bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Clinical and Genomic Implications of Luminal and Basal Subtypes Across Carcinomas
Authors: Zhao Shuang G. , Chen William S. , Das Rajdeep , Chang S. Laura , Tomlins Scott A. , Chou Jonathan , Quigley David A. , Dang Ha X. , Barnard Travis J. , Mahal Brandon A. , Gibb Ewan A. , Liu Yang , Davicioni Elai , Duska Linda R. , Posadas Edwin M. , Jolly Shruti , Spratt Daniel E. , Nguyen Paul L. , Maher Christopher A. , Small Eric J. , Feng Felix Y.
Published: April 2023

AbstractPurpose:
Carcinomas originate from epithelial tissues, which have apical (luminal) and basal orientations. The degree of luminal versus basal differentiation in cancer has been shown to be biologically important in some carcinomas and impacts treatment response.
Experimental Design:
Although prior studies have focused on individual cancer types, we used a modified clinical-grade classifier (PAM50) to subtype 8,764 tumors across 22 different carcinomas into luminal A, luminal B, and basal-like tumors.
Results:
We found that all epithelial tumors demonstrated similar gene expression–based luminal/basal subtypes. As expected, basal-like tumors were associated with increased expression of the basal markers KRT5/6 and KRT14, and luminal-like tumors were associated with increased expression of the luminal markers KRT20. Luminal A tumors consistently had improved outcomes compared with basal across many tumor types, with luminal B tumors falling between the two. Basal tumors had the highest rates of TP53 and RB1 mutations and copy number loss. Luminal breast, cervical, ovarian, and endometrial tumors had increased ESR1 expression, and luminal prostate, breast, cervical, and bladder tumors had increased androgen receptor (AR) expression. Furthermore, luminal B tumors had the highest rates of AR and ESR1 mutations and had increased sensitivity in vitro to bicalutamide and tamoxifen. Luminal B tumors were more sensitive to gemcitabine, and basal tumors were more sensitive to docetaxel.
Conclusions:
This first pan-carcinoma luminal/basal subtyping across epithelial tumors reveals global similarities across carcinomas in the transcriptome, genome, clinical outcomes, and drug sensitivity, emphasizing the biological and translational importance of these luminal versus basal subtypes.
Data from NRF2 through RPS6 Activation Is Related to Anti-HER2 Drug Resistance in HER2-Amplified Gastric Cancer
Authors: Gambardella Valentina , Gimeno-Valiente Francisco , Tarazona Noelia , Ciarpaglini Carolina Martinez , Roda Desamparados , Fleitas Tania , Tolosa Pablo , Cejalvo Juan Miguel , Huerta Marisol , Roselló Susana , Castillo Josefa , Cervantes Andrés
Published: April 2023

AbstractPurpose:
Despite the clinical advantage of the combination of trastuzumab and platinum-based chemotherapy in HER2-amplified tumors, resistance will eventually develop. The identification of molecular mechanisms related to primary and acquired resistance is needed.
Experimental Design:
We generated lapatinib- and trastuzumab-resistant clones deriving from two different HER2-amplified gastric cancer cell lines. Molecular changes such as protein expression and gene-expression profile were evaluated to detect alterations that could be related to resistance. Functional studies in vitro were corroborated in vivo. The translational relevance of our findings was verified in a patient cohort.
Results:
We found RPS6 activation and NRF2 to be related to anti-HER2 drug resistance. RPS6 or NRF2 inhibition with siRNA reduced viability and resistance to anti-HER2 drugs. In knockdown cells for RPS6, a decrease of NRF2 expression was demonstrated, suggesting a potential link between these two proteins. The use of a PI3K/TORC1/TORC2 inhibitor, tested in vitro and in vivo, inhibited pRPS6 and NRF2 expression and caused cell and tumor growth reduction, in anti–HER2-resistant models. In a cohort of HER2-amplified patients treated with trastuzumab and chemotherapy, a high level of NRF2 at baseline corresponds with worse progression-free survival.
Conclusions:
NRF2 through the PI3K/AKT/mTOR/RPS6 pathway could be a potential effector of resistance to anti-HER2 drugs in our models. RPS6 inhibition decreases NRF2 expression and restores sensitivity in HER2-amplified gastric cancer in vitro and in vivo. High NRF2 expression in gastric cancer patients predicts resistance to treatment. RPS6 and NRF2 inhibition could prevent resistance to anti-HER2 drugs.
Data from Perioperative Dynamic Changes in Circulating Tumor DNA in Patients with Lung Cancer (DYNAMIC)
Authors: Chen Kezhong , Zhao Heng , Shi Yanbin , Yang Fan , Wang Lien Tu , Kang Guannan , Nie Yuntao , Wang Jun
Published: April 2023

AbstractPurpose:
No study has investigated the precise perioperative dynamic changes in circulating tumor DNA (ctDNA) in any patients with early-stage cancer. This study (DYNAMIC) investigated perioperative dynamic changes in ctDNA and determined the appropriate detection time of ctDNA-based surveillance for surgical patients with lung cancer.

Experimental Design: Consecutive patients who underwent curative-intent lung resections were enrolled prospectively (NCT02965391). Plasma samples were obtained at multiple prespecified time points including before surgery (time A), during surgery after tumor resection (time B–time D), and after surgery (time P1–time P3). Next-generation sequencing–based detection platform was performed to calculate the plasma mutation allele frequency. The primary endpoint was ctDNA half-life after radical tumor resection.
Results:
Thirty-six patients showed detectable mutations in time A. The plasma ctDNA concentration showed a rapid decreasing trend after radical tumor resection, with the average mutant allele fraction at times A, B, C, and D being 2.72%, 2.11%, 1.14%, and 0.17%, respectively. The median ctDNA half-life was 35.0 minutes. Patients with minimal residual disease (MRD) detection had a significant slower ctDNA half-life than those with negative MRD (103.2 minutes vs. 29.7 minutes, P = 0.001). The recurrence-free survival of patients with detectable and undetectable ctDNA concentrations at time P1 was 528 days and 543 days, respectively (P = 0.657), whereas at time P2 was 278 days and 637 days, respectively (P = 0.002).
Conclusions:
ctDNA decays rapidly after radical tumor resection. The ctDNA detection on the third day after R0 resection can be used as the baseline value for postoperative lung cancer surveillance.
Data from First-in-Human Study of Mivebresib (ABBV-075), an Oral Pan-Inhibitor of Bromodomain and Extra Terminal Proteins, in Patients with Relapsed/Refractory Solid Tumors
Authors: Piha-Paul Sarina A. , Sachdev Jasgit C. , Barve Minal , LoRusso Patricia , Szmulewitz Russell , Patel Sapna Pradyuman , Lara Primo N. , Chen Xiaotian , Hu Beibei , Freise Kevin J. , Modi Dimple , Sood Anjla , Hutti Jessica E. , Wolff Johannes , O'Neil Bert H.
Published: April 2023

AbstractPurpose:
Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-in-human study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors.
Patients and Methods:
A 3 + 3 dose escalation for different mivebresib dosing schedules [daily, Monday/Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity.
Results:
Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2–3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8–1.9).
Conclusions:
On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.
Data from 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers
Authors: Yang Hailing , Shu Zhang , Jiang Yongying , Mao Weiqun , Pang Lan , Redwood Abena , Jeter-Jones Sabrina L. , Jennings Nicholas B. , Ornelas Argentina , Zhou Jinhua , Rodriguez-Aguayo Cristian , Bartholomeusz Geoffrey , Iles LaKesla R. , Zacharias Niki M. , Millward Steven W. , Lopez-Berestein Gabriel , Le Xiao-Feng , Ahmed Ahmed A. , Piwnica-Worms Helen , Sood Anil K. , Bast Robert C. , Lu Zhen
Published: April 2023

AbstractPurpose:
Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases.

Experimental Design: Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) depletion on cell metabolomics, extracellular acidification rate, nicotinamide adenine dinucleotide phosphate, reactive oxygen species (ROS), and apoptosis were studied in multiple ovarian and breast cancer cell lines. Four breast and ovarian human xenografts and a breast cancer patient-derived xenograft (PDX) were used to examine the knockdown effect of PFKFB2 on tumor cell growth in vivo.
Results:
Knockdown of PFKFB2 inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type TP53 (wtTP53). Silencing PFKFB2 significantly inhibited tumor growth and enhanced paclitaxel sensitivity in four xenografts derived from two ovarian and two breast cancer cell lines, and prolonged survival in a triple-negative breast cancer PDX. Transfection of siPFKFB2 increased the glycolysis rate, but decreased the flow of intermediates through the pentose–phosphate pathway in cancer cells with wtTP53, decreasing NADPH. ROS accumulated after PFKFB2 knockdown, which stimulated Jun N-terminal kinase and p53 phosphorylation, and induced apoptosis that depended upon upregulation of p21 and Puma.
Conclusions:
PFKFB2 is a novel target whose inhibition can enhance the effect of paclitaxel-based primary chemotherapy upon ovarian and breast cancers retaining wtTP53.
Data from Genetic Polymorphisms Predisposing the Interleukin 6–Induced APOBEC3B-UNG Imbalance Increase HCC Risk via Promoting the Generation of APOBEC-Signature HBV Mutations
Authors: Liu Wenbin , Wu Jianfeng , Yang Fan , Ma Longteng , Ni Chong , Hou Xiaomei , Wang Ling , Xu Aijing , Song Jiahui , Deng Yang , Xian Linfeng , Li Zixiong , Wang Shuo , Chen Xi , Yin Jianhua , Han Xue , Li Chengzhong , Zhao Jun , Cao Guangwen
Published: April 2023

AbstractPurpose:
APOBEC3-UNG imbalance contributes to hepatitis B virus (HBV) inhibition and somatic mutations. We aimed to explore the associations between hepatocellular carcinoma (HCC) risk and genetic polymorphisms predisposing the imbalance.

Experimental Design: Genetic polymorphisms at APOBEC3 promoter and UNG enhancer regions were genotyped in 5,621 participants using quantitative PCR. HBV mutations (nt.1600–nt.1945, nt.2848–nt.155) were determined by Sanger sequencing. Dual-luciferase reporter assay was applied to detect the transcriptional activity. Effects of APOBEC3B/UNG SNPs and expression levels on HCC prognosis were evaluated with a cohort of 400 patients with HCC and public databases, respectively.
Results:
APOBEC3B rs2267401-G allele and UNG rs3890995-C allele significantly increased HCC risk. rs2267401-G allele was significantly associated with the generation of APOBEC-signature HBV mutation whose frequency consecutively increased from asymptomatic HBV carriers to patients with HCC. Multiplicative interaction of rs2267401-G allele with rs3890995-C allele increased HCC risk, with an adjusted OR (95% confidence interval) of 1.90 (1.34–2.81). rs2267401 T-to-G and rs3890995 T-to-C conferred increased activities of APOBEC3B promoter and UNG enhancer, respectively. IL6 significantly increased APOBEC3B promoter activity and inhibited UNG enhancer activity, and these effects were more evident in those carrying rs2267401-G and rs3890995-C, respectively. APOBEC3B rs2267401-GG genotype, higher APOBEC3B expression, and higher APOBEC3B/UNG expression ratio in HCCs indicated poor prognosis. APOBEC-signature somatic mutation predicts poor prognosis in HBV-free HCCs rather than in HBV-positive ones.
Conclusions:
Polymorphic genotypes predisposing the APOBEC3B-UNG imbalance in IL6-presenting microenvironment promote HCC development, possibly via promoting the generation of high-risk HBV mutations. This can be transformed into specific prophylaxis of HBV-caused HCC.
Data from Localized Treatment with Oncolytic Adenovirus Delta-24-RGDOX Induces Systemic Immunity against Disseminated Subcutaneous and Intracranial Melanomas
Authors: Jiang Hong , Shin Dong Ho , Nguyen Teresa T. , Fueyo Juan , Fan Xuejun , Henry Verlene , Carrillo Caroline C. , Yi Yanhua , Alonso Marta M. , Collier Tiara L. , Yuan Ying , Lang Frederick F. , Gomez-Manzano Candelaria
Published: April 2023

AbstractPurpose:
Intratumoral injection of oncolytic adenovirus Delta-24-RGDOX induces efficacious antiglioma immunity in syngeneic glioma mouse models. We hypothesized that localized treatment with the virus is effective against disseminated melanomas.
Experimental Design:
We tested the therapeutic effect of injecting Delta-24-RGDOX into primary subcutaneous (s.c.) B16-Red-FLuc tumors in s.c./s.c. and s.c./intracranial (i.c.) melanoma models in C57BL/6 mice. Tumor growth and in vivo luciferase-expressing ovalbumin-specific (OT-I/Luc) T cells were monitored with bioluminescence imaging. Cells were profiled for surface markers with flow cytometry.
Results:
In both s.c./s.c. and s.c./i.c. models, 3 injections of Delta-24-RGDOX significantly inhibited the growth of both the virus-injected s.c. tumor and untreated distant s.c. and i.c. tumors, thereby prolonging survival. The surviving mice were protected from rechallenging with the same tumor cells. The virus treatment increased the presence of T cells and the frequency of effector T cells in the virus-injected tumor and mediated the same changes in T cells from peripheral blood, spleen, and brain hemispheres with untreated tumor. Moreover, Delta-24-RGDOX decreased the numbers of exhausted T cells and regulatory T cells in the virus-injected and untreated tumors. Consequently, the virus promoted the in situ expansion of tumor-specific T cells and their migration to tumors expressing the target antigen.
Conclusions:
Localized intratumoral injection of Delta-24-RGDOX induces an in situ antovaccination of the treated melanoma, the effect of which changes the immune landscape of the treated mice, resulting in systemic immunity against disseminated s.c. and i.c. tumors.
Data from Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non–Small Cell Lung Cancer
Authors: Gray Jhanelle E. , Saltos Andreas , Tanvetyanon Tawee , Haura Eric B. , Creelan Ben , Antonia Scott J. , Shafique Michael , Zheng Hong , Dai Wenjie , Saller James J. , Chen Zhihua , Tchekmedyian Nishan , Goas Kristen , Thapa Ram , Boyle Theresa A. , Chen Dung-Tsa , Beg Amer A.
Published: April 2023

AbstractPurpose:
Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase I/Ib trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non–small cell lung cancer.
Patients and Methods:
Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens.
Results:
Thirty-three patients were treated (13 in phase I, 20 in phase Ib). In phase I, both ICI-naïve and ICI-pretreated patients were enrolled to determine dose-limiting toxicities (DLT). No DLTs were observed, and the recommended phase I dose was pembrolizumab 200 mg and vorinostat 400 mg. Any-grade adverse events were mainly fatigue (33%) and nausea/vomiting (27%). Of six ICI-naïve and 24 ICI-pretreated patients evaluable for response, four (13%) had partial response [two confirmed, one unconfirmed with subsequent prolonged stable disease (SD), one unconfirmed with subsequent progressive disease (PD)], 16 (53%) had SD, and 10 (33%) had PD for a DCR of 67%. In the ICI-pretreated cohort, three patients (one confirmed, two unconfirmed) had partial response and 10 had SD. Pretreatment CD8+ T-cell presence in tumor stromal regions was associated with treatment benefit.
Conclusions:
Pembrolizumab plus vorinostat was well tolerated and demonstrated preliminary antitumor activity despite progression on prior ICI treatment.
Data from Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes and Immunotherapy Outcome in Metastatic Melanoma
Authors: Wong Pok Fai , Wei Wei , Smithy James W. , Acs Balazs , Toki Maria I. , Blenman Kim R.M. , Zelterman Daniel , Kluger Harriet M. , Rimm David L.
Published: April 2023

AbstractPurpose:
Because durable response to programmed cell death 1 (PD-1) inhibition is limited to a subset of melanoma patients, new predictive biomarkers could have clinical utility. We hypothesize that pretreatment tumor-infiltrating lymphocyte (TIL) profiles could be associated with response.
Experimental Design:
Pretreatment whole tissue sections from 94 melanoma patients treated with anti–PD-1 therapy were profiled by multiplex immunofluorescence to perform TIL quantification (CD4, CD8, CD20) and assess TIL activation (CD3, GZMB, Ki67). Two independent image analysis technologies were used: inForm (PerkinElmer) to determine cell counts, and AQUA to measure protein by quantitative immunofluorescence (QIF). TIL parameters by both methodologies were correlated with objective response or disease control rate (ORR/DCR) by RECIST 1.1 and survival outcome.
Results:
Pretreatment lymphocytic infiltration, by cell counts or QIF, was significantly higher in complete or partial response than in stable or progressive disease, particularly for CD8 (P < 0.0001). Neither TIL activation nor dormancy was associated with outcome. CD8 associations with progression-free survival (HR > 3) were independently significant in multivariable analyses and accounted for similar CD3 associations in anti–PD-1-treated patients. CD8 was not associated with melanoma prognosis in the absence of immunotherapy. Predictive performance of CD8 cell count (and QIF) had an area under the ROC curve above 0.75 (ORR/DCR), which reached 0.83 for ipilimumab plus nivolumab.
Conclusions:
Pretreatment lymphocytic infiltration is associated with anti–PD-1 response in metastatic melanoma. Quantitative TIL analysis has potential for application in digital precision immuno-oncology as an “indicative” companion diagnostic.
Data from TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG)
Authors: Werbrouck Coralie , Evangelista Cláudia C.S. , Lobón-Iglesias María-Jesús , Barret Emilie , Le Teuff Gwénaël , Merlevede Jane , Brusini Romain , Kergrohen Thomas , Mondini Michele , Bolle Stéphanie , Varlet Pascale , Beccaria Kevin , Boddaert Nathalie , Puget Stéphanie , Grill Jacques , Debily Marie-Anne , Castel David
Published: April 2023

AbstractPurpose:
Diffuse intrinsic pontine gliomas (DIPG) are the most severe pediatric brain tumors. Although accepted as the standard therapeutic, radiotherapy is only efficient transiently and not even in every patient. The goal of the study was to identify the underlying molecular determinants of response to radiotherapy in DIPG.
Experimental Design:
We assessed in vitro response to ionizing radiations in 13 different DIPG cellular models derived from treatment-naïve stereotactic biopsies reflecting the genotype variability encountered in patients at diagnosis and correlated it to their principal molecular alterations. Clinical and radiologic response to radiotherapy of a large cohort of 73 DIPG was analyzed according to their genotype. Using a kinome-wide synthetic lethality RNAi screen, we further identified target genes that can sensitize DIPG cells to ionizing radiations.
Results:
We uncover TP53 mutation as the main driver of increased radioresistance and validated this finding in four isogenic pairs of TP53WT DIPG cells with or without TP53 knockdown. In an integrated clinical, radiological, and molecular study, we show that TP53MUT DIPG patients respond less to irradiation, relapse earlier after radiotherapy, and have a worse prognosis than their TP53WT counterparts. Finally, a kinome-wide synthetic lethality RNAi screen identifies CHK1 as a potential target, whose inhibition increases response to radiation specifically in TP53MUT cells.
Conclusions:
Here, we demonstrate that TP53 mutations are driving DIPG radioresistance both in patients and corresponding cellular models. We suggest alternative treatment strategies to mitigate radioresistance with CHK1 inhibitors. These findings will allow to consequently refine radiotherapy schedules in DIPG.
Data from IL23-Producing Human Lung Cancer Cells Promote Tumor Growth via Conversion of Innate Lymphoid Cell 1 (ILC1) into ILC3
Authors: Koh Jaemoon , Kim Hye Young , Lee Youngha , Park In Kyu , Kang Chang Hyun , Kim Young Tae , Kim Ji-Eun , Choi Murim , Lee Won-Woo , Jeon Yoon Kyung , Chung Doo Hyun
Published: April 2023

AbstractPurpose:
The plasticity of innate lymphoid cells (ILCs) has been reported in vitro and in the microenvironment of the intestine. However, whether ILC plasticity contributes to regulation of the tumor microenvironment remains unknown. In this study, we explored plasticity of ILCs in human lung cancer.
Experimental Design:
We analyzed immune subsets and cytokine expression in lung cancers freshly obtained from 80 patients and explored conversion of ILC1 into ILC3 in coculture with lung cancer cells. Prognostic effects of converted ILC3 and related pathway were evaluated by retrospective cohort composed of 875 patients with lung cancer.
Results:
Low percentages of ILC1, and high percentages of ILC3 were found in pulmonary squamous cell carcinomas (SqCC) but not adenocarcinomas (ADC). In non–small-cell lung cancers, the percentage of ILC3 was associated with IL23 expression in tumor cells but not immune cells. In cocultures, tumor cells of SqCCs converted ILC1 into ILC3 by producing IL23, thus promoting IL17-mediated tumor cell proliferation. Consistently, among IL17+ immune cells, the percentages of ILCs were higher in SqCCs than ADCs. Furthermore, the numbers of CD3−RORγt+ ILC3, IL17 expression level, and IL23- or IL17RA-expressing tumor cells were associated with short survival of patients with SqCC but not ADC.
Conclusions:
Conversion from ILC1 into ILC3 by IL23-producing SqCCs promotes IL17-mediated tumor progression, resulting in a poor prognosis.
Data from Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals RB1 Signaling as a Novel Mediator and Biomarker
Authors: Parada Carolina A. , Osbun Joshua W. , Busald Tina , Karasozen Yigit , Kaur Sumanpreet , Shi Min , Barber Jason , Adidharma Widya , Cimino Patrick J. , Pan Catherine , Gonzalez-Cuyar Luis F. , Rostomily Robert , Born Donald E. , Zhang Jing , Ferreira Manuel
Published: April 2023

AbstractPurpose:
Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short.
Experimental Design:
Mass spectrometry (MS)–based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables.
Results:
The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas.
Conclusions:
RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.
Data from The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition
Authors: Parmar Kalindi , Kochupurakkal Bose S. , Lazaro Jean-Bernard , Wang Zhigang C. , Palakurthi Sangeetha , Kirschmeier Paul T. , Yang Chunyu , Sambel Larissa A. , Färkkilä Anniina , Reznichenko Elizaveta , Reavis Hunter D. , Dunn Connor E. , Zou Lee , Do Khanh T. , Konstantinopoulos Panagiotis A. , Matulonis Ursula A. , Liu Joyce F. , D'Andrea Alan D. , Shapiro Geoffrey I.
Published: April 2023

AbstractPurpose:
PARP inhibitors are approved for the treatment of high-grade serous ovarian cancers (HGSOC). Therapeutic resistance, resulting from restoration of homologous recombination (HR) repair or replication fork stabilization, is a pressing clinical problem. We assessed the activity of prexasertib, a checkpoint kinase 1 (CHK1) inhibitor known to cause replication catastrophe, as monotherapy and in combination with the PARP inhibitor olaparib in preclinical models of HGSOC, including those with acquired PARP inhibitor resistance.
Experimental Design:
Prexasertib was tested as a single agent or in combination with olaparib in 14 clinically annotated and molecularly characterized luciferized HGSOC patient-derived xenograft (PDX) models and in a panel of ovarian cancer cell lines. The ability of prexasertib to impair HR repair and replication fork stability was also assessed.
Results:
Prexasertib monotherapy demonstrated antitumor activity across the 14 PDX models. Thirteen models were resistant to olaparib monotherapy, including 4 carrying BRCA1 mutation. The combination of olaparib with prexasertib was synergistic and produced significant tumor growth inhibition in an olaparib-resistant model and further augmented the degree and durability of response in the olaparib-sensitive model. HGSOC cell lines, including those with acquired PARP inhibitor resistance, were also sensitive to prexasertib, associated with induction of DNA damage and replication stress. Prexasertib also sensitized these cell lines to PARP inhibition and compromised both HR repair and replication fork stability.
Conclusions:
Prexasertib exhibits monotherapy activity in PARP inhibitor–resistant HGSOC PDX and cell line models, reverses restored HR and replication fork stability, and synergizes with PARP inhibition.
Data from HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma
Authors: Faião-Flores Fernanda , Emmons Michael F. , Durante Michael A. , Kinose Fumi , Saha Biswarup , Fang Bin , Koomen John M. , Chellappan Srikumar P. , Maria-Engler Silvya Stuchi , Rix Uwe , Licht Jonathan D. , Harbour J. William , Smalley Keiran S.M.
Published: April 2023

AbstractPurpose:
The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. This study has used multiomics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance.

Experimental Design: Mass spectrometry–based proteomics and RNA-Seq were used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified, and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo models of uveal melanoma.
Results:
We identified a number of putative escape pathways that were upregulated following MEK inhibition, including the PI3K/AKT pathway, ROR1/2, and IGF-1R signaling. MEK inhibition was also associated with increased GPCR expression, particularly the endothelin B receptor, and this contributed to therapeutic escape through ET-3–mediated YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo, the MEK-HDAC inhibitor combination outperformed either agent alone, leading to a long-term decrease of tumor growth in both subcutaneous and liver metastasis models and the suppression of adaptive PI3K/AKT and YAP signaling.
Conclusions:
Together, our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in advanced uveal melanoma.
Data from BRAF and DIS3 Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma
Authors: Boyle Eileen M. , Ashby Cody , Tytarenko Ruslana G. , Deshpande Shayu , Wang Hongwei , Wang Yan , Rosenthal Adam , Sawyer Jeffrey , Tian Erming , Flynt Erin , Hoering Antje , Johnson Sarah K. , Rutherford Michael W. , Wardell Christopher P. , Bauer Michael A. , Dumontet Charles , Facon Thierry , Thanendrarajan Sharmilan , Schinke Carolina D. , Zangari Maurizio , van Rhee Frits , Barlogie Bart , Cairns David , Jackson Graham , Thakurta Anjan , Davies Faith E. , Morgan Gareth J. , Walker Brian A.
Published: April 2023

AbstractPurpose:
Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets.
Experimental Design:
We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials.
Results:
As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF, making up 44% of patients. Double-Hit and BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF-mutated patients showed co-occurring alterations in KRAS, NRAS, or activating BRAF mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance.
Conclusions:
Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches.
Data from A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF-mutated Melanoma to MAPK Inhibitors
Authors: Aloia Andrea , Müllhaupt Daniela , Chabbert Christophe D. , Eberhart Tanja , Flückiger-Mangual Stefanie , Vukolic Ana , Eichhoff Ossia , Irmisch Anja , Alexander Leila T. , Scibona Ernesto , Frederick Dennie T. , Miao Benchun , Tian Tian , Cheng Chaoran , Kwong Lawrence N. , Wei Zhi , Sullivan Ryan J. , Boland Genevieve M. , Herlyn Meenhard , Flaherty Keith T. , Zamboni Nicola , Dummer Reinhard , Zhang Gao , Levesque Mitchell P. , Krek Wilhelm , Kovacs Werner J.
Published: April 2023

AbstractPurpose:
Treatment of BRAFV600E-mutant melanomas with MAPK inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand nonmutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi.
Experimental Design:
By screening proteins expressed on the cell surface of melanoma cells, we identified the fatty acid transporter CD36 as the most consistently upregulated protein upon short-term treatment with MAPKi. We further investigated the effects of MAPKi on fatty acid metabolism using in vitro and in vivo models and analyzing patients' pre- and on-treatment tumor specimens.
Results:
Melanoma cells treated with MAPKi displayed increased levels of CD36 and of PPARα-mediated and carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). While CD36 is a useful marker of melanoma cells during adaptation and drug-tolerant phases, the upregulation of CD36 is not functionally involved in FAO changes that characterize MAPKi-treated cells. Increased FAO is required for BRAFV600E-mutant melanoma cells to survive under the MAPKi-induced metabolic stress prior to acquiring drug resistance. The upfront and concomitant inhibition of FAO, glycolysis, and MAPK synergistically inhibits tumor cell growth in vitro and in vivo.
Conclusions:
Thus, we identified a clinically relevant therapeutic approach that has the potential to improve initial responses and to delay acquired drug resistance of BRAFV600E-mutant melanoma.
Data from TRIB3 Stabilizes High TWIST1 Expression to Promote Rapid APL Progression and ATRA Resistance
Authors: Lin Jian , Zhang Wu , Niu Li-Ting , Zhu Yong-Mei , Weng Xiang-Qin , Sheng Yan , Zhu Jiang , Xu Jie
Published: April 2023

AbstractPurpose:
The resistance to differentiation therapy and early death caused by fatal bleeding endangers the health of a significant proportion of patients with acute promyelocytic leukemia (APL). This study aims to investigate the molecular mechanisms of all-trans retinoic acid (ATRA) resistance and uncover new potential therapeutic strategies to block the rapid progression of early death.
Experimental Design:
The important role of TWIST1 in APL leukemogenesis was first determined by gain- and loss-of-function assays. We then performed in vivo and in vitro experiments to explore the interaction of TWIST1 and TRIB3 and develop a potential peptide-initiated therapeutic opportunity to protect against early death and induction therapy resistance in patients with APL.
Results:
We found that the epithelial–mesenchymal transition (EMT)-inducing transcription factor TWIST1 is highly expressed in APL cells and is critical for leukemic cell survival. TWIST1 and TRIB3 were highly coexpressed in APL cells compared with other subtypes of acute myeloid leukemia cells. We subsequently demonstrated that TRIB3 could bind to the WR domain of TWIST1 and contribute to its stabilization by inhibiting its ubiquitination. TRIB3 depletion promoting TWIST1 degradation reverses resistance to induction therapy and improves sensitivity to ATRA. On the basis of a detailed functional screen of synthetic peptides, we discovered a peptide analogous to the TWIST1 WR domain that specifically represses APL cell survival by disrupting the TRIB3/TWIST1 interaction.
Conclusions:
Our data not only define the essential role of TWIST1 as an EMT-TF in patients with APL but also suggest that disrupting the TRIB3/TWIST1 interaction reverses induction therapy resistance and blocks rapid progression of APL early death.

See related commentary by Peeke and Gritsman, p. 6018
Data from PD-L1 Expression and Clinical Outcomes to Cabozantinib, Everolimus, and Sunitinib in Patients with Metastatic Renal Cell Carcinoma: Analysis of the Randomized Clinical Trials METEOR and CABOSUN
Authors: Flaifel Abdallah , Xie Wanling , Braun David A. , Ficial Miriam , Bakouny Ziad , Nassar Amin H. , Jennings Rebecca B. , Escudier Bernard , George Daniel J. , Motzer Robert J. , Morris Michael J. , Powles Thomas , Wang Evelyn , Huang Ying , Freeman Gordon J. , Choueiri Toni K. , Signoretti Sabina
Published: April 2023

AbstractPurpose:
Programmed death-ligand 1 (PD-L1) status by IHC is prognostic in metastatic renal cell carcinoma (mRCC), and its role as a potential predictive biomarker is under investigation. Using tumor tissue from the METEOR (NCT01865747) and CABOSUN (NCT01835158) clinical trials, we explored whether PD-L1 expression and the extent of the immune cell infiltrate can serve as prognostic and/or predictive biomarkers for cabozantinib and other targeted agents.
Experimental Design:
IHC double staining for PD-L1 and CD45/CD163 (immune cell markers) was performed on tumor tissue from METEOR (n = 306) and CABOSUN (n = 110) clinical trials. Immune cell density and MET expression levels were also analyzed. Our primary aim was to correlate progression-free survival (PFS) by independent central review with PD-L1 status in patients treated with cabozantinib, everolimus (METEOR), or sunitinib (CABOSUN). Overall survival (OS) was also interrogated.
Results:
Tumor cell (TC) PD-L1 expression (≥1% cutoff) was detected in 29% and 23% of tumors from patients in the METEOR and CABOSUN trials, respectively. On univariate analysis, patients with PD-L1–positive TC had poorer PFS and OS than patients with PD-L1–negative TC on both trials, independent of therapy. On multivariable analysis and when combining the two trials, the association between TC PD-L1 expression and OS was statistically significant for all patients (P = 0.034) and for patients treated with cabozantinib only (P = 0.038). Cabozantinib was associated with improved PFS (HR < 0.70) and OS (HR < 0.85) compared with everolimus and sunitinib irrespective of PD-L1 expression.
Conclusions:
Higher PD-L1 expression results in worse clinical outcomes in mRCC treated with targeted therapy. Furthermore, PD-L1 expression is not predictive of response to cabozantinib therapy.
Data from The Caspase-3/PKCδ/Akt/VEGF-A Signaling Pathway Mediates Tumor Repopulation during Radiotherapy
Authors: Cheng Jin , He Sijia , Wang Min , Zhou Ling , Zhang Zhengxiang , Feng Xiao , Yu Yang , Ma Jingjing , Dai Chenyun , Zhang Shengping , Sun Lianhui , Gong Yanping , Wang Yiwei , Zhao Minghui , Luo Yuntao , Liu Xinjian , Tian Ling , Li Chuanyuan , Huang Qian
Published: April 2023

AbstractPurpose:
Tumor repopulation is known as a major cause of treatment failure and/or tumor recurrence after radiotherapy. The underlying mechanism remains unclear. Our previous study demonstrated that irradiated apoptotic cells mediated tumor repopulation, in which caspase-3 played an important role. Herein, we investigated downstream effectors of caspase-3 involved in this process.
Experimental Design:
A dominant-negative protein kinase Cδ (DN_PKCδ) mutant that could not be cleaved by caspase-3 and therefore could not be activated by irradiation-induced apoptosis was constructed. DN_PKCδ stably transduced tumor cells were compared with wild-type tumor cells for their growth stimulation effects in in vitro and in vivo tumor repopulation models. Downstream effectors of caspase-3 and PKCδ were investigated. The role of PKCδ was further verified in human colorectal tumor specimens.
Results:
Inactivation of caspase-3 or caspase-7 attenuated tumor repopulation and weakened PKCδ cleavage. Both DN_PKCδ and PKCδ inhibitors restrained tumor repopulation both in vitro and in vivo. Phosphorylated Akt was attenuated in caspase-3–, caspase-7–, or PKCδ-inactivated tumor cells. Furthermore, expression of vascular endothelial growth factor (VEGF)-A but not hypoxia-inducible factor 1α (HIF1α) was decreased in PKCδ- or Akt-inactivated tumor cells. In addition, inhibition of p-Akt, HIF1α, VEGF-A, or VEGF-A receptor reduced tumor repopulation significantly. Finally, increased nuclear translocation of PKCδ in colorectal tumor specimens was associated with worse patient prognosis.
Conclusions:
The caspase-3/PKCδ/Akt/VEGF-A axis is involved in tumor repopulation and could be exploited as a potential target to enhance the efficacy of radiotherapy.
Data from Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors
Authors: Yap Timothy A. , Winter Jane N. , Giulino-Roth Lisa , Longley Jemma , Lopez Juanita , Michot Jean-Marie , Leonard John P. , Ribrag Vincent , McCabe Michael T. , Creasy Caretha L. , Stern Melissa , Pene Dumitrescu Teodora , Wang Xiaowei , Frey Steve , Carver Jennifer , Horner Thierry , Oh Choon , Khaled Ahmed , Dhar Arindam , Johnson Peter W.M.
Published: April 2023

AbstractPurpose:
Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers.
Patients and Methods:
This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses of GSK2816126 ranged from 50 to 3,000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen.
Results:
Forty-one patients (21 solid tumors, 20 lymphoma) received treatment. All patients experienced ≥1 adverse event (AE). Fatigue [22 of 41 (53.7%)] and nausea [20 of 41 (48.8%)] were the most common toxicity. Twelve (32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in 2 of 7 patients receiving 3,000 mg of GSK2816126; 2,400 mg was therefore established as the MTD. Following intravenous administration of 50 to 3,000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease, and 5 patients were unevaluable for antitumor response.
Conclusions:
The MTD of GSK2816126 was established at 2,400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.
Data from VEGFR1+ Metastasis–Associated Macrophages Contribute to Metastatic Angiogenesis and Influence Colorectal Cancer Patient Outcome
Authors: Freire Valls Aida , Knipper Karl , Giannakouri Evangelia , Sarachaga Víctor , Hinterkopf Sascha , Wuehrl Michael , Shen Ying , Radhakrishnan Praveenkumar , Klose Johannes , Ulrich Alexis , Schneider Martin , Augustin Hellmut G. , Ruiz de Almodovar Carmen , Schmidt Thomas
Published: April 2023

AbstractPurpose:
To investigate the clinical relevance of macrophages in liver metastasis of colorectal cancer and their influence on angiogenesis and patient survival. Moreover to evaluate specific blood monocytes as markers of disease recurrence.

Experimental design: In a mouse model with spontaneous liver metastasis, the angiogenic characteristics of tumor- and metastasis (MAM)-associated macrophages were evaluated. Macrophages and the vasculature from 130 primary tumor (pTU) and 123 patients with liver metastasis were assessed. In vivo and in human samples, the clinical relevance of macrophage VEGFR1 expression was analyzed. Blood samples from patients (n = 157, 80 pTU and 77 liver metastasis) were analyzed for assessing VEGFR1-positive (VEGFR1+) cells as suitable biomarkers of disease recurrence.
Results:
The number of macrophages positively correlated with vascularization in metastasis. Both in the murine model as well as in primary isolated human cells, a subpopulation of MAMs expressing VEGFR1 were found highly angiogenic. While VEGFR1 expression in pTU patients did not predict prognosis; high percentage of VEGFR1+ cells in liver metastasis was associated with worse patient outcome. Interestingly, VEGFR1+-circulating monocytes in blood samples from patients with liver metastasis not only predicted progression but also site of recurrence.
Conclusions:
Our findings identify a new subset of proangiogenic VEGFR1+ MAMs in colorectal cancer that support metastatic growth and may become a liquid biomarker to predict disease recurrence in the liver.