bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Advances in Understanding the Human Fungal Pathogen Hypoxia Response in Disease Progression
Authors: Puerner Charles , Vellanki Sandeep , Strauch Julianne L. , Cramer Robert A.
Published: September 2023

Fungal-mediated disease progression and antifungal drug efficacy are significantly impacted by the dynamic infection microenvironment. At the site of infection, oxygen often becomes limiting and induces a hypoxia response in both the fungal pathogen and host cells. The fungal hypoxia response impacts several important aspects of fungal biology that contribute to pathogenesis, virulence, antifungal drug susceptibility, and ultimately infection outcomes. In this review, we summarize recent advances in understanding the molecular mechanisms of the hypoxia response in the most common human fungal pathogens, discuss potential therapeutic opportunities, and highlight important areas for future research.
Dupilumab’s Impact on Blood Parameters in Nasal Polyposis: 18-Month Follow-Up in Real Life
Authors: Loperfido Antonella , Ciofalo Andrea , Cavaliere Carlo , Begvarfaj Elona , Cascone Francesca , Alfonzo Giacomo , Cadeddu Rosalba , Millarelli Stefano , Bellocchi Gianluca , Greco Antonio , de Vincentiis Marco , Masieri Simonetta
Published: September 2023

Background. Dupilumab represents the first approved biological for severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP). Objective. Aim of this paper is to provide a multicentric real-life study about treatment with dupilumab for CRSwNP with a special focus on blood parameters and IgE, IgG, and IgA. Method. A retrospective data collection was jointly conducted at the Otolaryngology departments of San Camillo Forlanini Hospital and University of Rome “La Sapienza” from December 2020 to January 2023. Results. A total of 130 patients were included in the study. Monitoring our patients for 18 months, we observed a reduction in nasal polyposis and an improvement in symptoms and their impact on quality of life. Regarding blood tests, a transient increase in blood eosinophils was found in most cases. Total IgE showed a gradual decrease in values. IgG and IgA also showed a slight reduction of values, while remaining within normal ranges. Conclusion. To the best of our knowledge, this is the first study to evaluate the impact of dupilumab on several blood parameters in patients receiving treatment for CRswNP. Further studies are needed to confirm our results and to understand the underlying immunological mechanisms.
An Accurate and Fast Method for Improving ADC Nonlinearity
Authors: Mohammedali Mohammed Abdulmahdi , Al-Gayem Qais
Published: September 2023

Errors in analog-to-digital conversion (ADC) occur due to internal links or other electronic parts; faults that may occur during code conversion cannot be overlooked because signal digitalisation demands a large dynamic range and high resolution. This paper presents a new and accurate self-test method to compensate for one of the most effective errors of ADC because of its effect, which may result in a missing code, which is a differential nonlinear (DNL) of a 10-bit SAR-ADC. The proposed method includes three stages: DNL error modelling for nonideal system implementation, detection, and correction. To evaluate the proposed technique, sinusoidal and sawtooth signals are applied as analog inputs to the proposed system. Adaptivity, speed, and accuracy are the main motivations of this work, which provide high accuracy compared to other techniques, up to 9.6 ENOB and 59.2 SNR with sawtooth signal and 9.5 ENOB and 59.2 SNR with sinewave signals.
Supplementary Data from N6-methyladenosine Modification of FZR1 mRNA Promotes Gemcitabine Resistance in Pancreatic Cancer
Authors: Su Jiachun , Li Rui , Chen Ziming , Liu Shaoqiu , Zhao Hongzhe , Deng Shuang , Zeng Lingxing , Xu Zilan , Zhao Sihan , Zhou Yifan , Li Mei , He Xiaowei , Liu Ji , Xue Chunling , Bai Ruihong , Zhuang Lisha , Zhou Quanbo , Zhang Shaoping , Chen Rufu , Huang Xudong , Lin Dongxin , Zheng Jian , Zhang Jialiang
Published: September 2023

Proteins identified in RNA pulldown and mass spectrometry analysis with FZR1[m6A] or FZR1[A].
Data from ESRRB Inhibits the TGFβ Signaling Pathway to Drive Cell Proliferation in Cervical Cancer
Authors: Li Qin-Shu , Zheng Peng-Sheng
Published: September 2023

Abstract
Estrogen-related receptor β (ESRRB) is a member of the orphan nuclear receptor family and mediates stem cell self-renewal and early embryonic development. Previous studies have also reported that ESRRB plays a role in the development and progression of breast cancer and prostate cancer. In this study, we observed that ESRRB was highly expressed in cervical cancer and was associated with disease progression. Knocking out ESRRB using CRISPR/Cas9 gene editing in cervical cancer cells induced cell-cycle arrest at the transition from the G0–G1 phase to the S phase, resulting in inhibition of cell proliferation in vitro and reduced tumor growth in vivo. Conversely, ectopic expression of ESRRB significantly promoted the proliferation of cervical cancer cells. ESRRB activated transcription of SMAD7, a TGFβ pathway inhibitor, which blocked phosphorylation and nuclear translocation of SMAD2/3 to the nucleus, thereby downregulating CDKN1A and upregulating CCNA2 and MYC. In turn, MYC transactivated ESRRB and upregulated SMAD7, thus forming a positive feedback loop with ESRRB. Together, these findings identify the tumor-promoting function of ESRRB in cervical cancer and reveal a mechanism by which ESRRB stimulates cell proliferation to promote cancer progression.
Significance:
The ESRRB/SMAD7/MYC-positive feedback loop inhibits TGFβ signaling to activate cell-cycle progression and promote proliferation in cervical cancer, thereby driving tumor growth.
Data from Oncogenic ASPM Is a Regulatory Hub of Developmental and Stemness Signaling in Cancers
Authors: Tsai Kelvin K. , Bae Byoung-Il , Hsu Chung-Chi , Cheng Li-Hsin , Shaked Yuval
Published: September 2023

Abstract
Despite recent advances in molecularly targeted therapies and immunotherapies, the effective treatment of advanced-stage cancers remains a largely unmet clinical need. Identifying driver mechanisms of cancer aggressiveness can lay the groundwork for the development of breakthrough therapeutic strategies. Assembly factor for spindle microtubules (ASPM) was initially identified as a centrosomal protein that regulates neurogenesis and brain size. Mounting evidence has demonstrated the pleiotropic roles of ASPM in mitosis, cell-cycle progression, and DNA double-strand breaks (DSB) repair. Recently, the exon 18–preserved isoform 1 of ASPM has emerged as a critical regulator of cancer stemness and aggressiveness in various malignant tumor types. Here, we describe the domain compositions of ASPM and its transcript variants and overview their expression patterns and prognostic significance in cancers. A summary is provided of recent progress in the molecular elucidation of ASPM as a regulatory hub of development- and stemness-associated signaling pathways, such as the Wnt, Hedgehog, and Notch pathways, and of DNA DSB repair in cancer cells. The review emphasizes the potential utility of ASPM as a cancer-agnostic and pathway-informed prognostic biomarker and therapeutic target.
Data from Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in breast cancer
Authors: Marin Arnaldo , Mamun Abdullah Al , Patel Hima , Akamatsu Hiroaki , Ye Dan , Sudhan Dhivya R. , Eli Lisa , Marcelain Katherine , Brown Benjamin P. , Meiler Jens , Arteaga Carlos L. , Hanker Ariella B.
Published: September 2023

Abstract
HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKIs) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. It is unknown whether these secondary HER2 mutations, other than the HER2T798I gatekeeper mutation, are causal to neratinib resistance. Herein, we show that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling, which was blocked by combined inhibition of HER2 and MEK. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer.
Data from N6-methyladenosine Modification of FZR1 mRNA Promotes Gemcitabine Resistance in Pancreatic Cancer
Authors: Su Jiachun , Li Rui , Chen Ziming , Liu Shaoqiu , Zhao Hongzhe , Deng Shuang , Zeng Lingxing , Xu Zilan , Zhao Sihan , Zhou Yifan , Li Mei , He Xiaowei , Liu Ji , Xue Chunling , Bai Ruihong , Zhuang Lisha , Zhou Quanbo , Zhang Shaoping , Chen Rufu , Huang Xudong , Lin Dongxin , Zheng Jian , Zhang Jialiang
Published: September 2023

Abstract
The therapeutic options for treating pancreatic ductal adenocarcinoma (PDAC) are limited, and resistance to gemcitabine, a cornerstone of PDAC chemotherapy regimens, remains a major challenge. N6-methyladenosine (m6A) is a prevalent modification in mRNA that has been linked to diverse biological processes in human diseases. Herein, by characterizing the global m6A profile in a panel of gemcitabine-sensitive and gemcitabine-insensitive PDAC cells, we identified a key role for elevated m6A modification of the master G0–G1 regulator FZR1 in regulating gemcitabine sensitivity. Targeting FZR1 m6A modification augmented the response to gemcitabine treatment in gemcitabine-resistant PDAC cells both in vitro and in vivo. Mechanistically, GEMIN5 was identified as a novel m6A mediator that specifically bound to m6A-modified FZR1 and recruited the eIF3 translation initiation complex to accelerate FZR1 translation. FZR1 upregulation maintained the G0–G1 quiescent state and suppressed gemcitabine sensitivity in PDAC cells. Clinical analysis further demonstrated that both high levels of FZR1 m6A modification and FZR1 protein corresponded to poor response to gemcitabine. These findings reveal the critical function of m6A modification in regulating gemcitabine sensitivity in PDAC and identify the FZR1–GEMIN5 axis as a potential target to enhance gemcitabine response.
Significance:
Increased FZR1 translation induced by m6A modification engenders a gemcitabine-resistant phenotype by inducing a quiescent state and confers a targetable vulnerability to improve treatment response in PDAC.
Data from Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma
Authors: Gulay Kevin Christian Montecillo , Zhang Xinlian , Pantazopoulou Vasiliki , Patel Jay , Esparza Edgar , Pran Babu Deepa Sheik , Ogawa Satoshi , Weitz Jonathan , Ng Isabella , Mose Evangeline S. , Pu Minya , Engle Dannielle D. , Lowy Andrew M. , Tiriac Hervé
Published: September 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 antitumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.
Significance:
KRAS-mutant pancreatic cancer models, including KRAS inhibitor–resistant models, show exquisite sensitivity to combined pan-ERBB and KRAS targeting, which provides the rationale for testing this drug combination in clinical trials.
DPP9 Stabilizes NRF2 to Suppress Ferroptosis and Induce Sorafenib Resistance in Clear Cell Renal Cell Carcinoma
Authors: Chang Kun , Chen Yingji , Zhang Xuanzhi , Zhang Wei , Xu Ning , Zeng Bohan , Wang Yue , Feng Tao , Dai Bo , Xu Fujiang , Ye Dingwei , Wang Chenji
Published: September 2023

The KEAP1-NRF2 axis is the principal regulator of cellular responses to oxidative and electrophilic stressors. NRF2 hyperactivation is frequently observed in many types of cancer and promotes cancer initiation, progression, metastasis, and resistance to various therapies. Here, we determined that dipeptidyl peptidase 9 (DPP9) is a regulator of the KEAP1-NRF2 pathway in clear cell renal cell carcinoma (ccRCC). DPP9 was markedly overexpressed at the mRNA and protein levels in ccRCC, and high DPP9 expression levels correlated with advanced tumor stage and poor prognosis in patients with ccRCC. Protein affinity purification to identify functional partners of DPP9 revealed that it bound to KEAP1 via a conserved ESGE motif. DPP9 disrupted KEAP1-NRF2 binding by competing with NRF2 for binding to KEAP1 in an enzyme-independent manner. Upregulation of DPP9 led to stabilization of NRF2, driving NRF2-dependent transcription and thereby decreasing cellular reactive oxygen species levels. Moreover, DPP9 overexpression suppressed ferroptosis and induced resistance to sorafenib in ccRCC cells, which was largely dependent on the NRF2 transcriptional target SLC7A11. Collectively, these findings indicate that the accumulation of DPP9 results in hyperactivation of the NRF2 pathway to promote tumorigenesis and intrinsic drug resistance in ccRCC.

Significance:

DPP9 overcomes oxidative stress and suppresses ferroptosis in ccRCC by binding to KEAP1 and promoting NRF2 stability, which drives tumor development and sorafenib resistance.
Intratumoral Bacteria as Mediators of Cancer Immunotherapy Response
Authors: Sfanos Karen S.
Published: September 2023

Multiple lines of evidence spanning from animal models to human clinical trials indicate that the microbiome influences cancer immunotherapy response. Whereas initial studies focused exclusively on the gastrointestinal (gut) microbiota–tumor axis, more recent studies have examined the possibility that bacteria located within tumor cells or within the tumor microenvironment mediate cancer treatment response. Strikingly, this phenomenon has been demonstrated in cancers that arise in anatomic locations that are traditionally thought to be devoid of resident microbiota. In this issue of Cancer Research, Wu and colleagues examine the effects of intratumoral bacterial signatures on treatment response in the setting of neoadjuvant chemotherapy combined with immunotherapy (NACI) in the treatment of esophageal squamous cell carcinoma (ESCC). The study reports that intratumoral Streptococcus, presumably due to bacterial translocation from the gut, predicts the treatment efficacy of NACI in murine models as well as individuals with ESCC. These new findings further highlight the possibility that the presence of intratumoral microbes as well as their associated metabolites influence both the tumor immune microenvironment and immunotherapy efficacy. These findings also raise the intriguing possibility of cross-reactivity between tumor and bacterial antigens. Given that the gut microbiome is potentially a modifiable factor via diet, prebiotics/probiotics, and fecal microbiota transplantation, among other strategies, further exploration into the mechanisms by which gut and/or intratumoral bacteria influence antitumor immunity is certainly warranted.

See related article by Wu et al., p. 3131
Supplementary Table S8 from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: September 2023

Multivariable Cox Proportional Hazard for PFS in HER2-targeted retrospective cohort (n=217).
Suppl. Figure 6 from Endoglin, a Novel Biomarker and Therapeutical Target to Prevent Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis
Authors: González-Muñoz Teresa , Di Giannatale Angela , García-Silva Susana , Santos Vanesa , Sánchez-Redondo Sara , Savini Claudia , Graña-Castro Osvaldo , Blanco-Aparicio Carmen , Fischer Suzanne , De Wever Olivier , Creus-Bachiller Edgar , Ortega-Bertran Sara , Pisapia David J. , Rodríguez-Peralto Jose L. , Fernández-Rodríguez Juana , Pérez-Portabella Cleofé Romagosa , Alaggio Rita , Benassi Maria Serena , Pazzaglia Laura , Scotlandi Katia , Ratner Nancy , Yohay Kaleb , Theuer Charles P. , Peinado Héctor
Published: September 2023

Dual inhibition of ENG and MEK efficiently blocks ENG-Smad1/5 and MAPK/ERK pathway activation in ST88-14 cells.
Supplementary Figure S1 from Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial
Authors: Abel Melissa L. , Takahashi Nobuyuki , Peer Cody , Redon Christophe E. , Nichols Samantha , Vilimas Rasa , Lee Min-Jung , Lee Sunmin , Shelat Meenakshi , Kattappuram Robbie , Sciuto Linda , Pinkiert Danielle , Graham Chante , Butcher Donna , Karim Baktiar , Sharma Ajit Kumar , Malin Justin , Kumar Rajesh , Schultz Christopher W. , Goyal Shubhank , del Rivero Jaydira , Krishnamurthy Manan , Upadhyay Deep , Schroeder Brett , Sissung Tristan , Tyagi Manoj , Kim Jung , Pommier Yves , Aladjem Mirit , Raffeld Mark , Figg William Douglas , Trepel Jane , Xi Liqiang , Desai Parth , Thomas Anish
Published: September 2023

Berzosertib pharmacodynamic assessment
Supplementary Table S5 from Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer
Authors: Cornwell Abigail C. , Tisdale Arwen A. , Venkat Swati , Maraszek Kathryn E. , Alahmari Abdulrahman A. , George Anthony , Attwood Kristopher , George Madison , Rempinski Donald , Franco-Barraza Janusz , Seshadri Mukund , Parker Mark D. , Cortes Gomez Eduardo , Fountzilas Christos , Cukierman Edna , Steele Nina G. , Feigin Michael E.
Published: September 2023

Supplementary Table S5. Pancreatic Cancer Time-to-Event Outcomes: Multivariate Summaries.
Supplementary Table S1 from Integrated Multimodal Analyses of DNA Damage Response and Immune Markers as Predictors of Response in Metastatic Triple-Negative Breast Cancer in the TNT Trial (NCT00532727)
Authors: Tovey Holly , Sipos Orsolya , Parker Joel S. , Hoadley Katherine A. , Quist Jelmar , Kernaghan Sarah , Kilburn Lucy , Salgado Roberto , Loi Sherene , Kennedy Richard D. , Roxanis Ioannis , Gazinska Patrycja , Pinder Sarah E. , Bliss Judith , Perou Charles M. , Haider Syed , Grigoriadis Anita , Tutt Andrew , Cheang Maggie Chon U.
Published: September 2023

Supplementary table 1 - Biomarkers of interest
Supplementary Figure S2 from Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer
Authors: Cornwell Abigail C. , Tisdale Arwen A. , Venkat Swati , Maraszek Kathryn E. , Alahmari Abdulrahman A. , George Anthony , Attwood Kristopher , George Madison , Rempinski Donald , Franco-Barraza Janusz , Seshadri Mukund , Parker Mark D. , Cortes Gomez Eduardo , Fountzilas Christos , Cukierman Edna , Steele Nina G. , Feigin Michael E.
Published: September 2023

Supplementary Figure S2. LOR and ALP promote collagen deposition but do not impact tumor growth
Figure 1 from Integrated Multimodal Analyses of DNA Damage Response and Immune Markers as Predictors of Response in Metastatic Triple-Negative Breast Cancer in the TNT Trial (NCT00532727)
Authors: Tovey Holly , Sipos Orsolya , Parker Joel S. , Hoadley Katherine A. , Quist Jelmar , Kernaghan Sarah , Kilburn Lucy , Salgado Roberto , Loi Sherene , Kennedy Richard D. , Roxanis Ioannis , Gazinska Patrycja , Pinder Sarah E. , Bliss Judith , Perou Charles M. , Haider Syed , Grigoriadis Anita , Tutt Andrew , Cheang Maggie Chon U.
Published: September 2023

CONSORT diagram showing the number of primary tumor samples included in analyses and reasons for exclusions.
Supplementary Table S6B from Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Derry Jonathan M.J. , Burns Connor , Frazier Jason P. , Beirne Emily , Grenley Marc , DuFort Christopher C. , Killingbeck Emily , Leon Michael , Williams Claire , Gregory Mark , Houlton Jeffrey , Clayburgh Daniel , Swiecicki Paul , Huszar Dennis , Berger Allison , Klinghoffer Richard A.
Published: September 2023

Enrichment analysis for genes Downregulated by Subasumstat
Supplementary Figure S8 from Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment
Authors: Derry Jonathan M.J. , Burns Connor , Frazier Jason P. , Beirne Emily , Grenley Marc , DuFort Christopher C. , Killingbeck Emily , Leon Michael , Williams Claire , Gregory Mark , Houlton Jeffrey , Clayburgh Daniel , Swiecicki Paul , Huszar Dennis , Berger Allison , Klinghoffer Richard A.
Published: September 2023

UMAP Cluster Analysis for Patients 7 and 8
Data from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: September 2023

AbstractPurpose:
To determine the role of CD49d for response to Bruton's tyrosine kinase inhibitors (BTKi) in patients with chronic lymphocytic leukemia (CLL).
Patients and Methods:
In patients treated with acalabrutinib (n = 48), CD49d expression, VLA-4 integrin activation, and tumor transcriptomes of CLL cells were assessed. Clinical responses to BTKis were investigated in acalabrutinib- (n = 48; NCT02337829) and ibrutinib-treated (n = 73; NCT01500733) patients.
Results:
In patients treated with acalabrutinib, treatment-induced lymphocytosis was comparable for both subgroups but resolved more rapidly for CD49d+ cases. Acalabrutinib inhibited constitutive VLA-4 activation but was insufficient to block BCR and CXCR4–mediated inside–out activation. Transcriptomes of CD49d+ and CD49d− cases were compared using RNA sequencing at baseline and at 1 and 6 months on treatment. Gene set enrichment analysis revealed increased constitutive NF-κB and JAK–STAT signaling, enhanced survival, adhesion, and migratory capacity in CD49d+ over CD49d− CLL that was maintained during therapy. In the combined cohorts of 121 BTKi-treated patients, 48 (39.7%) progressed on treatment with BTK and/or PLCG2 mutations detected in 87% of CLL progressions. Consistent with a recent report, homogeneous and bimodal CD49d-positive cases (the latter having concurrent CD49d+ and CD49d− CLL subpopulations, irrespective of the traditional 30% cutoff value) had a shorter time to progression of 6.6 years, whereas 90% of cases homogenously CD49d− were estimated progression-free at 8 years (P = 0.0004).
Conclusions:
CD49d/VLA-4 emerges as a microenvironmental factor that contributes to BTKi resistance in CLL. The prognostic value of CD49d is improved by considering bimodal CD49d expression.

See related commentary by Tissino et al., p. 3560
Data from Phase II Study of Docetaxel and Trametinib in Patients with KRAS Mutation Positive Recurrent Non–Small Cell Lung Cancer (NSCLC; SWOG S1507, NCT-02642042)
Authors: Gadgeel Shirish M. , Miao Jieling , Riess Jonathan W. , Moon James , Mack Philip C. , Gerstner Gregory J. , Burns Timothy F. , Taj Asma , Akerley Wallace L. , Dragnev Konstantin H. , Laudi Noel , Redman Mary W. , Gray Jhanelle E. , Gandara David R. , Kelly Karen
Published: September 2023

AbstractPurpose:
Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and comutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC.
Patients and Methods:
S1507 is a single-arm phase II study assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients, with at least 25 with G12C mutation. The design was two-stage design to rule out a 17% RR, within the overall population at the one-sided 3% level and within the G12C subset at the 5% level.
Results:
Between July 18, 2016, and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% [95% confidence interval (CI), 22–48] overall and 28% (95% CI, 10–53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, and neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR, 2.85; 95% CI, 1.16–7.01), and RR (0% vs. 56%, P = 0.004) were worse in patients with TP53 mutated versus wild-type cancers.
Conclusions:
RRs were significantly improved in the overall population. Contrary to preclinical studies, the combination showed no improvement in efficacy in G12C patients. Comutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation.

See related commentary by Cantor and Aggarwal, p. 3563
Data from Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors
Authors: Vieito Maria , Moreno Victor , Spreafico Anna , Brana Irene , Wang Judy S. , Preis Meir , Hernández Tatiana , Genta Sofia , Hansen Aaron R. , Doger Bernard , Galvao Vladimir , Lenox Laurie , Brown Regina J. , Kalota Anna , Mehta Jaydeep , Pastore Friederike , Patel Bharvin , Mistry Pankaj , Gu Junchen , Lauring Josh , Patel Manish R.
Published: September 2023

AbstractPurpose:
In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178.
Patients and Methods:
Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated.
Results:
Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months.
Conclusions:
JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.
Data from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria Tiago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Yuyat , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: September 2023

AbstractPurpose:
We report updated clinical outcomes from a phase II study of pembrolizumab, trastuzumab, and chemotherapy (PTC) in metastatic esophagogastric cancer in conjunction with outcomes from an independent Memorial Sloan Kettering (MSK) cohort.
Patients and Methods:
The significance of pretreatment 89Zr-trastuzumab PET, plasma circulating tumor DNA (ctDNA) dynamics, and tumor HER2 expression and whole exome sequencing was evaluated to identify prognostic biomarkers and mechanisms of resistance in patients treated on-protocol with PTC. Additional prognostic features were evaluated using a multivariable Cox regression model of trastuzumab-treated MSK patients (n = 226). Single-cell RNA sequencing (scRNA-seq) data from MSK and Samsung were evaluated for mechanisms of therapy resistance.
Results:
89Zr-trastuzumab PET, scRNA-seq, and serial ctDNA with CT imaging identified how pre-treatment intrapatient genomic heterogeneity contributes to inferior progression-free survival (PFS). We demonstrated that the presence of intensely avid lesions by 89Zr-trastuzumab PET declines in tumor-matched ctDNA by 3 weeks, and clearance of tumor-matched ctDNA by 9 weeks were minimally invasive biomarkers of durable PFS. Paired pre- and on-treatment scRNA-seq identified rapid clearance of HER2-expressing tumor clones with expansion of clones expressing a transcriptional resistance program, which was associated with MT1H, MT1E, MT2A, and MSMB expression. Among trastuzumab-treated patients at MSK, ERBB2 amplification was associated with improved PFS, while alterations in MYC and CDKN2A/B were associated with inferior PFS.
Conclusions:
These findings highlight the clinical relevance of identifying baseline intrapatient heterogeneity and serial ctDNA monitoring of HER2-positive esophagogastric cancer patients to identify early evidence of treatment resistance, which could guide proactive therapy escalation or deescalation.
Data from Poor Outcome in Postpartum Breast Cancer Patients Is Associated with Distinct Molecular and Immunologic Features
Authors: Lefrère Hanne , Moore Kat , Floris Giuseppe , Sanders Joyce , Seignette Iris M. , Bismeijer Tycho , Peters Dennis , Broeks Annegien , Hooijberg Erik , Van Calsteren Kristel , Neven Patrick , Warner Ellen , Peccatori Fedro Alessandro , Loibl Sibylle , Maggen Charlotte , Han Sileny N. , Jerzak Katarzyna J. , Annibali Daniela , Lambrechts Diether , de Visser Karin E. , Wessels Lodewyk , Lenaerts Liesbeth , Amant Frédéric
Published: September 2023

AbstractPurpose:
Patients with postpartum breast cancer diagnosed after cessation of breastfeeding (postweaning, PP-BCPW) have a particularly poor prognosis compared with patients diagnosed during lactation (PP-BCDL), or to pregnant (Pr-BC) and nulliparous (NP-BC) patients, regardless of standard prognostic characteristics. Animal studies point to a role of the involution process in stimulation of tumor growth in the mammary gland. However, in women, the molecular mechanisms that underlie this poor prognosis of patients with PP-BCPW remain vastly underexplored, due to of lack of adequate patient numbers and outcome data.
Experimental Design:
We explored whether distinct prognostic features, common to all breast cancer molecular subtypes, exist in postpartum tumor tissue. Using detailed breastfeeding data, we delineated the postweaning period in PP-BC as a surrogate for mammary gland involution and performed whole transcriptome sequencing, immunohistochemical, and (multiplex) immunofluorescent analyses on tumor tissue of patients with PP-BCPW, PP-BCDL, Pr-BC, and NP-BC.
Results:
We found that patients with PP-BCPW having a low expression level of an immunoglobulin gene signature, but high infiltration of plasma B cells, have an increased risk for metastasis and death. Although PP-BCPW tumor tissue was also characterized by an increase in CD8+ cytotoxic T cells and reduced distance among these cell types, these parameters were not associated with differential clinical outcomes among groups.
Conclusions:
These data point to the importance of plasma B cells in the postweaning mammary tumor microenvironment regarding the poor prognosis of PP-BCPW patients. Future prospective and in-depth research needs to further explore the role of B-cell immunobiology in this specific group of young patients with breast cancer.
Data from Identifying Mechanisms of Resistance by Circulating Tumor DNA in EVOLVE, a Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer at Time of PARP Inhibitor Progression
Authors: Lheureux Stephanie , Prokopec Stephenie D. , Oldfield Leslie E. , Gonzalez-Ochoa Eduardo , Bruce Jeffrey P. , Wong Derek , Danesh Arnavaz , Torti Dax , Torchia Jonathan , Fortuna Alexander , Singh Sharanjit , Irving Matthew , Marsh Kayla , Lam Bernard , Speers Vanessa , Yosifova Aleksandra , Oaknin Ana , Madariaga Ainhoa , Dhani Neesha C. , Bowering Valerie , Oza Amit M. , Pugh Trevor J.
Published: September 2023

AbstractPurpose:
To evaluate the use of blood cell–free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high-grade serous ovarian cancer (HGSOC).
Experimental Design:
We used targeted sequencing (TS) to analyze 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled in a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib (PARPi) after progression on PARPi alone. cfDNA was collected at baseline, before treatment cycle 2, and at end of treatment. These were compared with whole-exome sequencing (WES) of baseline tumor tissues.
Results:
At baseline (time of initial PARPi progression), cfDNA tumor fractions were 0.2% to 67% (median, 3.25%), and patients with high ctDNA levels (>15%) had a higher tumor burden (sum of target lesions; P = 0.043). Across all timepoints, cfDNA detected 74.4% of mutations known from prior tumor WES, including three of five expected BRCA1/2 reversion mutations. In addition, cfDNA identified 10 novel mutations not detected by WES, including seven TP53 mutations annotated as pathogenic by ClinVar. cfDNA fragmentation analysis attributed five of these novel TP53 mutations to clonal hematopoiesis of indeterminate potential (CHIP). At baseline, samples with significant differences in mutant fragment size distribution had shorter time to progression (P = 0.001).
Conclusions:
Longitudinal testing of cfDNA by TS provides a noninvasive tool for detection of tumor-derived mutations and mechanisms of PARPi resistance that may aid in directing patients to appropriate therapeutic strategies. With cfDNA fragmentation analyses, CHIP was identified in several patients and warrants further investigation.
Data from A Novel HOXA10-Associated 5-Gene–Based Prognostic Signature for Stratification of Short-term Survivors of Pancreatic Ductal Adenocarcinoma
Authors: Kisling Sophia G. , Atri Pranita , Shah Ashu , Cox Jesse L. , Sharma Sunandini , Smith Lynette M. , Ghersi Dario , Batra Surinder K.
Published: September 2023

AbstractPurpose:
Despite the significant association of molecular subtypes with poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC), few efforts have been made to identify the underlying pathway(s) responsible for this prognosis. Identifying a clinically relevant prognosis-based gene signature may be the key to improving patient outcomes.
Experimental Design:
We analyzed the transcriptomic profiles of treatment-naïve surgically resected short-term survivor (STS) and long-term survivor (LTS) tumors (GSE62452) for expression and survival, followed by validation in several datasets. These results were corroborated by IHC analysis of PDAC-resected STS and LTS tumors. The mechanism of this differential survival was investigated using CIBERSORT and pathway analyses.
Results:
We identified a short-surviving prognostic subtype of PDAC with a high degree of significance (P = 0.018). One hundred thirty genes in this novel subtype were found to be regulated by a master regulator, homeobox gene HOXA10, and a 5-gene signature derived from these genes, including BANF1, EIF4G1, MRPS10, PDIA4, and TYMS, exhibited differential expression in STSs and a strong association with poor survival. This signature was further associated with the proportion of T cells and macrophages found in STSs and LTSs, demonstrating a potential role in PDAC immunosuppression. Pathway analyses corroborated these findings, revealing that this HOXA10-driven prognostic signature is associated with immune suppression and enhanced tumorigenesis.
Conclusions:
Overall, these findings reveal the presence of a HOXA10-associated prognostic subtype that can be used to differentiate between STS and LTS patients of PDAC and inform on the molecular interactions that play a role in this poor prognosis.
BACH1 Loss Exerts Antitumor Effects on Mantle Cell Lymphoma Cells via Inducing a Tumor-Intrinsic Innate Immune Response and Cell-Cycle Arrest
Authors: Li Guilan , Feng Min , Zhang Ziting , Liu Jiangyuan , Zhang Han
Published: September 2023

BTB and CNC homology 1 (BACH1) is a transcription repressor that regulates multiple physiological processes, including intracellular heme homeostasis and immune responses. Increasing lines of evidence indicate that BACH1 reshapes metastasis and metabolism of human solid tumors. However, its potential roles in mantle cell lymphoma (MCL) remain largely unknown. Here, we found that silencing BACH1 in MCL cells induced markedly cell-cycle arrest and cell apoptosis, whereas overexpression of BACH1 exhibited the opposite patterns. Increased BACH1 levels not only promoted tumor growth and dispersal in xenografts, but also conferred a long-term poor prognosis in patients with MCL. Interestingly, RNA sequencing analysis revealed noncanonical function of BACH1 in regulation of type I interferon (IFNI) response, DNA replication and repair, and cell cycle. Mechanistically, zinc finger and BTB domain containing 20 (ZBTB20) and HMG-box transcription factor 1 (HBP1) were for the first time identified as two novel downstream targets repressed by BACH1 in MCL cells. Further double-knockdown functional assays confirmed that loss of BACH1 induced ZBTB20-mediated IFNα production and HBP1-mediated cell-cycle arrest, indicating that BACH1-centered regulatory network may be a novel targetable vulnerability in MCL cells.

Implications:

BACH1 serves as a pleotropic regulator of tumor-intrinsic innate immune response and cell-cycle progression, disruption of which may offer a promising therapeutic strategy for MCL treatment.
Abstract IA12: Fluorescence guided surgery: Rapidly evolving applications
Authors: Rosenthal Eben L. , Hom Marisa L. , Lu Goulan
Published: September 2023

Despite advances in operative technology, intraoperative methods have not improved cancer detection during surgery in the past 30 years. We propose to test the combination of high-resolution/depth-limited imaging properties of optical imaging agents with the low-resolution/tissue penetrating properties of nuclear agents for detection of primary tumors and regional lymph nodes. We propose that combined optical and nuclear imaging can detect tumor fragments less than 1 mm3 in vivo during removal of head and neck cancers. In fact, nuclear PET imaging alone may be highly successful - The current standard of care for evaluation and surveillance of regional and metastatic disease in head and neck squamous cell carcinoma (HNSCC) is FDG-PET/CT scan, which is highly sensitive but not specific. To address this, we show that a head and neck cancer, tumor-specific PET radiopharmaceutical can improve diagnostic specificity in this patient population.

Citation Format: Eben L. Rosenthal, Marisa L. Hom, Goulan Lu. Fluorescence guided surgery: Rapidly evolving applications [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr IA12.
Abstract PO-007: A phase 2 open-label study of conditionally active biologic, ozuriftamab vedotin (BA3021) in PD-1/L1 failure patients with recurrent or metastatic squamous cell carcinoma of the head and neck
Authors: Ho Alan L. , Adkins Douglas R. , Lorch Jochen , Thomas Jacob S. , Grewal Jaspreet S.
Published: September 2023

Background: Ozuriftamab vedotin (BA3021) is a conditionally active biologic (CAB) anti-receptor tyrosine kinase orphan receptor 2 (ROR2) humanized monoclonal antibody (IgG1) conjugated to monomethyl auristatin E (MMAE) using a cleavable linker (CAB ROR2 ADC) (Short, et al., 2014, Chang, et al. 2021). Conditional and reversible binding by CABs is designed to reduce off-tumor toxicity and immunogenicity, avoid tissue-mediated drug deposition, and improve pharmacokinetics (PK). ROR2 is a cell-surface transmembrane receptor protein tyrosine kinase highly expressed in several tumor types including head and neck squamous cell cancer (HNSCC). Increased ROR2 expression has been associated with tumor resistance to chemotherapy, programmed death-1 (PD-1) inhibitors, molecular targeted therapy, and radiation therapy. A pronounced unmet need exists as the majority of patients with recurrent or metastatic HNSCC experience disease progression with existing therapies (Chow 2020). Trial Design: BA3021-002 is a multi-center, open-label, single-arm Phase 2 study (n=40) designed to evaluate the efficacy and safety of BA3021 in patients previously treated with PD-(L)1 with ROR-2 expressing recurrent or metastatic HNSCC. Eligible patients include those with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria. Failure to prior treatment is defined as documented disease progression after no more than one PD-1/L1 inhibitor either administered as monotherapy or in combination therapy. Pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and biomarker assessments will be performed. Enrollment is ongoing (NCT05271604) References Chang, H.W., Frey, G., Liu, H., Steinman, L., Boyle, W.J. and Short, J.M. Proc. Natl. Acad. Sci. 2021 Mar. 2; 118(9). Chow LQ. Head and neck cancer. N Engl J Med. 2020 Jan 2;382(1):60–72. doi: 10.1056/NEJMra1715715 Short, J.M. Nature Biotechnology 2014 Nov 8, 13(20).

Citation Format: Alan L. Ho, Douglas R. Adkins, Jochen Lorch, Jacob S. Thomas, Jaspreet S. Grewal. A phase 2 open-label study of conditionally active biologic, ozuriftamab vedotin (BA3021) in PD-1/L1 failure patients with recurrent or metastatic squamous cell carcinoma of the head and neck [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-007.
Abstract PO-018: Pathological analysis of newly established immunocompetent mice with full HPV16 genome integration
Authors: Li Xue , Kothari Aditi , Rehmani Hina , Yarbrough Wendell G. , Issaeva Natalia
Published: September 2023

Human papillomaviruses (HPV) are associated with both benign and malignant epithelial lesions. High-risk HPV subtype HPV 16 is the causative agent of cervical and the majority of oropharyngeal squamous cell carcinomas. Despite the continuous increase in the disease burden, mechanisms and pathways of HPV16-induced cancer growth are not fully understood, thus leading to suboptimal treatment. In the last few decades, several transgenic mouse models were developed, which helped tremendously in the study of HPV-induced carcinogenesis. However, all existent HPV transgenic mice were targeted early genes expression driven by an artificial promoter and did not encompass the functionality of the whole HPV genome, including the upstream regulatory region (URR) that contains HPV promoters, regulatory elements, and a replication origin, limited our ability to investigate HPV-associated malignant transformation and the role of host factors in this process. Therefore, we generated HPV16 transgenic mice by using CRISPR/Cas9-mediated genome editing to insert the full-length HPV16 genome into the Rosa26 locus. Two founder mice, with single HPV copy and with tandem HPV integration, were used to establish mouse colonies. Interestingly, regardless of HPV copy number, approximately 50% of the HPV knock-in mice exhibited early death during the first 2 weeks after birth, while surviving pups were significantly smaller than the same-age wild-type mice and had severe hair loss. Intriguingly, the growth retardant and hair loss phenotype in the HPV16 knock-in mice disappeared in approximately 4 weeks, most likely indicating that viral genes compromise specific stages of mouse development. We evaluated the expression of HPV genes during development, in different mouse organs, and in established fibroblasts and epithelial cell cultures. Our newly established HPV16 knock-in mouse model provides viral gene expression from natural viral promoters offering an essential basis to explore the role of cellular factors in HPV-driven pathologies.

Citation Format: Xue Li, Aditi Kothari, Hina Rehmani, Wendell G. Yarbrough, Natalia Issaeva. Pathological analysis of newly established immunocompetent mice with full HPV16 genome integration [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-018.