bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1714: CRACD/KIAA1211 loss drives cell plasticity and immune evasion of small cell lung cancer
Authors: Zhang Shengzhe , Kim Kee-Bum , Huang Yuanjian , Kim Dong-Wook , Kim Bongjun , Ko Kyung-Pil , Zou Gengyi , Zhang Jie , Jun Sohee , Kirk Nicole A. , Hwang Ye Eun , Ban Young Ho , Chan Joseph M. , Rudin Charles M. , Park Kwon-Sik , Park Jae-Il 
Published: June 2023

Abstract
Small cell lung carcinoma (SCLC) is a lethal neuroendocrine type of lung cancer with limited therapeutic options. Despite recent advances in cancer immunotherapy, its efficacy is limited to a small subset of SCLC patient tumors. The molecular origin of the refractoriness to immunotherapy remains elusive. CRACD (Capping protein inhibiting regulator of actin dynamics; KIAA1211/CRAD) gene is frequently mutated and transcriptionally downregulated in SCLC. Cracd knockout (KO) causes the transformation of preneoplastic neuroendocrine cells and significantly accelerates SCLC development in a mouse model initiated by the loss of Rb1, Trp53, and Rbl2 in the lung epithelium. Cracd KO induces tumor cell plasticity generating deregulated cell lineage trajectories of SCLC tumors. Strikingly, Cracd KO SCLC tumors display the complete loss of CD8+ T cells due to epigenetic suppression of the MHC-I pathway. Furthermore, single-cell transcriptomic analyses of SCLC patient samples classified SCLC by concurrent features: CRACD inactivation and tumor antigen presentation impairment. This study suggests CRACD as a tumor suppressor of SCLC that regulates proliferation and immune recognition of cells, providing novel insight into the mechanism of SCLC evading immune surveillance.
Citation Format: Shengzhe Zhang, Kee-Bum Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Kyung-Pil Ko, Gengyi Zou, Jie Zhang, Sohee Jun, Nicole A. Kirk, Ye Eun Hwang, Young Ho Ban, Joseph M. Chan, Charles M. Rudin, Kwon-Sik Park, Jae-Il Park. CRACD/KIAA1211 loss drives cell plasticity and immune evasion of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1714.
Abstract 186: Cellos: High-throughput deconvolution of 3D organoid dynamics at cellular resolution for cancer pharmacology
Authors: Mukashyaka Patience , Kumar Pooja , Mellert Dave , Nicholas Shadae , Noorbakhsh Javad , Brugiolo Mattia , Anczukow Olga , Liu Edison T. , Chuang Jeffrey H. 
Published: June 2023

Abstract
Three-dimensional (3D) culture models, such as organoids, are flexible systems to interrogate cellular growth, multicellular spatial architecture, and morphology in response to drug treatment, including the potential to resolve the individual behaviors and interactions of mixed cancer cell populations. However, new computational methods to segment and analyze 3D models at cellular resolution are needed to realize these possibilities. Here we report Cellos (Cell Organoid Segmentation), an accurate, high throughput image analysis pipeline for 3D organoid and nuclear segmentation analysis. Cellos segments 3D organoids using classical algorithms and segments nuclei using a Stardist-3D convolutional neural network trained on a manually annotated dataset of 3,862 cells from 36 organoids confocally imaged at 5 μm z-resolution. To evaluate the capabilities of Cellos, we then analyzed 74,450 organoids with 1.65 million cells from multiple experiments on triple negative breast cancer organoids containing clonal mixtures with complex cisplatin sensitivity. Cellos was able to accurately distinguish cell ratios in organoids in 96-well plates to within 2.99% and was effective for fluorescently labelled nuclei and independent DAPI stained datasets. Cellos was able to recapitulate traditional luminescence based drug responses by analyzing 3D images, including parallel analysis of multiple cancer clones in the same well. Moreover, Cellos was able to identify organoid and nuclear morphology feature changes associated with treatment. Finally, Cellos enables 3D analysis of cell spatial relationships, which we used to detect ecological affinity between cancer cells, beyond expectations from local cell division or organoid composition. Cellos provides powerful tools to perform high throughput analysis for pharmacological testing and biological investigation of organoids based on 3D imaging.
Citation Format: Patience Mukashyaka, Pooja Kumar, Dave Mellert, Shadae Nicholas, Javad Noorbakhsh, Mattia Brugiolo, Olga Anczukow, Edison T. Liu, Jeffrey H. Chuang. Cellos: High-throughput deconvolution of 3D organoid dynamics at cellular resolution for cancer pharmacology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 186.
Abstract 1866: D02, a novel, non-blocking antibody targeting IL2RA, exhibits significant anti-tumor activity in IL2RA-humanized mice
Authors: Cao Shuzhen , Zhang Wenjiao , Lin Qingcong 
Published: June 2023

Abstract
Regulatory T cells, or Tregs, are a subset of CD4+ T cells that negatively regulate immune responses to promote their resolution and protect against autoimmunity. Infiltration of Tregs in the tumor microenvironment (TME), and a low ratio of effector T cells to Tregs, is frequently associated with tumor progression and poor prognosis. The alpha subunit of the IL-2 cytokine receptor (IL2RA), a component of the high-affinity IL-2 receptor along with the β and γ subunits (IL2Rβγ), is constitutively expressed on Tregs and transiently expressed on effector T cells. IL-2 is a key cytokine for effector T cell survival and cytolytic responses. We aimed to discover an IL2RA-targeting antibody capable of depleting Tregs but permitting IL-2 stimulation of effector T cells in the TME. We developed a fully human IgG1 antibody specific to IL2RA, D02, from our proprietary RenMab™ mice, which contain the entire human immunoglobulin variable domain. D02 binds both human and cynomolgus monkey IL2RA with high affinity without hindering IL2RA-IL-2 binding or inhibiting IL-2 signaling. To evaluate the safety and efficacy of D02 in vivo, we established a syngeneic mouse tumor model in IL2RA-humanized mice. We observed that D02 potently inhibited MC38 (colon adenocarcinoma) tumor growth at 10 mg/kg. Further studies will aim to characterize the effect of D02 on the ratio of effector T cells to Tregs in the TME. These data indicate that D02 is a novel, IL2RA-specific monoclonal antibody that uniquely exhibits significant anti-tumor activity in vivo while preserving IL-2 signaling to effector T cells.
Citation Format: Shuzhen Cao, Wenjiao Zhang, Qingcong Lin. D02, a novel, non-blocking antibody targeting IL2RA, exhibits significant anti-tumor activity in IL2RA-humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1866.
Abstract 2011: Polycondensate-epitope vaccine augments anti-cancer T lymphocyte responses and induces long-term immune memory
Authors: Hu Xiaomeng , Tang Li 
Published: June 2023

Abstract
Background: Personalized cancer vaccines are promising treatments to induce or augment antitumor responses. Despite the observed benefits in early-phase clinical studies, the clinical efficacy of cancer vaccines remains modest. Here, we aim to develop a vaccine delivery strategy to enhance the antitumor efficacy of cancer vaccines.
Method: We developed polycondensate-epitope vaccines (PEVs) for co-delivering of major histocompatibility complex (MHC) I and II-restricted peptides (OVA257-264 and OVA323-339) to elicit antigen-specific CD4+ and CD8+ T cells for long-term antitumor immunity. PEVs were prepared by polymerizing amino-functionalized MHC I and MHC II-restricted peptides with a TLR1/2 agonist, Pam3CSK4, using a responsive linker. We characterized the physical properties (size, MW) and responsiveness of the prepared PEVs. The immunogenicity was evaluated in mice via flow cytometry and ELISpot assay. We finally assessed the antitumor efficacy in both prophylactic and therapeutic tumor models.
Results: The prepared PEVs have an average size of 20 nm to 50 nm, &gt;95% incorporating efficiency, and a remarkably high loading capacity of antigens and adjuvants (57.18~ 61.3 wt/wt %). PEVs consisting of both MHC I and MHC II-restricted OVA peptides induced robust antigen-specific CD4+ and CD8+ T cell responses and long-term memory immune response against tumors. The vaccine-induced CD8+ and CD4+ T cells exhibited high proliferative capacity and polyfunctionality upon antigen restimulation ex vivo. In a prophylactic model, mice immunized by PEVs completely rejected the first and the second challenge of YUMM1.7-OVA tumor cells with 100% rejection rate. In a therapeutic model, treatment with PEVs loaded OVA257-264 and OVA323-339 peptides induced marked tumor regression in mice bearing established YUMM1.7-OVA tumors showing enhanced anti-tumor efficacy as compared to PEVs loaded with CD8 epitope alone.
Conclusion: Our results demonstrate that PEV is a promising vaccine delivery strategy for eliciting highly effective and durable anti-cancer immune responses.
Citation Format: Xiaomeng Hu, Li Tang. Polycondensate-epitope vaccine augments anti-cancer T lymphocyte responses and induces long-term immune memory [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2011.
Abstract 2012: A novel antibody-drug conjugate platform enabling high drug-to-antibody ratios and greater payload flexibility
Authors: Juen Ludovic , Collier Adam J. , Tolcher Anthony W. , Ouberai Myriam M. 
Published: June 2023

Abstract
Historically, increasing the drug-to-antibody ratio (DAR) in an antibody-drug conjugate (ADC) significantly raises aggregation propensity as a result of the hydrophobicity of the payload. Consequently, DARs are commonly limited to 4, forcing developers to incorporate very high potency payloads to achieve the required efficacy. This, combined with chemical instability and off-target uptake, often results in dose-limiting toxicities and narrow therapeutic indexes.
In this study, we used a novel and flexible multivalent linker technology to construct two ADCs targeting HER-2 with the monoclonal antibody, trastuzumab and interchain cysteine bioconjugation. One ADC incorporated monomethyl auristatin E (MMAE) as the drug payload at average DAR 16 whilst the second incorporated the camptothecin analog, SN38, as the drug payload also at average DAR 16. The ADCs were characterized by liquid chromatography-mass spectrometry (LC-MS), size-exclusion chromatography (SEC), hydrophobic interaction chromatography (HIC) and SDS-PAGE and were then tested for efficacy in a range of HER-2 positive cell lines in vitro, and tumor growth inhibition studies using NCI-N87 cells in a mouse xenograft.
Both ADCs remained &gt; 95% monomeric (no aggregation) and demonstrated greater chemical stability in ex-vivo serum stability studies compared to comparator ADC constructs utilizing a clinically validated linker and the same payload release chemistry. In in vitro cell killing studies, the ADCs demonstrated target-specific cell killing with the SN38 average DAR 16 ADC achieving a disproportionate 30-fold increase in IC50 (by ADC concentration) compared to a DAR 8 comparator. Dose dependent tumor growth inhibition was observed in an HER-2 positive NCI-N87 mouse xenograft model with no change in mouse body weight, and good systemic exposure.
These data demonstrate our capability, using a novel multivalent linker technology, to construct ADCs with DARs considerably greater than DAR 8 which are chemically stable, shield payloads from hydrophobic interactions (no aggregation), demonstrate good in vivo exposure profiles and which are highly efficacious in vitro and in vivo.
Higher DARs will permit the incorporation of lower potency and targeted small molecule payloads into ADCs which will result in targeted cancer therapeutics with wider therapeutic indexes through the delivery of greater concentrations of payload to the tumor microenvironment and lower, payload-associated, dose-limiting toxicity.
Citation Format: Ludovic Juen, Adam J. Collier, Anthony W. Tolcher, Myriam M. Ouberai. A novel antibody-drug conjugate platform enabling high drug-to-antibody ratios and greater payload flexibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2012.
Abstract 202: Perfused patient-derived tumor organoid models with autologous immune cells for preclinical drug development
Authors: Millard Melissa , Dance Natalie , DesRochers Teresa M. 
Published: June 2023

Abstract
The paradigm shift towards inclusion of primary patient samples in preclinical drug development bottlenecks at the tissue procurement step due to an on-going lack of ’research-ready’ tumor samples. Organoid technology was developed as a solution to this hurdle. Their ability to expand in culture makes them a renewable resource similar to cell lines while recapitulating key properties of the primary tissue, including tumor heterogeneity, structural organization and drug responses. As preclinical drug development continues to adopt organoid-based screening technology and immune-oncology agents continue to be advanced, there is high demand for more complex organoid-based models capable of more accurately predicting individual patient drug responses. Due to their development process, the vast majority of organoids do not contain immune cells, resulting in the need to utilize allogeneic immune cells for any immune cell involved interrogation of the models. Maintaining the immune cells for incorporation with the organoid model can overcome this hindrance. Additionally, perfused organoid models offer a complex, ex vivo model with the ability to replicate the mechanical forces imparted by blood flow and interstitial pressure. Compared to 2D and static 3D cultures, perfused 3D culture models show enhanced proliferative and migratory capacities and can be sustained as long-term cultures. In our previous studies, DNA methylation signatures in patient-derived breast microtumors grown in Kiyatec’s 3DKUBE™ perfusion bioreactor matched the primary tissues of derivation. Given the need for more complex biology when assessing immune-oncology agents, the physiological relevance in maintaining gene expression ex vivo, and the capability to sustain long-term viability, the impact of autologous immune cells and perfusion on the success of organotypic culture was investigated across a panel of primary patient tumors. Immune cells were profiled for status and activity and imaging and viability assays were used to evaluate static and perfused 3D organoid models for differences in viability and morphology. PCR was used to examine how mechanically transduced forces alter gene expression and DNA methylation signatures. Drug responses were measured using our KIYA-Predict™ platform, comparing organoid drug responses to primary tissue drug responses. Results of this study provide insight on alternative methods of organotypic culture and evidence for the utilization of more complex tissue modeling in preclinical drug development.
Citation Format: Melissa Millard, Natalie Dance, Teresa M. DesRochers. Perfused patient-derived tumor organoid models with autologous immune cells for preclinical drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 202.
Abstract 2025: Phosphoproteomic profiling following MAP3K1 kinase inhibition identifies NPM1 as a novel substrate
Authors: Boghean Lidia , Singh Sarbjit , Mangalaparthi Kiran , Shukla Surendra K. , Kizhake Smitha , Kizhake Amritha , Wishka Donn , Mallareddy Jayapal Reddy , Morris Joel , Grothaus Paul , Singh Pankaj K. , Pandey Akhilesh , Natarajan Amarnath 
Published: June 2023

Abstract
In response to diverse cellular cues, MAP3K1, a mitogen-activated protein kinase, participates in various cancer signaling networks including the NFκB, JNK, ERK, and p38 pathways. Functioning as a signaling kinase in these oncogenic pathways, MAP3K1 contributes to tumor growth and metastasis, thus making it an attractive therapeutic target for cancer. Structure-guided design using MAP3K1 AlphaFold and Schrödinger GLIDE led to the development of 51-106, a selective MAP3K1 small molecule inhibitor. Profiling using the KiNativTM platform in a cellular matrix revealed 51-106 as a selective ATP-competitive MAP3K1 inhibitor. 51-106 blocked TNFα-induced MAP3K1-IKKβ-mediated NFκB activity. Phosphoproteomics analysis following MAP3K1 inhibition by 51-106 showed a dose dependent decrease in NPM1 T199 phosphorylation indicating NPM1 as a novel substrate of MAP3K1. NPM1 plays a critical role in DNA damage repair; consistently we observed a dose dependent S-phase arrest upon MAP3K1 inhibition by 51-106, suggesting a dysfunctional DNA damage response. Higher MAP3K1 transcript level in pancreatic cancer patients is associated with poorer (50% vs. 15%) 5-year survival. Treatment of pancreatic cancer cell lines with the MAP3K1 inhibitor 51-106 inhibited cell growth and migration. In combination studies, 51-106 synergistically inhibited growth with gemcitabine in LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC) cell lines in vitro and in KPC syngeneic orthotopic implantation mouse model of pancreatic cancer in vivo. Our study is the first to identify NPM1 as a potential substrate of MAP3K1, and these results warrant the investigation of MAP3K1 inhibition as a therapeutic option in cancer.
Citation Format: Lidia Boghean, Sarbjit Singh, Kiran Mangalaparthi, Surendra K. Shukla, Smitha Kizhake, Amritha Kizhake, Donn Wishka, Jayapal Reddy Mallareddy, Joel Morris, Paul Grothaus, Pankaj K. Singh, Akhilesh Pandey, Amarnath Natarajan. Phosphoproteomic profiling following MAP3K1 kinase inhibition identifies NPM1 as a novel substrate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2025.
Abstract 2105: Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer
Authors: Malone Shawn , Wallis Christopher , Morgan Scott , Kishan Amar , Le Amy Tu Trinh , Malone Julia , Sun Yilun , Spratt Daniel , Saad Fred , Roy Soumyajit 
Published: June 2023

Abstract
Background: Studies on metastatic hormone sensitive prostate cancer have shown that metachronous presentation has a better prognosis compared to synchronous disease. However, it remains unknown if such association is pertinent in metastatic castrate resistant prostate cancer (mCRPC). We performed a secondary analysis of ACIS study to determine if the response to dual androgen receptor axis-targeted therapy (ARAT) in in docetaxel naïve metastatic castrate resistant prostate cancer (mCRPC) varies based on M-stage at diagnosis and if prior local therapy plays an effect modifying role in the association of M-stage at presentation with survival.
Patients and Methods: In this phase III randomized controlled trial, mCRPC patients with no prior exposure to androgen biosynthesis signaling inhibitors were randomly assigned to either apalutamide or placebo combined with abiraterone and prednisone. Cox regression models were applied for radiographic progression-free survival (rPFS), overall survival (OS) with interaction terms between M-stage and treatment regimen. Multivariable Cox regression analyses were performed to determine the adjusted association of M-stage with rPFS and OS after considering the effect modification by prior local therapy (LT).
Results: Among 972 evaluable patients -432 had M0, 334 had M1 at diagnosis while M-stage was unknown in 206. We did not find any statistically significant heterogeneity of treatment effect on rPFS (interaction p=0.13; HR for placebo in M0 group: 1.42 [1.13-1.79]; M1/unknown group: 1.11 [0.90-1.37]), and OS (interaction p=0.87; HR for placebo in M0 group: 1.02 [0.81-1.29], and M1/unknown group: 1.00 [0.82-1.23]) based on M-stage at diagnosis. There was no significant association of M-stage with rPFS (HR for LT group: 1.08 [0.84-1.40], HR for no LT: 0.91 [0.67-1.24]) and OS (HR for LT: 1.04 [0.81-1.33] and no LT: 0.95 [0.70-1.29]) with no significant heterogeneity depending on receipt of LT (interaction p-value of 0.94 and 0.93, respectively).
Conclusion: We did not find a statistically significant heterogeneity in efficacy of dual ARAT based on synchronous versus metachronous presentation. M-stage was not found to be a predictor for rPFS and OS after considering effect modification by prior LT.
Citation Format: Shawn Malone, Christopher Wallis, Scott Morgan, Amar Kishan, Amy Tu Trinh Le, Julia Malone, Yilun Sun, Daniel Spratt, Fred Saad, Soumyajit Roy. Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2105.