bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Comprehensive Pharmacogenomic Profiling of Malignant Pleural Mesothelioma Identifies a Subgroup Sensitive to FGFR Inhibition
Authors: Quispel-Janssen Josine M. , Badhai Jitendra , Schunselaar Laurel , Price Stacey , Brammeld Jonathan , Iorio Francesco , Kolluri Krishna , Garnett Matthew , Berns Anton , Baas Paul , McDermott Ultan , Neefjes Jacques , Alifrangis Constantine
Published: April 2023

Abstract
Purpose: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models and correlated sensitivity with a range of molecular features to detect biomarkers of drug response.

Experimental design: We utilized a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalized and primary early-passage mesothelioma lines, alongside comprehensive molecular characterization using Illumina whole-exome sequencing, copy-number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models.

Results: A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harbored genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in an MPM mouse xenograft model and by BAP1 knockdown and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. BAP1 loss was associated with activation of MAPK signaling. These associations were confirmed in a cohort of MPM patient samples.

Conclusions: A subgroup of mesotheliomas cell lines harbor sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies. Clin Cancer Res; 24(1); 84–94. ©2017 AACR.
Data from Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer
Authors: Flanagan James M. , Wilson Angela , Koo Chail , Masrour Nahal , Gallon John , Loomis Erick , Flower Kirsty , Wilhelm-Benartzi Charlotte , Hergovich Alexander , Cunnea Paula , Gabra Hani , Braicu Elena Ioana , Sehouli Jalid , Darb-Esfahani Silvia , Vanderstichele Adriaan , Vergote Ignace , Kreuzinger Caroline , Castillo-Tong Dan Cacsire , Wisman G. Bea A. , Berns Els MJJ , Siddiqui Nadeem , Paul James , Brown Robert
Published: April 2023

Abstract
Purpose: DNA damage repair can lead to epigenetic changes. DNA mismatch repair proteins bind to platinum DNA adducts and at sites of DNA damage can recruit the DNA methylating enzyme DNMT1, resulting in aberrant methylation. We hypothesised that DNA damage repair during platinum-based chemotherapy may cause aberrant DNA methylation in normal tissues of patients such as blood.

Experimental Design: We used Illumina 450k methylation arrays and bisulphite pyrosequencing to investigate methylation at presentation and relapse in blood DNA from patients with ovarian cancer enrolled in the SCOTROC1 trial (n = 247) and in a cohort of ovarian tumor DNA samples collected at first relapse (n = 46). We used an ovarian cancer cell line model to investigate the role of the DNA mismatch repair gene MLH1 in platinum-induced methylation changes.

Results: Specific CpG methylation changes in blood at relapse are observed following platinum-based chemotherapy and are associated with patient survival, independent of other clinical factors [hazard ratio, 3.7; 95% confidence interval, 1.8–7.6, P = 2.8 × 10−4]. Similar changes occur in ovarian tumors at relapse, also associated with patient survival (hazard ratio, 2.6; 95% confidence interval, 1.0–6.8, P = 0.048). Using an ovarian cancer cell line model, we demonstrate that functional mismatch repair increases the frequency of platinum-induced methylation.

Conclusions: DNA methylation in blood at relapse following chemotherapy, and not at presentation, is informative regarding survival of patients with ovarian cancer. Functional DNA mismatch repair increases the frequency of DNA methylation changes induced by platinum. DNA methylation in blood following chemotherapy could provide a noninvasive means of monitoring patients' epigenetic responses to treatment without requiring a tumor biopsy. Clin Cancer Res; 23(9); 2213–22. ©2016 AACR.
Data from DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets
Authors: Hanaford Allison R. , Archer Tenley C. , Price Antoinette , Kahlert Ulf D. , Maciaczyk Jarek , Nikkhah Guido , Kim Jong Wook , Ehrenberger Tobias , Clemons Paul A. , Dančík Vlado , Seashore-Ludlow Brinton , Viswanathan Vasanthi , Stewart Michelle L. , Rees Matthew G. , Shamji Alykhan , Schreiber Stuart , Fraenkel Ernest , Pomeroy Scott L. , Mesirov Jill P. , Tamayo Pablo , Eberhart Charles G. , Raabe Eric H.
Published: April 2023

Abstract
Purpose: We used human stem and progenitor cells to develop a genetically accurate novel model of MYC-driven Group 3 medulloblastoma. We also developed a new informatics method, Disease-model Signature versus Compound-Variety Enriched Response (“DiSCoVER”), to identify novel therapeutics that target this specific disease subtype.

Experimental Design: Human neural stem and progenitor cells derived from the cerebellar anlage were transduced with oncogenic elements associated with aggressive medulloblastoma. An in silico analysis method for screening drug sensitivity databases (DiSCoVER) was used in multiple drug sensitivity datasets. We validated the top hits from this analysis in vitro and in vivo.

Results: Human neural stem and progenitor cells transformed with c-MYC, dominant-negative p53, constitutively active AKT and hTERT formed tumors in mice that recapitulated Group 3 medulloblastoma in terms of pathology and expression profile. DiSCoVER analysis predicted that aggressive MYC-driven Group 3 medulloblastoma would be sensitive to cyclin-dependent kinase (CDK) inhibitors. The CDK 4/6 inhibitor palbociclib decreased proliferation, increased apoptosis, and significantly extended the survival of mice with orthotopic medulloblastoma xenografts.

Conclusions: We present a new method to generate genetically accurate models of rare tumors, and a companion computational methodology to find therapeutic interventions that target them. We validated our human neural stem cell model of MYC-driven Group 3 medulloblastoma and showed that CDK 4/6 inhibitors are active against this subgroup. Our results suggest that palbociclib is a potential effective treatment for poor prognosis MYC-driven Group 3 medulloblastoma tumors in carefully selected patients. Clin Cancer Res; 22(15); 3903–14. ©2016 AACR.
Data from Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib
Authors: Kraft Ira L. , Akshintala Srivandana , Zhu Yuelin , Lei Haiyan , Derse-Anthony Claudia , Dombi Eva , Steinberg Seth M. , Lodish Maya , Waguespack Steven G. , Kapustina Oxana , Fox Elizabeth , Balis Frank M. , Merino Maria J. , Meltzer Paul S. , Glod John W. , Shern Jack F. , Widemann Brigitte C.
Published: April 2023

Abstract
Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.

Experimental Design: We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression.

Results: Seventeen patients [8 male, age 13 (9–17)* years] enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1–9.7+)* years with treatment ongoing in 9 patients. Best response was partial response in 10, stable disease in 6, and progressive disease in one patient. Duration of response was 7.4 (0.6–8.7+)* and 4.9 (0.6–7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4–5.7)* years after progression. Median progression-free survival (PFS) was 6.7 years [95% confidence interval (CI): 2.3 years–undefined] and 5-year overall survival (OS) was 88.2% (95% CI: 60.6%–96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression-free survival was 6.7 years (95% CI: 3.1–undefined) and 5-year overall survival was 93.8% (95% CI: 63.2%–99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n = 11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance [*median (range)].

Conclusions: This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib. Clin Cancer Res; 24(4); 753–65. ©2017 AACR.
Data from Development of a Function-Blocking Antibody Against Fibulin-3 as a Targeted Reagent for Glioblastoma
Authors: Nandhu Mohan S. , Behera Prajna , Bhaskaran Vivek , Longo Sharon L. , Barrera-Arenas Lina M. , Sengupta Sadhak , Rodriguez-Gil Diego J. , Chiocca E. Antonio , Viapiano Mariano S.
Published: April 2023

Abstract
Purpose: We sought a novel approach against glioblastomas (GBM) focused on targeting signaling molecules localized in the tumor extracellular matrix (ECM). We investigated fibulin-3, a glycoprotein that forms the ECM scaffold of GBMs and promotes tumor progression by driving Notch and NFκB signaling.

Experimental Design: We used deletion constructs to identify a key signaling motif of fibulin-3. An mAb (mAb428.2) was generated against this epitope and extensively validated for specific detection of human fibulin-3. mAb428.2 was tested in cultures to measure its inhibitory effect on fibulin-3 signaling. Nude mice carrying subcutaneous and intracranial GBM xenografts were treated with the maximum achievable dose of mAb428.2 to measure target engagement and antitumor efficacy.

Results: We identified a critical 23-amino acid sequence of fibulin-3 that activates its signaling mechanisms. mAb428.2 binds to that epitope with nanomolar affinity and blocks the ability of fibulin-3 to activate ADAM17, Notch, and NFκB signaling in GBM cells. mAb428.2 treatment of subcutaneous GBM xenografts inhibited fibulin-3, increased tumor cell apoptosis, and enhanced the infiltration of inflammatory macrophages. The antibody reduced tumor growth and extended survival of mice carrying GBMs as well as other fibulin-3–expressing tumors. Locally infused mAb428.2 showed efficacy against intracranial GBMs, increasing tumor apoptosis and reducing tumor invasion and vascularization, which are enhanced by fibulin-3.

Conclusions: To our knowledge, this is the first rationally developed, function-blocking antibody against an ECM target in GBM. Our results offer a proof of principle for using “anti-ECM” strategies toward more efficient targeted therapies for malignant glioma. Clin Cancer Res; 24(4); 821–33. ©2017 AACR.
Data from Tamoxifen Metabolism and Efficacy in Breast Cancer: A Prospective Multicenter Trial
Authors: Neven Patrick , Jongen Lynn , Lintermans Anneleen , Van Asten Kathleen , Blomme Chantal , Lambrechts Diether , Poppe An , Wildiers Hans , Dieudonné Anne-Sophie , Brouckaert Olivier , Decloedt Jan , Berteloot Patrick , Verhoeven Didier , Joerger Markus , Vuylsteke Peter , Wynendaele Wim , Casteels Minne , Van Huffel Sabine , Lybaert Willem , Van Ginderachter Johan , Paridaens Robert , Vergote Ignace , Dezentjé Vincent Olaf , Van Calster Ben , Guchelaar Henk-Jan
Published: April 2023

Abstract
Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS).

Experimental Design: A prospective observational multicenter study included postmenopausal women with an estrogen receptor–positive breast cancer receiving first-line tamoxifen, 20 mg daily in the neoadjuvant or metastatic setting, recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS), and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS.

Results: Endoxifen levels were available for 247 of all 297 patients (83%), of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, and the OR of ORR was 1.008 per μg/L increase in endoxifen (95% confidence interval, 0.971–1.046; P = 0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS.

Conclusions: Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or metastatic setting. Clin Cancer Res; 24(10); 2312–8. ©2018 AACR.
Data from Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy
Authors: Mancarella Caterina , Pasello Michela , Ventura Selena , Grilli Andrea , Calzolari Linda , Toracchio Lisa , Lollini Pier-Luigi , Donati Davide Maria , Picci Piero , Ferrari Stefano , Scotlandi Katia
Published: April 2023

Abstract
Purpose: Large-scale sequencing studies have indicated that besides genomic alterations, the posttranscriptional regulation of gene expression or epigenetic mechanisms largely influences the clinical behavior of Ewing sarcoma. We investigated the significance of the RNA-binding protein IGF2BP3 in the regulation of Ewing sarcoma aggressiveness.

Experimental Design: Explorative study was performed in 14 patients with localized Ewing sarcoma using RNA sequencing. Next, 128 patients with localized Ewing sarcoma were divided into two cohorts. In the training set, 29 Ewing sarcoma samples were analyzed using Affymetrix GeneChip arrays. In the validation set, 99 Ewing sarcoma samples were examined using qRT-PCR. Patient-derived cell lines and experimental models were used for functional studies.

Results:Univariate and multivariate analyses indicated IGF2BP3 as a potent indicator of poor prognosis. Furthermore, ABCF1 mRNA was identified as a novel partner of IGF2BP3. Functional studies indicated IGF2BP3 as an oncogenic driver and ABCF1 mRNA as a sponge that by binding IGF2BP3, partly repressed its functions. The combined evaluation of IGF2BP3 and ABCF1 could identify different patient outcomes—high IGF2BP3 and low ABCF1 levels indicated poor survival (25%), whereas low IGF2BP3 and high ABCF1 levels indicated favorable survival (85.5%). The bromodomain and extraterminal domain inhibitor (BETi) JQ1 decreased IGF2BP3 expression, modified the expression of its validated targets and inhibited the capability of Ewing sarcoma cells to grow under anchorage-independent conditions.

Conclusions: The combined assessment of IGF2BP3 and ABCF1 predicts recurrence in Ewing sarcoma patients. Thus, for patients with high expression of IGF2BP3 and poor probability of survival, the use of BETis should be clinically evaluated. Clin Cancer Res; 24(15); 3704–16. ©2018 AACR.
Data from Precision Oncology Decision Support: Current Approaches and Strategies for the Future
Authors: Kurnit Katherine C. , Dumbrava Ecaterina E. Ileana , Litzenburger Beate , Khotskaya Yekaterina B. , Johnson Amber M. , Yap Timothy A. , Rodon Jordi , Zeng Jia , Shufean Md Abu , Bailey Ann M. , Sánchez Nora S. , Holla Vijaykumar , Mendelsohn John , Shaw Kenna Mills , Bernstam Elmer V. , Mills Gordon B. , Meric-Bernstam Funda
Published: April 2023

Abstract
With the increasing availability of genomics, routine analysis of advanced cancers is now feasible. Treatment selection is frequently guided by the molecular characteristics of a patient's tumor, and an increasing number of trials are genomically selected. Furthermore, multiple studies have demonstrated the benefit of therapies that are chosen based upon the molecular profile of a tumor. However, the rapid evolution of genomic testing platforms and emergence of new technologies make interpreting molecular testing reports more challenging. More sophisticated precision oncology decision support services are essential. This review outlines existing tools available for health care providers and precision oncology teams and highlights strategies for optimizing decision support. Specific attention is given to the assays currently available for molecular testing, as well as considerations for interpreting alteration information. This article also discusses strategies for identifying and matching patients to clinical trials, current challenges, and proposals for future development of precision oncology decision support. Clin Cancer Res; 24(12); 2719–31. ©2018 AACR.
Data from Clinical Trial Characteristics and Barriers to Participant Accrual: The MD Anderson Cancer Center Experience over 30 years, a Historical Foundation for Trial Improvement
Authors: Tang Chad , Sherman Steven I. , Price Mellanie , Weng Jun , Davis Suzanne E. , Hong David S. , Yao James C. , Buzdar Aman , Wilding George , Lee J. Jack
Published: April 2023

Abstract
Purpose: Slow-accruing clinical trials delay the translation of basic biomedical research, contribute to increasing health care costs, and may prohibit trials from reaching their original goals.

Experimental Design: We analyzed a prospectively maintained institutional database that tracks all clinical studies at the MD Anderson Cancer Center (Houston, TX). Inclusion criteria were activated phase I–III trials, maximum projected accrual ≥10 participants, and activation prior to March 25, 2011. The primary outcome was slow accrual, defined as <2 participants per year. Correlations of trial characteristics with slow accrual were assessed with logistic regression.

Results: A total of 4,269 clinical trials met inclusion criteria. Trials were activated between January 5, 1981, and March 25, 2011, with a total of 145,214 participants enrolled. Median total enrolment was 16 [interquartile range (IQR), 5–34], with an average enrolment rate of 8.7 participants per year (IQR, 3.3–17.7). There were 755 (18%) trials classified as slow accruing. On multivariable analysis, slow accrual exhibited robust associations with national cooperative group trials (OR = 4.16, P < 0.0001 vs. industry sponsored), time from trial activation to first enrolment (OR = 1.13 per month, P < 0.0001), and maximum targeted accrual (OR = 0.16 per log10 increase, P < 0.0001). Recursive partitioning analysis identified trials requiring more than 70 days (2.3 months) between activation and first participant enrolment as having higher odds of slow accrual (23% vs. 5%, OR = 5.56, P < 0.0001).

Conclusions: We identified factors associated with slow trial accrual. Given the lack of data on clinical trials at the institutional level, these data will help build a foundation from which targeted initiatives may be developed to improve the clinical trial enterprise. Clin Cancer Res; 23(6); 1414–21. ©2017 AACR.
Data from Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer
Authors: McCoach Caroline E. , Blakely Collin M. , Banks Kimberly C. , Levy Benjamin , Chue Ben M. , Raymond Victoria M. , Le Anh T. , Lee Christine E. , Diaz Joseph , Waqar Saiama N. , Purcell William T. , Aisner Dara L. , Davies Kurtis D. , Lanman Richard B. , Shaw Alice T. , Doebele Robert C.
Published: April 2023

Abstract
Purpose: Patients with advanced non–small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a noninvasive way to identify ALK fusions and actionable resistance mechanisms without an invasive biopsy.

Patients and Methods: The Guardant360 (G360; Guardant Health) deidentified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma.

Results: Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ, KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK-positive patients had no history of targeted therapy (cohort 1), with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, and 11 tissue insufficient). Follow-up of 3 of the 5 tissue-negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 to 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR-activating mutations, an ALK fusion was identified on progression (cohort 4; 4 STRN, 1 EML4; one both STRN and EML4); five harbored EGFR T790M.

Conclusions: In this cohort of cfDNA-detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a noninvasive means of detecting targetable alterations and characterizing resistance mechanisms on progression. Clin Cancer Res; 24(12); 2758–70. ©2018 AACR.
Data from Establishing a Preclinical Multidisciplinary Board for Brain Tumors
Authors: Nimmervoll Birgit V. , Boulos Nidal , Bianski Brandon , Dapper Jason , DeCuypere Michael , Shelat Anang , Terranova Sabrina , Terhune Hope E. , Gajjar Amar , Patel Yogesh T. , Freeman Burgess B. , Onar-Thomas Arzu , Stewart Clinton F. , Roussel Martine F. , Guy R. Kipling , Merchant Thomas E. , Calabrese Christopher , Wright Karen D. , Gilbertson Richard J.
Published: April 2023

Abstract
Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.

Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with “standard-of-care” surgery and radiotherapy.

Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP.

Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC. Clin Cancer Res; 24(7); 1654–66. ©2018 AACR.
Data from PBX3 Is Part of an EMT Regulatory Network and Indicates Poor Outcome in Colorectal Cancer
Authors: Lamprecht Sebastian , Kaller Markus , Schmidt Eva Marina , Blaj Cristina , Schiergens Tobias S. , Engel Jutta , Jung Andreas , Hermeking Heiko , Grünewald Thomas G.P. , Kirchner Thomas , Horst David
Published: April 2023

Abstract
Purpose: Colorectal cancers are composed of phenotypically different tumor cell subpopulations within the same core genetic background. Here, we identify high expression of the TALE transcription factor PBX3 in tumor cells undergoing epithelial–mesenchymal transition (EMT), analyze PBX3 regulation, and determine clinical associations in colorectal cancer.

Experimental design: We used transcriptomic and in situ analyses to identify PBX3 expression in colorectal cancer and cell biology approaches to determine its regulation and function. Clinical associations were analyzed in independent tissue collections and gene expression datasets of colorectal cancers with recorded follow-up data.

Results: PBX3 was expressed in tumor cells with high WNT activity undergoing EMT at the leading tumor edge of colorectal cancers, whereas stromal cells were PBX3 negative. PBX3 expression was induced by WNT activation and by the EMT transcription factors SNAIL and ZEB1, whereas these effects were mediated indirectly through microRNA miR-200. PBX3 was required for a full EMT phenotype in colon cancer cells. On the protein level, PBX3 expression indicated poor cancer-specific and disease-free survival in a cohort of 244 UICC stage II colorectal cancers, and was associated with metastasis in a case–control collection consisting of 90 cases with or without distant metastasis. On the mRNA level, high PBX3 expression was strongly linked to poor disease-free survival.

Conclusions: PBX3 is a novel indicator of EMT in colorectal cancer, part of an EMT regulatory network, and a promising prognostic predictor that may aid in therapeutic decision making for patients with colorectal cancer. Clin Cancer Res; 24(8); 1974–86. ©2018 AACR.
Data from BQ323636.1, a Novel Splice Variant to NCOR2, as a Predictor for Tamoxifen-Resistant Breast Cancer
Authors: Gong Chun , Man Ellen P.S. , Tsoi Ho , Lee Terence K.W. , Lee Paul , Ma Sai-Ting , Wong Lai-San , Luk Mai-Yee , Rakha Emad A. , Green Andrew R. , Ellis Ian O. , Lam Eric W.-F. , Cheung Kwok-Leung , Khoo Ui-Soon
Published: April 2023

Abstract
Purpose: Adjuvant tamoxifen treatment revolutionized the management of estrogen receptor (ER)–positive breast cancers to prevent cancer recurrence; however, drug resistance compromises its clinical efficacy. The mechanisms underlying tamoxifen resistance are not fully understood, and no robust biomarker is available to reliably predict those who will be resistant. Here, we study BQ323636.1, a novel splice variant of the NCOR2 gene, and evaluate its efficacy in predicting tamoxifen resistance in patients with breast cancer.

Experimental Design: A monoclonal anti-BQ323636.1 antibody that specifically recognizes the unique epitope of this splice variant was generated for in vitro mechanistic studies and for in vivo analysis by immunohistochemistry on tissue microarrays of two independent cohorts of 358 patients with more than 10 years clinical follow-up data, who had ER-positive primary breast cancer and received adjuvant tamoxifen treatment. An orthotopic mouse model was also used.

Results: Overexpression of BQ323636.1 conferred resistance to tamoxifen in both in vitro and in an orthotopic mouse model. Mechanistically, coimmunoprecipitation showed BQ323636.1 could bind to NCOR2 and inhibit the formation of corepressor complex for the suppression of ER signaling. Nuclear BQ3232636.1 overexpression in patients samples was significantly associated with tamoxifen resistance (P = 1.79 × 10−6, sensitivity 52.9%, specificity 72.0%). In tamoxifen-treated patients, nuclear BQ323636.1 overexpression was significantly correlated with cancer metastasis and disease relapse. Nuclear BQ323636.1 was also significantly associated with poorer overall survival (P = 1.13 × 10−4) and disease-specific survival (P = 4.02 × 10−5).

Conclusions: These findings demonstrate that BQ323636.1 can be a reliable biomarker to predict tamoxifen resistance in patients with ER-positive breast cancer. Clin Cancer Res; 24(15); 3681–91. ©2018 AACR.

See related commentary by Jordan, p. 3480
Data from HER3-Mediated Resistance to Hsp90 Inhibition Detected in Breast Cancer Xenografts by Affibody-Based PET Imaging
Authors: Martins Carlos D. , Da Pieve Chiara , Burley Thomas A. , Smith Rhodri , Ciobota Daniela M. , Allott Louis , Harrington Kevin J. , Oyen Wim J.G. , Smith Graham , Kramer-Marek Gabriela
Published: April 2023

Abstract
Purpose: Recent studies have highlighted a role of HER3 in HER2-driven cancers (e.g., breast cancer), implicating the upregulation of the receptor in resistance to HER-targeted therapies and Hsp90 inhibitors (e.g., AUY922). Therefore, we have developed an affibody-based PET radioconjugate that quantitatively assesses HER3 changes induced by Hsp90 inhibition in vivo.

Experimental Design: ZHER3:8698 affibody molecules were conjugated via the C-terminus cysteine to DFO-maleimide for 89Zr radiolabeling. The probe was characterized in vitro and in vivo in a panel of human breast cell lines and xenograft models with varying HER3 receptor levels. In addition, the radioconjugate was investigated as a tool to monitor the outcome of AUY922, an Hsp90 inhibitor, in an MCF-7 xenograft model.

Results: We demonstrated that 89Zr-DFO-ZHER3:8698 can track changes in receptor expression in HER3-positive xenograft models and monitor the outcome of AUY922 treatment. Our in vitro findings showed that MCF-7 cells, which are phenotypically different from BT474, develop resistance to treatment with AUY922 through HER3/IGF-1Rβ–mediated signaling. Of note, the lack of response in vitro due to HER3 recovery was confirmed in vivo using 89Zr-DFO-ZHER3:8698–based imaging. Upon AUY922 treatment, higher radioconjugate uptake was detected in treated MCF-7 xenografts, correlating with an AUY922-induced HER3 upregulation concomitant with an increase in IGF-1Rβ expression.

Conclusions: These data underline the potential of HER3-based PET imaging to noninvasively provide information about HER3 expression and to identify patients not responding to targeted therapies due to HER3 recovery. Clin Cancer Res; 24(8); 1853–65. ©2018 AACR.
Data from Further Investigation of the Role of ACYP2 and WFS1 Pharmacogenomic Variants in the Development of Cisplatin-Induced Ototoxicity in Testicular Cancer Patients
Authors: Drögemöller Britt I. , Brooks Beth , Critchley Carol , Monzon José G. , Wright Galen E.B. , Liu Geoffrey , Renouf Daniel J. , Kollmannsberger Christian K. , Bedard Philippe L. , Hayden Michael R. , Gelmon Karen A. , Carleton Bruce C. , Ross Colin J.D.
Published: April 2023

Abstract
Purpose: Adverse drug reactions such as ototoxicity, which occurs in approximately one-fifth of adult patients who receive cisplatin treatment, can incur large socioeconomic burdens on patients with testicular cancer who develop this cancer during early adulthood. Recent genome-wide association studies have identified genetic variants in ACYP2 and WFS1 that are associated with cisplatin-induced ototoxicity. We sought to explore the role of these genetic susceptibility factors to cisplatin-induced ototoxicity in patients with testicular cancer.

Experimental Design: Extensive clinical and demographic data were collected for 229 patients with testicular cancer treated with cisplatin. Patients were genotyped for two variants, ACYP2 rs1872328 and WFS1 rs62283056, that have previously been associated with hearing loss in cisplatin-treated patients. Analyses were performed to investigate the association of these variants with ototoxicity in this cohort of adult patients with testicular cancer.

Results: Pharmacogenomic analyses revealed that ACYP2 rs1872328 was significantly associated with cisplatin-induced ototoxicity [P = 2.83 × 10−3, OR (95% CI):14.7 (2.6–84.2)]. WFS1 rs62283056 was not significantly associated with ototoxicity caused by cisplatin (P = 0.39); however, this variant was associated with hearing loss attributable to any cause [P = 5.67 × 10−3, OR (95% CI): 3.2 (1.4–7.7)].

Conclusions: This study has provided the first evidence for the role of ACYP2 rs1872328 in cisplatin-induced ototoxicity in patients with testicular cancer. These results support the use of this information to guide the development of strategies to prevent cisplatin-induced ototoxicity across cancers. Further, this study has highlighted the importance of phenotypic differences in replication studies and has provided further evidence for the role of WFS1 rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment. Clin Cancer Res; 24(8); 1866–71. ©2018 AACR.
Data from Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA
Authors: Goldberg Sarah B. , Narayan Azeet , Kole Adam J. , Decker Roy H. , Teysir Jimmitti , Carriero Nicholas J. , Lee Angela , Nemati Roxanne , Nath Sameer K. , Mane Shrikant M. , Deng Yanhong , Sukumar Nitin , Zelterman Daniel , Boffa Daniel J. , Politi Katerina , Gettinger Scott N. , Wilson Lynn D. , Herbst Roy S. , Patel Abhijit A.
Published: April 2023

Abstract
Purpose: Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy.

Experimental Design: We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 patients with metastatic non–small cell lung cancer (NSCLC) receiving immune checkpoint inhibitor therapy. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multigene next-generation sequencing assay. We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement.

Results: Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753). Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA versus 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders versus nonresponders (median, 205.5 vs. 69 days; P < 0.001). A ctDNA response was associated with superior progression-free survival [hazard ratio (HR), 0.29; 95% CI, 0.09–0.89; P = 0.03], and superior overall survival (HR, 0.17; 95% CI, 0.05–0.62; P = 0.007).

Conclusions: A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC. Clin Cancer Res; 24(8); 1872–80. ©2018 AACR.
Data from Dual Inhibition of PIK3C3 and FGFR as a New Therapeutic Approach to Treat Bladder Cancer
Authors: Chen Chun-Han , Changou Chun A. , Hsieh Tsung-Han , Lee Yu-Ching , Chu Cheng-Ying , Hsu Kai-Cheng , Wang Hao-Ching , Lin Yu-Chen , Lo Yan-Ni , Liu Yun-Ru , Liou Jing-Ping , Yen Yun
Published: April 2023

Abstract
Purpose: MPT0L145 has been developed as a FGFR inhibitor exhibiting significant anti-bladder cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms.

Experimental Design: Autophagy flux, morphology, and intracellular organelles were evaluated by Western blotting, transmission electron microscope, and fluorescence microscope. Molecular docking and surface plasmon resonance assay were performed to identify drug–protein interaction. Lentiviral delivery of cDNA or shRNA and CRISPR/Cas9-mediated genome editing was used to modulate gene expression. Mitochondrial oxygen consumption rate was measured by a Seahorse XFe24 extracellular flux analyzer, and ROS level was measured by flow cytometry.

Results: MPT0L145 persistently increased incomplete autophagy and phase-lucent vacuoles at the perinuclear region, which were identified as enlarged and alkalinized late-endosomes. Screening of a panel of lipid kinases revealed that MPT0L145 strongly inhibits PIK3C3 with a Kd value of 0.53 nmol/L. Ectopic expression of PIK3C3 reversed MPT0L145-increased cell death and incomplete autophagy. Four residues (Y670, F684, I760, D761) at the ATP-binding site of PIK3C3 are important for the binding of MPT0L145. In addition, MPT0L145 promotes mitochondrial dysfunction, ROS production, and DNA damage, which may in part, contribute to cell death. ATG5-knockout rescued MPT0L145-induced cell death, suggesting simultaneous induction of autophagy is crucial to its anticancer activity. Finally, our data demonstrated that MPT0L145 is able to overcome cisplatin resistance in bladder cancer cells.

Conclusions: MPT0L145 is a first-in-class PIK3C3/FGFR inhibitor, providing an innovative strategy to design new compounds that increase autophagy, but simultaneously perturb its process to promote bladder cancer cell death. Clin Cancer Res; 24(5); 1176–89. ©2017 AACR.
Data from Vitamin D–Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating the Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription
Authors: Huang Yu-Fang , Wu Yi-Hui , Cheng Wen-Fang , Peng Shu-Ling , Shen Wan-Lin , Chou Cheng-Yang
Published: April 2023

Abstract
Purpose: Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D–binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC.

Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines.

Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor–binding protein-2/Akt axis, and induced suppression of vitamin D–responsive genes. A NF-κB p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation.

Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC. Clin Cancer Res; 24(13); 3217–28. ©2018 AACR.
Data from Prediction of the Optimal Dosing Regimen Using a Mathematical Model of Tumor Uptake for Immunocytokine-Based Cancer Immunotherapy
Authors: Ribba Benjamin , Boetsch Christophe , Nayak Tapan , Grimm Hans Peter , Charo Jehad , Evers Stefan , Klein Christian , Tessier Jean , Charoin Jean Eric , Phipps Alex , Pisa Pavel , Teichgräber Volker
Published: April 2023

Abstract
Purpose: Optimal dosing is critical for immunocytokine-based cancer immunotherapy to maximize efficacy and minimize toxicity. Cergutuzumab amunaleukin (CEA-IL2v) is a novel CEA-targeted immunocytokine. We set out to develop a mathematical model to predict intratumoral CEA-IL2v concentrations following various systemic dosing intensities.

Experimental Design: Sequential measurements of CEA-IL2v plasma concentrations in 74 patients with solid tumors were applied in a series of differential equations to devise a model that also incorporates the peripheral concentrations of IL2 receptor–positive cell populations (i.e., CD8+, CD4+, NK, and B cells), which affect tumor bioavailability of CEA-IL2v. Imaging data from a subset of 14 patients were subsequently utilized to additionally predict antibody uptake in tumor tissues.

Results: We created a pharmacokinetic/pharmacodynamic mathematical model that incorporates the expansion of IL2R-positive target cells at multiple dose levels and different schedules of CEA-IL2v. Model-based prediction of drug levels correlated with the concentration of IL2R-positive cells in the peripheral blood of patients. The pharmacokinetic model was further refined and extended by adding a model of antibody uptake, which is based on drug dose and the biological properties of the tumor. In silico predictions of our model correlated with imaging data and demonstrated that a dose-dense schedule comprising escalating doses and shortened intervals of drug administration can improve intratumoral drug uptake and overcome consumption of CEA-IL2v by the expanding population of IL2R-positive cells.

Conclusions: The model presented here allows simulation of individualized treatment plans for optimal dosing and scheduling of immunocytokines for anticancer immunotherapy. Clin Cancer Res; 24(14); 3325–33. ©2018 AACR.

See related commentary by Ruiz-Cerdá et al., p. 3236
Data from A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma
Authors: Magrangeas Florence , Kuiper Rowan , Avet-Loiseau Hervé , Gouraud Wilfried , Guérin-Charbonnel Catherine , Ferrer Ludovic , Aussem Alexandre , Elghazel Haytham , Suhard Jérôme , Der Sakissian Henri , Attal Michel , Munshi Nikhil C. , Sonneveld Pieter , Dumontet Charles , Moreau Philippe , van Duin Mark , Campion Loïc , Minvielle Stéphane
Published: April 2023

Abstract
Purpose: Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy. This study aimed to identify loci that affect susceptibility to this toxicity.

Experimental Design: A genome-wide association study (GWAS) of 370,605 SNPs was performed to identify risk variants for developing severe bortezomib-induced peripheral neuropathy (BiPN) in 469 patients with multiple myeloma who received bortezomib–dexamethasone therapy prior to autologous stem cell in randomized clinical trials of the Intergroupe Francophone du Myelome (IFM) and findings were replicated in 114 patients with multiple myeloma of the HOVON-65/GMMG-HD4 clinical trial.

Results: An SNP in the PKNOX1 gene was associated with BiPN in the exploratory cohort [rs2839629; OR, 1.89, 95% confidence interval (CI), 1.45–2.44; P = 7.6 × 10−6] and in the replication cohort (OR, 2.04; 95% CI, = 1.11–3.33; P = 8.3 × 10−3). In addition, rs2839629 is in strong linkage disequilibrium (r2 = 0.87) with rs915854, located in the intergenic region between PKNOX1 and cystathionine-ß-synthetase (CBS). Expression quantitative trait loci mapping showed that both rs2839629 and rs915854 genotypes have an impact on PKNOX1 expression in nerve tissue, whereas rs2839629 affects CBS expression in skin and blood.

Conclusions: The use of GWAS in multiple myeloma pharmacogenomics has identified a novel candidate genetic locus mapping to PKNOX1 and in the immediate vicinity of CBS at 21q22.3 associated with the severe bortezomib-induced toxicity. The proximity of these two genes involved in neurologic pain whose tissue-specific expression is modified by the two variants provides new targets for neuroprotective strategies. Clin Cancer Res; 22(17); 4350–5. ©2016 AACR.
Data from TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer
Authors: Mercogliano María F. , De Martino Mara , Venturutti Leandro , Rivas Martín A. , Proietti Cecilia J. , Inurrigarro Gloria , Frahm Isabel , Allemand Daniel H. , Deza Ernesto Gil , Ares Sandra , Gercovich Felipe G. , Guzmán Pablo , Roa Juan C. , Elizalde Patricia V. , Schillaci Roxana
Published: April 2023

Abstract
Purpose: Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it.

Experimental Design: Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab.

Results: TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008).

Conclusions: We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636–48. ©2016 AACR.