bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Bayesian Machine Learning Enables Identification of Transcriptional Network Disruptions Associated with Drug-Resistant Prostate Cancer
Authors: Blatti Charles , de la Fuente Jesús , Gao Huanyao , Marín-Goñi Irene , Chen Zikun , Zhao Sihai D. , Tan Winston , Weinshilboum Richard , Kalari Krishna R. , Wang Liewei , Hernaez Mikel
Published: April 2023

Abstract
Survival rates of patients with metastatic castration-resistant prostate cancer (mCRPC) are low due to lack of response or acquired resistance to available therapies, such as abiraterone (Abi). A better understanding of the underlying molecular mechanisms is needed to identify effective targets to overcome resistance. Given the complexity of the transcriptional dynamics in cells, differential gene expression analysis of bulk transcriptomics data cannot provide sufficient detailed insights into resistance mechanisms. Incorporating network structures could overcome this limitation to provide a global and functional perspective of Abi resistance in mCRPC. Here, we developed TraRe, a computational method using sparse Bayesian models to examine phenotypically driven transcriptional mechanistic differences at three distinct levels: transcriptional networks, specific regulons, and individual transcription factors (TF). TraRe was applied to transcriptomic data from 46 patients with mCRPC with Abi-response clinical data and uncovered abrogated immune response transcriptional modules that showed strong differential regulation in Abi-responsive compared with Abi-resistant patients. These modules were replicated in an independent mCRPC study. Furthermore, key rewiring predictions and their associated TFs were experimentally validated in two prostate cancer cell lines with different Abi-resistance features. Among them, ELK3, MXD1, and MYB played a differential role in cell survival in Abi-sensitive and Abi-resistant cells. Moreover, ELK3 regulated cell migration capacity, which could have a direct impact on mCRPC. Collectively, these findings shed light on the underlying transcriptional mechanisms driving Abi response, demonstrating that TraRe is a promising tool for generating novel hypotheses based on identified transcriptional network disruptions.
Significance:
The computational method TraRe built on Bayesian machine learning models for investigating transcriptional network structures shows that disruption of ELK3, MXD1, and MYB signaling cascades impacts abiraterone resistance in prostate cancer.
Data from DNA Methylation Landscapes of Prostate Cancer Brain Metastasis Are Shaped by Early Driver Genetic Alterations
Authors: Gallon John , Rodriguez-Calero Antonio , Benjak Andrej , Akhoundova Dilara , Maletti Sina , Amstutz Ursula , Hewer Ekkehard , Genitsch Vera , Fleischmann Achim , Rushing Elisabeth J. , Grobholz Rainer , Fischer Ingeborg , Jochum Wolfram , Cathomas Gieri , Osunkoya Adeboye O. , Bubendorf Lukas , Moch Holger , Thalmann George , Feng Felix Y. , Gillessen Silke , Ng Charlotte K.Y. , Rubin Mark A. , Piscuoglio Salvatore
Published: April 2023

Abstract
Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive SPOP-mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion sampling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in SPOP-mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand–receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation.
Significance:
DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.
Data from Single-cell discovery and multi-omic characterization of therapeutic targets in multiple myeloma
Authors: Yao Lijun , Wang Julia T. , Jayasinghe Reyka G. , O'Neal Julie , Tsai Chia-Feng , Rettig Michael P. , Song Yizhe , Liu Ruiyang , Zhao Yanyan , Ibrahim Omar M. , Fiala Mark A. , Fortier Julie M. , Chen Siqi , Gehrs Leah , Martins Rodrigues Fernanda , Wendl Michael C. , Kohnen Danny , Shinkle Andrew , Cao Song , Foltz Steven M. , Zhou Daniel Cui , Storrs Erik , Wyczalkowski Matthew A. , Mani Smrithi , Goldsmith Scott R. , Zhu Ying , Hamilton Mark , Liu Tao , Chen Feng , Vij Ravi , Ding Li , DiPersio John F.
Published: April 2023

Abstract
Multiple myeloma (MM) is a highly refractory hematological cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which are previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA-sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA-sequencing reiterated top candidates, further affirming the ability of single cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy.
Data from Neutrophil conversion to a tumor-killing phenotype underpins effective microbial therapy
Authors: Yam Andrew O. , Bailey Jacqueline , Lin Francis , Jakovija Arnolda , Youlten Scott E. , Counoupas Claudio , Gunzer Matthias , Bald Tobias , Woodruff Trent M. , Triccas James A. , Goldstein Leonard D. , Gallego-Ortega David , Grey Shane T. , Chtanova Tatyana
Published: April 2023

Abstract
The inflammatory microenvironment of solid tumors creates a pro-tumorigenic milieu that resembles chronic inflammation akin to a subverted wound healing response. Here we investigated the effect of converting the tumor microenvironment from a chronically inflamed state to one of acute microbial inflammation by injecting microbial bioparticles directly into tumors. Intratumoral microbial bioparticle injection led to rapid and dramatic changes in the tumor immune composition, the most striking of which was a substantial increase in the presence of activated neutrophils. In situ photoconversion and intravital microscopy indicated that tumor neutrophils transiently switched from sessile producers of vascular endothelial growth factor to highly motile neutrophils that clustered to make neutrophil-rich domains in the tumor. The neutrophil clusters remodeled tumor tissue and repressed tumor growth. Single cell transcriptional analysis of microbe-stimulated neutrophils showed a profound shift in gene expression towards heightened activation and anti-microbial effector function. Microbe-activated neutrophils also upregulated chemokines known to regulate neutrophil and CD8+ T cell recruitment. Microbial therapy also boosted CD8+ T cell function and enhanced the therapeutic benefit of checkpoint inhibitor therapy in tumor-bearing mice and provided protection in a model of tumor recurrence. These data indicate that one of the major effector mechanisms of microbial therapy is the conversion of tumor neutrophils from a wound healing to an acutely activated cytotoxic phenotype, highlighting a rationale for broader deployment of microbial therapy in the treatment of solid cancers.
Data from Dysregulation of mitochondrial translation caused by CBFB deficiency cooperates with mutant PIK3CA and is a vulnerability in breast cancer
Authors: Malik Navdeep , Kim Young-Im , Yan Hualong , Tseng Yu-Chou , du Bois Wendy , Ayaz Gamze , Tran Andy D. , Vera Ramírez Laura , Yang Howard H. , Michalowski Aleksandra M. , Kruhlak Michael , Lee Maxwell , Hunter Kent W. , Huang Jing
Published: April 2023

Abstract
Understanding functional interactions between cancer mutations is an attractive strategy for discovering unappreciated cancer pathways and developing new combination therapies to improve personalized treatment. However, distinguishing driver gene pairs from passenger pairs remains challenging. Here, we designed an integrated omics approach to identify driver gene pairs by leveraging genetic interaction analyses of top mutated breast cancer genes and the proteomics interactome data of their encoded proteins. This approach identified that PIK3CA oncogenic gain‐of-function (GOF) and CBFB loss‐of‐function (LOF) mutations cooperate to promote breast tumor progression in both mice and humans. The transcription factor CBFB localized to mitochondria and moonlighted in translating the mitochondrial genome. Mechanistically, CBFB enhanced the binding of mitochondrial mRNAs to TUFM, a mitochondrial translation elongation factor. Independent of mutant PI3K, mitochondrial translation defects caused by CBFB LOF led to multiple metabolic reprogramming events, including defective oxidative phosphorylation (OXPHOS), the Warburg effect, and autophagy/mitophagy addiction. Furthermore, autophagy and PI3K inhibitors synergistically killed breast cancer cells and impaired the growth of breast tumors, including patient‐derived xenografts (PDXs) carrying CBFB LOF and PIK3CA GOF mutations. Thus, our study offers mechanistic insights into the functional interaction between mutant PI3K and mitochondrial translation dysregulation in breast cancer progression and provides a strong preclinical rationale for combining autophagy and PI3K inhibitors in precision medicine for breast cancer.
Data from Active Remodeling of Capillary Endothelium via Cancer Cell–Derived MMP9 Promotes Metastatic Brain Colonization
Authors: Karreman Matthia A. , Bauer Alexander T. , Solecki Gergely , Berghoff Anna S. , Mayer Chanté D. , Frey Katharina , Hebach Nils , Feinauer Manuel J. , Schieber Nicole L. , Tehranian Cedric , Mercier Luc , Singhal Mahak , Venkataramani Varun , Schubert Marc C. , Hinze Daniel , Hölzel Michael , Helfrich Iris , Schadendorf Dirk , Schneider Stefan W. , Westphal Dana , Augustin Hellmut G. , Goetz Jacky G. , Schwab Yannick , Wick Wolfgang , Winkler Frank
Published: April 2023

Abstract
Crossing the blood–brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding of the mechanisms of cancer cell extravasation from brain microcapillaries is limited as the underlying cellular and molecular processes cannot be adequately investigated using in vitro models and endpoint in vivo experiments. Using ultrastructural and functional imaging, we demonstrate that dynamic changes of activated brain microcapillaries promote the mandatory first steps of brain colonization. Successful extravasation of arrested cancer cells occurred when adjacent capillary endothelial cells (EC) entered into a distinct remodeling process. After extravasation, capillary loops were formed, which was characteristic of aggressive metastatic growth. Upon cancer cell arrest in brain microcapillaries, matrix-metalloprotease 9 (MMP9) was expressed. Inhibition of MMP2/9 and genetic perturbation of MMP9 in cancer cells, but not the host, reduced EC projections, extravasation, and brain metastasis outgrowth. These findings establish an active role of ECs in the process of cancer cell extravasation, facilitated by cross-talk between the two cell types. This extends our understanding of how host cells can contribute to brain metastasis formation and how to prevent it.
Significance:
Tracking single extravasating cancer cells using multimodal correlative microscopy uncovers a brain seeding mechanism involving endothelial remodeling driven by cancer cell–derived MMP9, which might enable the development of approaches to prevent brain metastasis.

See related commentary by McCarty, p. 1167
Data from Pertuzumab, Trastuzumab, and an Aromatase Inhibitor for HER2-Positive and Hormone Receptor–Positive Metastatic or Locally Advanced Breast Cancer: PERTAIN Final Analysis
Authors: Arpino Grazia , de la Haba Rodríguez Juan , Ferrero Jean-Marc , De Placido Sabino , Osborne C. Kent , Klingbiel Dirk , Revelant Valentine , Wohlfarth Christine , Poppe Raf , Rimawi Mothaffar F.
Published: April 2023

AbstractPurpose:
In PERTAIN's primary analysis (31 months’ median follow-up), adding pertuzumab to trastuzumab and an aromatase inhibitor (AI) with/without chemotherapy significantly improved progression-free survival (PFS) in patients with previously untreated HER2-positive and hormone receptor–positive metastatic or locally advanced breast cancer (M/LABC). A potentially enhanced treatment effect was observed in patients with no induction chemotherapy. We present the final analysis (>6 years’ median follow-up).
Patients and Methods:
Patients (N = 258) were randomized 1:1 to pertuzumab (loading/maintenance: 840/420 mg) plus trastuzumab (loading/maintenance: 8/6 mg/kg) every 3 weeks and an AI (1 mg anastrozole or 2.5 mg letrozole daily; Arm A), or trastuzumab and an AI (Arm B). Induction chemotherapy was at investigator discretion. Primary endpoint: PFS. Key secondary endpoints: overall survival (OS) and safety.
Results:
Median PFS was 20.6 versus 15.8 months in Arms A and B, respectively (stratified HR, 0.67; P = 0.006). Median OS was 60.2 versus 57.2 months (stratified HR, 1.05; P = 0.78). Pertuzumab treatment effect was potentially enhanced in patients with no induction chemotherapy (26.6 vs. 12.5 months). Any-grade adverse events (AE) occurred in 122 patients per arm (96.1% vs. 98.4%); grade ≥ 3 AEs in 72 (56.7%) and 51 (41.1%); serious AEs in 46 (36.2%) and 28 (22.6%).
Conclusions:
The PFS benefit of pertuzumab was maintained and OS was similar between arms at final analysis. Adding pertuzumab may enhance activity in patients who do not require first-line chemotherapy for M/LABC. No new safety concerns were reported. These data provide additional evidence of the role of first-line pertuzumab and trastuzumab in HER2-positive M/LABC.
Abstract CT240: On-going phase 1A clinical trial for AG01 an first-in-class anti-progranulin (GP88) monoclonal antibody in patients with advanced malignancies
Authors: Tkaczuk Katherine R. , Rosenblatt Paula , Mehra Ranee , Scilla Katherine A. , Tait Nancy , Caple Katerra , Yue Binbin , Serrero Ginette
Published: April 2023

Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats which is the largest member of the granulin-epithelin protein family. PGRN/GP88 has been demonstrated as a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC), lung prostate, ovarian and digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence in breast, lung cancers while elevated serum PGRN/GP88 level in metastatic breast, lung, ovarian and prostate cancer patients. Elevated PGRN/GP88 levels are associated with poor outcomes such as progression and shortened survival. An anti-human PGRN/GP88 monoclonal antibody able to inhibit PGRN/GP88 action in vitro and in vivo has been developed, chimerized and expressed in CHO cells. All IND enabling activities including pharmacology, GMP manufacturing, formulation and GLP toxicology studies have been conducted. The IND application has been filed and cleared by the Food and Drug Administration. A first-in-human, first-in-class phase 1 safety and efficacy clinical study of AG01 in patients with solid tumors and advanced disease with special focus on patients with breast, lung and ovarian cancers has been initiated and is on-going at the University of Maryland Greenebaum Cancer Center. The trial is registered as NCT05627960 to clinicaltrials.gov site. Supported by grants R44CA162629 and R44CA224718 from the National Cancer Institute to GS.

Citation Format: Katherine R. Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine A. Scilla, Nancy Tait, Katerra Caple, Binbin Yue, Ginette Serrero. On-going phase 1A clinical trial for AG01 an first-in-class anti-progranulin (GP88) monoclonal antibody in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT240.
Abstract CT249: A study to evaluate the safety and tolerability of the covalent phosphoinositide-3-kinase (PI3K)-alpha Inhibitor, TOS-358, in adult subjects with select solid tumors
Authors: Fakih Marwan , Sohal Davendra P. , Hafez Navid , Berlin Jordan D. , Hari Kimberly , Trifan Ovid C.
Published: April 2023

Background: TOS-358 is an orally available, highly selective covalent inhibitor of PI3Kα capable of achieving a deep and durable inhibition of PI3K-AKT signaling with virtually no off-target effects. In patient-derived xenograft models, TOS-358 has shown anti-cancer activity in several different tumor types including breast, colorectal, gastric, head and neck, bladder, and esophageal cancer, and its’ activity was superior to non-covalent compounds targeting PI3Kα. Administered at the equivalent dose, TOS-358 has shown a good safety profile in 28-day repeat dose toxicity studies in rats and dogs.

Methods: The TOS-358-001 study is a multicenter dose escalation (phase 1) and dose expansion (phase 1b) clinical study evaluating the safety, tolerability, and preliminary efficacy of TOS-358. Eligible subjects are adults with one of protocol-defined tumor types, known PIK3CA mutation or amplification, adequate organ function, ECOG performance status 0 or 1, available archived or fresh tumor tissue for PIK3CA mutation detection and no prior treatment with PI3K, AKT or mTOR inhibitors (except subjects with breast cancer). The phase 1 portion of the study follows a 3+3 dose escalation design and is intended to determine the minimum effective dose (MED) and the maximum tolerated dose (MTD) of TOS-358 when administered orally on a once daily (QD) or a twice daily (BID) schedule, and the recommended phase 2 dose (RP2D). Cohort expansions at the MTD and MED to support the RP2D selection are planned. The phase 1b portion of the study will enroll subjects with tumor PIK3CA mutations or amplifications in several tumor-specific cohorts (colorectal, gastric, non-small cell lung, breast, squamous cell carcinoma of the head and neck, urothelial and select gynecological cancers) to further assess the safety and tolerability of TOS-358 and to evaluate the initial efficacy of the investigational agent. Enrolment to the study commences in US with European sites planned to open later in 2023. Clinical trial information: NCT05683418.

Citation Format: Marwan Fakih, Davendra P. Sohal, Navid Hafez, Jordan D. Berlin, Kimberly Hari, Ovid C. Trifan. A study to evaluate the safety and tolerability of the covalent phosphoinositide-3-kinase (PI3K)-alpha Inhibitor, TOS-358, in adult subjects with select solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT249.
Abstract CT267: ENB-003, an ETBR antagonist, in combination with pembrolizumab for advanced solid tumor: The ENBolden trial
Authors: Jamal Sumayah , Nagrial Adnan , Carlino Matteo , Cosman Rasha , Joshua Anthony , Eek Richard , Piha-Paul Sarina , Hamid Omid , Liu Jenny
Published: April 2023

Programmed cell death 1 (PD-1) inhibitors have minimal effect in ovarian cancer (OC) and pancreatic ductal adenocarcinoma (PDAC). Selective endothelin B receptor (ETBR) blockade stimulates T cell tumor infiltration and synergizes with anti-PD-1 therapy in OC and PDAC mouse models. We are conducting an ongoing Phase Ib, open-label dose escalation study to assess the safety and tolerability of the selective ETBR antagonist ENB-003 (vodudeutentan) in combination with pembrolizumab in metastatic PDAC, OC and other advanced solid tumors (NCT04205227). The primary objectives are safety and tolerability. Secondary objectives include overall survival (OS), progression free survival (PFS), and disease control rate (DCR). Chemotherapy-resistant PDAC and platinum refractory/platinum resistant OC patients were microsatellite stable (MSS). The ENB-003 plus pembrolizumab combination was well tolerated across 6 dosing cohorts with no increase in toxicity above what is typically observed with pembrolizumab as a single agent. Encouraging preliminary efficacy signals have been observed. The DCR across 21 patients is 43% including 8 patients with stable disease (38%) and 1 (5%) with partial response (PR). The DCR for OC is 100% including 3 patients with stable disease (75%) and one MSS, PDL1 negative platinum refractory patient with a 95% PR (25%) of 12-month duration. In the current and final cohort, 3 PAC patients have been treated. One 4th line PDAC patient has exceeded 6-month survival (33%). We also observed a 7-month arrest of disease progression in a tonsillar SCC patient with innate resistance to anti-PD1. These data suggest that ETBR blockade is well tolerated, may expand the benefit of anti-PD1 in drug resistant solid tumors and warrants further study in subsequent trials.

Citation Format: Sumayah Jamal, Adnan Nagrial, Matteo Carlino, Rasha Cosman, Anthony Joshua, Richard Eek, Sarina Piha-Paul, Omid Hamid, Jenny Liu. ENB-003, an ETBR antagonist, in combination with pembrolizumab for advanced solid tumor: The ENBolden trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT267.
Abstract LB003: BI 907828: A highly potent MDM2-p53 antagonist suitable for intermittent dose schedules
Authors: Gollner Andreas , Sini Patrizia , Rudolph Dorothea , Weinstabl Harald , Ramharter Juergen , Weyer-Czernilofsky Ulrike , Golubovic Bojana , Grempler Rolf , Pitarch Alejandro Pérez , Sailer Reinhard , McConnell Darryl B. , Kraut Norbert
Published: April 2023

The E3 ligase MDM2 controls the tumor suppressor function of p53, which is encoded by the TP53gene. Compounds designed to bind to MDM2 preventing its interaction with p53 restore the ability of p53 to combat the pathogenic processes that underly cancer development. It has become clear from early clinical experience that thrombocytopenia represents an on-target, dose-limiting toxicity that may restrict the therapeutic utility of first-generation MDM2 inhibitors. Dosing less frequently, while maintaining efficacious exposure levels, has been proposed as an approach to mitigate side effects and improve the therapeutic window. In this -Late Breaking- session we present the discovery and preclinical evaluation of BI 907828, a highly potent, orally bioavailable and selective molecule binding to MDM2 and preventing its interaction with p53. The compound was designed to have a long half-life to enable intermittent dosing schedules in the clinic where it showed a manageable safety profile in a Phase Ia/Ib, dose-escalation/expansion study and encouraging signs of antitumor activity in patients with advanced DDLPS and WDLPS. BI 907828 is actively investigated in several clinical trials including the Phase II/III Brightline-1 study that aims to evaluate whether it is superior to doxorubicin in the first-line treatment of advanced/metastatic DDLPS. BI 907828 belongs to the class of spiro-oxindole MDM2-p53 antagonists and was discovered starting from an optimized core structure with improved chemical stability. Structure-based medicinal chemistry optimization including rigidification of the scaffold were key to accomplish the desired profile which was tested preclinically in several in vivo MDM2-amplified xenograft models where treatment with BI 907828 showed efficient tumor growth inhibition and regression.

Citation Format: Andreas Gollner, Patrizia Sini, Dorothea Rudolph, Harald Weinstabl, Juergen Ramharter, Ulrike Weyer-Czernilofsky, Bojana Golubovic, Rolf Grempler, Alejandro Pérez Pitarch, Reinhard Sailer, Darryl B. McConnell, Norbert Kraut. BI 907828: A highly potent MDM2-p53 antagonist suitable for intermittent dose schedules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB003.
Abstract LB006: Interactome analysis identifies signaling pathways activated by ETV6-NTRK3 oncogenic gene fusions
Authors: Kinnunen Matias , Liu Xiaonan , Salokas Kari , Keskitalo Salla , Varjosalo Markku
Published: April 2023

Chromosomal translocations creating fusion genes are among the most common mutation class of known cancer genes, and they have long been identified as driver mutations in certain types of cancer. Recently, oncogenic fusion genes (oncofusions, OFs) have been found in many hematological and solid tumors, demonstrating that translocations are a common cause of malignancy. The frequency of recurrent gene fusions varies depending of the specific type of cancer, but currently identified translocations are estimated to drive up-to 20% of cancer morbidity. In many occasions the oncofusion is the sole driver of oncogenesis when present and certain oncofusion pairs are typically found in one or few specific cancers.

ETV6-NTRK3 (EN) oncofusion, is a product of the chromosomal t(12; 15)(p13; q25) translocation, which fuses the N-terminal SAM (sterile alpha motif) domain of ETV6 to the C-terminal protein tyrosine kinase domain of NTRK3 (also known as TrkC). EN is expressed from the ETV6 promoter in the fused chromosome 15. The ETV6 promoter is generally more active, than NTRK3 promoter, and causes EN fusions to be expressed more highly in several tissues and especially in bone marrow and salivary glands. ETV6 forms fusions with many kinases, which are found in hematological malignancies and solid tumors. Except for ETV6-NTRK3, other ETV6-kinase fusions are reported in either hematological or solid malignancies and ETV6-NTRK3 further distinguishes itself by being also reported in several subtypes in both cases. Four EN variants with alternating break points have since been detected in a wide range of human cancers. To provide insight into EN oncogenesis, we employed a proximity labeling mass spectrometry approach to define the molecular context of the EN fusions. We identify 237 high-confidence interactors, which link EN fusions to several key signaling pathways, including ERBB, Insulin and JAK/STAT. We then assess the effects of EN variants on these pathways, and show that the pan NTRK inhibitor selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis of defines the molecular framework in which EN oncofusions operate to promote cancer.

Citation Format: Matias Kinnunen, Xiaonan Liu, Kari Salokas, Salla Keskitalo, Markku Varjosalo. Interactome analysis identifies signaling pathways activated by ETV6-NTRK3 oncogenic gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB006.
Abstract LB021: KN-052, a novel PDL1/OX40 bispecific antibody, exhibits potent antitumor efficacy
Authors: Xu Ting , Wang Pilin , Fu Yang-Xin , Guo Kangping , Peng Jianjian
Published: April 2023

KN052 is a recombinant PDL1/OX40 bispecific antibody which can block PDL1 and PD1/CD80 pathway and active the OX40 signal pathway at the same time. Inhibited PDL1 can block cancer cells to evade T-cell-mediated immune responses and restores T-cell activation and antitumor responses. On the other hand, biding to OX40 which normally expressed on Treg cells can induce ADCC effect and kill the Treg cells. There is a synergistic effect between the blocking of PDL1 pathway and the activation of OX40 signal pathway in cell base assay. PBMCs from four healthy donors showed significant T cell activation effect under the stimulation of superantigen SEB, and the activity of PBMCs from three healthy donors was significantly stronger than that of two single target control antibodies alone and in combination. The anti-tumor activity of KN052 was evaluated by using hPD-L1/hOX40 humanized mouse with MC38 MCA205 syngeneic model. Significant anti-tumor effects were observed in both models in a dose-dependent manner. The HNSTD (highest non-severely toxic dose) of KN052 was determined as 30mg/kg in cynomolgus monkeys. These preclinical data demonstrated acceptable PK and safety profile of KN052 and indicated its potential in a variety of tumors.

Citation Format: Ting Xu, Pilin Wang, Yang-Xin Fu, Kangping Guo, Jianjian Peng. KN-052, a novel PDL1/OX40 bispecific antibody, exhibits potent antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB021.
Abstract LB066: Machine learning algorithm for drug discovery targeting new co-transcription factors of HIF1A
Authors: Zhang Yuxiang , Wang Saidi , Hu Haiyan , Li Xiaoman
Published: April 2023

Hypoxia-inducible factor 1 alpha (HIF1A) activation drives cellular adaption to low oxygen stress in malignant and non-malignant cells. HIF1A transcriptionally regulates many genes in key processes like angiogenesis and metastasis, facilitating the cell’s survival. Interestingly, HIF1A is able to carry out its regulatory functions by forming protein-protein interactions with its co-transcription factors. Since low oxygen conditions are frequently present in cancerous cells, we predict that these co-transcription factors could serve as new cancer therapeutic targets. Our recent work has thus focused on identifying motifs in HIF1A ChIP-Seq sequences and discovering novel HIF1A co-transcription factors. In this study, we leveraged cutting-edge deep learning methods, including a hybrid convolutional neural network (CNN) and recurrent neural network (RNN) based motif-discovery model, and discovered several novel motifs. We also look to predict potential therapeutic drugs against the identified co-transcription factors using a machine-learning drug discovery model that evaluates therapies based on their half-maximal inhibitory concentration (IC50). We have so far found several small molecules that could adequately modulate the activity of the identified co-transcription factors. Our results could lead to new therapeutic approaches against HIF1A-dependent cancers such as colon, breast, gastric, lung, brain, and prostate.

Citation Format: Yuxiang Zhang, Saidi Wang, Haiyan Hu, Xiaoman Li. Machine learning algorithm for drug discovery targeting new co-transcription factors of HIF1A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB066.
Abstract LB069: Predictive modeling of drug sensitivity based on the genetic dependency
Authors: Song Bicna , Chao Lumen , Cheng Xiaolong , Gao Yuan , Shan Ruocheng , Li Wei
Published: April 2023

Functional genetic screens have been frequently used to repurpose existing drugs or to identify new drug targets. However, the associations between hits on screens and candidate drugs have been unclear, and a manual approach to directly infer drug candidates from “druggable” candidates suffers from its laborious, ad hoc investigation and low accuracy. Here, we describe a systematic approach to explore the associations between genetic dependencies and drug sensitivity of cancer cell lines and to identify potential drug repositioning opportunities. We first developed drug sensitivity predictive models trained on genome-wide CRISPR-Cas9 knockout viability profiles and large-scale drug response screens of 4,518 drugs from DepMap. We obtained the highest predictive power from the decision-tree-based models and observed previously reported associations between gene perturbation and drug response. For example, cancer cells that are more sensitive to TP53 or MDM2 perturbation were more sensitive to MDM inhibitors, and EGFR or ERBB2 dependency strongly predicted the sensitivity of cells to EGFR inhibitors. Interestingly, for 3,260 drugs with known targets, only 1.5% of these genes were selected as top features to predict drug sensitivity, indicating that genes that are not the direct targets of drugs should be considered. In addition, we applied our models to the CRISPR-Cas9 knockout screens that target 1,805 “druggable” genes and predicted the sensitivity of cancer cells to known and novel drugs. Furthermore, we were able to validate the candidate drugs using cell viability assays. Finally, a multi-class classification deep learning model, based on the TorchDrug framework, reaches higher recall values than a decision-tree-based method but with much lower precision values. Our study provided the first systematic evaluation between large-scale gene dependency and drug responses. The machine learning predictive model provides an in-silico approach to perform drug screens from functional genetic screens.

Citation Format: Bicna Song, Lumen Chao, Xiaolong Cheng, Yuan Gao, Ruocheng Shan, Wei Li. Predictive modeling of drug sensitivity based on the genetic dependency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB069.
Abstract LB073: NCI’s broad-use collections: Accelerating discovery process by improving access to individual-level genomics and other -omics data
Authors: Pruitt Freddie L. , Feolo Michael , Jagu Subhashini , Auvil Jaime Guidry
Published: April 2023

Genomic data sharing increases our understanding of factors that influence health and diseases by enabling additional research questions from secondary data users, increasing statistical power through combining multiple data sources, facilitating reproducibility and validation of research results, and supporting innovation with the development of research tools and methodologies. Research using large-scale genomic and other-omics data is no longer limited by storage space or slow downloading speed for individual datasets. Innovations like cloud infrastructure enable computing over many datasets at multiple locations at once. These developments have increased the need for faster, more efficient processes for data access and sharing. To support scientific exploration and meet the demand for analysis of biomedical data, the National Cancer Institute (NCI) has created two large collections of the broad-use studies within the database of Genotypes and Phenotypes (dbGaP). These collections comply with the consent of the study (data use limitations) for how secondary access to studies are determined. NCI’s Collection of Datasets for General Research Use comprises 284 studies with individual-level data sets, and permits approved users to explore broad research interest, including methods and tool development. NCI’s Collection of Datasets for Health, Medical, and Biomedical (HMB) Research Purposes is comprised of 65 studies of individual-level that are permitted for research interests specific to any health, medical, or biomedical research only. The HMB collection could be used for methods and tool development; research interests involving ancestry/populations studies must be dependent on a health/medical condition. Through these collections, investigators will have the potential to add access to 349 datasets to their approved research projects or submit a new project request for access to the broad-use collections. As new genomic studies are registered by NCI for release through dbGaP, they will be automatically added to these collections. NCI anticipates through the implementation of these broad-use collections a requestor could have access to approximately 70% of NCI’s studies in controlled-access repositories.The streamlined access to broad-use datasets expedites data sharing and potentially accelerates the discovery process. This approach reduces redundancies for obtaining controlled-access data.

Citation Format: Freddie L. Pruitt, Michael Feolo, Subhashini Jagu, Jaime Guidry Auvil. NCI’s broad-use collections: Accelerating discovery process by improving access to individual-level genomics and other -omics data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB073.
Abstract LB076: A novel spatial trajectory inference method for detecting regional breast cancer progression from spatial transcriptomics data
Authors: Pham Duy , Nguyen Quan
Published: April 2023

Spatial transcriptomics is a rapidly emerging field that allows for the study of gene expression within a tissue sample. This technology has the potential to provide valuable insights into the molecular mechanisms underlying cancer progression and could be particularly useful in identifying specific regional cancer progression. By studying the regional spatial trajectory of cancer progression, we can develop more targeted therapies and better predict the likelihood of metastasis. Additionally, analyzing gene expression patterns in specific regions of the tissue can reveal the molecular mechanisms driving cancer growth in those areas, potentially uncovering new therapeutic targets.

In this study, we created a spatial trajectory analysis method, named as stLearn - PSeudo-Time-Space (PSTS) algorithm, to investigate specific regional cancer progression. Spatial trajectory analysis is a statistical method that allows for the identification of patterns of transitional gene expression over time and space within a tissue sample. In detail, this method incorporates spatial features, such as tissue sub-structure locations and gene expression changes, to model the trajectory from a single snapshot of transcriptomics data. Also, we evaluated the effectiveness of PSTS by utilizing the cancer progression model in human breast cancer samples.

Using this approach, we were able to identify specific regions within the breast tissue that displayed distinct progression branching trajectories patterns of transitional gene expression associated with ductal carcinoma in situ and invasive ductal carcinoma. These regions were found to be characterized by a high level of cellular diversity and were associated with aggressive forms of breast cancer.

The results of this study suggest that spatial transcriptomics and spatial trajectory analysis could be a powerful tool for identifying specific regional cancer progression and may help to inform the biomarkers for the development of targeted therapies for breast cancer.

Overall, this study highlights the potential of spatial transcriptomics and spatial trajectory analysis to provide valuable insights into the molecular mechanisms underlying cancer progression and could have significant implications for the diagnosis and treatment of cancer.

Citation Format: Duy Pham, Quan Nguyen. A novel spatial trajectory inference method for detecting regional breast cancer progression from spatial transcriptomics data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB076.
Abstract LB089: ACE2016: an off-the-shelf EGFR-targeting γδ2 T cell therapy against EGFR-expressing solid tumors
Authors: Li Hao-Kang , Wu Tai-Sheng , Leng Pei-Ru , Kuo Yi-Chiu , Cheng Zih-Fei , Lee Chia-Yun , Lin Yan-Liang , Tang Sai-Wen , Hsiao Shih-Chia
Published: April 2023

Introduction: CAR-αβT therapies have been shown to improve clinical outcomes in hematological malignancies; however, solid tumors still remain as challenges to CAR-αβT therapies due to tumor microenvironment, limited tumor infiltration or antigen escape. Previous research findings indicate γδ2 T cells are involved in tumor surveillance by responding to phosphoantigen overexpressed by most of cancers. The antibody cell conjugation (ACC) technology has the advantage to link cancer-targeting antibodies on cell surface of immune cells without genetic modification. This study applies ACC technology to generate an off-the-shelf EGFR-targeting γδ2 T cell therapy ACE2016, and presents the promising potency of ACE2016 against EGFR-expressing cancer cells.

Methods: γδ2 T cells were expanded from healthy donor PBMCs and αβ T cell population were depleted. Both γδ2 T cells and αEGFR were covalently conjugated to selected DNA aptamers that enable DNA hybridization to generate EGFR-targeting γδ2 T cells, ACE2016. The characteristics and antibody conjugation of ACE2016 was evaluated by flow cytometry, and in vitro cytotoxicity and in vivo anti-tumor potency was investigated using luminescence-based cytotoxicity assay and the orthotopical model with EGFR-expressing cancer cells, respectively.

Results: ACE2016 showed nearly 100 % of αEGFR antibody conjugation and exhibited EGFR-specific binding activity. These features conferred ACE2016 with enhanced in vitro cytotoxicity against EGFR-expressing cancer cells compared to unconjugated γδ2 T cells, while ACE2016 and γδ2 T cells showed no significant difference of anti-tumor potency against EGFR-negative cancer cells. Further characterization studies demonstrated that co-cultured with target cells significantly activated ACE2016 along with enhanced degranulation and cytokine production without measurable IL-6 secretion. Moreover, ACE2016 suppressed EGFR-expressing breast cancer cells in vivo in the orthotopic xenograft model without weight loss or toxicological observations.

Conclusion: ACE2016, an EGFR-targeting γδ2 T cell product, was successfully generated as an effective off-the-shelf treatment for EGFR-expressing solid tumors. This study provides the evidence for the in vitro and in vivo efficacy of ACE2016 against EGFR-expressing cancer cells to support the clinical application against EGFR-expressing tumors.

Citation Format: Hao-Kang Li, Tai-Sheng Wu, Pei-Ru Leng, Yi-Chiu Kuo, Zih-Fei Cheng, Chia-Yun Lee, Yan-Liang Lin, Sai-Wen Tang, Shih-Chia Hsiao. ACE2016: an off-the-shelf EGFR-targeting γδ2 T cell therapy against EGFR-expressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB089.
Abstract LB130: Single-cell multiomics analysis of myelodysplastic syndrome predicts clinical response to DNA methylation inhibitor therapy
Authors: Campillo-Marcos Ignacio , Casado-Pelaez Marta , Davalos Veronica , Ferrer Gerardo , Mata Caterina , Mereu Elisabetta , Valcarcel David , Molero Antonieta , Zamora Lurdes , Palomo Laura , Acha Pamela , Manzanares Ana , Solé Francesc , Esteller Manel
Published: April 2023

Epigenetic alterations, such as DNA methylation aberrations, are a hallmark of human cancer. This observation has led to the assessment of hypomethylating agents (HMAs) as potential drugs to treat oncological patients, being considered the clinical approval of these pharmacological compounds in the therapy of myeloid malignancies as one of the main achievements of this scientific field. A good example is myelodysplastic syndrome (MDS), a pre-leukemia disorder that can evolve into acute myeloid leukemia (AML), where very few therapeutic options were available until the introduction of HMAs. However, it remains unsolved how we can predict if an MDS patient will response or not to the epigenetic drug and for how long. Using the great analytical power of the newly developed single-cell technologies, we have herein tackled this issue. To study the evolution of the clonal molecular and cellular architecture MDS upon the treatment with HMAs, we performed single-cell DNA sequencing (scDNA-seq) of an amplicon panel for 53 genes commonly mutated in myeloid malignancies and single-cell protein sequencing (scProt-seq) of 45 cell-surface proteins to provide a simultaneous landscape of the genetic setting and immunophenotype. We sequenced hundreds of thousands of cells from these MDS patients where paired bone marrow samples were obtained at the time of diagnosis and at the end of at least six cycles of azacitidine treatment. Our study has unveiled that the co-occurrence of particular truncating or stop codon mutations in the same myeloid progenitor cell; the multibranched dynamics of the mutant clones; and the persistence of particular cell lineages with distinct mutational profiles (such as non-classical monocytes and CD8+ effector T-cells) can predict the clinical response of MDS patients to HMA therapy.

Citation Format: Ignacio Campillo-Marcos, Marta Casado-Pelaez, Veronica Davalos, Gerardo Ferrer, Caterina Mata, Elisabetta Mereu, David Valcarcel, Antonieta Molero, Lurdes Zamora, Laura Palomo, Pamela Acha, Ana Manzanares, Francesc Solé, Manel Esteller. Single-cell multiomics analysis of myelodysplastic syndrome predicts clinical response to DNA methylation inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB130.