, defined as involving ongoing, bidirectional, and mutually beneficial interactions among participants and researchers where participants are included as an integral part throughout the research process, is critical for cancer research and a central tenet of the Cancer Moonshot. As described by the National Cancer Institute (NCI), engaging patients and the public in cancer research is critical to understanding the biology of cancer, how to prevent and treat it, and how to deliver care to all people with cancer.
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Journal of Clinical Oncology
Plasma Kidney Injury Molecule-1 for Preoperative Prediction of Renal Cell Carcinoma Versus Benign Renal Masses, and Association with Clinical Outcomes
Xu W, Niman SM, Liu X, Maremanda KP, Takakura A, Freedman ML, Xie W, McDermott DF, Choueiri TK, Catalano PJ, Sabbisetti V, Bonventre JV, Bhatt RS
PURPOSE: Both clear cell and papillary renal cell carcinomas (RCCs) overexpress kidney injury molecule-1 (KIM-1). We investigated whether plasma KIM-1 (pKIM-1) may be a useful risk stratification tool among patients with suspicious renal masses.
METHODS: Prenephrectomy pKIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have clear cell RCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository, of whom 184 had RCC. We assessed the relationship between pKIM-1, surgical pathology, and clinical outcomes.
RESULTS: In Cohort 1, pKIM-1 distinguished RCC versus benign masses with area under the receiver operating curve (AUC-ROC, 0.81 [95% CI, 0.76 to 0.86]). In Cohort 2 (cT1a only), pKIM-1 distinguished RCC versus benign masses (AUC-ROC, 0.74 [95% CI, 0.67 to 0.80]) and the addition of pKIM-1 to an established nomogram for predicting malignancy improved the model AUC-ROC (0.65 [95% CI, 0.57 to 0.74] v 0.78 [95% CI, 0.72 to 0.85]). A pKIM-1 cutpoint identified using Cohort 2 demonstrated sensitivity of 92.5% and specificity of 60% for identifying RCC in Cohort 1. In long-term follow-up of RCC cases (Cohort 1), higher prenephrectomy pKIM-1 was associated with worse metastasis-free survival (multivariable MFS hazard ratio [HR] 1.29 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.53) and overall survival (multivariable OS HR 1.31 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.54). In long-term follow-up of Cohort 2, no metastatic events occurred, consistent with the favorable prognosis of resected cT1a RCC.
CONCLUSION: Among patients with renal masses, pKIM-1 is associated with malignant pathology, worse MFS, and risk of death. pKIM-1 may be useful for selecting patients with renal masses for intervention versus surveillance.
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Journal of the National Cancer Institute
TP53-Associated Early Breast Cancer: New Observations from a Large Cohort
Sandoval RL, Tianyu L, Bychkovsky BL, Cahill S, Tayob N, Garber JE
BACKGROUND: A recent large, well-annotated international cohort of patients with Li-Fraumeni syndrome and early-stage breast cancer was examined for shared features.
METHODS: This multicenter cohort study included women with a germline TP53 pathogenic or likely pathogenic variant and nonmetastatic breast cancer diagnosed between 2002 and 2022. Clinical and genetic data were obtained from institutional registries and clinical charts. Descriptive statistics were used to summarize proportions, and differences were assessed using ?2 or Wilcoxon rank sum tests. Metachronous contralateral breast cancer risk, radiation-induced sarcoma risk, and recurrence-free survival were analyzed using the Kaplan-Meier methodology.
RESULTS: Among 227 women who met study criteria, the median age of first breast cancer diagnosis was 37?years (range?=?21-71), 11.9% presented with bilateral synchronous breast cancer, and 18.1% had ductal carcinoma in situ only. In total, 166 (73.1%) patients underwent mastectomies, including 67 bilateral mastectomies as first breast cancer surgery. Among those patients with retained breast tissue, the contralateral breast cancer rate was 25.3% at 5 years. Among 186 invasive tumors, 72.1% were stages I to II, 48.9% were node negative, and the most common subtypes were hormone receptor-positive/HER2-negative (40.9%) and hormone receptor positive/HER2 positive (34.4%). At a median follow-up of 69.9?months (interquartile range?=?32.6-125.9), invasive hormone receptor-positive/HER2-negative disease had the highest recurrence risk among the subtypes (5-year recurrence-free survival?=?61.1%, P?=?.001). Among those who received radiation therapy (n?=?79), the 5-year radiation-induced sarcoma rate was 4.8%.
CONCLUSION: We observed high rates of ductal carcinoma in situ, hormone receptor-positive, and HER2-positive breast cancers, with a worse outcome in the hormone receptor-positive/HER2-negative luminal tumors, despite appropriate treatment. Confirmation of these findings in further studies could have implications for breast cancer care in those with Li-Fraumeni syndrome.
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Nature Chemical Biology
Covalent Inhibition of Pro-Apoptotic BAX
McHenry MW, Shi P, Camara CM, Cohen DT, Adhikary U, Gygi MA, Yang K, Gygi SP, Walensky LD
BCL-2-associated X protein (BAX) is a promising therapeutic target for activating or restraining apoptosis in diseases of pathologic cell survival or cell death, respectively. In response to cellular stress, BAX transforms from a quiescent cytosolic monomer into a toxic oligomer that permeabilizes the mitochondria, releasing key apoptogenic factors. The mitochondrial lipid trans-2-hexadecenal (t-2-hex) sensitizes BAX activation by covalent derivatization of cysteine 126 (C126). In this study, we performed a disulfide tethering screen to discover C126-reactive molecules that modulate BAX activity. We identified covalent BAX inhibitor 1 (CBI1) as a compound that selectively derivatizes BAX at C126 and inhibits BAX activation by triggering ligands or point mutagenesis. Biochemical and structural analyses revealed that CBI1 can inhibit BAX by a dual mechanism of action: conformational constraint and competitive blockade of lipidation. These data inform a pharmacologic strategy for suppressing apoptosis in diseases of unwanted cell death by covalent targeting of BAX C126.
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Nature Communications
Clinical Outcomes and ctDNA Correlates for CAPOX BETR: A Phase II Trial of Capecitabine, Oxaliplatin, Bevacizumab, Trastuzumab in Previously Untreated Advanced HER2+ Gastroesophageal Adenocarcinoma
Singh H, Lowder KE, Kapner K, Zheng H, McCleary NJ, Abrams TA, Chan JA, Regan EM, Klempner SJ, Hannigan AM, Remland J, Brais LK, Andrews E, Yurgelun M, Cleary JM, Rubinson DA, Ritterhouse LL, Maron G, Aguirre AJ, Meyerhardt JA, Gardecki E, Lennerz JK, Wolpin BM, Enzinger PC
Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.
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Nature Communications
End-to-End Reproducible AI Pipelines in Radiology Using the Cloud
Bontempi D, Nuernberg L, Pai S, Krishnaswamy D, Thiriveedhi V, Hosny A, Mak RH, Kikinis R, Fedorov A, Aerts HJWL
Artificial intelligence (AI) algorithms hold the potential to revolutionize radiology. However, a significant portion of the published literature lacks transparency and reproducibility, which hampers sustained progress toward clinical translation. Although several reporting guidelines have been proposed, identifying practical means to address these issues remains challenging. Here, we show the potential of cloud-based infrastructure for implementing and sharing transparent and reproducible AI-based radiology pipelines. We demonstrate end-to-end reproducibility from retrieving cloud-hosted data, through data pre-processing, deep learning inference, and post-processing, to the analysis and reporting of the final results. We successfully implement two distinct use cases, starting from recent literature on AI-based biomarkers for cancer imaging. Using cloud-hosted data and computing, we confirm the findings of these studies and extend the validation to previously unseen data for one of the use cases. Furthermore, we provide the community with transparent and easy-to-extend examples of pipelines impactful for the broader oncology field. Our approach demonstrates the potential of cloud resources for implementing, sharing, and using reproducible and transparent AI pipelines, which can accelerate the translation into clinical solutions.
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Nature Communications
Lineage-Specific Canonical and Non-Canonical Activity of EZH2 in Advanced Prostate Cancer Subtypes
Venkadakrishnan VB, Presser AG, Booker MA, Traphagen NA, Weng K, Voss NCE, Mahadevan NR, Mizuno K, Idahor O, Ku SY, Bakht MK, Borah AA, Herbert ZT, Tolstorukov MY, Barbie DA, Brown M, Beltran H
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.
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Nature Communications
53BP1 Loss Elicits cGAS-STING-Dependent Antitumor Immunity in Ovarian and Pancreatic Cancer
Sun Y, Patterson-Fortin J, Han S, Li Z, Hirohashi Y, Kilgas S, Yi JK, Spektor A, Fendler W, Konstantinopoulos PA, Chowdhury D
53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the 'leaky' DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.
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Proceedings of the National Academy of Sciences of the U.S.A.
Reconstruction of Single-Cell Lineage Trajectories and Identification of Diversity in Fates During the Epithelial-to-Mesenchymal Transition
Cheng YC, McDonald TO, Michor F
Exploring the complexity of the epithelial-to-mesenchymal transition (EMT) unveils a diversity of potential cell fates; however, the exact timing and mechanisms by which early cell states diverge into distinct EMT trajectories remain unclear. Studying these EMT trajectories through single-cell RNA sequencing is challenging due to the necessity of sacrificing cells for each measurement. In this study, we employed optimal-transport analysis to reconstruct the past trajectories of different cell fates during TGF-beta-induced EMT in the MCF10A cell line. Our analysis revealed three distinct trajectories leading to low EMT, partial EMT, and high EMT states. Cells along the partial EMT trajectory showed substantial variations in the EMT signature and exhibited pronounced stemness. Throughout this EMT trajectory, we observed a consistent downregulation of the EED and EZH2 genes. This finding was validated by recent inhibitor screens of EMT regulators and CRISPR screen studies. Moreover, we applied our analysis of early-phase differential gene expression to gene sets associated with stemness and proliferation, pinpointing ITGB4, LAMA3, and LAMB3 as genes differentially expressed in the initial stages of the partial versus high EMT trajectories. We also found that CENPF, CKS1B, and MKI67 showed significant upregulation in the high EMT trajectory. While the first group of genes aligns with findings from previous studies, our work uniquely pinpoints the precise timing of these upregulations. Finally, the identification of the latter group of genes sheds light on potential cell cycle targets for modulating EMT trajectories.
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Blood Advances
Inhibition of MICA and MICB Shedding Enhances Memory-Like NK Cell-Mediated Cytotoxicity Against Multiple Myeloma
Tahri S, Piccinelli S, Su NK, Dong H, Vergara Cadavid J, Lightbody ED, Cao A, Alberge JB, Rahmat M, Getz G, Wucherpfennig KW, Ghobrial IM, Romee R
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Blood Advances
Venetoclax Resistance Leads to Broad Resistance to Standard-of-Care Anti-MM Agents, but not to Immunotherapies
Deng S, Derebail S, Weiler VJ, Fong Ng J, Maroto-Martin E, Chatterjee M, Giorgetti G, Chakraborty C, Kalhotra P, Du T, Yao Y, Prabhala R, Shammas M, Gulla A, Aktas Samur A, Samur MK, Anderson KC, Fulciniti M, Munshi NC
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Clinical Cancer Research
Integrative Multi-Omic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies
Jovanovic B, Richardson ET, DiLullo M, Attaya V, Kasparian J, Mohammed-Abreu A, Kirkner G, Hughes ME, Lin NU, Mittendorf EA, Schnitt SJ, Tolaney SM
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Clinical Cancer Research
Personalized ctDNA for Monitoring Disease Status in Head and Neck Squamous Cell Carcinoma
Hanna GJ, Dennis MJ, Scarfo N, Mullin MS, Sethi RKV, Sehga K, Annino DJ Jr, Goguen LA, Haddad RI, Tishler RB, Margalit DN, Uppaluri R, Schoenfeld JD, Rettig EM
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Expert Review of Hematology
Targeting Ikaros and Aiolos: Reviewing Novel Protein Degraders for the Treatment of Multiple Myeloma, with a Focus on Iberdomide and Mezigdomide
Liu Y, Mo CC, Hartley-Brown MA, Sperling AS, Midha S, Yee AJ, Bianchi G, Piper C, Tattersall A, Nadeem O, Laubach JP, Richardson PG
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Hematology Oncology Clinics of North America
Ductal Carcinoma In Situ
Bychkovsky BL, Myers S, Warren LEG, De Placido P, Parsons HA
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