Blood
Abatacept for Acute Graft-Versus-Host Disease Prophylaxis After Unrelated Donor Hematopoietic Cell Transplantation
Kean LS, Bratrude B, Betz K
Abatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first FDA-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URD-HCT). We investigated its impact in URD-HCT patients using Center for International Blood and Marrow Transplant Research data for 7/8-human leukocyte antigen (HLA)-mismatched (MMUD) or 8/8-HLA-matched (MUD) URD-HCT recipients between 2011-2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapse-free survival (RFS) for abatacept+CNI/MTX vs CNI/MTX, CNI/MTX+antithymocyte globulin (ATG), and post-transplant cyclophosphamide-based prophylaxis (PT-Cy); other outcomes included aGVHD, chronic GVHD, non-relapse mortality, and relapse. For 7/8-MMUDs, day-180 OS (primary endpoint supporting FDA approval) was significantly higher for abatacept+CNI/MTX vs CNI/MTX (98%vs75%; p=0.0028). Two-year OS was significantly higher for abatacept+CNI/MTX vs CNI/MTX (83%vs55%; p=0.0036), CNI/MTX+ATG (83%vs46%; p=0.0005) and similar to PT-Cy (80%vs68%; p=0.2325). Two-year RFS was significantly higher for abatacept+CNI/MTX vs CNI/MTX (74%vs49%; p=0.0098) and CNI/MTX+ATG (77%vs35%; p=0.0002), and similar vs PT-Cy (72%vs56%; p=0.1058). For 8/8-MUDs, 2-year OS was similar with abatacept+CNI/MTX vs CNI/MTX (70%vs62%; p=0.2569), CNI/MTX+ATG (75%vs64%; p=0.1048), and PT-Cy (74%vs69%; p=0.5543). Two-year RFS for abatacept+CNI/MTX was numerically higher vs CNI/MTX (63%vs52%; p=0.1497) with an improved hazard ratio (HR: 0.46 [0.25-0.86]), and vs CNI/MTX+ATG (66%vs55%; p=0.1193; HR: 0.39 [0.21-0.73]). Two-year RFS was similar vs PT-Cy (68%vs57%; p=0.2356; HR: 0.54 [0.26-1.11]). For both 7/8-MMUD and 8/8-MUD recipients, abatacept+CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX+ATG; outcomes were similar to PT-Cy-based regimens. Abatacept+CNI/MTX has potential to facilitate unrelated donor pool expansion for HCT.
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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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Gastroenterology
Taming Lynch Syndrome: The Remarkable Power of Prevention for One Family
Yurgelun MB
Up until the late twentieth century, familial adenomatous polyposis was the only widely accepted form of inherited colorectal cancer (CRC) susceptibility. Familial colorectal cancer (CRC) without polyposis was initially reported by Warthin in the early 1900s. Decades later, Lynch and Krush identified additional similar families and followed up the progeny of Warthin’s family, coining the term “Cancer Family Syndrome”, and later “hereditary nonpolyposis CRC” (HNPCC). In spite of such reports, however, there remained considerable skepticism about the existence of HNPCC, with such familial CRC clustering often attributed to statistical chance or other etiologies such as oncogenic viruses. The linkage of HNPCC to the microsatellite instability (MSI) mutational signature and defective DNA mismatch repair (MMR) function in 1993, however, quickly led to the discovery of four MMR genes, and germline pathogenic variants (PVs) which were confirmed to cause HNPCC, now known as Lynch syndrome (LS).
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Journal of Clinical Oncology
Elective Pelvic Lymph Node Radiation Therapy and the Risk of Death in Patients with Unfavorable-Risk Prostate Cancer: A Postrandomization Analysis
Sayan M, Loffredo M, McMahon E, Moningi S, Orio PF, Nguyen PL, D'Amico AV
PURPOSE: Although a contemporary randomized clinical trial has led to the use of whole-pelvic radiation therapy (WPRT), long-term data evaluating a potential reduction in mortality are lacking and are addressed in the current study.
MATERIALS AND METHODS: From 2005 to 2015, 350 men with localized, unfavorable-risk prostate cancer (PC) were randomly assigned to receive androgen deprivation therapy (ADT) and RT plus docetaxel versus ADT and RT. Treatment of the pelvic lymph nodes was at the discretion of the treating physician. Multivariable Cox and Fine and Grays regression analyses were performed to assess whether a significant association existed between radiation treatment volume and all-cause mortality (ACM) and PC-specific mortality (PCSM), respectively, adjusting for known PC prognostic factors and comorbidity. An interaction term between age (categorized by dichotomization at 65 years to enable clinical interpretation and applicability of the results and which approximates the median (66 years [IQR, 61-70]) and radiation treatment volume was included in the analysis.
RESULTS: After a median follow-up of 10.20 years (IQR, 7.96-11.41), 89 men died (25.43%); of these, 42 died of PC (47.19%). Of the 350 randomly assigned patients, 88 (25.14%) received WPRT. In men younger than 65 years, WPRT was associated with a significantly lower ACM risk (adjusted hazard ratio [AHR], 0.33 [95% CI, 0.11 to 0.97]; P = .04) and lower PCSM risk (AHR, 0.17 [95% CI, 0.02 to 1.35]; P = .09) after adjusting for covariates, whereas this was not the case for men 65 years or older.
CONCLUSION: WPRT has the potential to reduce mortality in younger men with unfavorable-risk PC.
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JAMA Oncology
Immunotherapy Before Chemoradiotherapy-More Is Better?
Florez N
In early 2018, the PACIFIC trial regimen was approved by the US Food and Drug Administration before many immune checkpoint inhibitors (ICIs) were approved for first-line treatment of metastatic non–small cell lung cancer (NSCLC). In this trial, patients with unresectable stage III NSCLC received durvalumab for 1 year after chemoradiation therapy (CRT). This changed the disease’s paradigm with a considerably improved overall survival. However, no further research in this space had occurred until more recently; the once very debated stage III disease was dormant when advances were occurring in early-stage and genomic-driven NSCLC.
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Molecular Cell
The Splicing Factor CCAR1 Regulates the Fanconi Anemia/BRCA Pathway
Harada N, Asada S, Jiang L, Nguyen H, Moreau L, Marina RJ, Adelman K, Iyer DR, D'Andrea AD
The twenty-three Fanconi anemia (FA) proteins cooperate in the FA/BRCA pathway to repair DNA interstrand cross-links (ICLs). The cell division cycle and apoptosis regulator 1 (CCAR1) protein is also a regulator of ICL repair, though its possible function in the FA/BRCA pathway remains unknown. Here, we demonstrate that CCAR1 plays a unique upstream role in the FA/BRCA pathway and is required for FANCA protein expression in human cells. Interestingly, CCAR1 co-immunoprecipitates with FANCA pre-mRNA and is required for FANCA mRNA processing. Loss of CCAR1 results in retention of a poison exon in the FANCA transcript, thereby leading to reduced FANCA protein expression. A unique domain of CCAR1, the EF hand domain, is required for interaction with the U2AF heterodimer of the spliceosome and for excision of the poison exon. Taken together, CCAR1 is a splicing modulator required for normal splicing of the FANCA mRNA and other mRNAs involved in various cellular pathways.
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Nature Biotechnology
A CAR Enhancer Increases the Activity and Persistence of CAR T Cells
Rakhshandehroo T, Mantri SR, Moravej H, Louis BBV, Salehi Farid A, Munaretto L, Khan RMM, Wolff A, Farkash Z, Cong M, Kuhnast A, Nili A, Lee UJ, Allen HH, Berland L, Simkova E, Uslu SC, Tavakolpour S, Rowley JE, Codet E, Shahbazian H, Baral J, Pyrdol J, Jacobson CA, Nadeem O, Wucherpfennig KW, Rashidian M
Although chimeric antigen receptor (CAR) T cell therapies have demonstrated promising clinical outcomes, durable remissions remain limited. To extend the efficacy of CAR T cells, we develop a CAR enhancer (CAR-E), comprising a CAR T cell antigen fused to an immunomodulatory molecule. Here we demonstrate this strategy using B cell maturation antigen (BCMA) CAR T cells for the treatment of multiple myeloma, with a CAR-E consisting of the BCMA fused to a low-affinity interleukin 2 (IL-2). This selectively induces IL-2 signaling in CAR T cells upon antigen-CAR binding, enhancing T cell activation and antitumor activity while reducing IL-2-associated toxicities. We show that the BCMA CAR-E selectively binds CAR T cells and increases CAR T cell proliferation, clearance of tumor cells and development of memory CAR T cells. The memory cells retain the ability to re-expand upon restimulation, effectively controlling tumor growth upon rechallenge. Mechanistic studies reveal the involvement of both CAR and IL-2 receptor endodomains in the CAR-E mechanism of action. The CAR-E approach avoids the need for specific engineering and enables CAR T cell therapy with lower cell doses.
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Nature Chemical Biology
Template-Assisted Covalent Modification Underlies Activity of Covalent Molecular Glues
Li YD, Ma MW, Hunkeler M, Puvar K, Rutter JC, Lumpkin RJ, Sandoval B, Jin CY, Schmoker AM, Ficarro SB, Cheong H, Metivier RJ, Wang MY, Xu S, Groendyke BJ, Sigua LH, Tavares I, Zou C, Tsai JM, Park PMC, Yoon H, Sperling HT, Marto JA, Qi J, Nowak RP, Donovan KA, S?abicki M, Fischer ES, Ebert BL
Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed 'template-assisted covalent modification'. We identified a new series of BRD4 molecular glue degraders that recruit CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58. This process stabilizes the formation of BRD4-degrader-DCAF16 ternary complex and facilitates BRD4 degradation. Supporting generalizability, we found that a subset of degraders also induces GAK-BRD4BD2 interaction through trans-labeling of GAK. Together, our work establishes 'template-assisted covalent modification' as a mechanism for covalent molecular glues, which opens a new path to proximity-driven pharmacology.
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Cancer Science
Clinicopathological, Molecular, and Prognostic Features of Colorectal Carcinomas with KRAS c.34G>T (p.G12C) Mutation
Ugai S, Yao Q, Takashima Y, Zhong Y, Matsuda K, Kawamura H, Okadome K, Song M, Meyerhardt JA, Giannakis M, Nowak JA, Ugai T, Ogino S
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Cell Metabolism
Development of a Functional Beige Fat Cell Line Uncovers Independent Subclasses of Cells Expressing UCP1 and the Futile Creatine Cycle
Vargas-Castillo A, Sun Y, Smythers AL, Grauvogel L, Dumesic PA, Emont MP, Tsai LT, Rosen ED, Zammit NW, Ordonez M, Chouchani ET, Gygi SP, Spiegelman BM
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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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