bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Resolving the pathogenesis of anaplastic Wilms tumors through spatial mapping of cancer cell evolution
Authors: Rastegar Bahar , Andersson Natalie , Petersson Alexandra , Karlsson Jenny , Chattopadhyay Subhayan , Valind Anders , Jansson Caroline , Durand Geoffroy , Romerius Patrik , Jirstrom Karin , Holmquist Mengelbier Linda , Gisselsson David
Published: September 2024

Abstract
Purpose: While patients with intermediate-risk Wilms tumors (WT) now have an overall survival rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia (DA) have an overall survival of only around 50%. We here identify key events in the pathogenesis of DA by mapping cancer cell evolution over anatomic space in WTs. Experimental Design: We spatially mapped subclonal landscapes in a retrospective cohort of 20 WTs using high-resolution copy number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole mount sections were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments. Results: Compared to non-DA WTs, tumors with DA showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type allele in different regions. Morphological features of anaplasia increased with copy number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, while clonal sweeps were rare within these compartments. Conclusions: WTs with DA display significantly more complex phylogenies compared to non-DA WTs, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.
Data from Plasma 25-hydroxyvitamin D levels and survival in stage III colon cancer: Findings from CALGB/SWOG 80702 (Alliance)
Authors: Wang Qiao-Li , Ma Chao , Yuan Chen , Shi Qian , Wolpin Brian M. , Zhang Yin , Fuchs Charles S. , Meyer Jeffrey , Zemla Tyler , Cheng En , Kumthekar Priya , Guthrie Katherine A. , Couture Felix , Kuebler Philip , Kumar Pankaj , Tan Benjamin , Krishnamurthi Smitha , Goldberg Richard M. , Venook Alan , Blanke Charles , Shields Anthony F. , O'Reilly Eileen M. , Meyerhardt Jeffrey A. , Ng Kimmie
Published: September 2024

Abstract
Purpose: To assess whether higher plasma 25-hydroxyvitamin D (25[OH]D) are associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Patients and Methods: Plasma samples were collected from 1437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of CRP, IL-6, and sTNF-R2. Results: Vitamin D deficiency (25(OH)D<12 ng/ml) was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, non-deficient vitamin D status (≥12 ng/ml) was significantly associated with improved DFS, OS and TTR (all Plog-rank<0.05), with multivariable-adjusted hazard ratios of 0.68 (95% confidence interval [CI], 0.51-0.92) for DFS, 0.57 (0.40-0.80) for OS, and 0.71 (0.52-0.98) for TTR. A U-shaped dose-response pattern was observed for DFS and OS (both Pnon-linearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (P mediation=0.04) for DFS and 11.8% (P mediation=0.05) for OS, whereas CRP and IL-6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Non-deficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate if adjuvant vitamin D supplementation improves patient outcomes.
Data from Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) trial in acquired PARP-inhibitor-resistant homologous recombination deficient ovarian cancer
Authors: Wethington Stephanie L. , Shah Payal D. , Martin Lainie , Tanyi Janos L. , Latif Nawar , Morgan Mark , Torigian Drew A. , Rodriguez Diego , Smith Simon A. , Dean Emma , Domchek Susan M. , Drapkin Ronny , Shih Ie-Ming , Brown Eric J. , Hwang Wei-Ting , Armstrong Deborah K. , Gaillard Stephanie , Giuntoli Robert , Simpkins Fiona
Published: September 2024

Abstract
Purpose: Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to poly-ADP ribose polymerase inhibitors (PARPi) overcomes PARPi-resistance in high grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi(olaparib) and ATRi(ceralasertib) in patients with acquired PARPi-resistant HGSOC. Patients and Methods: Eligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR) deficient HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; >12 months 1st-line or >6 months ≥2nd-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300mg twice daily and ceralasertib 160mg daily on days 1-7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR). Results: Thirteen patients enrolled were evaluable for safety and 12 for efficacy. 62%(n=8) had germline BRCA1/2 mutations, 23% (n=3) somatic BRCA1/2 mutations, and 15%(n=2) HR-deficient tumors. Prior PARPi indication was treatment for recurrence (54%, n=7), 2nd line-maintenance (38%, n=5), and frontline treatment with carboplatin/paclitaxel (8%, n=1). There were 6 partial responses yielding an ORR of 50% (95% CI:0.15, 0.72). Median treatment duration was 8 cycles (range 4-23+). Grade(G) 3/4 toxicities were 38%(n=5); 15%(n=2) G3 anemia, 23%(n=3) G3 thrombocytopenia, 8% (n=1) G4 neutropenia. Four patients required dose-reductions. No patient discontinued treatment due to toxicity. Conclusion: Combination olaparib and ceralasertib is tolerable and shows activity in HR-deficient platinum-sensitive recurrent HGSOC that benefited and then progressed with PARPi as the penultimate regimen. These data suggest that ceralasertib re-sensitizes PARPi resistant HGSOCs to olaparib, warranting further investigation.
Data from Multicenter randomized double-blind phase III trial of donafenib in progressive radioactive iodine-refractory differentiated thyroid cancer
Authors: Lin Yansong , Qin Shukui , Yang Hui , Shi Feng , Yang Aimin , Han Xingmin , Liu Bin , Li Zhiyong , Ji Qinghai , Tang Lijun , Deng Zhiyong , Ding Yong , Fu Wei , Xie Xianhe , Li Linfa , He Xiaohui , Lv Zhongwei , Ma Qingjie , Shen Zan , Guo Zhuming , Chen Zhendong , Cui Yali , Tan Jian , Gao Zairong , Jing Shanghua , Lu Keyi , Luo Xianyang , Zhang Yuan , Fang Yong , Li Zhendong , Cheng Yizhuang , Lei Shangtong , Luan Sha , Chen Guang , Wang Guihua , Wu Liqing , Liu Lingling
Published: September 2024

Abstract
Purpose: The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumour activity and safety of donafenib in Chinese RAIR-DTC patients. Patients and Methods: This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n=128) or matched placebo (n=63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. Results: Donafenib demonstrated prolonged median PFS over placebo (12.9 vs. 6.4 months, HR 0.39, 95% CI 0.25-0.61, p<0.0001) in Chinese RAIR-DTC patients. Improved ORR (23.3% vs. 1.7%, p=0.0002) and DCR (93.3% vs. 79.3%,p=0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥3 treatment-related adverse events included hypertension (13.3%) and hand-foot syndrome (12.5%), 42.2% underwent dose reduction or interruption and 6.3% experienced discontinuation. Conclusions: Donafenib was well-tolerated, and demonstrated clinical benefit in terms of improved PFS, ORR and DCRin patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for RAIR-DTC patients.
Data from Integrative single-cell and bulk transcriptomes analyses identify intrinsic HNSCC subtypes with distinct prognoses and therapeutic vulnerabilities
Authors: Dai Yibin , Wang Ziyu , Xia Yingcao , Li Jin , Wu Yaping , Wang Yanling , Jiang Hongbing , Cheng Jie
Published: September 2024

Abstract
Purpose: Tumor heterogeneity in head neck squamous cell carcinoma (HNSCC) profoundly compromises patient stratification, treatment planning and prognostic prediction, which underscores the urgent need for more effective molecular subtyping for this malignancy. Here, we sought to define the intrinsic epithelial subtypes for HNSCC by integrative analyses of single-cell and bulk RNA sequencing datasets from multiple cohorts and assess their molecular features and clinical significance. Experimental design: Malignant epithelial cells were identified from scRNA-seq datasets and subtyped based on differentially expressed genes. Subtype-specific genomic/epigenetic abnormalities, molecular signaling, regulatory network, immune landscape and patient survival were characterized. Therapeutic vulnerabilities were further predicted based on drug sensitivity datasets from cell lines, patient-derived xenograft models and real-world clinical outcomes. Novel signatures for prognostication and therapeutic prediction were developed by machine learning and independently validated. Results: Three intrinsic consensus molecular subtypes (iCMS1-3) for HNSCC were proposed from scRNA-seq analyses and recapitulated in 1325 patients from independent cohorts using bulk datasets. iCMS1 was characterized by EGFR amplification/activation, stromal-enriched environment, epithelial-to-mesenchymal transition, worst survival and sensitivities to EGFR inhibitor. iCMS2 was featured by HPV+ oropharyngeal predilection, immune-hot, susceptibilities to anti-PD-1 and best prognosis. Moreover, iCMS3 displayed immune-desert and sensitivities to 5-FU and MEK, STAT3 inhibitors. Three novel, robust signatures derived from iCMS subtype-specific transcriptomics features were developed by machine learning for patient prognostication and cetuximab and anti-PD-1 response predictions. Conclusions: These findings reiterate molecular heterogeneity of HNSCC and advantages of scRNA-seq in pinpointing cellular diversities in complex cancer ecosystems. Our HNSCC iCMS regime might facilitate patient stratification and precision medicine.
Data from Patient Specific Targeting of the T-cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases
Authors: Lucero Olivia M. , Lee Ji-Ann , Bowman Jenna , Johnson Kara , Sapparapu Gopal , Thomas John K. , Fan Guang , Chang Bill H. , Thiel-Klare Karina , Eide Christopher A. , Okada Craig , Palazzolo Mike , Lind Evan , Kosaka Yoko , Druker Brian J. , Lydon Nicholas , Bowers Peter M.
Published: September 2024

Abstract
Purpose: Targeted therapeutics are a goal of medicine. Methods for targeting T-cell lymphoma lack specificity for the malignant cell, leading to elimination of healthy cells. The T-cell receptor (TCR) is designed for antigen recognition. T-cell malignancies expand from a single clone which expresses one of 48 TCR variable beta (Vβ) genes, providing a distinct therapeutic target. We hypothesized that a monoclonal antibody that is exclusive to a specific Vβ would eliminate the malignant clone while having minimal effects on healthy T-cells. Experimental Design: We identified a patient with large granular T-cell leukemia, and sequenced his circulating T-cell population, 95% of which expressed Vβ13.3. We developed a panel of anti-Vβ13.3 antibodies to test for binding and elimination of the malignant T-cell clone. Results: Therapeutic antibody candidates bound the malignant clone with high affinity. Antibodies killed engineered cell lines expressing the patient TCR Vβ13.3 by antibody-dependent cellular cytotoxicity, TCR-mediated activation-induced cell death, and exhibited specific killing of patient malignant T-cells in combination with exogenous NK cells. EL4 cells expressing the patient’s TCR Vβ13.3 were also killed by antibody administration in an in vivo murine model. Conclusions: This approach serves as an outline for development of therapeutics that can treat clonal T-cell based malignancies and potentially other T-cell-mediated diseases.
Data from HLA class II loss and JAK1/2 deficiency coevolve in melanoma leading to CD4 T cell and IFNγ cross-resistance
Authors: Stupia Simone , Heeke Christina , Brüggemann Alicia , Zaremba Anne , Thier Beatrice , Kretz Julia , Sucker Antje , Philip Manuel , Zelinskyy Gennadiy , Ferrone Soldano , Roesch Alexander , Horn Susanne , Hadaschik Eva , Schadendorf Dirk , Trilling Mirko , Dittmer Ulf , Griewank Klaus , Zhao Fang , Paschen Annette
Published: September 2024

Abstract
Purpose: Recent studies have demonstrated HLA class II (HLA-II)-dependent killing of melanoma cells by cytotoxic CD4 T cells. We investigated evolution of HLA-II-loss tumors that escape cytotoxic CD4 T cell activity and contribute to immunotherapy resistance. Experimental Design: Melanoma cells from longitudinal metastases were studied for constitutive and interferon-inducible HLA-II expression, sensitivity towards autologous CD4 T cells, and immune evasion by HLA-II loss. Clinical significance of HLA-II-low tumors was determined by analysis of transcriptomic data sets from patients with immune checkpoint blockade (ICB). Results: Analysis of longitudinal samples revealed strong inter-metastatic heterogeneity in melanoma cell-intrinsic HLA-II expression and subclonal HLA-II loss. Tumor cells from early lesions either constitutively expressed HLA-II, sensitizing to cytotoxic CD4 T cells, or induced HLA-II and gained CD4 T cell sensitivity in the presence of IFNγ. In contrast, late outgrowing subclones displayed a stable CD4 T cell-resistant HLA-II-loss phenotype. These cells lacked not only constitutive but also IFNγ-inducible HLA-II due to JAK1/2-STAT1 pathway inactivation. Coevolution of JAK1/2 deficiency and HLA-II loss established melanoma cross-resistance to IFNγ and CD4 T cells, as detected in distinct stage IV metastases. In line with their immune-evasive phenotype, HLA-II-low melanomas showed reduced CD4 T cell infiltrates and correlated with disease progression under ICB. Conclusions: Our study links melanoma resistance to CD4 T cells, IFNγ, and ICB at the level of HLA-II, highlighting the significance of tumor cell-intrinsic HLA-II antigen presentation in disease control and calling for strategies to overcome its downregulation for improvement of patient outcome
Data from Targeting BET proteins downregulates miR-33a to promote synergy with PIM inhibitors in CMML
Authors: Letson Christopher T. , Balasis Maria E. , Newman Hannah , Binder Moritz , Vedder Alexis , Kinose Fumi , Ball Markus , Kruer Traci , Quintana Ariel , Lasho Terra L. , Finke Christy M. , Almada Luciana L. , Grants Jennifer M. , Zhang Guolin , Fernandez-Zapico Martin E. , Gaspar-Maia Alexandre , Lancet Jeffrey , Komrokji Rami , Haura Eric , Sallman David A. , Reuther Gary W. , Karsan Aly , Rix Uwe , Patnaik Mrinal M. , Padron Eric
Published: September 2024

Abstract
Background: Preclinical studies in myeloid neoplasms have demonstrated efficacy of Bromodomain and Extra-Terminal protein inhibitors (BETi). However, BETi demonstrate poor single agent activity in clinical trials. Several studies suggest that combination with other anti-cancer inhibitors may enhance the efficacy of BETi. Experimental Design: To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and PDX models of disease. We utilized standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models. Results: We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Further, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy. Conclusion: Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data supports further clinical investigation of this combination.
Data from Genetic alterations detected by circulating tumor DNA in HER2-low metastatic breast cancer
Authors: Hensing Whitney L. , Gerratana Lorenzo , Clifton Katherine , Medford Arielle J. , Velimirovic Marko , Shah Ami N. , D'Amico Paolo , Reduzzi Carolina , Zhang Qiang , Dai Charles S. , Denault Elyssa N. , Bagegni Nusayba A. , Opyrchal Mateusz , Ademuyiwa Foluso O. , Bose Ron , Behdad Amir , Ma Cynthia X. , Bardia Aditya , Cristofanilli Massimo , Davis Andrew A.
Published: September 2024

Abstract
Introduction: About 50% of breast cancers are defined as HER2-low and may benefit from HER2-directed antibody-drug conjugates (ADC). While tissue sequencing has evaluated potential differences in genomic profiles for patients with HER2-low breast cancer, genetic alterations in circulating tumor DNA (ctDNA) have not been well described. Materials and Methods: We retrospectively analyzed 749 patients with metastatic breast cancer (MBC) and ctDNA evaluation by Guardant360TM from three academic medical centers. Tumors were classified as HER2-low, HER2-0 (IHC 0) or HER2-positive. Single nucleotide variants (SNVs), copy number variants (CNVs), and oncogenic pathways were compared across the spectrum of HER2 expression. Overall survival (OS) was evaluated by HER2 status and according to oncogenic pathways. Results: Patients with HER2-low had higher rates of PIK3CA mutations (RRR 1.57, P=0.024) compared to HER2-0 MBC. There were no differences in ERBB2 alterations or oncogenic pathways between HER2-low and HER2-0 MBC. Patients with HER2-positive MBC had more ERBB2 alterations (RRR 12.43, P=0.002 for amplification; RRR 3.22, P=0.047 for mutations, in the HR+ cohort), fewer ERS1 mutations (RRR 0.458, P=0.029) and fewer ER pathway alterations (RRR 0.321, P<0.001). There was no difference in OS for HER2-low and HER2-0 MBC (HR 1.01, 95% CI 0.79-1.29), while OS was improved in HER2-positive MBC (HR 0.32, 95% CI 0.21-0.49, P<0.001). Conclusions: We observed a higher rate of PIK3CA mutations, but no significant difference in ERBB2 alterations, oncogenic pathways, or prognosis, between HER2-low and HER2-0 MBC. If validated, our findings support the conclusion that HER2-low MBC does not represent a unique biological subtype.
Data from Targeting BCL2 overcomes resistance and augments response to aurora kinase B inhibition by AZD2811 in small cell lung cancer
Authors: Ramkumar Kavya , Tanimoto Azusa , Della Corte Carminia M. , Stewart C. Allison , Wang Qi , Shen Li , Cardnell Robert J. , Wang Jing , Polanska Urszula M. , Andersen Courtney , Saeh Jamal , Pease J. Elizabeth , Travers Jon , Fabbri Giulia , Gay Carl M. , Urosevic Jelena , Byers Lauren A.
Published: September 2024

Abstract
Purpose: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. AURKB inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy. Experimental design: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n=57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage and apoptosis were measured by flow cytometry and western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models. Results: AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA approved BCL2 inhibitor. Conclusions: BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.
Data from The DRD2 antagonist haloperidol mediates autophagy-induced ferroptosis to increase temozolomide sensitivity by promoting endoplasmic reticulum stress in glioblastoma
Authors: Shi Linyong , Chen Hanning , Chen Kunxiang , Zhong Chengzong , Song Chong , Huang Yifeng , Wang Tong , Chen Lei , Li Chiyang , Huang Annie , Li Hong , Lu Yuntao
Published: September 2024

Abstract
Purpose:Temozolomide (TMZ) resistance remains a major obstacle in the treatment of glioblastoma (GBM). The combination of TMZ with another agent could offer an improved treatment option if it could overcome chemoresistance and prevent side effects. Here, we determined the critical drug that cause ferroptosis in GBM cells and elucidated the possible mechanism by which drug combination overcomes chemoresistance. Experimental Design:Haloperidol/TMZ synergism was assessed in GBM cell lines with different DRD2 expression in vitro and in vivo. Inhibitors of ferroptosis, autophagy, endoplasmic reticulum stress and cAMP/PKA were used to validate the specific mechanisms by which haloperidol and TMZ induce ferroptosis in GBM cells. Results: In the present work, we demonstrate that the dopamine D2 receptor (DRD2) level is increased by TMZ in a time-dependent manner and is inversely correlated with TMZ sensitivity in GBM. The DRD2 antagonist haloperidol (HP), a butylbenzene antipsychotic, markedly induces ferroptosis and effectively enhances TMZ efficacy in vivo and in vitro. Mechanistically, HP suppressed the effect of TMZ on cAMP by antagonizing DRD2 receptor activity, and the increases in cAMP/PKA triggered endoplasmic reticulum stress, which led to autophagy and ferroptosis. Furthermore, elevated autophagy mediates downregulation of FTH1 expression at the posttranslational level in an autophagy-dependent manner and ultimately leads to ferroptosis. Conclusions:Our results provide experimental evidence for repurposing HP as an effective adjunct therapy to inhibit adaptive TMZ resistance in order to enhance the efficacy of chemoradiotherapy in GBM, a strategy that may have broad prospects for clinical application.
Data from The prognostic effect of immune cell infiltration depends on molecular subtype in Endometrioid Ovarian Carcinomas
Authors: Heinze Karolin , Cairns Evan S. , Thornton Shelby , Harris Bronwyn , Milne Katy , Grube Marcel , Meyer Charlotte , Karnezis Anthony N. , Fereday Sian , Garsed Dale W. , Leung Samuel C.Y. , Chiu Derek S. , Moubarak Malak , Harter Philipp , Heitz Florian , McAlpine Jessica N. , DeFazio Anna , Bowtell David D.L. , Goode Ellen L. , Pike Malcolm , Ramus Susan J. , Pearce C. Leigh , Staebler Annette , Köbel Martin , Kommoss Stefan , Talhouk Aline , Nelson Brad H. , Anglesio Michael S.
Published: September 2024

Abstract
Purpose: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10-20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas (EC) including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, though tumor initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. Experimental Design: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex immunohistochemistry and immunofluorescence, we examine the prevalence of T cell lineage, B cell lineage, macrophages, and populations with PD-1 or PD-L1 across subtypes of ENOC. Results: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (OS p>0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular subtype (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (DSS HR:4.0 CI 1.1-14.7, p<0.05). Similar to EC, molecular subtype stratification was generally superior to immune response in predicting outcomes. Conclusions: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.
Data from B-cell receptor pathway mutations are infrequent in patients with chronic lymphocytic leukemia on continuous ibrutinib therapy
Authors: Woyach Jennifer A. , Ghia Paolo , Byrd John C. , Ahn Inhye E. , Moreno Carol , O'Brien Susan M. , Jones Daniel , Cheung Leo W.K. , Chong Elizabeth , Kwei Kevin , Dean James P. , James Danelle F. , Wiestner Adrian
Published: September 2024

Abstract
Purpose: Acquired mutations in Bruton’s tyrosine kinase (BTK) or phospholipase C-γ2 (PLCG2) genes are associated with clinical progressive disease (PD) in patients with chronic lymphocytic leukemia (CLL) treated with BTK inhibitors. Data on mutation rates in patients without PD on ibrutinib treatment are limited. Experimental Design: We evaluated frequency and time to detection of BTK and PLCG2 mutations in peripheral blood samples from 388 patients (n=238) or relapsed/refractory (n=150) CLL across 5 clinical trials. Results: With median follow-up of 35 months (range, 0-72) without PD at last sampling, mutations in BTK (3%), PLCG2 (2%) or both genes (1%) were rare in previously untreated patients. With median follow-up of 35 months (range, 1-70) without PD at last sample, mutations in BTK (30%), PLCG2 (7%), or both genes (5%) were more common in patients with relapsed/refractory CLL. Median time to first detection of BTK C481S mutation was not reached in previously untreated patients and was >5 years in patients with relapsed/refractory CLL. Among patients evaluable at PD, previously untreated patients (n=12) had lower rates than those with relapsed/refractory disease (n=45) of BTK (25% vs 49%) and PLCG2 mutations (8% vs 13%). Time from first detection of BTK C481S mutation to PD was 11.3 months in 1 previously untreated patient and median 8.5 months (range, 0-35.7) among 23 patients with relapsed/refractory CLL. Conclusions: This systematic investigation describes development of mutations over time in patients without PD and informs the potential clinical opportunity to optimize ongoing benefits for such patients.
Data from Efficacy and quality-of-life following involved nodal radiotherapy for head and neck squamous cell carcinoma: the INRT-AIR phase II clinical trial
Authors: Sher David J. , Moon Dominic H. , Vo Dat , Wang Jing , Chen Liyuan , Dohopolski Michael , Hughes Randall , Sumer Baran D. , Ahn Chul , Avkshtol Vladimir
Published: September 2024

Abstract
Purpose: Elective neck irradiation (ENI) has long been considered mandatory when treating head and neck squamous cell carcinoma (HNSCC) with definitive radiotherapy, but it is associated with significant dose to normal organs-at-risk (OAR). In this prospective phase II study, we investigated the efficacy and tolerability of eliminating ENI and strictly treating involved and suspicious lymph nodes (LN) with intensity-modulated radiation therapy. Patients and Methods: Patients with newly-diagnosed HNSCC of the oropharynx, larynx and hypopharynx were eligible for enrollment. Each LN was characterized as involved or suspicious based on radiologic criteria and an in-house artificial intelligence-based classification model. Gross disease received 70 Gray (Gy) in 35 fractions and suspicious LN were treated to 66.5 Gy, without ENI. The primary endpoint was solitary elective volume recurrence, with secondary endpoints including patterns-of-failure and patient-reported outcomes. Results: Sixty-seven patients were enrolled, with 18 larynx/hypopharynx and 49 oropharynx cancer. With a median follow-up of 33.4 months, the 2-year risk of solitary elective nodal recurrence was 0%. Gastrostomy tubes were placed in 14 (21%), with median removal after 2.9 months for disease-free patients; no disease-free patient is chronically dependent. Grade 1/2 dermatitis was seen in 90%/10%. There was no significant decline in composite MD Anderson Dysphagia Index (MDADI) scores after treatment, with means of 89.1 and 92.6 at 12 and 24 months, respectively. Conclusions: These results suggest that eliminating ENI is oncologically sound for HNSCC, with highly favorable quality-of-life outcomes. Additional prospective studies are needed to support this promising paradigm before implementation in any non-trial setting.
Data from The GENIE BPC NSCLC cohort: a real-world repository integrating standardized clinical and genomic data for 1,846 patients with non-small cell lung cancer
Authors: Choudhury Noura J. , Lavery Jessica A. , Brown Samantha , de Bruijn Ino , Jee Justin , Tran Thinh Ngoc. , Rizvi Hira , Arbour Kathryn C. , Whiting Karissa , Shen Ronglai , Hellmann Matthew , Bedard Philippe L. , Yu Celeste , Leighl Natasha , LeNoue-Newton Michele , Micheel Christine , Warner Jeremy L. , Ginsberg Michelle S. , Plodkowski Andrew , Girshman Jeffrey , Sawan Peter , Pillai Shirin , Sweeney Shawn M. , Kehl Kenneth L. , Panageas Katherine S. , Schultz Nikolaus , Schrag Deb , Riely Gregory J.
Published: September 2024

Abstract
Purpose: We describe the clinical and genomic landscape of the non-small cell lung cancer (NSCLC) cohort of the AACR Project GENIE Biopharma Collaborative (BPC). Experimental Design: 1,846 patients with NSCLC whose tumors were sequenced from 2014 to 2018 at four institutions participating in AACR GENIE were randomly chosen for curation using the PRISSMMÔ data model. Progression-free survival (PFS) and overall survival (OS) were estimated for patients treated with standard therapies. Results: In this cohort, 44% of tumors harbored a targetable oncogenic alteration, with EGFR (20%), KRAS G12C (13%) and oncogenic fusions (ALK, RET and ROS1; 5%) as the most frequent. Median OS (mOS) on first-line platinum-based therapy without immunotherapy was 17.4 mo (95% confidence interval (CI) 14.9,19.5 mo). For second-line therapies, mOS was 9.2 mo (95% CI 7.5,11.3 mo) for immune checkpoint inhibitors (ICI) and 6.4 mo (95% CI 5.1,8.1 mo) for docetaxel +/- ramucirumab. In a subset of patients treated with ICI in the second-line or later setting, median RECIST PFS (2.5 mo; 95% CI 2.2, 2.8) and median real-world PFS based on imaging reports (2.2 mo; 95% CI 1.7,2.6) were similar. In exploratory analysis of the impact of tumor mutational burden (TMB) on survival on ICI treatment in the second-line or higher setting, TMB z-score harmonized across gene panels was associated with improved OS (univariable HR 0.85, p=0.03, n=247 patients). Conclusions: The GENIE BPC cohort provides comprehensive clinico-genomic data for patients with NSCLC, which can improve understanding of real-world patient outcomes.
Data from Phase I trial of ganitumab plus dasatinib to cotarget the insulin-like growth factor 1 receptor and Src family kinase YES in rhabdomyosarcoma
Authors: Akshintala Srivandana , Sundby R. Taylor. , Bernstein Donna , Glod John W. , Kaplan Rosandra N. , Yohe Marielle E. , Gross Andrea M. , Derdak Joanne , Lei Haiyan , Pan Alexander , Dombi Eva , Palacio-Yance Isabel , Herrera Kailey R. , Miettinen Markku M. , Chen Helen X. , Steinberg Seth M. , Helman Lee J. , Mascarenhas Leo , Widemann Brigitte C. , Navid Fariba , Shern Jack F. , Heske Christine M.
Published: September 2024

Abstract
Purpose: Antibodies against IGF-1R have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF-1R antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in RMS patients (NCT03041701). Patients and Methods: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined based on cycle 1 dose-limiting toxicities (DLTs). Results: Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response (PR) for four cycles, and one had stable disease (SD) for six cycles. Genomic studies from cell-free DNA correlated with disease response. Conclusions: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every two weeks was safe and tolerable. This combination had a disease control rate of 22% at five months.
Data from CDK4/6-MEK inhibition in MPNSTs causes plasma cell infiltration, sensitization to PD-L1 blockade, and tumor regression
Authors: Kohlmeyer Jordan L. , Lingo Joshua J. , Kaemmer Courtney A. , Scherer Amanda , Warrier Akshaya , Voigt Ellen , Raygoza Garay Juan A , McGivney Gavin R. , Brockman Qierra R. , Tang Amy , Calizo Ana , Pollard Kai , Zhang Xiaochun , Hirbe Angela C. , Pratilas Christine A. , Leidinger Mariah , Breheny Patrick , Chimenti Michael S. , Sieren Jessica C. , Monga Varun , Tanas Munir R. , Meyerholz David K. , Darbro Benjamin W. , Dodd Rebecca D. , Quelle Dawn E.
Published: September 2024

Abstract
Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting CDK4/6, MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. Experimental Design: Patient-matched MPNSTs and precursor lesions were examined by FISH, RNAseq, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDXs), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response. Results: Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression. Conclusions: CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.
Data from Phase 1 Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment
Authors: Roschewski Mark , Patel Manish R. , Reagan Patrick M. , Saba Nakhle S. , Collins Graham P. , Arkenau Hendrik-Tobias , de Vos Sven , Nuttall Barret , Acar Melih , Burke Kathleen , White Rafael D. , Udriste Maria , Sharma Shringi , Dougherty Brian , Stetson Daniel , Jenkins David , Mortlock Andrew , Forcina Alessandra , Munugalavadla Veerendra , Flinn Ian
Published: September 2024

Abstract
Background: Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL, but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL. Methods: Final results of the Phase 1 study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion (Days 1, 3, 5 [Cycle 1]; weekly infusions starting Day 8, Cycle 1) was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. Results: Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in one patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n=17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders. Conclusion: Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.
Data from HLA-I Evolutionary Divergence Confers Response to PD-1 Blockade plus Chemotherapy in Untreated Advanced Non–Small Cell Lung Cancer
Authors: Jiang Tao , Jin Qiqi , Wang Jiahao , Wu Fengying , Chen Jian , Chen Gongyan , Huang Yunchao , Chen Jianhua , Cheng Ying , Wang QiMing , Pan Yueyin , Zhou Jianying , Shi Jianhua , Xu Xingxiang , Lin LiZhu , Zhang Wei , Zhang Yiping , Liu Yunpeng , Fang Yong , Feng Jifeng , Wang Zhehai , Hu Sheng , Fang Jian , Shu Yongqian , Cui Jiuwei , Hu Yi , Yao Wenxiu , Li Xingya , Lin Xiaoyan , Wang Rui , Wang Yongsheng , Shi Wei , Feng Gaohua , Ni Jun , Mao Beibei , Ren Dandan , Sun Huaibo , Zhang Henghui , Chen Luonan , Zhou Caicun , Ren Shengxiang
Published: September 2024

AbstractPurpose:
PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non–small cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined.
Experimental Design:
We integrated clinical, genomic, and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase III trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED).
Results:
High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in those who received PD-1 blockade plus chemotherapy [in the CameL trial, ORR: 81.8% vs. 53.2%; P = 0.032; PFS: hazard ratio (HR), 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; in the CameL-sq trial, ORR: 89.2% vs. 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 0.002], but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS, and OS in both trials. Moreover, the joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell–mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype.
Conclusions:
These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy.

See related commentary by Dimou, p. 4706
Data from Randomized Trial of a Personalized Dendritic Cell Vaccine after Autologous Stem Cell Transplant for Multiple Myeloma
Authors: Chung David J. , Shah Nina , Wu Juan , Logan Brent , Bisharat Lina , Callander Natalie , Cheloni Giulia , Anderson Kenneth , Chodon Thinle , Dhakal Binod , Devine Steven , Somaiya Dutt Poorvi , Efebera Yvonne , Geller Nancy , Ghiasuddin Haider , Hematti Peiman , Holmberg Leona , Howard Alan , Johnson Bryon , Karagkouni Dimitra , Lazarus Hillard M. , Malek Ehsan , McCarthy Philip , McKenna David , Mendizabal Adam , Nooka Ajay , Munshi Nikhil , O'Donnell Lynn , Rapoport Aaron P. , Reese Jane , Rosenblatt Jacalyn , Soiffer Robert , Stroopinsky Dina , Uhl Lynne , Vlachos Ioannis S. , Waller Edmund K. , Young James W. , Pasquini Marcelo C. , Avigan David
Published: September 2024

Abstract
Purpose: Vaccination with dendritic cell (DC)/multiple myeloma (MM) fusions has been shown to induce the expansion of circulating MM-reactive lymphocytes and consolidation of clinical response following autologous hematopoietic cell transplant (autoHCT). Patients and Methods: In this randomized phase II trial (NCT02728102), we assessed the effect of DC/MM fusion vaccination, GM-CSF, and lenalidomide maintenance as compared to control arms of GM-CSF and lenalidomide or lenalidomide maintenance alone on clinical response rates and induction of MM-specific immunity at 1-year post-transplant. Results: The study enrolled 203 patients, with 140 randomized post-transplantation. Vaccine production was successful in 63/68 patients. At 1 year, rates of CR were 52.9% (vaccine) and 50% (control) (p=0.37, 80% CI 44.5%, 61.3% and 41.6%, 58.4%, respectively), and rates of VGPR or better were 85.3% (vaccine) and 77.8% (control) (p=0.2). Conversion to CR at 1 year was 34.8% (vaccine) and 27.3% (control) (p=0.4). Vaccination induced a statistically significant expansion of MM-reactive T cells at 1 year as compared to prior to vaccination (p=0.024) and in contrast to the non-vaccine arm (p=0.026). Single-cell transcriptomics revealed clonotypic expansion of activated CD8 cells and shared dominant clonotypes between patients at 1-year post-transplant. Conclusions: DC/MM fusion vaccination with lenalidomide did not result in a statistically significant increase in CR rates at 1-year post-transplant but was associated with a significant increase in circulating MM-reactive lymphocytes indicative of tumor-specific immunity. Site-specific production of a personalized cell therapy with centralized product characterization was effectively accomplished in the context of a multicenter cooperative group study.
Data from A Phase 1b trial of AVID200, a TGFβ 1/3 trap, in patients with myelofibrosis
Authors: Mascarenhas John , Migliaccio Anna Rita , Kosiorek Heidi , Bhave Rupali , Palmer Jeanne , Kuykendall Andrew , Mesa Ruben , Rampal Raajit K. , Gerds Aaron T. , Yacoub Abdulraheem , Pettit Kristen , Talpaz Moshe , Komrokji Rami , Kremyanskaya Marina , Gonzalez Agapito , Fabris Frank , Johnson Kathryn , Dougherty Mikaela , McGovern Erin , Arango Ossa Juan , Domenico Dylan , Farnoud Noushin , Weinberg Rona Singer. , Kong Amy , Najfeld Vesna , Vannucchi Alessandro Maria. , Arciprete Francesca , Zingariello Maria , Falchi Mario , Salama Mohamed E. , Mead-Harvey Carolyn , Dueck Amylou , Varricchio Lilian , Hoffman Ronald
Published: September 2024

Abstract
Purpose: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGF-β, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, down-regulates anti-tumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGF-β 1/3 trap, reduced TGF-β1 induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PCs) with wild-type JAK2 rather than JAK2V617F. Methods and Patients: We conducted an investigator-initiated, multicenter, phase 1b trial of AVID200 monotherapy in 21 advanced MF patients. Results: No dose limiting toxicity was identified at the three dose levels tested and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGF-β1 levels, and pSMAD2 in MF cells. Conclusions: AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of MF patients and should be evaluated further in thrombocytopenic MF patients in combination with agents that target aberrant MF intracellular signaling pathways.