bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening
Authors: Beshiri Michael L. , Tice Caitlin M. , Tran Crystal , Nguyen Holly M. , Sowalsky Adam G. , Agarwal Supreet , Jansson Keith H. , Yang Qi , McGowen Kerry M. , Yin JuanJuan , Alilin Aian Neil , Karzai Fatima H. , Dahut William L. , Corey Eva , Kelly Kathleen
Published: April 2023

Abstract
Purpose: Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high-throughput and mechanistic analysis.

Experimental Design: Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested >20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin.

Results: All PDX models proliferated as organoids in culture. Greater than 50% could be continuously cultured long-term in modified conditions; however, none of the PDXs could be established long-term as organoids under previously reported conditions. In addition, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs was conserved in organoids. Lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in BRCA2−/− organoids, similar to responses observed in patients.

Conclusions: The LuCaP PDX/organoid models provide an expansive, genetically characterized platform to investigate the mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC. Clin Cancer Res; 24(17); 4332–45. ©2018 AACR.
Data from A Gallium-67/68–Labeled Antibody Fragment for Immuno-SPECT/PET Shows Low Renal Radioactivity Without Loss of Tumor Uptake
Authors: Uehara Tomoya , Yokoyama Miki , Suzuki Hiroyuki , Hanaoka Hirofumi , Arano Yasushi
Published: April 2023

Abstract
Purpose: This study was undertaken to evaluate the renal radioactivity levels of a newly designed 67Ga-labeled antibody fragment with a linkage cleaved by enzymes present on the brush border membrane (BBM) lining the lumen of the renal tubule.

Experimental Design: 67Ga-labeled S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) was conjugated with an antibody Fab fragment through a Met-Val-Lys linkage (67Ga-NOTA-MVK-Fab) considering that a Met-Val sequence is a substrate of enzymes on the renal BBM and 67Ga-NOTA-Met is excreted from the kidney into the urine. The enzymatic recognition of the linkage was evaluated with a low-molecular-weight 67Ga-NOTA-Met-Val-Lys derivative. Biodistribution of radioactivity after injection of 67Ga-NOTA-MVK-Fab into mice was compared with 67Ga-NOTA-conjugated Fab fragments through a Met-Ile linkage that liberates 67Ga-NOTA-Met (67Ga-NOTA-MI-Fab) or a conventional thiourea linkage (67Ga-NOTA-Fab).

Results: The MVK linkage remained stable in plasma and was recognized by enzymes on renal BBM to liberate 67Ga-NOTA-Met. When injected into mice, all three 67Ga-labeled Fab exhibited similar blood clearance rates and tumor accumulation. Significant differences were observed in the kidney where 67Ga-NOTA-MVK-Fab registered the lowest renal radioactivity levels from early postinjection time (P < 0.05), followed by 67Ga-NOTA-MI-Fab, which was well reflected in the SPECT/CT images.

Conclusions: These findings indicated that our proposal of liberating a radiolabeled compound to urinary excretion from antibody fragments at the renal BBM to reduce the renal radioactivity levels was applicable to 67/68Ga-labeled antibody fragments. Because antibody fragments and constructs share similar metabolic fates in the kidney, the present labeling procedure would also apply to a variety of antibody fragments and constructs of interest. Clin Cancer Res; 24(14); 3309–16. ©2018 AACR.
Data from Impact of Emergent Circulating Tumor DNA RAS Mutation in Panitumumab-Treated Chemoresistant Metastatic Colorectal Cancer
Authors: Kim Tae Won , Peeters Marc , Thomas Anne , Gibbs Peter , Hool Kristina , Zhang Jianqi , Ang Agnes Lee , Bach Bruce Allen , Price Timothy
Published: April 2023

Abstract
Purpose: The accumulation of emergent RAS mutations during anti-EGFR therapy is of interest as a mechanism for acquired resistance to anti-EGFR treatment. Plasma analysis of circulating tumor (ct) DNA is a minimally invasive and highly sensitive method to determine RAS mutational status.

Experimental Design: This biomarker analysis of the global phase III ASPECCT study used next-generation sequencing to detect expanded RAS ctDNA mutations in panitumumab-treated patients. Plasma samples collected at baseline and posttreatment were analyzed categorically for the presence of RAS mutations by the PlasmaSelect-R 64-gene panel at 0.1% sensitivity.

Results: Among panitumumab-treated patients with evaluable plasma samples at baseline (n = 238), 188 (79%) were wild-type (WT) RAS, and 50 (21%) were mutant RAS. Of the 188 patients with baseline ctDNA WT RAS status, 164 had evaluable posttreatment results with a 32% rate of emergent RAS mutations. The median overall survival for WT and RAS mutant status by ctDNA at baseline was 13.7 (95% confidence interval, 11.5–15.4) and 7.9 months (6.4–9.6), respectively (P < 0.0001). Clinical outcomes were not significantly different between patients with and without emergent ctDNA RAS mutations.

Conclusions: Although patients with baseline ctDNA RAS mutations had worse outcomes than patients who were WT RAS before initiating treatment, emergent ctDNA RAS mutations were not associated with less favorable patient outcomes in panitumumab-treated patients. Further research is needed to determine a clinically relevant threshold for baseline and emergent ctDNA RAS mutations. Clin Cancer Res; 24(22); 5602–9. ©2018 AACR.
Data from PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma
Authors: Chung Elaine Y. , Mai Yun , Shah Urvi A. , Wei Yongqiang , Ishida Elise , Kataoka Keisuke , Ren Xiaoxin , Pradhan Kith , Bartholdy Boris , Wei Xiaolei , Zou Yiyu , Zhang Jinghang , Ogawa Seishi , Steidl Ulrich , Zang Xingxing , Verma Amit , Janakiram Murali , Ye B. Hilda
Published: April 2023

AbstractPurpose:
To evaluate therapeutic activity of PAK inhibition in ATLL and to characterize the role of PAK isoforms in cell proliferation, survival, and adhesion of ATLL cells in preclinical models.
Experimental Design:
Frequency and prognostic impact of PAK2 amplification were evaluated in an ATLL cohort of 370 cases. Novel long-term cultures and in vivo xenograft models were developed using primary ATLL cells from North American patients. Two PAK inhibitors were used to block PAK kinase activity pharmacologically. siRNA-based gene silencing approach was used to genetically knockdown (KD) PAK1 and PAK2 in ATLL cell lines.
Results:
PAK1/2/4 are the three most abundantly expressed PAK family members in ATLL. PAK2 amplifications are seen in 24% of ATLLs and are associated with worse prognosis in a large patient cohort. The pan-PAK inhibitor PF-3758309 (PF) has strong in vitro and in vivo activity in a variety of ATLL preclinical models. These activities of PF are likely attributed to its ability to target several PAK isoforms simultaneously because genetic silencing of either PAK1 or PAK2 produced more modest effects. PAK2 plays a major role in CADM1-mediated stromal interaction, which is an important step in systemic dissemination of the disease. This finding is consistent with the observation that PAK2 amplification is more frequent in aggressive ATLLs and correlates with inferior outcome.
Conclusions:
PAK2, a gene frequently amplified in ATLL, facilitates CADM1-mediated stromal interaction and promotes survival of ATLL cells. Taken together, PAK inhibition may hold significant promise as a targeted therapy for aggressive ATLLs.
Data from Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study
Authors: Atkins Michael B. , Hodi F. Stephen , Thompson John A. , McDermott David F. , Hwu Wen-Jen , Lawrence Donald P. , Dawson Nancy A. , Wong Deborah J. , Bhatia Shailender , James Marihella , Jain Lokesh , Robey Seth , Shu Xinxin , Homet Moreno Blanca , Perini Rodolfo F. , Choueiri Toni K. , Ribas Antoni
Published: April 2023

Abstract
Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.

Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.

Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.

Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805–15. ©2018 AACR.
Data from Targeting the CDK4/6-Rb Pathway Enhances Response to PI3K Inhibition in PIK3CA-Mutant Lung Squamous Cell Carcinoma
Authors: Shi Ruoshi , Li Ming , Raghavan Vibha , Tam Shirley , Cabanero Michael , Pham Nhu-An , Shepherd Frances A. , Moghal Nadeem , Tsao Ming-Sound
Published: April 2023

AbstractPurpose:
Lung squamous cell carcinoma (LUSC) is a major subtype of non–small cell lung cancer characterized by multiple genetic alterations, particularly PI3K pathway alterations which have been identified in over 50% of LUSC cases. Despite being an attractive target, single-agent PI3K inhibitors have demonstrated modest response in LUSC. Thus, novel combination therapies targeting LUSC are needed.
Experimental Design:
PI3K inhibitors alone and in combination with CDK4/6 inhibitors were evaluated in previously established LUSC patient-derived xenografts (PDX) using an in vivo screening method. Screening results were validated with in vivo expansion to 5 to 8 mice per arm. Pharmacodynamics studies were performed to confirm targeted inhibition of compounds.
Results:
Consistent with results from The Cancer Genome Atlas analysis of LUSC, genomic profiling of our large cohort of LUSC PDX models identified PI3K pathway alterations in over 50% of the models. In vivo screening using PI3K inhibitors in 12 of these models identified PIK3CA mutation as a predictive biomarker of response (<20% tumor growth compared with baseline/vehicle). Combined inhibition of PI3K and CDK4/6 in models with PIK3CA mutation resulted in greater antitumor effects compared with either monotherapy alone. In addition, the combination of the two drugs achieved targeted inhibition of the PI3K and cell-cycle pathways.
Conclusions:
PIK3CA mutations predict response to PI3K inhibitors in LUSC. Combined PI3K and CDK4/6 inhibition enhances response to either single agents alone. Our findings provide a rationale for clinical testing of combined PI3K and CDK4/6 inhibitors in PIK3CA-mutant LUSC.
Data from Paclitaxel Plasma Concentration after the First Infusion Predicts Treatment-Limiting Peripheral Neuropathy
Authors: Hertz Daniel L. , Kidwell Kelley M. , Vangipuram Kiran , Li Feng , Pai Manjunath P. , Burness Monika , Griggs Jennifer J. , Schott Anne F. , Van Poznak Catherine , Hayes Daniel F. , Lavoie Smith Ellen M. , Henry N. Lynn
Published: April 2023

Abstract
Purpose: Paclitaxel exposure, specifically the maximum concentration (Cmax) and amount of time the concentration remains above 0.05 μmol/L (Tc>0.05), has been associated with the occurrence of paclitaxel-induced peripheral neuropathy. The objective of this study was to validate the relationship between paclitaxel exposure and peripheral neuropathy.

Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m2 × 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of and 16–26 hours after the first infusion to estimate Cmax and Tc>0.05. Patient-reported peripheral neuropathy was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with Tc>0.05. Secondary analyses were conducted using Cmax as an alternative exposure parameter and testing each parameter with a secondary endpoint of the occurrence of peripheral neuropathy–induced treatment disruption.

Results: In 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity (P < 0.05), but neither Tc>0.05 (P = 0.27) nor Cmax (P = 0.99). In analyses of the secondary endpoint, cumulative dose (OR = 1.46; 95% confidence interval (CI), 1.18–1.80; P = 0.0008) and Tc>0.05 (OR = 1.79; 95% CI, 1.06–3.01; P = 0.029) or Cmax (OR = 2.74; 95% CI, 1.45–5.20; P = 0.002) were associated with peripheral neuropathy–induced treatment disruption.

Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting peripheral neuropathy in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents peripheral neuropathy in these patients. Clin Cancer Res; 24(15); 3602–10. ©2018 AACR.
Data from Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies
Authors: Odegaard Justin I. , Vincent John J. , Mortimer Stefanie , Vowles James V. , Ulrich Bryan C. , Banks Kimberly C. , Fairclough Stephen R. , Zill Oliver A. , Sikora Marcin , Mokhtari Reza , Abdueva Diana , Nagy Rebecca J. , Lee Christine E. , Kiedrowski Lesli A. , Paweletz Cloud P. , Eltoukhy Helmy , Lanman Richard B. , Chudova Darya I. , Talasaz AmirAli
Published: April 2023

Abstract
Purpose: To analytically and clinically validate a circulating cell-free tumor DNA sequencing test for comprehensive tumor genotyping and demonstrate its clinical feasibility.

Experimental Design: Analytic validation was conducted according to established principles and guidelines. Blood-to-blood clinical validation comprised blinded external comparison with clinical droplet digital PCR across 222 consecutive biomarker-positive clinical samples. Blood-to-tissue clinical validation comprised comparison of digital sequencing calls to those documented in the medical record of 543 consecutive lung cancer patients. Clinical experience was reported from 10,593 consecutive clinical samples.

Results: Digital sequencing technology enabled variant detection down to 0.02% to 0.04% allelic fraction/2.12 copies with ≤0.3%/2.24–2.76 copies 95% limits of detection while maintaining high specificity [prevalence-adjusted positive predictive values (PPV) >98%]. Clinical validation using orthogonal plasma- and tissue-based clinical genotyping across >750 patients demonstrated high accuracy and specificity [positive percent agreement (PPAs) and negative percent agreement (NPAs) >99% and PPVs 92%–100%]. Clinical use in 10,593 advanced adult solid tumor patients demonstrated high feasibility (>99.6% technical success rate) and clinical sensitivity (85.9%), with high potential actionability (16.7% with FDA-approved on-label treatment options; 72.0% with treatment or trial recommendations), particularly in non–small cell lung cancer, where 34.5% of patient samples comprised a directly targetable standard-of-care biomarker.

Conclusions: High concordance with orthogonal clinical plasma- and tissue-based genotyping methods supports the clinical accuracy of digital sequencing across all four types of targetable genomic alterations. Digital sequencing's clinical applicability is further supported by high rates of technical success and biomarker target discovery. Clin Cancer Res; 24(15); 3539–49. ©2018 AACR.
Data from Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study
Authors: Toulmonde Maud , Blay Jean-Yves , Bouche Olivier , Mir Olivier , Penel Nicolas , Isambert Nicolas , Duffaud Florence , Bompas Emmanuelle , Esnaud Thomas , Boidot Romain , Geneste Damien , Ghiringhelli François , Lucchesi Carlo , Bellera Carine A. , Le Loarer François , Italiano Antoine
Published: April 2023

AbstractPurpose:
CDKN2A loss is frequent in gastrointestinal stromal tumors (GISTs) and associated with aggressive outcome. Palbociclib is a CDK4 inhibitor with preclinical antitumor efficacy in tumors with P16/CDKN2A loss.
Patients and Methods:
This is a multicenter single-arm phase II clinical trial assessing safety and efficacy of palbociclib in patients with advanced GIST bearing CDKN2A gene loss. Adults with unresectable locally advanced or metastatic, refractory to at least imatinib and sunitinib, measurable and documented progressive disease (PD) as per RECIST 1.1, and CDKN2A deletion centrally assessed were eligible. Patients received palbociclib 125 mg orally daily on a 21 days on/7 days off dosing schedule, until PD or unacceptable toxicity. The primary endpoint was 4-month non-PD rate according to RECIST 1.1.
Results:
As of May 2017, 71 patients had been included in the study, and 29 patients (40.3%) met the molecular eligibility requirement. Twenty-five patients (86.2%) had grade 1–2 adverse events (AEs) and 12 patients (41.4%) grade 3–4 AEs possibly related to the drug. The planned interim statistical analysis performed after central histologic and radiological review showed that 19 (86.4%) out of the first 22 evaluable patients had PD at 4 months. CDKN2A status had no impact either on overall survival or outcome on previous standard lines of treatment. Translational analysis suggested upregulation of CCNE1 or downregulation of CDKN1A/P21 or LRRC3B as potential mechanisms of resistance.
Conclusions:
Palbociclib has no significant clinical activity as a single agent in P16/CDKN2A–deleted GIST refractory to imatinib and sunitinib.
Data from Copper Chelation as Targeted Therapy in a Mouse Model of Oncogenic BRAF-Driven Papillary Thyroid Cancer
Authors: Xu MengMeng , Casio Michael , Range Danielle E. , Sosa Julie A. , Counter Christopher M.
Published: April 2023

Abstract
Purpose: Sixty percent of papillary thyroid cancers (PTC) have an oncogenic (V600E) BRAF mutation. Inhibitors of BRAF and its substrates MEK1/2 are showing clinical promise in BRAFV600E PTC. PTC progression can be decades long, which is challenging in terms of toxicity and cost. We previously found that MEK1/2 require copper (Cu) for kinase activity and can be inhibited with the well-tolerated and economical Cu chelator tetrathiomolybdate (TM). We therefore tested TM for antineoplastic activity in BRAFV600E-positive PTC.

Experimental Design: The efficacy of TM alone and in combination with current standard-of-care lenvatinib and sorafenib or BRAF and MEK1/2 inhibitors vemurafenib and trametinib was examined in BRAFV600E-positive human PTC cell lines and a genetically engineered mouse PTC model.

Results: TM inhibited MEK1/2 kinase activity and transformed growth of PTC cells. TM was as or more potent than lenvatinib and sorafenib and enhanced the antineoplastic activity of sorafenib and vemurafenib. Activated ERK2, a substrate of MEK1/2, overcame this effect, consistent with TM deriving its antineoplastic activity by inhibiting MEK1/2. Oral TM reduced tumor burden and vemurafenib in a BrafV600E-positive mouse model of PTC. This effect was ascribed to a reduction of Cu in the tumors. TM reduced P-Erk1/2 in mouse PTC tumors, whereas genetic reduction of Cu in developing tumors trended towards a survival advantage. Finally, TM as a maintenance therapy after cessation of vemurafenib reduced tumor volume in the aforementioned PTC mouse model.

Conclusions: TM inhibits BRAFV600E-driven PTC through inhibition of MEK1/2, supporting clinical evaluation of chronic TM therapy for this disease. Clin Cancer Res; 24(17); 4271–81. ©2018 AACR.
Data from Functions and Mechanisms of Tumor Necrosis Factor-α and Noncoding RNAs in Bone-Invasive Pituitary Adenomas
Authors: Zhu Haibo , Guo Jing , Shen Yutao , Dong Wei , Gao Hua , Miao Yazhou , Li Chuzhong , Zhang Yazhuo
Published: April 2023

Abstract
Purpose: To explore the molecular mechanism and prognosis of bone-invasive pituitary adenomas (BIPA).

Experimental design: A total of 274 patients with pituitary adenomas were followed up. Transcriptomic microarrays analysis was performed on 10 pituitary adenomas, including five BIPAs and five non-bone-invasive pituitary adenomas (NBIPA). The targeted molecular markers were validated by qRT-PCR, IHC, ELISA, and osteoclast differentiation.

Results: Clinical variable analyses revealed a significant correlation between bone invasion and female sex, large tumor volume, non-gross total resection (NGTR), and tumor regrowth. BIPAs had worse progression-free survival (PFS) than did NBIPAs in the NGTR and nonfunctional pituitary adenoma (NFPA) groups. Gene ontology functional and KEGG pathway analyses showed that the biological processes and pathways were primarily immune and inflammatory pathways. Pathway act work showed that osteoclast differentiation pathway was significantly implicated in the pathway network. BIPAs had higher expression of TNFα than that of NBIPAs on IHC. In vitro, TNFα could induce RAW264.7 cells to differentiate into mature osteoclasts, leading to bone destruction. NR_033258, lncRNA SNHG24, miR-181c-5p, and miR-454-3p can regulate TNFα expression.

Conclusions: BIPAs had worse PFS than did NBIPAs in the NGTR and NFPA groups. Inflammatory and immune factors play an important role in BIPAs. TNFα can directly induce osteoclast differentiation in BIPAs. NR_033258, lncRNA SNHG24, miR-181c-5p, and miR-454-3p can regulate TNFα expression. TNFα and its related lncRNAs and miRNAs represent potential therapeutic targets for bone-invasive pituitary adenomas in the future. Clin Cancer Res; 24(22); 5757–66. ©2018 AACR.
Data from Activated and Exhausted MAIT Cells Foster Disease Progression and Indicate Poor Outcome in Hepatocellular Carcinoma
Authors: Duan Meng , Goswami Shyamal , Shi Jie-Yi , Wu Lin-Jie , Wang Xiao-Ying , Ma Jia-Qiang , Zhang Zhao , Shi Yang , Ma Li-Jie , Zhang Shu , Xi Rui-Bin , Cao Ya , Zhou Jian , Fan Jia , Zhang Xiao-Ming , Gao Qiang
Published: April 2023

AbstractPurpose:
Innate immunity is an indispensable arm of tumor immune surveillance, and the liver is an organ with a predominance of innate immunity, where mucosal-associated invariant T (MAIT) cells are enriched. However, little is known about the phenotype, functions, and immunomodulatory role of MAIT cells in hepatocellular carcinoma (HCC).

Experimental Design: The distribution, phenotype, and function of MAIT cells in patients with HCC were evaluated by both flow cytometry (FCM) and in vitro bioassays. Transcriptomic analysis of MAIT cells was also performed. Prognostic significance of tumor-infiltrating MAIT cells was validated in four independent cohorts of patients with HCC.
Results:
Despite their fewer densities in HCC tumor than normal liver, MAIT cells were significantly enriched in the HCC microenvironment compared with other mucosa-associated organs. Tumor-derived MAIT cells displayed a typical CCR7−CD45RA−CD45RO+CD95+ effector memory phenotype with lower costimulatory and effector capabilities. Tumor-educated MAIT cells significantly upregulated inhibitory molecules like PD-1, CTLA-4, TIM-3, secreted significantly less IFNγ and IL17, and produced minimal granzyme B and perforin while shifting to produce tumor-promoting cytokines like IL8. Transcriptome sequencing confirmed that tumor-derived MAIT cells were reprogrammed toward a tumor-promoting direction by downregulating genes enriched in pathways of cytokine secretion and cytolysis effector function like NFKB1 and STAT5B and by upregulating genes like IL8, CXCL12, and HAVCR2 (TIM-3). High infiltration of MAIT cells in HCC significantly correlated with an unfavorable clinical outcome, revealed by FCM, qRT-PCR, and multiplex IHC analyses, respectively.
Conclusions:
HCC-infiltrating MAIT cells were functionally impaired and even reprogrammed to shift away from antitumor immunity and toward a tumor-promoting direction.

See related commentary by Carbone, p. 3199
Data from Role of Elevated PHIP Copy Number as a Prognostic and Progression Marker for Cutaneous Melanoma
Authors: Bezrookove Vladimir , Nosrati Mehdi , Miller James R. , De Semir David , Dar Altaf A. , Vosoughi Elham , Vaquero Edith , Sucker Antje , Lazar Alexander J. , Gershenwald Jeffrey E. , Davies Michael A. , Schadendorf Dirk , Kashani-Sabet Mohammed
Published: April 2023

Abstract
Purpose: Previous studies have indicated an important role for pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis. Here we aimed to confirm the role of PHIP copy number in successive stages of melanoma progression.

Experimental Design: PHIP copy number was examined using FISH in three independent cohorts by recording the percentage of cells harboring ≥3 copies of PHIP. The impact of PHIP copy number on survival was assessed using Cox regression analysis. The enrichment of PHIP was assessed in various molecular melanoma subtypes. PHIP expression was analyzed in The Cancer Genome Atlas (TCGA) melanoma cohort.

Results: Elevated PHIP copy number was significantly predictive of reduced distant metastasis-free survival (DMFS) and disease-specific survival (DSS), and increased prevalence of ulceration in primary melanoma (cohort No. 1). By multivariate analysis, PHIP FISH scores were independently predictive of DMFS and DSS. PHIP copy number was enriched in metastatic melanomas harboring mutant NRAS or expressing PTEN protein (cohort No. 2). PHIP copy number was significantly elevated in metastatic melanomas when compared with matched primary tumors from the same patient (cohort No. 3). Several of these associations were replicated using TCGA cohort analysis.

Conclusions: These results underscore the important role of PHIP copy-number elevation in melanoma progression, and identify molecular subtypes of melanoma in which PHIP is enriched. Finally, as elevated PHIP copy number appears to be selected for during the progression of primary to metastatic melanoma, these results confirm PHIP as a promising therapeutic target for melanoma. Clin Cancer Res; 24(17); 4119–25. ©2018 AACR.
Data from Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR
Authors: Veiga Sónia R. , Ge Xuemei , Mercer Carol A. , Hernández-Álvarez María I. , Thomas Hala Elnakat , Hernandez-Losa Javier , Ramón y Cajal Santiago , Zorzano Antonio , Thomas George , Kozma Sara C.
Published: April 2023

Abstract
Purpose: Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mTOR for the treatment of HCC. However, such inhibitors induce hyperglycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor phenformin could reverse both side effects, impose an energetic stress on cancer cells, and suppress the growth of HCC.

Experimental Design: Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated preclinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival.

Results: We found phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with phenformin, was highly efficacious in controlling tumor burden. However, more strikingly, pretreatment with phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival.

Conclusions: Treatment of HCC cells in vitro with the biguanide phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC. Clin Cancer Res; 24(15); 3767–80. ©2018 AACR.
Data from Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis
Authors: Rieunier Guillaume , Wu Xiaoning , Macaulay Valentine M. , Lee Adrian V. , Weyer-Czernilofsky Ulrike , Bogenrieder Thomas
Published: April 2023

Abstract
Bone metastases are a frequent complication of cancer that are associated with considerable morbidity. Current treatments may temporarily palliate the symptoms of bone metastases but often fail to delay their progression. Bones provide a permissive environment because they are characterized by dynamic turnover, secreting factors required for bone maintenance but also stimulating the establishment and growth of metastases. Insulin-like growth factors (IGF) are the most abundant growth factors in bone and are required for normal skeletal development and function. Via activation of the IGF-1 receptors (IGF-1R) and variant insulin receptors, IGFs promote cancer progression, aggressiveness, and treatment resistance. Of specific relevance to bone biology, IGFs contribute to the homing, dormancy, colonization, and expansion of bone metastases. Furthermore, preclinical evidence suggests that tumor cells can be primed to metastasize to bone by a high IGF-1 environment in the primary tumor, suggesting that bone metastases may reflect IGF dependency. Therapeutic targeting of the IGF axis may therefore provide an effective method for treating bone metastases. Indeed, anti–IGF-1R antibodies, IGF-1R tyrosine kinase inhibitors, and anti–IGF-1/2 antibodies have demonstrated antitumor activity in preclinical models of prostate and breast cancer metastases, either alone or in combination with other agents. Several studies suggest that such treatments can inhibit bone metastases without affecting growth of the primary tumor. Although previous trials of anti–IGF-1R drugs have generated negative results in unselected patients, these considerations suggest that future clinical trials of IGF-targeted agents may be warranted in patients with bone metastases.
Data from Radiomics Signature on Magnetic Resonance Imaging: Association with Disease-Free Survival in Patients with Invasive Breast Cancer
Authors: Park Hyunjin , Lim Yaeji , Ko Eun Sook , Cho Hwan-ho , Lee Jeong Eon , Han Boo-Kyung , Ko Eun Young , Choi Ji Soo , Park Ko Woon
Published: April 2023

Abstract
Purpose: To develop a radiomics signature based on preoperative MRI to estimate disease-free survival (DFS) in patients with invasive breast cancer and to establish a radiomics nomogram that incorporates the radiomics signature and MRI and clinicopathological findings.

Experimental Design: We identified 294 patients with invasive breast cancer who underwent preoperative MRI. Patients were randomly divided into training (n = 194) and validation (n = 100) sets. A radiomics signature (Rad-score) was generated using an elastic net in the training set, and the cutoff point of the radiomics signature to divide the patients into high- and low-risk groups was determined using receiver-operating characteristic curve analysis. Univariate and multivariate Cox proportional hazards model and Kaplan–Meier analysis were used to determine the association of the radiomics signature, MRI findings, and clinicopathological variables with DFS. A radiomics nomogram combining the Rad-score and MRI and clinicopathological findings was constructed to validate the radiomic signatures for individualized DFS estimation.

Results: Higher Rad-scores were significantly associated with worse DFS in both the training and validation sets (P = 0.002 and 0.036, respectively). The radiomics nomogram estimated DFS [C-index, 0.76; 95% confidence interval (CI); 0.74–0.77] better than the clinicopathological (C-index, 0.72; 95% CI, 0.70–0.74) or Rad-score–only nomograms (C-index, 0.67; 95% CI, 0.65–0.69).

Conclusions: The radiomics signature is an independent biomarker for the estimation of DFS in patients with invasive breast cancer. Combining the radiomics nomogram improved individualized DFS estimation. Clin Cancer Res; 24(19); 4705–14. ©2018 AACR.
Data from Radiomics of Multiparametric MRI for Pretreatment Prediction of Pathologic Complete Response to Neoadjuvant Chemotherapy in Breast Cancer: A Multicenter Study
Authors: Liu Zhenyu , Li Zhuolin , Qu Jinrong , Zhang Renzhi , Zhou Xuezhi , Li Longfei , Sun Kai , Tang Zhenchao , Jiang Hui , Li Hailiang , Xiong Qianqian , Ding Yingying , Zhao Xinming , Wang Kun , Liu Zaiyi , Tian Jie
Published: April 2023

AbstractPurpose:
We evaluated the performance of the newly proposed radiomics of multiparametric MRI (RMM), developed and validated based on a multicenter dataset adopting a radiomic strategy, for pretreatment prediction of pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer.
Experimental Design:
A total of 586 potentially eligible patients were retrospectively enrolled from four hospitals (primary cohort and external validation cohort 1–3). Quantitative imaging features were extracted from T2-weighted imaging, diffusion-weighted imaging, and contrast-enhanced T1-weighted imaging before NAC for each patient. With features selected using a coarse to fine feature selection strategy, four radiomic signatures were constructed based on each of the three MRI sequences and their combination. RMM was developed based on the best radiomic signature incorporating with independent clinicopathologic risk factors. The performance of RMM was assessed with respect to its discrimination and clinical usefulness, and compared with that of clinical information–based prediction model.
Results:
Radiomic signature combining multiparametric MRI achieved an AUC of 0.79 (the highest among the four radiomic signatures). The signature further achieved good performances in hormone receptor–positive and HER2-negative group and triple-negative group. RMM yielded an AUC of 0.86, which was significantly higher than that of clinical model in two of the three external validation cohorts.
Conclusions:
The study suggested a possibility that RMM provided a potential tool to develop a model for predicting pCR to NAC in breast cancer.
Data from Prognostic Significance of Tumor-Infiltrating B Cells and Plasma Cells in Human Cancer
Authors: Wouters Maartje C.A. , Nelson Brad H.
Published: April 2023

Abstract
There is abundant evidence that tumor-infiltrating CD8+ T cells contribute positively to antitumor immunity; however, the role of tumor-infiltrating B cells (TIL-B) and plasma cells (PC) remains controversial, leading to differing opinions about whether immunotherapies should be designed to enhance or inhibit these cells. Through a comprehensive PubMed search, we reviewed publications with cohorts of 50 or more cases in which the prognostic value of TIL-B/PC was assessed by immunohistochemistry and/or gene-expression analysis. Sixty-nine studies representing 19 cancers met our review criteria. The large majority of studies assessed TIL-B by immunohistochemical detection of CD20. Of these, 50.0% reported a positive prognostic effect for CD20+ TIL-B, whereas the remainder found a neutral (40.7%) or negative (9.3%) effect. These differences in prognostic effect were not attributable to cancer type, other clinicopathologic factors, or differing technical approaches. The prognostic significance of TIL-B/PC was generally concordant with that of CD3+ and/or CD8+ T cells, and the prognostic effect of T cells was generally stronger when TIL-B and/or PC were also present. Additionally, 21 studies inferred the presence of TIL-B/PC from gene-expression data, and a large majority reported a positive prognostic effect. Although more studies are required involving additional cancer types and independent patient cohorts, the weight of evidence supports a positive role for TIL-B and PC in antitumor immunity, suggesting that enhancement of these responses should be considered in the design of cancer immunotherapies.
Data from Parallel Accumulation of Tumor Hyaluronan, Collagen, and Other Drivers of Tumor Progression
Authors: Li Xiaoming , Shepard H. Michael , Cowell Jessica A. , Zhao Chunmei , Osgood Ryan J. , Rosengren Sanna , Blouw Barbara , Garrovillo Sheryl A. , Pagel Mark D. , Whatcott Clifford J. , Han Haiyong , Von Hoff Daniel D. , Taverna Darin M. , LaBarre Michael J. , Maneval Daniel C. , Thompson Curtis B.
Published: April 2023

Abstract
Purpose: The tumor microenvironment (TME) evolves to support tumor progression. One marker of more aggressive malignancy is hyaluronan (HA) accumulation. Here, we characterize biological and physical changes associated with HA-accumulating (HA-high) tumors.

Experimental Design: We used immunohistochemistry, in vivo imaging of tumor pH, and microdialysis to characterize the TME of HA-high tumors, including tumor vascular structure, hypoxia, tumor perfusion by doxorubicin, pH, content of collagen. and smooth muscle actin (α-SMA). A novel method was developed to measure real-time tumor-associated soluble cytokines and growth factors. We also evaluated biopsies of murine and pancreatic cancer patients to investigate HA and collagen content, important contributors to drug resistance.

Results: In immunodeficient and immunocompetent mice, increasing tumor HA content is accompanied by increasing collagen content, vascular collapse, hypoxia, and increased metastatic potential, as reflected by increased α-SMA. In vivo treatment of HA-high tumors with PEGylated recombinant human hyaluronidase (PEGPH20) dramatically reversed these changes and depleted stores of VEGF-A165, suggesting that PEGPH20 may also diminish the angiogenic potential of the TME. Finally, we observed in xenografts and in pancreatic cancer patients a coordinated increase in HA and collagen tumor content.

Conclusions: The accumulation of HA in tumors is associated with high tIP, vascular collapse, hypoxia, and drug resistance. These findings may partially explain why more aggressive malignancy is observed in the HA-high phenotype. We have shown that degradation of HA by PEGPH20 partially reverses this phenotype and leads to depletion of tumor-associated VEGF-A165. These results encourage further clinical investigation of PEGPH20. Clin Cancer Res; 24(19); 4798–807. ©2018 AACR.
Data from The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients
Authors: Zill Oliver A. , Banks Kimberly C. , Fairclough Stephen R. , Mortimer Stefanie A. , Vowles James V. , Mokhtari Reza , Gandara David R. , Mack Philip C. , Odegaard Justin I. , Nagy Rebecca J. , Baca Arthur M. , Eltoukhy Helmy , Chudova Darya I. , Lanman Richard B. , Talasaz AmirAli
Published: April 2023

Abstract
Purpose: Cell-free DNA (cfDNA) sequencing provides a noninvasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants.

Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. To facilitate interpretation of the genomic complexity of circulating tumor DNA in advanced, treated cancer patients, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality.

Results: Patterns and prevalence of cfDNA alterations in major driver genes for non–small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (The Cancer Genome Atlas and COSMIC; r = 0.90–0.99), with the principal differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naïve tumors. Upon applying novel cfDNA clonality and copy-number driver identification methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations (FDR = 5 × 10−7 for EGFR and ERBB2), in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel alterations and parallel evolution, was common in the cfDNA cohort and was enriched in patients with targetable driver alterations (>18.6% patients).

Conclusions: Together, these retrospective analyses of a large cfDNA sequencing data set reveal subclonal structures and emerging resistance in advanced solid tumors. Clin Cancer Res; 24(15); 3528–38. ©2018 AACR.
Data from Androgen Deprivation Therapy Potentiates the Efficacy of Vascular Targeted Photodynamic Therapy of Prostate Cancer Xenografts
Authors: Kim Kwanghee , Watson Philip A. , Lebdai Souhil , Jebiwott Sylvia , Somma Alexander J. , La Rosa Stephen , Mehta Dipti , Murray Katie S. , Lilja Hans , Ulmert David , Monette Sebastien , Scherz Avigdor , Coleman Jonathan A.
Published: April 2023

Abstract
Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared with active surveillance in patients with low-risk prostate cancer. The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk prostate cancer tumors.

Experimental Design: Transcriptome analysis of VTP-treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors.

Results: Gene set enrichment analysis identifies the enrichment of androgen-responsive gene sets within hours after VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared with either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum prostate-specific antigen (PSA) confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining 7 days after treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition.

Conclusions: Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced prostate cancer. Clin Cancer Res; 24(10); 2408–16. ©2018 AACR.
Data from False-Positive Plasma Genotyping Due to Clonal Hematopoiesis
Authors: Hu Yuebi , Ulrich Bryan C. , Supplee Julianna , Kuang Yanan , Lizotte Patrick H. , Feeney Nora B. , Guibert Nicolas M. , Awad Mark M. , Wong Kwok-Kin , Jänne Pasi A. , Paweletz Cloud P. , Oxnard Geoffrey R.
Published: April 2023

Abstract
Purpose: Plasma cell-free DNA (cfDNA) genotyping is increasingly used in cancer care, but assay accuracy has been debated. Because most cfDNA is derived from peripheral blood cells (PBC), we hypothesized that nonmalignant mutations harbored by hematopoietic cells (clonal hematopoiesis, CH) could be a cause of false-positive plasma genotyping.

Experimental Design: We identified patients with advanced non–small cell lung cancer (NSCLC) with KRAS, JAK2, or TP53 mutations identified in cfDNA. With consent, PBC DNA was tested using droplet digital PCR (ddPCR) or next-generation sequencing (NGS) to test for CH-derived mutations.

Results: We first studied plasma ddPCR results from 58 patients with EGFR-mutant NSCLC. Two had KRAS G12X detected in cfDNA, and both were present in PBC, including one where the KRAS mutation was detected serially for 20 months. We then studied 143 plasma NGS results from 122 patients with NSCLC and identified 5 JAK2 V617F mutations derived from PBC. In addition, 108 TP53 mutations were detected in cfDNA; for 33 of the TP53 mutations, PBC and tumor NGS were available for comparison, and 5 were present in PBC but absent in tumor, consistent with CH.

Conclusions: We find that most JAK2 mutations, some TP53 mutations, and rare KRAS mutations detected in cfDNA are derived from CH not tumor. Clinicians ordering plasma genotyping must be prepared for the possibility that mutations detected in plasma, particularly in genes mutated in CH, may not represent true tumor genotype. Efforts to use plasma genotyping for cancer detection may need paired PBC genotyping so that CH-derived mutations are not misdiagnosed as occult malignancy. Clin Cancer Res; 24(18); 4437–43. ©2018 AACR.

See related commentary by Bauml and Levy, p. 4352