bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2438: A retrospective pilot study to validate the utility of proteomic biomarkers in the blood for diagnosis of breast cancer
Authors: Jung So-Youn , Lee Eun-Gyeong , Han Jai Hong , Lee Seeyoun , Shin Soyeon , Lee Ju Yeon , Kim Sung-Soo , Kim Yumi , Noh Dong-Young 
Published: March 2024

Abstract
Background: Previously, three-protein signature (Mastocheck®, Bertis Inc.) from plasma has been launched to overcome the limitation of low accuracy of mammography. In addition, nine-protein signature from serum was newly developed to improve the accuracy of three-protein signature as a blood-based diagnostic tool. This study aimed to validate the diagnostic utility for breast cancer of nine-protein signature with comparison with three-protein signature.
Methods: A blood-based test using multiple reaction monitoring (MRM) by mass spectrometry to quantify nine proteins (APOC1, CHL1, FN1, VWF, PPBP, CLU, PRDX6, PRG4, and MMP9) in serum and three proteins (APOC1, CHL1, CA1; Mastocheck®) in plasma was investigated using blood of 30 health women and 30 breast cancer patients. Using the cut-off values confirmed by AI-based deep learning model, we evaluated the sensitivity, specificity, and accuracy of nine- and three-protein signature for detecting breast cancer.
Results: Among 60 cases, the sensitivity and specificity of nine-protein signature was 87.9% and 80.7% for diagnosis of breast cancer. These values were 20% and 10% higher than those of three-protein signature, respectively (66.7% of sensitivity and 70.0% of specificity). The accuracy of nine-and three-protein signature was 83.3% and 68.3%.
Conclusion: This study demonstrated that nine-protein signature could be a more accurate and effective tool for detecting breast cancer compare to three-protein signature). For a confirmatory study, we need to perform a large scaled validation study in future. Grants: This research was supported by Bertis, Republic of Korea (grant number: NCC 2341770-1)
Citation Format: So-Youn Jung, Eun-Gyeong Lee, Jai Hong Han, Seeyoun Lee, Soyeon Shin, Ju Yeon Lee, Sung-Soo Kim, Yumi Kim, Dong-Young Noh. A retrospective pilot study to validate the utility of proteomic biomarkers in the blood for diagnosis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2438.
Abstract 2451: Investigation of SIRT6 usefulness as a novel biomarker for oral cancer
Authors: Yoshii Haruka , Shimoda Ami , Mitsudo Kenji , Kioi Mitomu 
Published: March 2024

Abstract
Introduction: SIRT6 is one of the seven human sirtuin genes and is known to function as an onco-suppressor gene in colorectal and ovarian cancers, although it is up-regulated in other cancers. Thus, SIRT6 is considered performing both tumor-suppressing and promoting roles. However, the association of SIRT6 with oral squamous cell carcinoma (OSCC) and its role in OSCC pathogenesis are currently unclear. Currently, SCC or CYFRA are used as a tumor marker to assist in the diagnosis of OSCC in a clinical setting whereas its sensitivity is low. Therefor the development of a novel biomarker for early diagnosis and identification of new therapeutic targets is critical to resolve the pressing clinical issues related to the management of OSCC. This study aimed to investigate the expression and the relevance of SIRT6 in patients with OSCC and its potential as a biomarker for early detection and prognosis prediction.
Materials and Methods: This study enrolled 78 patients with OSCC and 9 patients with carcinoma in situ (CIS). The OSCC patients had undergone surgery or chemoradiotherapy (51 surgery and 27 chemoradiotherapy). The CIS patients had undergone surgery. Samples were also obtained from 10 patients with oral potentially malignant disorders (OPMDs). Biopsied or surgical resected samples were used for the study. We obtained 21 noncancerous tissues as normal tissues from the adjacent noncancerous tissues after tumor resection. Immunohistochemistry, quantitative real-time RT-PCR, and microarray analyses were performed to determine SIRT6 expression and its association with clinicopathological features in OSCC, CIS, and OPMDs using clinical paraffin embedded specimens.
Results: SIRT6 mRNA levels were higher in OSCC tissues than those in noncancerous tissues (p&lt;0.05). And SIRT6 protein expression levels were higher in OSCC, CIS and OPMDs tissues than those in noncancerous tissues (p&lt;0.05). SIRT6 expression was predominant in patients aged ≥65 years and significantly correlated with shorten overall survival. In the microarray analysis, some SIRT6-associated genes, such as ANXA2 was significantly up-regulated, and PIGC and RGPD4 were down-regulated in OSCC.
Conclusion: SIRT6 plays a role in tumor homeostasis, leading to a poor prognosis in OSCC. SIRT6 may represent a novel target not only for the treatment, but also as a prognostic marker in OSCC.
Citation Format: Haruka Yoshii, Ami Shimoda, Kenji Mitsudo, Mitomu Kioi. Investigation of SIRT6 usefulness as a novel biomarker for oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2451.
Abstract 2565: Vitamin D deficiency and outcomes in prostate cancer patients: A real-world database
Authors: Hart Lowell L. , Reeves James , Garofalo Stacey , Amick William 
Published: March 2024

Abstract
Introduction: Vitamin D is essential for many bodily functions, including bone health and the prevention of osteoporosis and rickets. In recent years, the importance of vitamin D metabolism in immune system regulation and cancer prevention has been studied with increased focus. With the advent of cancer immunotherapies this has become more important. Multiple recent publications document that vitamin D deficiency is prevalent in cancer patients. This has also been observed specifically in prostate cancer patients, with a high percentage of these deficient patients being of African- American ancestry. It has been theorized that high levels of vitamin D deficiency among African American prostate cancer patients could contribute to worse cancer outcomes and increased health disparities. However, routine vitamin D testing has not been commonly performed in the oncologic community. We hypothesized that deficient levels of vitamin D could lead to inferior prostate cancer outcomes in men with a wide range of ethnic and socio-economic backgrounds. In this project we recorded vitamin D levels in prostate cancer patients at a large community oncology group and evaluated them by stage, pathologic data, survival, race/ethnicity, and other clinical features.
Methods: This study is a retrospective, observational study of the data from the electronic medical records of patients with prostate cancer who received vitamin D level testing at Florida Cancer Specialists & Research Institute from 2008- 2023, throughout the state of Florida. All data used in this study will constitute secondary data, it will have been collected originally for clinical use in the general oncology practice setting. No date parameters or patient limits will be applied to this study, and all eligible patients are included.
Results: 451 patients with prostate cancer had determination of vitamin D levels, out of a total of 27,772 prostate cancer patients in the database. 38% of the prostate cancer patients analyzed had low 25-OH vitamin D levels (&lt;32 ng/ml). Patients with low vitamin D levels had an average Gleason score of 7.46. Patients with low vitamin D levels who died had an average survival of 144 months. Patients with low vitamin D levels who presented with localized disease had a 35% chance of eventually developing castrate-resistant disease. 45% of the low vitamin D group developed metastatic disease during their course of treatment. Further comparisons of vitamin D levels with pathologic data, survival/longevity, race/ethnicity, and clinical course will be evaluated and presented.
Citation Format: Lowell L. Hart, James Reeves, Stacey Garofalo, William Amick. Vitamin D deficiency and outcomes in prostate cancer patients: A real-world database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2565.
Abstract 2580: Targeting chromatin in ovarian cancer stem cells
Authors: Wang Yinu , Frederick Jane , Zhang Yaqi , Bartom Elizabeth Thomas , Bauer Greta , Tanner Edward , Backman Vadim , Matei Daniela 
Published: March 2024

Abstract
The dynamic organization of chromatin, governed by epigenetic modifiers, critically regulates cell plasticity and determines cell fate in both normal and malignant stem cells. We hypothesized that chromatin architecture plays a role in regulating transcriptional heterogeneity in ovarian cancer stem cells (OCSCs) to maintain stemness and chemoresistance. PWS microscopy showed that ALDH+ OCSCs derived displayed higher nuclear fractal dimension D signals (P&lt;0.05) than ALDH- non-OCSCs, indicating that chromatin in OCSCs possesses higher packing compared to non-OCSCs. Cut & TAG Sequencing showed that of the 3606-histone repressive H3K27m3 enriched regions (P&lt;0.05, fold change &gt;2), 3208 were detected in OCSCs while 398 peaks were present in non-OCSCs, consistent with findings supporting high D features in OCSCs. The active mark H3K4me3 was enriched at the promoter of stemness-associated genes, including SOX2, ALDH1A3, and FZD7 in OCSCs; and the repressive histone mark H3K27me3 was enriched at the promoter of the epithelial cell marker CDH1 in OCSCs. These results support that the chromatin of OCSCs contains open genomic regions, corresponding to stemness-associated genes and repressed regions associated with genes related to differentiation. RNA sequencing indicated that the coefficient of variance (COV) reflecting transcriptional heterogeneity in OCSCs was higher than in non-OCSCs at baseline. In response to platinum, genes with low baseline expression in OCSCs were most upregulated, supporting increased transcriptional heterogeneity in response to chemotherapy. Inhibitors of epigenetic modifiers (DNMTi, EZH2i, and Dot1Li) induced chromatin re-organization in OCSCs and promoted OCSCs transition toward differentiation, supporting that stemness-associated chromatin structure is targetable. We demonstrated that a Dot1L inhibitor (Dot1Li) targeted OCSCs by decreasing chromatin packing D, resulting in decreased transcriptional heterogeneity. In conclusion, OCSCs harbor highly packed chromatin, contributing to chemoresistance and cell plasticity. Epigenetic modifiers (such as Dot1Li) inhibit stemness by regulating chromatin organization and transcriptional malleability.
Citation Format: Yinu Wang, Jane Frederick, Yaqi Zhang, Elizabeth Thomas Bartom, Greta Bauer, Edward Tanner, Vadim Backman, Daniela Matei. Targeting chromatin in ovarian cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2580.
Abstract 2621: Preclinical Efficacy of DM002, a bispecific HER3 × MUC1 antibody-drug conjugate with a novel DNA topoisomerase I inhibitor, in solid tumor models
Authors: Zhang Yifu , Shang Chengzhang , Wang Nannan , An Gao , Guo Chaoshe , An W. Frank , Yang Yi 
Published: March 2024

Abstract
MUC1 is a known tumor-associated antigen (TAA), but previous anti-MUC1 agents have shown limited clinical efficacy due to neutralization by the soluble N-terminal autoproteolytic product of MUC1. More recently, HER3-targeted ADCs, such as Patritumab deruxtecan, have shown encouraging early clinical activity in a variety of tumors. However, the majority of patients did not exhibit response to paritumab deruxtecan treatment. Therefore, improved therapies targeting these TAAs are needed.
As HER3 and MUC1 are co-expressed in a wide range of cancer types, we hypothesized that simultaneous targeting of HER3 and MUC1 with a bispecific antibody-drug conjugate (bsADC) could potentially lead to increased efficacy, reduced resistance and improved safety in the clinical setting. We generated an anti-HER3 × MUC1 bispecific antibody using the fully human common light chain antibody transgenic mice (RenLite®).
The HER3 × MUC1 bsAb showed improved cell binding and internalization in vitro compared to the parental mAb, suggesting synergy between the two arms. We then conjugated the HER3xMUC1 bsAb with vcMMAE for proof-of-concept studies, or with our novel DNA topoisomerase I inhibitor linker/payload conjugates (BLD1102) to make DM002-BLD1102 bsADC. Both bsADCs potently inhibited the growth of HER3+MUC1+ PDX tumors. DM002-vcMMAE also showed greater in vivo efficacy than its parental mAb ADCs, consistent with their in vitro internalization activity. DM002-BLD1102 also showed strong anti-tumor activity in DM002-vcMMAE resistant PDX models, suggesting the superiority of this new DNA topoisomerase I inhibitor linker/payload over the classical vcMMAE linker/payload. In conclusion, the HER3 × MUC1 bsAb is a promising agent for the treatment of HER3 and MUC1 positive tumors.
Citation Format: Yifu Zhang, Chengzhang Shang, Nannan Wang, Gao An, Chaoshe Guo, W. Frank An, Yi Yang. Preclinical Efficacy of DM002, a bispecific HER3 × MUC1 antibody-drug conjugate with a novel DNA topoisomerase I inhibitor, in solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2621.
Abstract 2635: An epigenetic regulation targeting inhibitory receptors and attenuates CD8 T cell exhaustion in breast cancer
Authors: Lin You-Zhe , Wu Wan-Rong , Chung Feng-Chi , Shen Yi-Chun , Lee Chuan-Chun , Li Hong-Wei , Lin Guang-Jan , Chengx Wei-Chung , Wang Shao-Chun 
Published: March 2024

Abstract
T cell exhaustion is a state of dysfunctional T cell response characterized by prolonged antigen exposure and diminished effector functions, a significant cause of tumor tolerance, and poor response to immune checkpoint blockade (ICB) therapy. T cell exhaustion is a highly dynamic process involved with a network of genetic and epigenetic regulation that program the T cell functions. Epigenetic regulation by microRNAs targets multiple genes involved in T cell function and is expected to be a major contributor to the functional programming of tumor-associated T cells. However, the underlying causal mechanisms remain to be determined. Here, we show that the microRNA miR-379-5p is a critical epigenetic regulator for promoting T cell function and suppressing exhaustion induced by chronic stimulation. The microRNA is identified by integrating bioinformatic interrogation of the miRNA databases cross-referencing with the TCGA database for genes involved in T cell functioning and their correlation with clinical outcomes, coupled with molecular profiling of miRNAs in experimental T exhaustion. Notably, the expression levels of miR-379-5p in tumor tissues, which encompass cancer cells and the surrounding stromal components, including immune cells, are closely associated with favorable prognosis of various cancer types. Further molecular and cellular characterization of miR-379-5p entailing cell culture, animal models, and patient-derived tumor organoids shows that it exerts suppressive effects by targeting specific sequences in the 3’ untranslated region (UTR) of critical immune checkpoint genes in T cells, thereby enhances the effector functions of cytotoxic T cells for tumor clearance. Ectopic expression of miR-379-5p shifts the evolution of primary T cells toward memory-like effector cells while silencing miR-379-5p induces exhaustion and abrogates the cytotoxic activity of primary T cells. We further demonstrate that transcriptional downregulation of miR-379-5p in T cells by a nuclear receptor transcription factor which is responsible for initiating the exhausting process impairs the tumor suppression function of T cells. Our studies indicate that miR-379-5p can function as a tumor suppressor by protecting T cells from exhaustion and bears the potential for developing novel strategies to improve the response to ICB therapy in breast cancer.
Citation Format: You-Zhe Lin, Wan-Rong Wu, Feng-Chi Chung, Yi-Chun Shen, Chuan-Chun Lee, Hong-Wei Li, Guang-Jan Lin, Wei-Chung Chengx, Shao-Chun Wang. An epigenetic regulation targeting inhibitory receptors and attenuates CD8 T cell exhaustion in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2635.
Abstract 2656: The selective IKZF2 molecular glue degrader, PVTX-405, counters Treg immune suppression,shows significant tumor growth delay as single agent and synergistic response with immune checkpoint therapies (ICTs)
Authors: Dhruv Harshil D. , McEachern Donna , Bai Longchuan , Zhang Xuqing , Chen Zhixiang , Nagilla Rakesh , Behshad Elham , Han Bomie , Orth Peter , Rej Rohan , Kirchhoff Paul , Shin Niu , Jolivette Larry , Strickland Corey , Sui Zhihua , Priestley Scott , Wang Shaomeng , Mohammad Helai 
Published: March 2024

Abstract
Immunosuppressive regulatory T-cells (Tregs) are key modulators of tumor immune evasion and resistance to immune checkpoint therapies (ICTs). IKZF2 (Helios) is a transcription factor that is selectively expressed by Treg and has been shown to be essential for maintaining function and stability of Tregs in the face of inflammatory conditions that include autoimmune disease as well as cancer. Here we describe the discovery of PVTX-405, a potent and selective IKZF2 molecular glue degrader (DC50=6.3 nM). Our molecular glue degrader promotes a productive ternary complex with the E3 ubiquitin ligase substrate receptor cereblon (CRBN) to selectively degrade IKZF2 while sparing other CRBN neosubstrates (IKZF1/3, GSPT1, CK1a). PVTX-405 demonstrates rapid and selective degradation of IKZF2 in Jurkat cells in vitro, human PBMC derived Tregs ex vivo, and in cynomolgus monkeys in vivo. Degradation of IKZF2 in Jurkat cells leads to dose dependent increase in production of inflammatory cytokine IL-2. In ex vivo co-cultures of Tregs and effector T-cells, PVTX-405 reduces the suppressive activity of Tregs. To determine whether the relief of Treg suppressive activity observed in vitro and ex vivo can translate to anti-tumor activity in vivo we utilized CRBNI391V(humanized CRBN) mice. We developed a novel MC38 syngeneic tumor model to test both monotherapy and combination efficacy in an immune-competent setting. Once daily oral administration of PVTX-405 as single agent significantly delays the growth of MC38 tumors. Further, in vivo treatment of PVTX-405 in combination with ICTs, anti-PD1 or anti-LAG3, significantly increased animal survival and led to durable tumor regressions compared to ICTs alone. Together, these results demonstrate a strong synergy between ICTs and Treg destabilization through pharmacological degradation of IKZF2 and represent a promising combination strategy for treatment of cancer.
Citation Format: Harshil D. Dhruv, Donna McEachern, Longchuan Bai, Xuqing Zhang, Zhixiang Chen, Rakesh Nagilla, Elham Behshad, Bomie Han, Peter Orth, Rohan Rej, Paul Kirchhoff, Niu Shin, Larry Jolivette, Corey Strickland, Zhihua Sui, Scott Priestley, Shaomeng Wang, Helai Mohammad. The selective IKZF2 molecular glue degrader, PVTX-405, counters Treg immune suppression,shows significant tumor growth delay as single agent and synergistic response with immune checkpoint therapies (ICTs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2656.
Abstract 2679: Myeloid olfactory receptors in melanoma
Authors: Benson Elayne M. , Ley Klaus , Orecchioni Marco , Hedrick Catherine C. 
Published: March 2024

Abstract
Olfactory receptors are commonly found in the nasal cavity and function to detectodorants. However, very recent studies have determined that innate immune cells,including monocytes and macrophages, express olfactory receptors. OLFR2 (OR6A2 inhumans), was recently linked to atherosclerosis development through interaction with itsligand, octanal. Increased levels of octanal are considered as a risk factor foratherosclerosis. Conversely, octanal levels are associated with lower cancer incidence,suggesting that OLFR2 may play a protective role in cancer. Indeed, data from TheCancer Genome Atlas for liver and brain cancers show that OLFR2 expression isassociated with increased patient survival. Here, we utilized an orthotopic melanomamouse model using B16 cancer cells in C57/BL6 mice that had been transplanted witheither wild type or OLFR2 knockout bone marrow to directly test the role of OLFR2 onimmune cells in regulating tumor growth. We found that hematopoietic deletion of OLFR2exacerbated melanoma tumor growth in these mice; again, supporting the notion thatOLFR2 is anti-tumoral. The OLFR2+ cells present in the tumor were myeloid cells.Monocytes, non-classical monocytes specifically, function to detect cancer cells in tumorseeding sites, and recruit NK cells for tumor cell destruction. OLFR2-deficientmacrophages were found to migrate less to tumor cells in an in vitro assay, suggestingthat OLFR2 is involved in the sensing of newly seeding tumor cells, likely through sensingoctanal. Studies are ongoing to determine the exact functions of OLFR2+ monocytes andmacrophages in the tumor microenvironment. OLFR2 may be one of several olfactoryreceptors that is utilized by myeloid cells as a defense mechanism for detection of newlyseeding or metastatic tumor cells. As olfactory receptors are easily druggable targets,understanding their role in cancer prevention could lead to emerging newimmunotherapies for cancer.
Citation Format: Elayne M. Benson, Klaus Ley, Marco Orecchioni, Catherine C. Hedrick. Myeloid olfactory receptors in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2679.