bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB132: In silico mutant neoantigen prediction - a promising avenue for target identification in human adrenocortical carcinoma
Authors: Landwehr Laura-Sophie , Appenzeller Silke , Ölsner Laura , Weigand Isabel , Sbiera Silviu , Fassnacht Martin , Kroiss Matthias 
Published: April 2023

Abstract
Introduction: Adrenocortical carcinoma (ACC) is one of the most aggressive endocrine malignancies and confers a poor prognosis in advanced stages. Effective treatments are lacking. The results of immune checkpoint inhibition were disappointing with few responders only deriving clinical benefit. For the development of novel immunotherapies such as tumor vaccines and T cell-based treatments, target identification is essential. Tumor-specific mutant neoantigens that may be recognized by T cells in the context of major histocompatibility complex (MHC) I are promising candidates.
Methods: We performed whole exome-sequencing in 10 ACC samples with matched blood controls. Somatic mutations were identified using an in house bioinformatics pipeline. By coupling POLYSOLVER for HLA typing with netMHCpan, in silico binding affinity of tumor-specific neoantigens to MHC was calculated taking into account both peptide and HLA sequence information. Strong binding (SB) was defined as &lt;0.5% rank, weak binding (WB) as 0.5-1.9% rank and no binding (NB) as &gt;2.0% rank of all peptides to MHC.
Results: Across 10 ACC patients, we identified 1067 unique somatic mutations (median 49.5, ranging from 15-590), affecting 989 different genes. Binding affinity changed for 414 predicted neoantigens from NB to WB, 80 from NB to SB and 82 from WB to SB. The mutant neoantigen load per patient ranged from 10 to 235 (mean 66.2) and was positively correlated to the total number of non-synonymous single nucleotide variants (R2 0.8977, 95% CI 0.79-0.99; p&lt;0.0001).
Discussion: This is the first study that demonstrates successful in silico neoantigen profiling in ACC. Mutant neoantigens were predicted to be present both in ACC with high and low tumor mutational burden. These data will pave the way for in vitro validation and hold potential to develop therapeutic cancer vaccines and T cell-based cancer immunotherapy in ACC.
Citation Format: Laura-Sophie Landwehr, Silke Appenzeller, Laura Ölsner, Isabel Weigand, Silviu Sbiera, Martin Fassnacht, Matthias Kroiss. In silico mutant neoantigen prediction - a promising avenue for target identification in human adrenocortical carcinoma [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 LB132.
Abstract LB154: Circ0003039 interacts with calreticulin to inhibit the progression of hepatocellular carcinoma by suppressing wnt/beta-catenin signaling pathway
Authors: Wang Yue-Ning , Zhou Yu-Feng , Liu Ji , Zhang Mei-Yin , Wang Shuo-Cheng , Mai Shi-Juan , Wang Hui-Yun 
Published: April 2023

Abstract
Background: Circular RNAs (circRNAs) are covalently closed and single-stranded RNAs which play critical roles in various biological processes and diseases including cancers. The functions and mechanisms of circRNAs in hepatocellular carcinoma (HCC) are still need to be clarified.
Methods: Custom circRNA microarray was performed to investigate the profile of circRNAs in HCC. Expression of circ0003039 and its clinical significance in 60 pairs of HCC and matched non-cancer liver tissues were identified and confirmed by microarray and quantitative RT-PCR. The biological functions of circ0003039 were investigated by gain-and loss-of-function experiments in vitro and in vivo. RNA pull-down, mass spectrometry, RNA-immunoprecipitation, Co-immunoprecipitation, fluorescent in situ hybridization were used to identify circ0003039-protein interaction. The downstream pathway regulated by circ0003039 was explored using RNA-seq and verified using western blot and immunofluorescence.
Results: Expression of circ0003039 was reduced in HCC tissues and positively associated with the overall survival of HCC patients. Circ0003039 was located in cytoplasm of HCC cells. Ectopic overexpression of circ0003039 inhibited the proliferation, colony formation, migration and invasion of HCC cells and the growth of HCC xenograft in mice, while knockdown of circ0003039 had opposite effects in HCC cells. Mechanistically, circ0003039 bound to the N-terminal domain of CALR protein and acted as a scaffold to enhance the interaction of CALR with CAPN2, which promoted the degradation of CALR protein by the enzymatic activity of CAPN2. Rescue experiments showed that circ0003039 inhibited HCC proliferation via suppressing CALR protein. Finally, we found that circ0003039 inhibited HCC cells by suppressing CALR-mediated wnt-βcatenin signaling pathway.
Conclusions: Our study demonstrates that circ0003039 bind to N-terminal domain of CALR and facilitated CAPN2 to degrade CALR protein, which inhibits the development and progression of HCC via suppressing CALR-mediated wnt-βcatenin signaling pathway, and circ0003039 is a potential prognostic biomarker and therapeutic target for HCC.
Citation Format: Yue-Ning Wang, Yu-Feng Zhou, Ji Liu, Mei-Yin Zhang, Shuo-Cheng Wang, Shi-Juan Mai, Hui-Yun Wang. Circ0003039 interacts with calreticulin to inhibit the progression of hepatocellular carcinoma by suppressing wnt/beta-catenin signaling pathway [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 LB154.
Abstract LB157: Cereblon inhibits prostate cancer progression and metastasis by negatively regulating 6PGD
Authors: Guchhait Koushik , Yoon Hyeon Seung , Shin Seungheon , An Hyun-Su , Nam Hye Seung , Yanqui-Rivera Francisco D. , Oña Samara M. , Mendez Miguel Á. , Park Seokjae , Kim Eun-Kyoung , Hwang Jong Yeon , Han Jee-Young , Chung Doo Yong , Park Daeho , Yang Su-Geun , Park Chul-Seung , Cho Steve K. 
Published: April 2023

Abstract
As the third enzyme of the pentose phosphate pathway (PPP), abnormally elevated levels of 6-phosphogluconate dehydrogenase (6PGD) have been documented in various human cancers. We demonstrate that reduced cereblon (CRBN) protein expression is the underlying mechanism of elevated 6PGD expression in metastatic prostate cancer cells. We establish 6PGD as a new endogenous substrate for CRBN by demonstrating that it interacts directly with CRBN and is ubiquitinated by CRL4CRBN. In addition, CRBN negatively regulates prostate cancer cell progression and metastasis, as abnormally high 6PGD, in the absence of sufficient CRBN, enhances the metastatic potential of prostate cancer in vitro and in vivo. Our findings show convincingly that carbohydrate metabolism regulated by 6PGD is linked to prostate cancer metastasis via CRBN. Based on these data, we propose that the 6PGD-CRBN axis may be a suitable target for further research into new therapeutics for mitigating prostate cancer metastasis.
Citation Format: Koushik Guchhait, Hyeon Seung Yoon, Seungheon Shin, Hyun-Su An, Hye Seung Nam, Francisco D. Yanqui-Rivera, Samara M. Oña, Miguel Á. Mendez, Seokjae Park, Eun-Kyoung Kim, Jong Yeon Hwang, Jee-Young Han, Doo Yong Chung, Daeho Park, Su-Geun Yang, Chul-Seung Park, Steve K. Cho. Cereblon inhibits prostate cancer progression and metastasis by negatively regulating 6PGD [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 LB157.
Abstract LB158: Rapid cancer cell perineural invasion utilizes amoeboid migration
Authors: Wang Qi , Marcadis Andrea , Kao Elizabeth , Chen Chun-Hao , Gusain Laxmi , Powers Ann , Bakst Richard , Deborde Sylvie , Wong Richard J. 
Published: April 2023

Abstract
The invasion of nerves by cancer cells, or perineural invasion (PNI), is potentiated by the nerve microenvironment and is associated with adverse clinical outcomes. However, the cancer cell characteristics that enable PNI are poorly defined. Here, we generated cell lines enriched for a rapid neural invasive phenotype by serially passaging pancreatic cancer cells in a murine sciatic nerve model of PNI. Cancer cells isolated from the leading edge of nerve invasion showed a progressively increasing nerve invasion velocity with higher passage number. Transcriptome analysis revealed an upregulation of proteins involving the plasma membrane, cell leading edge, and cell movement in the leading neural-invasive cells. Leading cells progressively became round and blebbed, lost focal adhesions and filipodia, and transitioned from mesenchymal to amoeboid phenotype. Leading cells acquired an increased ability to migrate through microchannel constrictions and associate with dorsal root ganglia than non-leading cells. ROCK inhibition reverted leading cells from an amoeboid to mesenchymal phenotype, reduced migration through microchannel constrictions, reduced neurite association, and reduced PNI in a murine sciatic nerve model. Cancer cells with rapid PNI exhibit an amoeboid phenotype, highlighting the plasticity of cancer migration mode in enabling rapid nerve invasion.
Citation Format: Qi Wang, Andrea Marcadis, Elizabeth Kao, Chun-Hao Chen, Laxmi Gusain, Ann Powers, Richard Bakst, Sylvie Deborde, Richard J. Wong. Rapid cancer cell perineural invasion utilizes amoeboid migration [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 LB158.
Abstract LB162: A multiplex organoid avatar drug testing platform for precision medicine
Authors: Patel Shrey , Khalili Sana , Moy Victoria , Gray Emma , Lyons Sawyer , Brents Riley , Banister Carolyn , Buckhaults Phillip J. 
Published: April 2023

Abstract
The promise of precision medicine is to improve patient outcomes by making better therapeutic choices based on cancer causing somatic mutations. This strategy has shown limited success in colorectal cancer, in part because the genetic rules governing resistance and sensitivity are not fully elucidated. Direct drug sensitivity testing of individual patient-derived organoids is an attractive addition to this decision process because it does not require understanding of all drug-somatic mutation interactions. Individual patients avatars can be challenged with a variety of drugs and response used to inform patient care. We have developed a panel of colon cancer organoid avatars and uniquely tagged each one with a lentiviral vector possessing identifying DNA sequence bar codes flanked by common PCR primers. Each bar-code is uniquely identifiable and quantifiable from a mixture of organoids by nanopore sequencing of a common PCR product. Treatment of the mixture of organoid avatars over time under multiple drug conditions and sampling at different time points allowed the real-time monitoring of relative Darwinian fitness of each organoid in the mixture. We demonstrated the utility of this approach at identifying both expected and novel drug responses for individual organoids. Resistance to both nutlin and irinotecan were correctly predicted by TP53 somatic mutations while sensitivity to both lapatinib and ibrutinib were best predicted by mutations in EGFR signaling pathway. Patterns of drug response revealed unexpected common mechanisms. Future work will focus on informing patient care decisions with these results and determining if improvements in patient outcomes are realized.
Citation Format: Shrey Patel, Sana Khalili, Victoria Moy, Emma Gray, Sawyer Lyons, Riley Brents, Carolyn Banister, Phillip J. Buckhaults. A multiplex organoid avatar drug testing platform for precision medicine [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 LB162.
Abstract LB202: Obesity-trained C1q+ macrophages compromiseT cell anti-tumor immunity
Authors: Zhang Tao , Liu Shimeng , Brown Myles 
Published: April 2023

Abstract
Adipose tissue in the mammary gland undergoes dramatic remodeling during obesity and is involved in ﻿numerous metabolic diseases. ﻿However, how obesity-driven remodeling in adipose tissue regulates anti-tumor immunity remains unclear. Here we provide the detailed cellular atlases of mouse mammary fat pad and tumor at single-cell resolution in lean and obese mice. By leveraging scRNA-seq, we found that high-fat feeding causes a marked increase of macrophage in adipose tissue. ﻿Interestingly, a subset of macrophages expressing high levels of C1q complex genes is accumulated in obese subjects. We found that glucocorticoid may as a key regulator of C1q+ macrophage identity. Synthetic glucocorticoid, Dexamethasone, triggers C1q expression in macrophages. We found that C1q+ macrophage derived C1q complex could suppress CD8+ T cell response, thus fueling breast cancer progression. In mouse TNBC tumor, we uncovered a specific inflammatory responsive tumor subset in obese tumors with high CCR2 ligand expression. Obesity-induced TNFα exposure triggers of breast cancer cells reprogramming and CCR2 ligand production. Consequently, CCR2 ligands promote macrophage into tumor. Moreover, depletion of macrophages by anti-CSF1R suppresses tumor growth in obese mice. Our findings define a novel fundamental mechanism of C1q+ macrophage involved in anti-tumor response in obesity.
Citation Format: Tao Zhang, Shimeng Liu, Myles Brown. Obesity-trained C1q+ macrophages compromiseT cell anti-tumor immunity [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 LB202.
Abstract LB210: RenNano® mice: A heavy-chain-only antibody platform for the generation of nanobody therapeutics
Authors: Hu Yiqing , Zhang Qi , Zhang Lijun , Zhang Yabo , Zhao Huizhen , Yao Jiawei , Yang Liu , Liu Baihong , Wang Shensen , Su Zhengfang , Hui Li , Lin Qingcong , Ma Qiangqiang , Shen Yuelei 
Published: April 2023

Abstract
Monoclonal antibodies have been used to successfully treat various diseases, including tumors, autoimmune diseases, and infectious diseases. Traditional antibodies are comprised of a tetramer of two heavy chains and two light chains, totaling 150 kDa in molecular weight. However, the large size of antibodies can limit the therapeutic application; in particular, the penetration of tumors and the blood brain barrier (BBB) is not always feasible. In contrast to traditional antibodies, heavy-chain-only antibodies (HCAbs) are significantly smaller (~75 kDa), as they contain only two heavy chains. Since the heavy chain variable domain of HCAbs (i.e., VHH or single domain antibody, sdAb, or nanobody) is solely responsible for antigen recognition, nanobodies can function independently as a therapeutic molecule, which may be advantageous for penetrating tumors or the BBB. Previously, we generated a fully human antibody mouse platform, RenMabTM, in which the murine heavy chain and kappa light chain variable domains were replaced by the full human heavy chain and kappa light chain V(D)J loci in situ. Here, we have further modified the RenMabTM model to generate a fully human heavy-chain-only antibody mouse model, termed RenNano®. The modified heavy chain constant regions of RenNano® mice allow them to spontaneously produce HCAbs. Flow cytometry and biolayer interferometry confirmed that RenNano®-derived HCAbs can bind antigens without light chains. Despite this reliance on the heavy chain only variable regions for antigen specificity, RenNano® mice can generate antigen-specific antibodies with high affinity (10−8 -10−9 KD) upon immunization with various antigens. In addition, many RenNano®-derived HCAbs exhibited a longer CDR3 length, which could promote the recognition of difficult-to-reach epitopes. Furthermore, RenNano®-derived HCAbs have favorable diversity, and excellent developability properties such as a higher degree of hydrophilicity. Anti-4-1BB HCAbs can also activate 4-1BB-NF-κB signaling in a dose-dependent manner, as demonstrated in reporter assays.
In summary, the full human heavy-chain-only antibody mice, RenNano®, can produce human HCAb with high affinity and good efficacy. Thus, RenNano® is a powerful platform to discover HCAb/nanobodies for various therapeutic applications.
Citation Format: Yiqing Hu, Qi Zhang, Lijun Zhang, Yabo Zhang, Huizhen Zhao, Jiawei Yao, Liu Yang, Baihong Liu, Shensen Wang, Zhengfang Su, Li Hui, Qingcong Lin, Qiangqiang Ma, Yuelei Shen. RenNano® mice: A heavy-chain-only antibody platform for the generation of nanobody therapeutics [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 LB210.
Abstract LB216: Discovery of BCG033, a novel anti-PTK7 x TROP2 bispecific antibody-drug conjugate with promising efficacy against triple-negative breast cancer
Authors: Yao Sufei , Shang Chengzhang , An Gao , Zhang Ellen , Lin Qingcong , Yang Yi 
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) accounts for 15-20% of metastatic breast cancer incidence, and remains an area of unmet clinical need due to the low rates of overall survival. Recently, the TROP2-targeting ADC sacituzumab govitecan has received an accelerated approval from the FDA for adult patients with metastatic TNBC, as more than 85% of TNBC is marked by TROP2 overexpression. However, the clinical efficacy of ADC therapies targeting TROP2 alone is limited by its on-target toxicity. In an effort to offer therapeutic alternatives that limit this toxicity, we sought to identify other targets to combat metastatic TNBC in combination with TROP2. PTK7 is highly expressed in breast cancer; notably, PTK7 expression is higher in TNBC than non-TNBC, and is correlated with worse prognosis, tumor metastasis and TNBC progression. PTK7 has also been demonstrated to be enriched in tumor-initiating cells (TICs) in low-passage TNBC, OVCA, and NSCLC patient-derived xenografts (PDXs). We generated fully human anti-human PTK7 x TROP2 bispecific antibodies (bsAbs) from RenLite® mice, which harbor the complete human heavy chain immunoglobulin variable domain with a common human kappa light chain for subsequent bispecific antibody assembly. These bsAbs demonstrated reactivity to human, monkey, and dog antigens, and showed enhanced internalization in vitro compared with parental PTK7 antibodies. In addition, these bsAbs showed favorable tumor cell selectivity, as there was minimal internalization of the monovalent antibodies. These bsAbs were than conjugated with Monomethyl auristatin E (MMAE) to generate anti-PTK7 x TROP2 bispecific ADC (BCG033) candidates. BCG033 candidates showed potent anti-tumor activity in several cell line-derived xenografts including TNBC xenografts, indicating that BCG033 has strong therapeutic potential in TNBC and other PTK7/TROP2 co-expressing cancers. Patient-derived TNBC xenografts with co-expression of PTK7 and TROP2 have been screened for future in vivo drug efficacy screening. In summary, BCG033 has the potential to exert anti-tumor efficacy in TNBC and other solid tumors co-expressing PTK7 and TROP2.
Citation Format: Sufei Yao, Chengzhang Shang, Gao An, Ellen Zhang, Qingcong Lin, Yi Yang. Discovery of BCG033, a novel anti-PTK7 x TROP2 bispecific antibody-drug conjugate with promising efficacy against triple-negative breast cancer [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 LB216.
Abstract LB222: An mRNA-based cancer vaccine multi-targeting KRAS mutations inhibits tumor growth by increasing immune response in KRAS mutant LL/2 mouse model
Authors: Shin Seung-Hyun , Han Youngjin , Lim Chang Gyu , Heo Yong Ho , Jeong Seongju , Kim Yu-Yon , Choi In Young 
Published: April 2023

Abstract
Kirsten rat sarcoma viral oncogene (KRAS) mutations are present in 26% of non-small cell lung cancer (NSCLC) patients (The Cancer Genome Atlas data). Studies have reported the presence of spatial or intra-tumoral heterogeneity of KRAS mutations. Though resistance to mutant KRAS inhibitors targeting a specific form of major KRAS mutations (e.g, G12C or G12D) is multifaceted, intra-tumoral heterogeneity of KRAS mutation is one of the crucial factors for the intrinsic resistance to the inhibitor. Multi-targeting of different KRAS mutations can prevent resistance due to the heterogeneity of KRAS mutations within a tumor. To achieve this, we incorporated an mRNA-based cancer vaccine containing transcripts for multiple KRAS mutant antigens. Our KRAS cancer vaccine (CV) candidate showed significantly attenuated tumor growth by 37% in the syngeneic KRAS G12C-expressing LL/2 tumor-bearing mice. CV treatment group showed significantly decreased tumor size by 45.4% after biopsy. Moreover, the mice treated with KRAS CV showed spleen enlarged by 42.6% indicating increased immune responses. To confirm, the expansion of T cells in the cancer vaccine-treated group, we collected tumor tissues and analyzed proportions of CD4+ and CD8+ T lymphocytes in the tumor. We found a 14.5-fold increase in infiltration of CD8+ T cells and a 0.5-fold increase in CD8+ CD44+ memory/effector T cells in the tumors from mice treated with KRAS CV. Whereas CD4+ Foxp3+ Treg cells were decreased by 3.9-fold in the tumor. HLA-A*02 is the most common MHC class I allele. To investigate the changes in MHC expression, we conducted FACS analysis using HLA-A*02 antibodies after ex vivo treatment of KRAS CV on the human peripheral blood mononuclear cells (hPBMCs). KRAS CV treatment facilitated higher proportions of HLA-A*02+ monocytes (CD14+) and B cells (CD19+). Though LL/2 tumor model has been considered an immunosuppressive model, our results suggest that the KRAS CV can significantly enhance immune responses, thereby suppressing tumor growth.
Citation Format: Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Yong Ho Heo, Seongju Jeong, Yu-Yon Kim, In Young Choi. An mRNA-based cancer vaccine multi-targeting KRAS mutations inhibits tumor growth by increasing immune response in KRAS mutant LL/2 mouse model [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 LB222.