bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Insurance Clearance for Early-Phase Oncology Clinical Trials Following the Affordable Care Act
Authors: Kehl Kenneth L. , Fullmer Cheryl P. , Fu Siqing , George Goldy C. , Hess Kenneth R. , Janku Filip , Karp Daniel D. , Kato Shumei , Kizer Cynthia K. , Kurzrock Razelle , Naing Aung , Pant Shubham , Piha-Paul Sarina A. , Subbiah Vivek , Tsimberidou Apostolia M. , Hong David S.
Published: April 2023

Abstract
Purpose: The Affordable Care Act (ACA) required that private insurance plans allow clinical trial participation and cover standard-of-care costs, but the impact of this provision has not been well-characterized. We assessed rates of insurance clearance for trial participation within our large early-phase clinical trials program, before and after implementation of the requirement.

Experimental Design: We analyzed the departmental database for the Clinical Center for Targeted Therapy (CCTT) at MD Anderson Cancer Center (Houston, TX). Among patients referred for sponsored trials, we described rates of insurance clearance and prolonged time to clearance (at least 14 days) from July 2012 to June 2013 (baseline), July 2013–December 2013 (following CCTT staffing changes in July 2103), and January 2014–June 2015 (following implementation of the ACA). We used multivariable logistic regression models to compare rates across these time periods.

Results: We identified 2,404 referrals for insurance clearance. Among privately insured patients, insurance clearance rates were higher for those referred from January 2014 to June 2015 than for those referred from July 2012 to June 2013 (OR, 4.72; 95% CI, 2.96–7.51). There was no association between referral period and clearance rates for Medicare/Medicaid patients (P = 0.25). Referral from January 2014 to June 2015 was associated with lower rates of prolonged clearance among both privately insured (OR 0.57; 95% CI, 0.38–0.86) and Medicare/Medicaid patients (OR 0.39; 95% CI, 0.19–0.83).

Conclusions: Within our large early-phase clinical trials program, insurance clearance rates among privately insured patients improved following implementation of the ACA's requirement for coverage of standard-of-care costs. Clin Cancer Res; 23(15); 4155–62. ©2017 AACR.
Data from Comprehensive Genetic Characterization of Human Thyroid Cancer Cell Lines: A Validated Panel for Preclinical Studies
Authors: Landa Iñigo , Pozdeyev Nikita , Korch Christopher , Marlow Laura A. , Smallridge Robert C. , Copland John A. , Henderson Ying C. , Lai Stephen Y. , Clayman Gary L. , Onoda Naoyoshi , Tan Aik Choon , Garcia-Rendueles Maria E.R. , Knauf Jeffrey A. , Haugen Bryan R. , Fagin James A. , Schweppe Rebecca E.
Published: April 2023

AbstractPurpose:
Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers.
Experimental Design:
We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers.
Results:
Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAFV600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization.
Conclusions:
This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.
Data from Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target
Authors: Perales-Puchalt Alfredo , Svoronos Nikolaos , Rutkowski Melanie R. , Allegrezza Michael J. , Tesone Amelia J. , Payne Kyle K. , Wickramasinghe Jayamanna , Nguyen Jenny M. , O'Brien Shane W. , Gumireddy Kiranmai , Huang Qihong , Cadungog Mark G. , Connolly Denise C. , Tchou Julia , Curiel Tyler J. , Conejo-Garcia Jose R.
Published: April 2023

Abstract
Purpose: To define the safety and effectiveness of T cells redirected against follicle-stimulating hormone receptor (FSHR)-expressing ovarian cancer cells.

Experimental Design: FSHR expression was determined by Western blotting, immunohistochemistry, and qPCR in 77 human ovarian cancer specimens from 6 different histologic subtypes and 20 human healthy tissues. The effectiveness of human T cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T cells.

Results: FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. Accordingly, T cells expressing full-length FSHR-redirected chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo. In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T cells persisted as memory lymphocytes without noticeable PD-1–dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor–transduced T cells away from targeted tumor cells.

Conclusions: T cells redirected against FSHR+ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries. Clin Cancer Res; 23(2); 441–53. ©2016 AACR.
Data from Noninvasive Imaging of Cycling Hypoxia in Head and Neck Cancer Using Intrinsic Susceptibility MRI
Authors: Panek Rafal , Welsh Liam , Baker Lauren C.J. , Schmidt Maria A. , Wong Kee H. , Riddell Angela M. , Koh Dow-Mu , Dunlop Alex , Mcquaid Dualta , d'Arcy James A. , Bhide Shreerang A. , Harrington Kevin J. , Nutting Christopher M. , Hopkinson Georgina , Richardson Cheryl , Box Carol , Eccles Suzanne A. , Leach Martin O. , Robinson Simon P. , Newbold Kate L.
Published: April 2023

Abstract
Purpose: To evaluate intrinsic susceptibility (IS) MRI for the identification of cycling hypoxia, and the assessment of its extent and spatial distribution, in head and neck squamous cell carcinoma (HNSCC) xenografts and patients.

Experimental Design: Quantitation of the transverse relaxation rate, R2*, which is sensitive to paramagnetic deoxyhemoglobin, using serial IS-MRI acquisitions, was used to monitor temporal oscillations in levels of paramagnetic deoxyhemoglobin in human CALR xenografts and patients with HNSCC at 3T. Autocovariance and power spectrum analysis of variations in R2* was performed for each imaged voxel, to assess statistical significance and frequencies of cycling changes in tumor blood oxygenation. Pathologic correlates with tumor perfusion (Hoechst 33342), hypoxia (pimonidazole), and vascular density (CD31) were sought in the xenografts, and dynamic contrast-enhanced (DCE) MRI was used to assess patient tumor vascularization. The prevalence of fluctuations within patient tumors, DCE parameters, and treatment outcome were reported.

Results: Spontaneous R2* fluctuations with a median periodicity of 15 minutes were detected in both xenografts and patient tumors. Spatially, these fluctuations were predominantly associated with regions of heterogeneous perfusion and hypoxia in the CALR xenografts. In patients, R2* fluctuations spatially correlated with regions of lymph nodes with low Ktrans values, typically in the vicinity of necrotic cores.

Conclusions: IS-MRI can be used to monitor variations in levels of paramagnetic deoxyhemoglobin, associated with cycling hypoxia. The presence of such fluctuations may be linked with impaired tumor vasculature, the presence of which may impact treatment outcome. Clin Cancer Res; 23(15); 4233–41. ©2017 AACR.
Data from Cross-talk between T Cells and Hematopoietic Stem Cells during Adoptive Cellular Therapy for Malignant Glioma
Authors: Wildes Tyler J. , Grippin Adam , Dyson Kyle A. , Wummer Brandon M. , Damiani David J. , Abraham Rebecca S. , Flores Catherine T. , Mitchell Duane A.
Published: April 2023

Abstract
Purpose: Adoptive T-cell immunotherapy (ACT) has emerged as a viable therapeutic for peripheral and central nervous system (CNS) tumors. In peripheral cancers, optimal efficacy of ACT is reliant on dendritic cells (DCs) in the tumor microenvironment. However, the CNS is largely devoid of resident migratory DCs to function as antigen-presenting cells during immunotherapy. Herein, we demonstrate that cellular interactions between adoptively transferred tumor-reactive T cells and bone marrow–derived hematopoietic stem and progenitor cells (HSPCs) lead to the generation of potent intratumoral DCs within the CNS compartment.

Experimental Design: We evaluated HSPC differentiation during ACT in vivo in glioma-bearing hosts and HSPC proliferation and differentiation in vitro using a T-cell coculture system. We utilized FACS, ELISAs, and gene expression profiling to study the phenotype and function of HSPC-derived cells ex vivo and in vivo. To demonstrate the impact of HSPC differentiation and function on antitumor efficacy, we performed survival experiments.

Results: Transfer of HSPCs with concomitant ACT led to the production of activated CD86+CD11c+MHCII+ cells consistent with DC phenotype and function within the brain tumor microenvironment. These intratumoral DCs largely supplanted abundant host myeloid-derived suppressor cells. We determined that during ACT, HSPC-derived cells in gliomas rely on T-cell–released IFNγ to differentiate into DCs, activate T cells, and reject intracranial tumors.

Conclusions: Our data support the use of HSPCs as a novel cellular therapy. Although DC vaccines induce robust immune responses in the periphery, our data demonstrate that HSPC transfer uniquely generates intratumoral DCs that potentiate T-cell responses and promote glioma rejection in situ. Clin Cancer Res; 24(16); 3955–66. ©2018 AACR.
Data from Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma
Authors: Delord Jean-Pierre , Robert Caroline , Nyakas Marta , McArthur Grant A. , Kudchakar Ragini , Mahipal Amit , Yamada Yasuhide , Sullivan Ryan , Arance Ana , Kefford Richard F. , Carlino Matteo S. , Hidalgo Manuel , Gomez-Roca Carlos , Michel Daniela , Seroutou Abdelkader , Aslanis Vassilios , Caponigro Giordano , Stuart Darrin D. , Moutouh-de Parseval Laure , Demuth Tim , Dummer Reinhard
Published: April 2023

Abstract
Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated BRAF-mutant melanoma.

Experimental Design: The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50–700 mg) or twice-daily (75–150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib.

Results: Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF V600E–mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar–plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months [95% confidence interval (CI), 7.4–not reached (NR)]. In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9–3.7).

Conclusions: Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. Clin Cancer Res; 23(18); 5339–48. ©2017 AACR.
Data from FOXM1 and FOXQ1 Are Promising Prognostic Biomarkers and Novel Targets of Tumor-Suppressive miR-342 in Human Colorectal Cancer
Authors: Weng Wenhao , Okugawa Yoshinaga , Toden Shusuke , Toiyama Yuji , Kusunoki Masato , Goel Ajay
Published: April 2023

Abstract
Purpose: Colorectal cancer ranks as the third most frequent cancer type, and its incidence continues to rise gradually worldwide, highlighting the need to identify previously unrecognized molecular events that propel development of this malignancy. Recent evidence suggests that dysregulated expression of FOX family of transcription factors may be critical in various genetic disorders as well as cancer; however, the functional and clinical significance of this pathway in colorectal cancer remains unclear.

Experimental Design and Results: Herein, we performed a systematic and comprehensive discovery step by evaluating the expression of FOX family members, and identified that FOXM1 and FOXQ1 are frequently overexpressed in colorectal cancer. We subsequently confirmed these findings in two large testing cohorts (n = 550) and an independent clinical validation cohort (n = 134), in which high expression of FOXM1 and FOXQ1 emerged as an independent prognostic factor in colorectal cancer patients. We corroborated these findings by performing functional assays in which knockdown of FOXM1 and FOXQ1 resulted in inhibited cell proliferation and suppressed migration and invasion in colorectal cancer cells. Furthermore, using bioinformatic approaches, we identified miR-342 as a novel regulator of both FOXM1 and FOXQ1. Overexpression or inhibition of miR-342 modulated the expression of both genes and contributed to phenotypic alterations in colorectal cancer cells, which was subsequently validated in a xenograft animal model.

Conclusions: Collectively, we have firstly identified FOXM1 and FOXQ1 as promising prognostic biomarkers in colorectal cancer patients, and provided novel evidence that therapeutic targeting of these genes or miR-342 may be a potential treatment approach in colorectal cancer patients. Clin Cancer Res; 22(19); 4947–57. ©2016 AACR.
Data from IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells
Authors: McMichael Elizabeth L. , Jaime-Ramirez Alena Cristina , Guenterberg Kristan D. , Luedke Eric , Atwal Lakhvir S. , Campbell Amanda R. , Hu Zhiwei , Tatum Armika S. , Kondadasula Sri Vidya , Mo Xiaokui , Tridandapani Susheela , Bloomston Mark , Ellison E. Christopher , Williams Terence M. , Bekaii-Saab Tanios , Carson William E.
Published: April 2023

Abstract
Purpose: Alternative strategies to EGFR blockage by mAbs is necessary to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status.

Experimental Design: NK cells from normal donors or donors with pancreatic cancer were used to assess ADCC, IFN-γ release, and T-cell chemotaxis toward human pancreatic cancer cell lines. The in vivo efficacy of IL-21 in combination with cetuximab was evaluated in a subcutaneous and intraperitoneal model of pancreatic cancer.

Results: NK cell lysis of cetuximab-coated wild-type and mutant kras pancreatic cancer cell lines were significantly higher following NK cell IL-21 treatment. In response to cetuximab-coated pancreatic tumor cells, IL-21–treated NK cells secreted significantly higher levels of IFN-γ and chemokines, increased chemotaxis of T cells, and enhanced NK cell signal transduction via activation of ERK and STAT1. Treatment of mice bearing subcutaneous or intraperitoneal EGFR-positive pancreatic tumor xenografts with mIL-21 and cetuximab led to significant inhibition of tumor growth, a result further enhanced by the addition of gemcitabine.

Conclusions: These results suggest that cetuximab treatment in combination with IL-21 adjuvant therapy in patients with EGFR-positive pancreatic cancer results in significant NK cell activation, irrespective of KRAS mutation status, and may be a potential therapeutic strategy. Clin Cancer Res; 23(2); 489–502. ©2016 AACR.
Data from Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma
Authors: Bhatia Shailender , Miller Natalie J. , Lu Hailing , Longino Natalie V. , Ibrani Dafina , Shinohara Michi M. , Byrd David R. , Parvathaneni Upendra , Kulikauskas Rima , ter Meulen Jan , Hsu Frank J. , Koelle David M. , Nghiem Paul
Published: April 2023

AbstractPurpose:
G100 is a toll-like receptor 4 (TLR4) agonist that triggers innate and adaptive antitumor immune responses in preclinical models. This pilot study assessed the safety, efficacy, and immunologic activity of intratumoral (IT) administration of G100 in patients with Merkel cell carcinoma (MCC).
Patients and Methods:
Patients with locoregional MCC (n = 3; cohort A) received neoadjuvant IT G100 (2 weekly doses at 5 μg/dose) followed by surgery and radiotherapy; patients with metastatic MCC (n = 7; cohort B) received 3 doses in a 6-week cycle and could receive additional cycles with/without radiotherapy.
Results:
IT G100 was safe and feasible in both neoadjuvant and metastatic settings. Treatment-related adverse events were mostly grade 1 or 2 injection-site reactions. IT G100 led to increased inflammation in the injected tumors with infiltration of CD8+ and CD4+ T cells and activation of immune-related genes. These proinflammatory changes were associated with local tumor regression and appeared to promote systemic immunity. All 3 cohort A patients successfully completed therapy; 2 patients remain recurrence free at 44+ and 41+ months, including 1 with a pathologic complete response after G100 alone. In cohort B, 2 patients achieved sustained partial responses, both lasting 33+ months after 2 cycles of therapy.
Conclusions:
In this first-in-human study, IT G100 induced antitumor immune responses, demonstrated acceptable safety, and showed encouraging clinical activity.

See related commentary by Marquez-Rodas et al., p. 1127
Data from Biochemical, Molecular, and Clinical Characterization of Succinate Dehydrogenase Subunit A Variants of Unknown Significance
Authors: Bannon Amber E. , Kent Jason , Forquer Isaac , Town Ajia , Klug Lillian R. , McCann Kelly , Beadling Carol , Harismendy Oliver , Sicklick Jason K. , Corless Christopher , Shinde Ujwal , Heinrich Michael C.
Published: April 2023

Abstract
Purpose: Patients who inherit a pathogenic loss-of-function genetic variant involving one of the four succinate dehydrogenase (SDH) subunit genes have up to an 86% chance of developing one or more cancers by the age of 50. If tumors are identified and removed early in these high-risk patients, they have a higher potential for cure. Unfortunately, many alterations identified in these genes are variants of unknown significance (VUS), confounding the identification of high-risk patients. If we could identify misclassified SDH VUS as benign or pathogenic SDH mutations, we could better select patients for cancer screening procedures and remove tumors at earlier stages.

Experimental Design: In this study, we combine data from clinical observations, a functional yeast model, and a computational model to determine the pathogenicity of 22 SDHA VUS. We gathered SDHA VUS from two primary sources: The OHSU Knight Diagnostics Laboratory and the literature. We used a yeast model to identify the functional effect of a VUS on mitochondrial function with a variety of biochemical assays. The computational model was used to visualize variants' effect on protein structure.

Results: We were able to draw conclusions on functional effects of variants using our three-prong approach to understanding VUS. We determined that 16 (73%) of the alterations are actually pathogenic, causing loss of SDH function, and six (27%) have no effect upon SDH function.

Conclusions: We thus report the reclassification of the majority of the VUS tested as pathogenic, and highlight the need for more thorough functional assessment of inherited SDH variants. Clin Cancer Res; 23(21); 6733–43. ©2017 AACR.
Data from Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate
Authors: Kato Shumei , Goodman Aaron , Walavalkar Vighnesh , Barkauskas Donald A. , Sharabi Andrew , Kurzrock Razelle
Published: April 2023

Abstract
Purpose: Checkpoint inhibitors demonstrate salutary anticancer effects, including long-term remissions. PD-L1 expression/amplification, high mutational burden, and mismatch repair deficiency correlate with response. We have, however, observed a subset of patients who appear to be “hyperprogressors,” with a greatly accelerated rate of tumor growth and clinical deterioration compared with pretherapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with “hyperprogression” after immunotherapy.

Experimental Design: Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N = 155). We defined hyperprogression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared with preimmunotherapy imaging, and >2-fold increase in progression pace.

Results: Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared with the 2 months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF <2 months. Two of 10 patients with EGFR alterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase).

Conclusions: Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for hyperprogression on immunotherapy. Further investigation is urgently needed. Clin Cancer Res; 23(15); 4242–50. ©2017 AACR.
Data from Gemcitabine Synergizes with Immune Checkpoint Inhibitors and Overcomes Resistance in a Preclinical Model and Mesothelioma Patients
Authors: Tallón de Lara Paulino , Cecconi Virginia , Hiltbrunner Stefanie , Yagita Hideo , Friess Martina , Bode Beata , Opitz Isabelle , Vrugt Bart , Weder Walter , Stolzmann Paul , Felley-Bosco Emanuela , Stahel Rolf A. , Tischler Verena , Britschgi Christian , Soldini Davide , van den Broek Maries , Curioni-Fontecedro Alessandra
Published: April 2023

AbstractPurpose:
Combination of immune checkpoint inhibitors with chemotherapy is under investigation for cancer treatment.
Experimental Design:
We studied the rationale of such a combination for treating mesothelioma, a disease with limited treatment options.
Results:
The combination of gemcitabine and immune checkpoint inhibitors outperformed immunotherapy alone with regard to tumor control and survival in a preclinical mesothelioma model; however, the addition of dexamethasone to gemcitabine and immune checkpoint inhibitors nullified the synergistic clinical response. Furthermore, treatment with gemcitabine plus anti-PD-1 resulted in an objective clinical response in two patients with mesothelioma, who were resistant to gemcitabine or anti-PD-1 as monotherapy.
Conclusions:
Thus, treatment of mesothelioma with a combination of gemcitabine with immune checkpoint inhibitors is feasible and results in synergistic clinical response compared with single treatment in the absence of steroids.
Data from PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors
Authors: Kluger Harriet M. , Zito Christopher R. , Turcu Gabriela , Baine Marina K. , Zhang Hongyi , Adeniran Adebowale , Sznol Mario , Rimm David L. , Kluger Yuval , Chen Lieping , Cohen Justine V. , Jilaveanu Lucia B.
Published: April 2023

Abstract
Purpose: With recent approval of inhibitors of PD-1 in melanoma, non–small cell lung cancer (NSCLC) and renal cell carcinoma, extensive efforts are under way to develop biomarkers predictive of response. PD-L1 expression has been most widely studied, and is more predictive in NSCLC than renal cell carcinoma or melanoma. We therefore studied differences in expression patterns across tumor types.

Experimental Design: We used tissue microarrays with tumors from NSCLC, renal cell carcinoma, or melanoma and a panel of cell lines to study differences between tumor types. Predictive studies were conducted on samples from 65 melanoma patients treated with PD-1 inhibitors alone or with CTLA-4 inhibitors, characterized for outcome. PD-L1 expression was studied by quantitative immunofluorescence using two well-validated antibodies.

Results: PD-L1 expression was higher in NSCLC specimens than renal cell carcinoma, and lowest in melanoma (P = 0.001), and this finding was confirmed in a panel of cell lines. In melanoma tumors, PD-L1 was expressed either on tumor cells or immune-infiltrating cells. The association between PD-L1 expression in immune-infiltrating cells and progression-free or overall-survival in melanoma patients treated with ipilimumab and nivolumab was stronger than PD-L1 expression in tumor cells, and remained significant on multivariable analysis.

Conclusions: PD-L1 expression in melanoma tumor cells is lower than NSCLC or renal cell carcinoma cells. The higher response rate in melanoma patients treated with PD-1 inhibitors is likely related to PD-L1 in tumor-associated inflammatory cells. Further studies are warranted to validate the predictive role of inflammatory cell PD-L1 expression in melanoma and determine its biological significance. Clin Cancer Res; 23(15); 4270–9. ©2017 AACR.
Data from Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia
Authors: Pandzic Tatjana , Larsson Jimmy , He Liqun , Kundu Snehangshu , Ban Kenneth , Akhtar-Ali Muhammad , Hellström Anders R. , Schuh Anna , Clifford Ruth , Blakemore Stuart J. , Strefford Jonathan C. , Baumann Tycho , Lopez-Guillermo Armando , Campo Elias , Ljungström Viktor , Mansouri Larry , Rosenquist Richard , Sjöblom Tobias , Hellström Mats
Published: April 2023

Abstract
Purpose: To identify resistance mechanisms for the chemotherapeutic drug fludarabine in chronic lymphocytic leukemia (CLL), as innate and acquired resistance to fludarabine-based chemotherapy represents a major challenge for long-term disease control.

Experimental Design: We used piggyBac transposon-mediated mutagenesis, combined with next-generation sequencing, to identify genes that confer resistance to fludarabine in a human CLL cell line.

Results: In total, this screen identified 782 genes with transposon integrations in fludarabine-resistant pools of cells. One of the identified genes is a known resistance mediator DCK (deoxycytidine kinase), which encodes an enzyme that is essential for the phosphorylation of the prodrug to the active metabolite. BMP2K, a gene not previously linked to CLL, was also identified as a modulator of response to fludarabine. In addition, 10 of 782 transposon-targeted genes had previously been implicated in treatment resistance based on somatic mutations seen in patients refractory to fludarabine-based therapy. Functional characterization of these genes supported a significant role for ARID5B and BRAF in fludarabine sensitivity. Finally, pathway analysis of transposon-targeted genes and RNA-seq profiling of fludarabine-resistant cells suggested deregulated MAPK signaling as involved in mediating drug resistance in CLL.

Conclusions: To our knowledge, this is the first forward genetic screen for chemotherapy resistance in CLL. The screen pinpointed novel genes and pathways involved in fludarabine resistance along with previously known resistance mechanisms. Transposon screens can therefore aid interpretation of cancer genome sequencing data in the identification of genes modifying sensitivity to chemotherapy. Clin Cancer Res; 22(24); 6217–27. ©2016 AACR.
Data from Methylomic Analysis of Ovarian Cancers Identifies Tumor-Specific Alterations Readily Detectable in Early Precursor Lesions
Authors: Pisanic Thomas R. , Cope Leslie M. , Lin Shiou-Fu , Yen Ting-Tai , Athamanolap Pornpat , Asaka Ryoichi , Nakayama Kentaro , Fader Amanda N. , Wang Tza-Huei , Shih Ie-Ming , Wang Tian-Li
Published: April 2023

AbstractPurpose:
High-grade serous ovarian carcinoma (HGSOC) typically remains undiagnosed until advanced stages when peritoneal dissemination has already occurred. Here, we sought to identify HGSOC-specific alterations in DNA methylation and assess their potential to provide sensitive and specific detection of HGSOC at its earliest stages.
Experimental Design:
MethylationEPIC genome-wide methylation analysis was performed on a discovery cohort comprising 23 HGSOC, 37 non-HGSOC malignant, and 36 histologically unremarkable gynecologic tissue samples. The resulting data were processed using selective bioinformatic criteria to identify regions of high-confidence HGSOC-specific differential methylation. Quantitative methylation-specific real-time PCR (qMSP) assays were then developed for 8 of the top-performing regions and analytically validated in a cohort of 90 tissue samples. Lastly, qMSP assays were used to assess and compare methylation in 30 laser-capture microdissected (LCM) fallopian tube epithelia samples obtained from cancer-free and serous tubal intraepithelial carcinoma (STIC) positive women.
Results:
Bioinformatic selection identified 91 regions of robust, HGSOC-specific hypermethylation, 23 of which exhibited an area under the receiver-operator curve (AUC) value ≥ 0.9 in the discovery cohort. Seven of 8 top-performing regions demonstrated AUC values between 0.838 and 0.968 when analytically validated by qMSP in a 90-patient cohort. A panel of the 3 top-performing genes (c17orf64, IRX2, and TUBB6) was able to perfectly discriminate HGSOC (AUC 1.0). Hypermethylation within these loci was found exclusively in LCM fallopian tube epithelia from women with STIC lesions, but not in cancer-free fallopian tubes.
Conclusions:
A panel of methylation biomarkers can be used to accurately identify HGSOC, even at precursor stages of the disease.
Data from Proliferation Markers Are Associated with MET Expression in Hepatocellular Carcinoma and Predict Tivantinib Sensitivity In Vitro
Authors: Rebouissou Sandra , La Bella Tiziana , Rekik Samia , Imbeaud Sandrine , Calatayud Anna-Line , Rohr-Udilova Nataliya , Martin Yoann , Couchy Gabrielle , Bioulac-Sage Paulette , Grasl-Kraupp Bettina , de Koning Leanne , Ganne-Carrié Nathalie , Nault Jean-Charles , Ziol Marianne , Zucman-Rossi Jessica
Published: April 2023

Abstract
Purpose: Tivantinib was initially reported as a selective MET inhibitor and is under phase III evaluation in "MET-high" hepatocellular carcinoma (HCC) patients. However, it has been also proposed as an antimitotic agent. We aimed to evaluate the antitumor effect of tivantinib in HCC cells by combining pharmacologic and molecular profiling.

Experimental Design: Sensitivity to tivantinib, JNJ-38877605, PHA-665752, vinblastine, and paclitaxel was tested in a panel of 35 liver cancer cell lines analyzed with exome sequencing, mRNA expression of 188 genes, and protein expression. Drug effect was investigated by Western blot analysis and mitotic index quantification. Expression of candidate biomarkers predicting drug response was analyzed in 310 HCCs.

Results: Tivantinib sensitivity profiles in the 35 cell lines were similar to those obtained with antimitotic drugs. It induced blockage of cell mitosis, and high cell proliferation was associated with sensitivity to tivantinib, vinblastine, and paclitaxel. In contrast, tivantinib did not suppress MET signaling, and selective MET inhibitors demonstrated an antiproliferative effect only in MHCC97H, the unique cell line displaying MET gene amplification. HCC tumors with high expression of cell proliferation genes defined a group of patients with poor survival. Interestingly, highly proliferative tumors also demonstrated high MET expression, likely explaining better therapeutic response of MET-high HCC patients to tivantinib.

Conclusions: Tivantinib acts as an antimitotic compound, and cell proliferation markers are the best predictors of its antitumor efficacy in cell lines. Ki67 expression should be tested in clinical trials to predict tivantinib response. Clin Cancer Res; 23(15); 4364–75. ©2017 AACR.
Data from Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone
Authors: Abbasi M. Reza , Rifatbegovic Fikret , Brunner Clemens , Mann Georg , Ziegler Andrea , Pötschger Ulrike , Crazzolara Roman , Ussowicz Marek , Benesch Martin , Ebetsberger-Dachs Georg , Chan Godfrey C.F. , Jones Neil , Ladenstein Ruth , Ambros Inge M. , Ambros Peter F.
Published: April 2023

Abstract
Purpose: Tumor relapse is the most frequent cause of death in stage 4 neuroblastomas. Since genomic information on the relapse precursor cells could guide targeted therapy, our aim was to find the most appropriate tissue for identifying relapse-seeding clones.

Experimental design: We analyzed 10 geographically and temporally separated samples of a single patient by SNP array and validated the data in 154 stage 4 patients.

Results: In the case study, aberrations unique to certain tissues and time points were evident besides concordant aberrations shared by all samples. Diagnostic bone marrow–derived disseminated tumor cells (DTCs) as well as the metastatic tumor and DTCs at relapse displayed a 1q deletion, not detected in any of the seven primary tumor samples. In the validation cohort, the frequency of 1q deletion was 17.8%, 10%, and 27.5% in the diagnostic DTCs, diagnostic tumors, and DTCs at relapse, respectively. This aberration was significantly associated with 19q and ATRX deletions. We observed a significant increased likelihood of an adverse event in the presence of 19q deletion in the diagnostic DTCs.

Conclusions: Different frequencies of 1q and 19q deletions in the primary tumors as compared with DTCs, their relatively high frequency at relapse, and their effect on event-free survival (19q deletion) indicate the relevance of analyzing diagnostic DTCs. Our data support the hypothesis of a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. Therefore, searching for biomarkers to identify the relapse-seeding clone should involve diagnostic DTCs alongside the tumor tissue. Clin Cancer Res; 23(15); 4224–32. ©2017 AACR.
Data from Phase I Dose-Escalation Study of the Anti-CD70 Antibody ARGX-110 in Advanced Malignancies
Authors: Aftimos Philippe , Rolfo Christian , Rottey Sylvie , Offner Fritz , Bron Dominique , Maerevoet Marie , Soria Jean-Charles , Moshir Mahan , Dreier Torsten , Van Rompaey Luc , Michot Jean-Marie , Silence Karen , Hultberg Anna , Gandini Domenica , de Haard Hans , Ribrag Vincent , Peeters Marc , Thibault Alain , Leupin Nicolas , Awada Ahmad
Published: April 2023

Abstract
Purpose: The purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in patients with CD70 expressing advanced malignancies.

Experimental Design: Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels (N = 26). ARGX-110 was administered intravenously every 3 weeks until progression or intolerable toxicity. Dose-limiting toxicity was evaluated in the 21 days following the first ARGX-110 administration (Cycle 1). Samples for pharmacokinetics and pharmacodynamics were collected.

Results: Dose-limiting toxicity was not observed and the maximum tolerated dose was not reached. ARGX-110 was generally well tolerated, with no dose-related increase in treatment-emergent adverse events (TEAE). The most common TEAE were fatigue and drug related infusion-related reactions (IRR). Of the 20 SAEs reported, five events, all IRRs, were considered related to ARGX-110. ARGX-110 demonstrates dose proportionality over the dose range 1 to 10 mg/kg, but not at 0.1 mg/kg and a terminal half-life of 10 to 13 days. The best overall response was stable disease (14/26) in all 26 evaluable patients with various malignancies and the mean duration of treatment was 15 weeks. No dose–response related antitumor activity was observed, but biomarker readouts provided signs of biological activity, particularly in patients with hematologic malignancies.

Conclusions: This dose-escalation phase I trial provides evidence of good tolerability of ARGX-110, pharmacokinetics, and preliminary antitumor activity at all dose levels in generally heavily pretreated patients with advanced CD70-positive malignancies. Clin Cancer Res; 23(21); 6411–20. ©2017 AACR.
Data from Consecutive Day HSP90 Inhibitor Administration Improves Efficacy in Murine Models of KIT-Driven Malignancies and Canine Mast Cell Tumors
Authors: London Cheryl A. , Acquaviva Jaime , Smith Donald L. , Sequeira Manuel , Ogawa Luisa Shin , Gardner Heather L. , Bernabe Louis Feo , Bear Misty D. , Bechtel Sandra A. , Proia David A.
Published: April 2023

AbstractPurpose:
STA-1474, prodrug of the heat shock protein 90 inhibitor (HSP90i) ganetespib, previously demonstrated activity in canine preclinical models of cancer; interestingly, prolonged infusions were associated with improved biologic activity. The purpose of this study was to identify the ideal treatment schedule for HSP90i in preclinical models of KIT-driven malignancies and in dogs with spontaneous mast cell tumors (MCT), where KIT is a known driver.
Experimental Design:
In vitro and murine xenograft experiments and clinical studies in dogs with MCTs were used to define the effects of HSP90i-dosing regimen on client protein downregulation and antitumor activity.
Results:
Continuous HSP90 inhibition led to durable destabilization of client proteins in vitro; however, transient exposure required >10× drug for comparable effects. In vivo, KIT was rapidly degraded following a single dose of HSP90i but returned to baseline levels within a day. HSP90 levels increased and stabilized 16 hours after HSP90i and were not elevated following a subsequent near-term exposure, providing a functional pool of chaperone to stabilize proteins and a means for greater therapeutic activity upon HSP90i reexposure. HSP90i administered on days 1 and 2 (D1/D2) demonstrated increased biologic activity compared with D1 treatment in KIT or EGFR-driven murine tumor models. In a trial of dogs with MCT, D1/D2 dosing of HSP90i was associated with sustained KIT downregulation, 50% objective response rate and 100% clinical benefit rate compared with D1 and D1/D4 schedules.
Conclusions:
These data provide further evidence that prolonged HSP90i exposure improves biologic activity through sustained downregulation of client proteins.
Data from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
Authors: Caumanns Joseph J. , Berns Katrien , Wisman G. Bea A. , Fehrmann Rudolf S.N. , Tomar Tushar , Klip Harry , Meersma Gert J. , Hijmans E. Marielle , Gennissen Annemiek M.C. , Duiker Evelien W. , Weening Desiree , Itamochi Hiroaki , Kluin Roelof J.C. , Reyners Anna K.L. , Birrer Michael J. , Salvesen Helga B. , Vergote Ignace , van Nieuwenhuysen Els , Brenton James , Braicu E. Ioana , Kupryjanczyk Jolanta , Spiewankiewicz Beata , Mittempergher Lorenza , Bernards René , van der Zee Ate G.J. , de Jong Steven
Published: April 2023

Abstract
Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models.

Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient–derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055.

Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient–derived xenograft models.

Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928–40. ©2018 AACR.
Data from A Variant of a Killer Cell Immunoglobulin-like Receptor Is Associated with Resistance to PD-1 Blockade in Lung Cancer
Authors: Trefny Marcel P. , Rothschild Sacha I. , Uhlenbrock Franziska , Rieder Dietmar , Kasenda Benjamin , Stanczak Michal A. , Berner Fiamma , Kashyap Abhishek S. , Kaiser Monika , Herzig Petra , Poechtrager Severin , Thommen Daniela S. , Geier Florian , Savic Spasenija , Jermann Philip , Alborelli Ilaria , Schaub Stefan , Stenner Frank , Früh Martin , Trajanoski Zlatko , Flatz Lukas , Mertz Kirsten D. , Zippelius Alfred , Läubli Heinz
Published: April 2023

AbstractPurpose:
PD-(L)1–blocking antibodies have clinical activity in metastatic non–small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade. Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways.
Experimental Design:
Peripheral blood mononuclear cells were collected from 35 patients with NSCLC receiving nivolumab monotherapy. Cellular changes, cytokine levels, gene expression, and polymorphisms were compared between responders and nonresponders to treatment. Findings were confirmed in additional cohorts of patients with NSCLC receiving immune checkpoint blockade.
Results:
We identified a genetic variant of a killer cell immunoglobulin-like receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in patients with NSCLC. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients, the progression-free survival was significantly associated with presence of the KIR3DS1 allele (HR, 1.72; 95% confidence interval, 1.10–2.68; P = 0.017). No relationship was seen in cohorts of patients with NSCLC who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be due to NK-cell dysfunction.
Conclusions:
We identified an association of the KIR3DS1 allelic variant with response to PD-1–targeted immunotherapy in patients with NSCLC. This finding links NK cells with response to PD-1 therapy. Although the findings are interesting, a larger analysis in a randomized trial will be needed to confirm KIRs as predictive markers for response to PD-1–targeted immunotherapy.