bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Identifying mechanisms of resistance by circulating tumour DNA in EVOLVE, a Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer at time of PARP Inhibitor Progression
Authors: Lheureux Stephanie , Prokopec Stephenie D. , Oldfield Leslie E. , Gonzalez-Ochoa Eduardo , Bruce Jeff P. , Wong Derek , Danesh Arnavaz , Torti Dax , Torchia Jonathan , Fortuna Alexander , Singh Sharanjit , Irving Matthew , Marsh Kayla , Lam Bernard , Speers Vanessa , Yosifova Aleksandra , Oaknin Ana , Madariaga Ainhoa , Dhani Neesha C. , Bowering Valerie , Oza Amit M. , Pugh Trevor J.
Published: September 2024

Abstract
Purpose To evaluate the use of blood cell-free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high grade serous ovarian cancer (HGSOC). Patients and Methods We used targeted sequencing (TS) to analyse 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled in a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib (PARPi) after progression on PARPi alone. cfDNA was collected at baseline, before treatment cycle 2, and at end of treatment. These were compared to whole exome sequencing (WES) of baseline tumour tissues. Results At baseline (time of initial PARPi progression), cfDNA tumour fractions were 0.2-67% (median 3.25%) and patients with high ctDNA levels (>15%) had a higher tumour burden (sum of target lesions; p = 0.043). Across all timepoints, cfDNA detected known from tumour WES with 74.4% sensitivity, and detected 3 of 5 expected BRCA1/2 reversion mutations. In addition, cfDNA identified 10 novel mutations not detected by WES, including 7 TP53 mutations annotated as pathogenic by ClinVar. cfDNA fragmentation analysis attributed 5 of these novel TP53 mutations to clonal hematopoiesis of indeterminate potential (CHIP). At baseline, samples with significant differences in mutant fragment size distribution had shorter time to progression (p = 0.001). Conclusions Longitudinal testing of cfDNA by TS provides a non-invasive tool for detection of tumour-derived mutations and mechanisms of PARPi resistance that may aid in directing patients to appropriate therapeutic strategies. With cfDNA fragmentation analyses, CHIP was identified in several patients and warrants further investigation.
Data from Dual role of CXCL8 in maintaining the mesenchymal state of glioblastoma stem cells and M2-like tumor-associated macrophages
Authors: Yuan Wei , Zhang Qian , Gu Danling , Lu Chenfei , Dixit Deobrat , Gimple Ryan C. , Gao Yisu , Gao Jiancheng , Li Daqi , Shan Danyan , Hu Lang , Li Lu , Li Yangqing , Ci Shusheng , You Hao , Yan Linping , Chen Kexin , Zhao Ningwei , Xu Chuanhai , Lan Jianyun , Liu Dong , Zhang Junxia , Shi Zhumei , Wu Qiulian , Yang Kailin , Zhao Linjie , Qiu Zhixin , Lv Deguan , Gao Wei , Yang Hui , Lin Fan , Wang Qianghu , Man Jianghong , Li Chaojun , Tao Weiwei , Agnihotri Sameer , Qian Xu , Mack Stephen C. , Zhang Nu , You Yongping , Rich Jeremy N. , Sun Guan , Wang Xiuxing
Published: September 2024

Abstract
Purpose: The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of glioblastoma stem cell populations and reprogramming the TIME to an immunosuppressive state. Experimental Design: We performed an integrative multi-omics analyses of RNA sequencing, GBM mRNA expression datasets, immune signatures, and epigenetic profiling to define the specific genes expressed in the mesenchymal GSC subsets. We then used patient-derived GSCs and xenograft murine model to investigate the mechanisms of tumor-intrinsic and extrinsic factor to maintain the mesenchymal state of GSCs and induce TAM polarization. Results: We identified CXCL8 was preferentially expressed and secreted by mesenchymal GSCs and activated PI3K/AKT and NF-κB signaling to maintain GSC proliferation, survival, and self-renewal through a cell-intrinsic mechanism. CXCL8 induced signaling through a CXCR2-JAK2/STAT3 axis in TAMs, which supported an M2-like TAM phenotype through a paracrine, cell-extrinsic pathway. Genetic- and small molecule-based inhibition of these dual complementary signaling cascades in GSCs and TAMs suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Conclusions: CXCL8 plays critical roles in maintaining the mesenchymal state of GSCs and M2-like TAM polarization in GBM, highlighting an interplay between cell-autonomous and cell-extrinsic mechanisms. Targeting CXCL8 and its downstream effectors may effectively improve GBM treatment.
Data from A Novel HOXA10-Associated 5 Gene-Based Prognostic Signature for Stratification of Short-Term Survivors of Pancreatic Ductal Adenocarcinoma
Authors: Kisling Sophia G. , Atri Pranita , Shah Ashu , Cox Jesse L. , Sharma Sunandini , Smith Lynette M. , Ghersi Dario , Batra Surinder K.
Published: September 2024

Abstract
Purpose: Despite the significant association of molecular subtypes with poor prognosis in pancreatic ductal adenocarcinoma (PDAC) patients, little effort has been made to identify the underlying pathway(s) responsible for this prognosis. Identifying a clinically relevant prognosis-based gene signature may be the key to improving patient outcomes. Experimental Design: We analyzed the transcriptomic profiles of treatment-naïve surgically resected short- and long-term survivor tumors (GSE62452) for expression and survival, followed by validation in several datasets. These results were corroborated by immunohistochemical analysis of PDAC-resected short- and long-term survivor tumors. The mechanism of this differential survival was investigated using CIBERSORT and pathway analyses. Results: We identified a short-surviving prognostic subtype of PDAC with a high degree of significance (p=0.018). One hundred thirty genes in this novel subtype were found to be regulated by a master regulator, HOXA10, and a five-gene signature derived from these genes, including BANF1, EIF4G1, MRPS10, PDIA4, and TYMS, exhibited differential expression in short-term survivors (STS) and a strong association with poor survival. This signature was further associated with the proportion of T-cells and macrophages found in STS and long-term survivors (LTS), demonstrating a potential role in PDAC immunosuppression. Pathway analyses corroborated these findings, revealing that this HOXA10-driven signature is associated with immune suppression and enhanced tumorigenesis. Conclusions: Overall, these findings reveal the presence of a HOXA10-associated prognostic subtype that can be used to differentiate between STS and LTS patients of PDAC and inform on the molecular interactions that play a role in this poor prognosis.
Data from ILUSTRO: Phase 2 Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma
Authors: Klempner Samuel J. , Lee Keun-Wook , Shitara Kohei , Metges Jean-Phillippe , Lonardi Sara , Ilson David H. , Fazio Nicola , Kim Tae Yong , Bai Li-Yuan , Moran Diarmuid , Yang Jianning , Arozullah Ahsan , Park Jung Wook , Raizer Jeffrey J. , Bang Yung-Jue , Shah Manish A.
Published: September 2024

Abstract
Background: Zolbetuximab, an IgG1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. We sought to examine zolbetuximab combinations in CLDN18.2-positive human epidermal growth factor receptor 2–negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Patients and methods: This phase 2 study assessed efficacy and safety of zolbetuximab, alone or with modified FOLFOX6 (mFOLFOX6) or pembrolizumab, in CLDN18.2-positive advanced/metastatic G/GEJ adenocarcinoma. Patients received zolbetuximab as monotherapy in third/later-line (Cohort 1A, n=30), with mFOLFOX6 in first-line (Cohort 2, n=21), or with pembrolizumab in third/later-line (Cohort 3A, n=3) treatment. The primary endpoint for Cohort 1A was objective response rate (ORR). Key secondary endpoints were ORR (Cohorts 2 and 3A), overall survival (OS; Cohort 1A), and progression-free survival (PFS) and safety (all cohorts). Results: ORR was 0% in Cohorts 1A and 3A, and 71.4% (95% CI, 47.82–88.72) in Cohort 2. Median PFS was 1.54 months (95% CI, 1.31–2.56) in Cohort 1A, 2.96 months (95% CI, 1.48–4.44) in Cohort 3A, and 17.8 months (95% CI, 8.05–25.69) in Cohort 2. Median OS in Cohort 1A was 5.62 months (95% CI, 2.27–11.53). Gastrointestinal adverse events occurred across cohorts (nausea, 63%–90% [grade ≥3, 4.8%–6.7%] and vomiting, 33%–67% [grade ≥3, 6.7%–9.5%]). Conclusions: Zolbetuximab plus mFOLFOX6 demonstrated promising efficacy in previously untreated patients with CLDN18.2-positive G/GEJ adenocarcinoma. These data support the first-line development of zolbetuximab in patients whose tumors are CLDN18.2 positive. Across cohorts, zolbetuximab treatment was tolerable with no new safety signals.
Data from Liquid biopsies with circulating plasma HPV–DNA measurements – a clinically applicable surveillance tool for HPV-positive oropharyngeal cancer patients
Authors: Jakobsen Kathrine K. , Bendtsen Simone K. , Pallisgaard Niels , Friborg Jeppe , Lelkaitis Giedrius , Grønhøj Christian , von Buchwald Christian
Published: September 2024

Abstract
Purpose: To evaluate the accuracy of cell-free human papillomavirus-DNA (cfHPV-DNA) measurements in liquid biopsies in predicting disease in HPV+/p16+ oropharyngeal squamous cell carcinoma (OPSCC) patients. Experimental Design: This is a prospective cohort study. Plasma samples were collected before treatment, and serially after curative intended therapy at follow-up visits 2 weeks, and 6, 9, 12, 18, 24, and 30 months after treatment. A Droplet Digital (dd)PCR assay comprising eight HPV genotypes was used. HPV genotypes found in plasma and tumour tissue were compared. We correlated biopsy- or imaging-verified tumour progression to cfHPV-DNA in follow-up samples. Results: We enrolled 72 HPV+/p16+ OPSCC patients. Baseline sensitivity for cfHPV-DNA detection was 97.2% (95% CI 90.3%–99.6). CfHPV-DNA copy number/millilitre plasma correlated with tumour stage. We found a 100% concordance between HPV genotype in tumour tissue and plasma. Fifty-four patients were followed with serial blood samples for a median of 19.7 months (Interquartile Range: 13.5–25.5 months). Forty-one patients had undetectable plasma cfHPV-DNA in all follow-up samples, and none developed recurrences. Thirteen patients were classified as cfHPV-DNA positive in a follow-up plasma sample. Of these, five patients developed a recurrence, and three had residual cancer. It was possible to detect cfHPV-DNA in plasma 97–166 days prior to the proven recurrence. Conclusion: Our study, comprising the largest study of HPV+/p16+ OPSCC patients, using an ultrasensitive multiplex HPV gene panel, revealed a high sensitivity of cfHPV-DNA detection in the liquid biopsies. We recommend serial plasma HPV samples for clinical monitoring of HPV+/p16+ OPSCC patients.
Data from Novel Genomic Risk Stratification Model for Primary Gastrointestinal Stromal Tumors (GIST) in the Imatinib and Adjuvant Therapy Era
Authors: Dermawan Josephine Kam Tai K. , Kelly Ciara , Gao Zhidong , Smith Shaleigh , Jadeja Bhumika , Singer Samuel , Tap William D. , Chi Ping , Antonescu Cristina R.
Published: September 2024

Abstract
Purpose: Traditional risk stratification schemes in gastrointestinal stromal tumors (GIST) had been defined in the pre-imatinib era and rely solely on clinicopathologic metrics. We hypothesize that genomic-based risk stratification is prognostically relevant in the current era of tyrosine kinase inhibitor (TKI) therapeutics. Experimental Design: Comprehensive mutational and copy number profiling using MSK-IMPACT was performed. We integrated clinicopathologic and genomic parameters and utilized an elastic-net penalized Cox proportional hazards machine learning model for outcome risk stratification. Results: A 3-tier genomic risk stratification model for recurrence-free survival (RFS) in 152 primary localized gastric and 80 small bowel GISTs was proposed. Gastric GISTs were classified as high risk if chr1p deletion or SDHB loss was present, and intermediate risk if chr14q deletion was present or KIT exon 11 mutation was absent. Small bowel GISTs were classified as high risk if MAX/MGA/MYC, CDKN2A or RB1 alterations was present, and intermediate risk if chr1p deletion or chr5q amplification was present. Compared to conventional risk stratification, genomic risk stratification both upgrades and downgrades, suggesting that conventional risk stratification may underestimate or overtreat some high-risk and low-risk patients, respectively. Longitudinal sequencing detected most KIT-independent genomic alterations at baseline. Subanalysis in 26 SDH-deficient GISTs revealed that presence of TP53 mutations or chr1q amplifications portends worse RFS and disease-free survival. Conclusions: We developed a novel, next-generation genomic risk stratification model for primary gastric and small bowel GISTs, complementing traditional clinicopathologic models. Future independent validation of our model in external cohorts is essential.
Data from Integrated genomic and transcriptomic analysis improves disease classification and risk stratification of MDS with ring sideroblasts.
Authors: Todisco Gabriele , Creignou Maria , Bernard Elsa , Björklund Ann-Charlotte , Moura Pedro Luis. , Tesi Bianca , Mortera Blanco Teresa , Sander Birgitta , Jansson Monika , Walldin Gunilla , Barbosa Indira , Reinsbach Susanne E. , Hofman Isabel Juliana. , Nilsson Christer , Yoshizato Tetsuichi , Dimitriou Marios , Chang David , Olafsdottir Svanhildur , Venckute Larsson Sigita , Tobiasson Magnus , Malcovati Luca , Woll Petter , Jacobsen Sten-Eirik W. , Papaemmanuil Elli , Hellström-Lindberg Eva
Published: September 2024

Abstract
Purpose: Ring sideroblasts (RS) define the low-risk myelodysplastic neoplasm (MDS) subgroup with RS but may also reflect erythroid dysplasia in higher-risk myeloid neoplasm. The benign behavior of MDS with RS (MDSRS+) is limited to SF3B1-mutated cases without additional high-risk genetic events, but one third of MDSRS+ carry no SF3B1 mutation, suggesting that different molecular mechanisms may underlie RS formation. We integrated genomic and transcriptomic analyses to evaluate whether transcriptome profiles may improve current risk stratification. Experimental design: We studied a prospective cohort of MDSRS+ patients irrespective of WHO class with regard to somatic mutations, copy number alterations and bone marrow CD34+ cell transcriptomes to assess whether transcriptome profiles add to prognostication and provide input on disease classification. Results: SF3B1, SRSF2 or TP53 multi-hit (MH) mutations were found in 89% of MDSRS+ cases, and each mutation category was associated with distinct clinical outcome, gene expression, and alternative splicing profiles. Unsupervised clustering analysis identified three clusters with distinct hemopoietic stem and progenitor (HSPC) composition, which only partially overlapped with mutation groups. IPSS-M and the transcriptome-defined proportion of megakaryocyte/erythroid progenitors (MEP) independently predicted survival in multivariable analysis. Conclusion: These results provide essential input on the molecular basis of SF3B1-unmutated MDSRS+ and propose HSPC quantification as a prognostic marker in myeloid neoplasms with RS.
Data from Specific targeting of Multiple Myeloma by Dual Split-signaling Chimeric Antigen Receptors T-cells directed against CD38 and CD138
Authors: van der Schans Jort J. , Wang Ziyu , van Arkel Jennemiek , van Schaik Thijs , Katsarou Afroditi , Ruiter Ruud , Baardemans Thomas , Yuan Huipin , de Bruijn Joost , Zweegman Sonja , van de Donk Niels W.C.J. , Groen Richard W.J. , Themeli Maria , Mutis Tuna
Published: September 2024

Abstract
Purpose: The success of BCMA-specific chimeric antigen receptor (CAR) T-cells illustrates the potential of this novel therapy for multiple myeloma (MM). Nonetheless, broadening CAR T-cell therapy beyond BCMA requires inventive strategies as there are only a few MM- or plasma cell-specific target antigens. We investigated the feasibility of achieving MM specificity by dual-split CD38/CD138 CAR targeting, whereby the stimulatory and costimulatory signals for T-cell activation are split into two separate stimulatory (sCAR) and costimulatory CARs (cCAR). Experimental Design: Using various combinations of CD38 and CD138 sCARs and cCARs with different affinities, we generated several dual-split CAR T-cells and analyzed them for MM-specific effector functions in vitro. The best-functioning CAR T-cells were tested in vivo in a murine xenograft model. Results: We found optimal designs of both CD38sCAR/CD138cCAR and CD138sCAR/CD38cCAR combinations, that effectively lysed MM cells, but spared single CD38 or CD138 positive healthy hematopoietic cells. While the CD38sCAR/CD138cCAR T-cells achieved MM-specific activity solely due to the low affinity of the CD38sCARs, the MM-specific cytotoxicity, cytokine release, and proliferation of CD138sCAR/CD38cCAR T‑cells were established through a true combinatorial stimulatory and costimulatory effect. The most optimal combination comprised a low affinity CD138sCAR combined with a high affinity CD38cCAR. These CD138sCAR/CD38cCAR T-cells also showed dual-antigen specific anti-MM effects in vivo. Importantly, they were also effective against MM cells from daratumumab pre-treated patients with decreased CD38 expression levels. Conclusions: We demonstrate the possibility to specifically target MM cells, even after CD38 targeted therapy, with carefully-designed dual-split CARs directed against CD38 and CD138.
Data from A pilot study omitting radiation in the treatment of children with newly diagnosed Wnt-activated medulloblastoma
Authors: Cohen Kenneth J. , Munjapara Vasu , Aguilera Dolly , Castellino Robert C. , Stapleton Stacie L. , Landi Daniel , Ashley David M. , Rodriguez Fausto J. , Hawkins Cynthia , Yang Edward , London Wendy , Chi Susan , Bandopadhayay Pratiti
Published: September 2024

Abstract
Purpose: Treatment of wingless (WNT)-activated medulloblastoma (WNT+MB) with surgery, irradiation (XRT) and chemotherapy results in excellent outcomes. We studied the efficacy of therapy de-intensification by omitting XRT entirely in children with WNT+MB. Patients and Methods: Tumors were molecularly screened to confirm the diagnosis of WNT+MB. Eligible children were treated within 31 days following surgery with nine cycles of adjuvant chemotherapy per ACNS0331. No XRT was planned. The primary endpoint was the occurrence of relapse, progression, or death in the absence of XRT within the first two years after study enrollment. Four events in the first 10 evaluable patients would result in early study closure. Results: Fourteen children were prescreened and nine met the protocol definition of WNT+MB. Six of the nine eligible patients consented to protocol therapy and five completed planned protocol therapy. The first two children enrolled relapsed shortly after therapy completion with local and leptomeningeal recurrences. The study was closed early due to safety concerns. Both children are surviving after XRT and additional chemotherapy. A third child relapsed at completion of therapy but died of progressive disease 35 months from diagnosis. Two children finished treatment but immediately received post-treatment XRT to guard against early relapse. The final child’s treatment was aborted in favor of a high-dose therapy/stem cell rescue approach. While OS at 5 years is 83%, no child received only planned protocol therapy with all receiving eventual XRT and/or alternative therapy. Conclusions: Radiation therapy is required to effectively treat children with WNT-altered medulloblastoma.
Supplementary Tables 1-11 from Arginase 1/2 inhibitor OATD-02: from discovery to first-in-man setup in cancer immunotherapy
Authors: Borek Bartlomiej , Nowicka Julita , Gzik Anna , Dziegielewski Marek , Jedrzejczak Karol , Brzezinska Joanna , Grzybowski Marcin , Stanczak Paulina , Pomper Paulina , Zagozdzon Agnieszka , Rejczak Tomasz , Matyszewski Krzysztof , Golebiowski Adam , Olczak Jacek , Lisiecki Kamil , Tyszkiewicz Magdalena , Kania Magdalena , Piasecka Sylwia , Cabaj Anna , Dera Paulina , Mulewski Krzysztof , Chrzanowski Jacek , Kusmirek Damian , Sobolewska Elzbieta , Magdycz Marta , Mucha Lukasz , Masnyk Marek , Golab Jakub , Nowotny Marcin , Nowak Elzbieta , Napiorkowska-Gromadzka Agnieszka , Pikul Stanislaw , Jazwiec Radoslaw , Dzwonek Karolina , Dobrzanski Pawel , Meyring Michael , Skowronek Krzysztof , Iwanowski Piotr , Zaslona Zbigniew , Blaszczyk Roman
Published: September 2024

In vitro activity; data collection of hARG1 – OATD-02 complex crystal; PK data; HED and MRSD calculations; projected human exposure to OATD-02
Supplementary Fig.S3 from MTX-13, a novel PTK7-directed antibody-drug conjugate with widened therapeutic index shows sustained tumor regressions for a broader spectrum of PTK7-positive tumors
Authors: Kong Chao , Pu Junyi , Zhao Qianqian , Weng Weining , Ma Linjie , Qian Yu , Hu Wenhao , Meng Xun , Meng Tao
Published: September 2024

Supplementary Fig.S3 shows PTK7 expression in tumor tissues and cell lines
Table S2 from T cell-intrinsic immunomodulatory effects of TAK-981 (subasumstat), a SUMO-activating enzyme inhibitor, in chronic lymphocytic leukemia
Authors: Lam Vi , Roleder Carly , Liu Tingting , Bruss Nur , Best Scott , Wang Xiaoguang , Phillips Tycel , Shouse Geoffrey , Berger Allison J. , Alinari Lapo , Wang Lili , Siddiqi Tanya , Pennock Nathan D. , Danilov Alexey V.
Published: September 2024

Table S2 shows fluorochrome-conjugated anti-mouse antibodies used for flow cytometry experiments
Table S4 from Pan-cancer pharmacogenomic analysis of patient-derived tumor cells utilizing clinically relevant drug exposures
Authors: Chang Stephen H. , Ice Ryan J. , Chen Michelle , Sidorov Maxim , Woo Rinette W.L. , Rodriguez-Brotons Aida , Jian Damon , Kim Han Kyul , Kim Angela , Stone David E. , Nazarian Ari , Oh Alyssia , Tranah Gregory J. , Nosrati Mehdi , de Semir David , Dar Altaf A. , Desprez Pierre-Yves , Kashani-Sabet Mohammed , Soroceanu Liliana , McAllister Sean D.
Published: September 2024

Supplementary Table 4 LOBICO PDXC % sens vs insens
Supplementary Figure 2 from Conditional dependency of LP-184 on prostaglandin reductase 1 is synthetic lethal in pancreatic cancers with DNA damage repair deficiencies
Authors: Restifo Diana , McDermott Joseph R. , Cvetkovic Dusica , Dos Santos Troy , Ogier Charline , Surumbayeva Aizhan , Handorf Elizabeth A. , Schimke Caleb , Ma Charlie , Cai Kathy Q. , Olszanski Anthony J. , Kathad Umesh , Bhatia Kishor , Sharma Panna , Kulkarni Aditya , Astsaturov Igor
Published: September 2024

Supplementary figure 2
Data from Comparison of Three Transcytotic Pathways for Distribution to Brain Metastases of Breast Cancer
Authors: Khan Imran , Gril Brunilde , Paranjape Anurag N. , Robinson Christina M. , Difilippantonio Simone , Biernat Wojciech , Bieńkowski Michał , Pęksa Rafal , Duchnowska Renata , Jassem Jacek , Brastianos Priscilla K. , Metellus Philippe , Bialecki Emilie , Woodroofe Carolyn C. , Wu Haitao , Swenson Rolf E. , Steeg Patricia S.
Published: September 2024

Abstract
Advances in drug treatments for brain metastases of breast cancer have improved progression free survival but new, more efficacious strategies are needed. Most chemotherapeutic drugs infiltrate brain metastases by moving between brain capillary endothelial cells, paracellular distribution, resulting in heterogeneous distribution, lower than that of systemic metastases. Herein, we tested three well-known transcytotic pathways through brain capillary endothelial cells as potential avenues for drug access: Transferrin receptor (TfR) peptide, Low density lipoprotein receptor 1 (LRP1) peptide, Albumin. Each was far-red labeled, injected into two hematogenous models of brain metastases, circulated for two different times, and their uptake quantified in metastases and uninvolved (nonmetastatic) brain. Surprisingly, all three pathways demonstrated distinct distribution patterns in vivo. Two were suboptimal: TfR distributed to uninvolved brain but poorly in metastases, while LRP1 was poorly distributed. Albumin distributed to virtually all metastases in both model systems, significantly greater than in uninvolved brain (P <0.0001). Further experiments revealed that albumin entered both macrometastases and micrometastases, the targets of treatment and prevention translational strategies. Albumin uptake into brain metastases was not correlated with the uptake of a paracellular probe (biocytin). We identified a novel mechanism of albumin endocytosis through the endothelia of brain metastases consistent with clathrin-independent endocytosis (CIE), involving the neonatal Fc receptor (FcRn), galectin-3 (Gal-3) and glycosphingolipids. Components of the CIE process were found on metastatic endothelial cells in human craniotomies. The data suggest a reconsideration of albumin as a translational mechanism for improved drug delivery to brain metastases and possibly other CNS cancers.
Data from IMiDs augment CD3-bispecific antibody induced CD8+ cell cytotoxicity and expansion by enhancing IL-2 production
Authors: Li Ji , Slaga Dionysos , Johnston Jennifer , Junttila Teemu T.
Published: September 2024

Abstract
Although CD3-bispecific antibodies have demonstrated promising activity in the treatment of hematological cancers, insufficient T cell co-stimulation may limit long-term responses.
Immunomodulatory drugs (IMiDs), routinely used in treating multiple myeloma (MM), possess pleiotropic anti-myeloma properties and have been described to enhance T cell responses similar to co-stimulatory signaling and may therefore have synergistic effects when combined with T cell bispecifics. In this report, we demonstrate that IMiDs substantially enhance tumor cell killing induced by CD3-bispecifics and increase CD8+ T cell proliferation and expansion. We further show that the beneficial effects of IMiDs on T cell function and expansion are mediated by enhanced IL-2 production by CD4+ T cells. Our studies provide mechanistic insight into the co-stimulatory properties of IMiDs and support combination treatments with T cell agonist therapies in a broad spectrum of indications.
Data from Activating an Adaptive Immune Response with a Telomerase-mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma
Authors: Mender Ilgen , Siteni Silvia , Barron Summer , Flusche Ann Marie , Kubota Naoto , Yu Chunhua , Cornelius Crystal , Tedone Enzo , Maziveyi Mazvita , Grichuk Anthony , Venkateswaran Niranjan , Conacci Sorrell Maralice , Hoshida Yujin , Kang Rui , Tang Daolin , Gryaznov Sergei , Shay Jerry W.
Published: September 2024

Abstract
A select group of hepatocellular carcinomas (HCC) patients benefit from surgical, radiological, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, since HCC is generally asymptomatic in its early stages, this not only leads to late diagnosis, but also to therapy resistance. The nucleoside analogue 6-thio-dG (THIO) is a first-in-class telomerase-mediated telomere-targeting anticancer agent. In telomerase expressing cancer cells, THIO is converted into the corresponding 5’-triphosphate, which is efficiently incorporated into telomeres by telomerase, activating telomere damage responses and apoptotic pathways. Here, we show how THIO is effective in controlling tumor growth and, when combined with immune checkpoint inhibitors, is even more effective in a T-cell dependent manner. We also show telomere stress induced by THIO increases both innate sensing and adaptive anti-tumor immunity in HCC. Importantly, the extracellular HMGB1 (high-mobility group box 1) protein acts as a prototypical endogenous DAMP (Damage Associated Molecular Pattern) in eliciting adaptive immunity by THIO. These results provide a strong rationale for combining telomere-targeted therapy with immunotherapy.
Data from An oncolytic poxvirus encoding hNIS, shows anti-tumor efficacy and allows tumor imaging in a liver cancer model
Authors: Chaurasiya Shyambabu , Valencia Hannah , Zhang Zhifang , Kim Sang-In , Yang Annie , Lu Jianming , Woo Yanghee , Warner Susanne G. , Ede Nicholas J. , Fong Yuman
Published: September 2024

Abstract
Oncolytic viruses (OVs) are live viruses that can selectively replicate in cancer cells. We have engineered an OV (CF33) to make it cancer-selective through the deletion of its J2R (thymidine kinase) gene. Additionally, this virus has been armed with a reporter gene, human sodium iodide symporter (hNIS), to facilitate non-invasive imaging of tumors using positron emission tomography (PET). In this study we evaluated the oncolytic properties of the virus (CF33-hNIS) in liver cancer model, and its usefulness in tumor imaging. The virus was found to efficiently kill liver cancer cells and the virus-mediated cell death exhibited characteristics of immunogenic death based on the analysis of 3 damage associate molecular patterns (DAMPs): calreticulin, ATP and HMGB1. Furthermore, local or systemic administration of a single dose of the virus showed anti-tumor efficacy against a liver cancer xenograft model in mice and significantly increased survival of treated mice. Lastly, PET scanning was performed following injection of the radioisotope I-124, for imaging of tumors, and a single dose of virus as low as 1E03 pfu, administered intratumorally (I.T.) or intravenously (I.V.), allowed for PET imaging of tumors. In conclusion, CF33-hNIS is safe and effective in controlling human tumor xenografts in nude mice, and it also facilitates non-invasive imaging of tumors.
Data from Identification of 2′,4′,6′-Trihydroxyacetophenone as Promising Cysteine Conjugate Beta-Lyase Inhibitor for Preventing Cisplatin-Induced Nephrotoxicity
Authors: Sukeda Nao , Fujigaki Hidetsugu , Ando Tatsuya , Ando Honomi , Yamamoto Yasuko , Saito Kuniaki
Published: September 2024

Abstract
Cisplatin is a chemotherapeutic agent used to treat many types of malignant tumors. However, irrespective of its potent anticancer properties and efficacy, nephrotoxicity is the dose-limiting factor of cisplatin treatment. Cisplatin infiltrates renal tubular cells in the kidneys and is metabolized by cysteine conjugate-beta lyase 1 (CCBL1) to form highly reactive thiol-cisplatin; this may mediate cisplatin's nephrotoxicity. Therefore, CCBL1 inhibition may prevent cisplatin-induced nephrotoxicity. Using a high-throughput screening assay, we identified 2′,4′,6′-trihydroxyacetophenone (THA) as an inhibitor of CCBL1. THA inhibited human CCBL1 β-elimination activity in a concentration-dependent manner. We further investigated the preventive effect of THA on cisplatin-induced nephrotoxicity. THA attenuated the effect of cisplatin on the viability of confluent renal tubular cells (LLC-PK1 cells) but had no effect on cisplatin-induced reduction of proliferation in the tumor cell lines (LLC and MDA-MB-231). THA pretreatment significantly attenuated cisplatin-induced increases in blood urea nitrogen, creatinine, cell damage score, and apoptosis of renal tubular cells in mice in a dose-dependent manner. Furthermore, THA pretreatment attenuated cisplatin-induced nephrotoxicity without compromising its antitumor activities in mice bearing subcutaneous syngeneic LLC tumors. THA could help prevent cisplatin-induced nephrotoxicity and may provide a new strategy for cisplatin-inclusive cancer treatments.
Data from Targeting up-regulated cIAP2 in SOX10-deficient drug tolerant melanoma
Authors: Glasheen McKenna Q. , Caksa Signe , Young Amelia G. , Wilski Nicole A. , Ott Connor A. , Chervoneva Inna , Flaherty Keith T. , Herlyn Meenhard , Xu Xiaowei , Aplin Andrew E. , Capparelli Claudia
Published: September 2024

Abstract
Drug tolerance and minimal residual disease (MRD) are likely to prelude acquired resistance to targeted therapy. Mechanisms that allow persister cells to survive in the presence of targeted therapy are being characterized but selective vulnerabilities for these subpopulations remain uncertain. We identified cellular inhibitor of apoptosis protein 2 (cIAP2) as being highly expressed in SOX10-deficient drug tolerant persister (DTP) melanoma cells. Here, we show that cIAP2 is sufficient to induce tolerance to MEK inhibitors, likely by decreasing the levels of cell death. Mechanistically, cIAP2 is upregulated at the transcript level in SOX10-deficient cells and the AP-1 complex protein, JUND, is required for its expression. Using a patient-derived xenograft model, we demonstrate that treatment with the cIAP1/2 inhibitor, birinapant, during the MRD phase delays the onset of resistance to BRAF inhibitor and MEK inhibitor combination therapy. Together, our data suggest that cIAP2 upregulation in SOX10-deficient subpopulations of melanoma cells induces drug tolerance to MAPK targeting agents and provides a rationale to test a novel therapeutical approach to target MRD.
Data from Intratumoral interleukin-15 improves efficacy of near-infrared photoimmunotherapy
Authors: Fukushima Hiroshi , Furusawa Aki , Kato Takuya , Wakiyama Hiroaki , Takao Seiichiro , Okuyama Shuhei , Choyke Peter L. , Kobayashi Hisataka
Published: September 2024

Abstract
Interleukin (IL)-15 is a potent inducer of differentiation and proliferation of CD8+ T and natural killer (NK) cells, making it a promising candidate for cancer immunotherapy. However, limited efficacy of systemic monotherapy utilizing intravenous IL-15 suggests needs for alternative routes of administration or combination treatment with other therapies. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective anti-cancer treatment that elicits massive release of tumor antigens and immunogenic signals. Here, we investigated whether intratumoral IL-15 can enhance the effectiveness of cancer cell-targeted NIR-PIT using syngeneic murine tumor models. Intratumoral injection of IL-15 was more effective than intraperitoneal IL-15 in vivo in suppressing tumor growth and inducing intratumoral immune responses. When the efficacy of CD44-targeted NIR-PIT was compared in vivo between IL-15-secreting MC38 (hIL-15-MC38) and parental MC38 tumors, the hIL-15-MC38/NIR-PIT group showed the best tumor growth inhibition and survival. Additionally, the hIL-15-MC38/NIR-PIT group showed significant dendritic cell maturation and significant increases in the number and Granzyme B expression of tumor-infiltrating CD8+ T, NK, and natural killer T cells compared to the treated parental line. Furthermore, intratumoral IL-15 injection combined with CD44-targeted NIR-PIT showed significant tumor control in MC38 and Pan02-luc tumor models. In bilateral tumor models, CD44-targeted NIR-PIT in hIL-15-MC38 tumors significantly suppressed the growth of untreated MC38 tumors, suggesting abscopal effects. Mice that achieved complete response after the combination therapy completely rejected later tumor rechallenge. In conclusion, local IL-15 administration synergistically improves the efficacy of cancer cell-targeted NIR-PIT probably by inducing stronger anti-cancer immunity, indicating its potential as an anti-cancer treatment strategy.
Data from Use of Payload Binding Selectivity Enhancers to Improve Therapeutic Index of Maytansinoid-Antibody-Drug Conjugates
Authors: Nguyen Toan Duc. , Bordeau Brandon M. , Balthasar Joseph P.
Published: September 2024

Abstract
Systemic exposure to released cytotoxic payload contributes to the dose-limiting off-target toxicities of anti-cancer antibody-drug conjugates (ADC). In this work, we present an "inverse targeting" strategy to optimize the therapeutic selectivity of maytansinoid-conjugated ADCs. Several anti-maytansinoid sdAbs were generated via phage-display technology with binding IC50s between 10-60 nM. Co-incubation of DM4 with the anti-maytansinoid sdAbs shifted the IC50 of DM4 up to 250-fold. Tolerability and efficacy of 7E7-DM4 ADC, an anti-CD123 DM4-conjugated ADC, were assessed in healthy and in tumor-bearing mice, with and without co-administration of an anti-DM4 sdAb. Co-administration with anti-DM4 sdAb reduced 7E7-DM4 induced-weight loss, where the mean values of percentage weight loss at nadir for mice receiving ADC+saline and ADC+sdAb were 7.9±3% and 3.8±1.3% (p<0.05). In tumor-bearing mice, co-administration of the anti-maytansinoid sdAb did not negatively affect the efficacy of 7E7-DM4 on tumor growth or survival following dosing of the ADC at 1 mg/kg (p=0.49) or at 10 mg/kg (p = 0.9). Administration of 7E7-DM4 at 100 mg/kg led to dramatic weight loss, with 80% of treated mice succumbing to toxicity prior to the appearance of mortality relating to tumor growth in control mice. However, all mice receiving co-dosing of 100 mg/kg 7E7-DM4 with anti-DM4 sdAb were able to tolerate the treatment, which enabled reduction in tumor volume to undetectable levels and to dramatic improvements in survival. In summary, we have demonstrated the utility and feasibility of the application of anti-payload antibody fragments for inverse targeting to improve the selectivity and efficacy of anti-cancer ADC therapy.
Data from Targeted Nanofitin-drug conjugates achieve efficient tumor delivery and therapeutic effect in an EGFR-positive mouse xenograft model
Authors: Huet Simon , Zeisser Labouebe Magali , Castro Rute , Jacquot Perrine , Pedrault Jessy , Viollet Sébastien , Van Simaeys Gaetan , Doumont Gilles , Larbanoix Lionel , Zindy Egor , Cunha António E. , Scapozza Leonardo , Cinier Mathieu
Published: September 2024

Abstract
Adjusting the molecular size, the valency and the pharmacokinetics of drug conjugates are as many leverages to improve their therapeutic window, notably by affecting tumor penetration, renal clearance and short systemic exposure. In that regard, small tumor-targeting ligands are gaining attention. In this study, we demonstrate the benefits of the small Nanofitin alternative scaffolds (7 kDa) as selective tumor-targeting modules for the generation of drug conjugates, focusing on Nanofitins B10 and D8 directed against the Epithelial Growth Factor Receptor (EGFR). Owing to their small size and monovalent format, the two Nanofitins displayed a fast and deep tumor penetration in EGFR-positive A431 xenografts in BALB/c nude mice after intravenous administration, yielding to a targeting of respectively 67.9%±14.1 and 98.9%±0.7 of the tumor cells as demonstrated by immunohistochemistry. Conjugation with the monomethyl auristatin E toxin provided homogeneous Nanofitin-drug conjugates, with an overall yield of ≥97%, for in vivo assessment in a curative xenograft model using bioluminescent, EGFR-positive, A431 cells in BALB/c nude mice. Internalization was found critical for efficient release of the toxin. Hence, the intravenous administration of the D8-based construct showed significant anti-tumor effect in vivo as determined by monitoring tumor volumes and bioluminescence levels over 2 months.
Supplementary Table 6 from Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: September 2024

Normalized Read Pileup and Differential Enrichment Clusters of MOLM13 H3K27Ac CUT&Tag (6 Hours After Drug Treatment) at Enhancers and Promoters
Supplementary Table 14 from Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: September 2024

Regulon Enrichment Analysis of Primary AML Blast Bulk RNA-seq from 681 Patient Samples
Supplementary Figure S5 from Overlaid transcriptome and proteome analyses identify mitotic kinesins as important targets of arylsulfonamide-mediated RBM39 degradation
Authors: Coomar Seemon , Mota Pedro , Penson Alexander , Schwaller Juerg , Abdel-Wahab Omar , Gillingham Dennis
Published: September 2024

Supplementary Figure S5
Supplementary Figure S12 from Single-Cell Evolutionary Analysis Reveals Drivers of Plasticity and Mediators of Chemoresistance in Small Cell Lung Cancer
Authors: Wollenzien Hannah , Tecleab Yohannes Afeworki A. , Szczepaniak-Sloane Robert , Restaino Anthony , Kareta Michael S.
Published: September 2024

GAGE2A and PAGE5 upregulation upon treatment of cisplatin and etoposide.
Supplementary Table 3 from Targeting the ATF6-mediated ER stress response and autophagy blocks integrin-driven prostate cancer progression
Authors: Macke Amanda J. , Pachikov Artem N. , Divita Taylor E. , Morris Mary E. , LaGrange Chad A. , Holzapfel Melissa S. , Kubyshkin Anatoly V. , Zyablitskaya Evgeniya Y. , Makalish Tatiana P. , Eremenko Sergey N. , Qiu Haowen , Riethoven Jean-Jack M. , Hemstreet George P. , Petrosyan Armen
Published: September 2024

Supplementary Table 3. The detailed information about orthotopic surgery, tumor sizes, and metastases.
Table S1 from HCK promotes high-grade serous ovarian cancer tumorigenesis through CD44 and NOTCH3 signaling
Authors: Khella Christen A. , Franciosa Lucyann , Rodriguez-Rodriguez Lorna , Rajkarnikar Resha , Mythreye Karthikeyan , Gatza Michael L.
Published: September 2024

Summary of the IHC staining of HCK in ovarian cancer tissue microarrays.
Table S5 from CBF-beta mitigates PI3K-alpha-specific inhibitor killing through PIM1 in PIK3CA mutant gastric cancer
Authors: Stanland Lyla J. , Ang Hazel X. , Hoj Jacob P. , Chu Yunqiang , Tan Patrick , Wood Kris C. , Luftig Micah A.
Published: September 2024

Genes present in each of the 8 clusters
Supplementary Figure 8 from Competing engagement of β-arrestin isoforms balances IGF1R/p53 signaling and controls melanoma cell chemotherapeutic responsiveness
Authors: Cismas Sonia , Pasca Sylvya , Crudden Caitrin , Troccoli Drakensjo Iara , Suleymanova Naida , Zhang Simin , Gebhard Benjamin , Song Dawei , Neo Shiyong , Shibano Takashi , Smith Terry J. , Calin George A. , Girnita Ada , Girnita Leonard
Published: September 2024

Effect of β-arrestin isoform imbalance on survival of patients with metastatic melanoma.
Data from BLEACH&STAIN 15-marker multiplexed imaging in 3098 human carcinomas reveals 6 major PD-L1-driven immune phenotypes with distinct spatial orchestration
Authors: Bady Elena , Moeller Katharina , Mandelkow Tim , Raedler Jonas B. , Yang Cheng , Ebner Julia , Lurati Magalie C.J. , Simon Ronald , Vettorazzi Eik , Buescheck Franziska , Luebke Andreas M. , Dum David , Menz Anne , Sauter Guido , Hoeflmayer Doris , Weidemann Soeren , Fraune Christoph , Uhlig Ria , Bernreuther Christian , Jacobsen Frank , Clauditz Till S. , Wilczak Waldemar , Burandt Eike , Steurer Stefan , Minner Sarah , Lennartz Maximilian , Blessin Niclas C.
Published: September 2024

Abstract
Multiplex fluorescence immunohistochemistry (mfIHC) approaches were yet either limited to 6 markers or limited to a small tissue size that hampers translational studies on large tissue microarray cohorts. Here we have developed a BLEACH&STAIN mfIHC method that enabled the simultaneous analysis of 15 biomarkers (PD-L1, PD-1, CTLA-4, panCK, CD68, CD163, CD11c, iNOS, CD3, CD8, CD4, FOXP3, CD20, Ki67, CD31) in 3098 tumor samples from 44 different carcinoma entities within one week. To facilitate automated immune checkpoint quantification on tumor and immune cells and study its spatial interplay an artificial intelligence-based framework –incorporating 17 different deep-learning systems– was established. Unsupervised clustering showed that the three PD-L1 phenotypes (PD-L1+tumor and immune cells, PD-L1+immune cells, PD-L1 negative) were either inflamed or non-inflamed. In the inflamed PD-L1+patients, spatial analysis revealed that an elevated intratumoral M2-macrophages as well as CD11c+dendritic cell infiltration (p<0.001 each) was associated with a high CD3+CD4±CD8±FOXP3±T-cell exclusion and a high PD-1 expression on T-cells (p<0.001 each). In breast cancer, the PD-L1 fluorescence intensity on tumor cells showed a significantly higher predictive performance for overall survival (AUC: 0.72, p<0.001) compared to the commonly used percentage of PD-L1+ tumor cells (AUC: 0.54). In conclusion, our deep learning-based BLEACH&STAIN framework facilitates rapid and comprehensive assessment of more than 60 spatially orchestrated immune cell subpopulations and its prognostic relevance.
Implications: The development of an easy-to-use high-throughput 15+1 multiplex fluorescence approach facilitates the in-depth understanding of the immune tumor microenvironment and enables to study the prognostic relevance of more than 130 immune cell subpopulations.
Data from Triple-negative breast cancer-derived extracellular vesicles promote a hepatic pre-metastatic niche via a cascade of microenvironment remodeling
Authors: Heo Woohang , Lee Woochan , Cheun Jong Ho , Lee Eun-Shin , Li Songbin , Kim Hoe suk , Son Hye-Youn , Kim Ju Hee , Woo Yeon Duk , Chung Doo Hyun , Yun Jihui , Jung Ji Gwang , Lee Han-Byoel , Han Wonshik , Kim Hong-Kyu , Kim Jong-Il , Moon Hyeong-Gon
Published: September 2024

Abstract
Triple negative breast cancer (TNBC) patients often develop metastases in visceral organs including the liver but the detailed molecular mechanisms of TNBC liver metastasis is not clearly understood. In this study, we tried to dissect the process of pre-metastatic niche formation in liver by using patient-derived xenograft (PDX) models of TNBC with different metastatic propensity. RNA sequencing of TNBC PDX models that successfully metastasized to liver showed up-regulation of Cx3cr1 gene in the liver microenvironment. In syngeneic breast cancer models, the Cx3cr1 up-regulation in liver preceded the development of cancer cell metastasis and was the results of recruitment of CX3CR1-expressing macrophages. The recruitment was induced by the CX3CL1 production from the liver endothelial cells and this CX3CL1-CX3CR1 signaling in the pre-metastatic niche resulted in up-regulation of MMP9 that promoted macrophage migration and cancer cell invasion. Additionally, our data suggest that the extra-cellular vesicles derived from the breast cancer cells induced the TNF-alpha expression in liver which leads to the CX3CL1 up-regulation. Lastly, the plasma CX3CL1 levels in 155 breast cancer patients were significantly associated with development of liver metastasis.

Implications: Our data provides previously unknown cascades regarding the molecular education of pre-metastatic niche in liver for TNBC.