bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7514: Tumor intrinsic CDC42BPB confers resistance to anti-PD-1 immune checkpoint blockade in breast cancer
Authors: Deshpande Ravindra Pramod , Wu Kerui , Wu Shih-Ying , Tyagi Abhishek , Hunting John , Ruiz Jimmy , Li Wencheng , Watabe Kounosuke 
Published: March 2024

Abstract
Immune checkpoint blockade has been used to treat breast cancer, but the clinical responses remain relatively poor, especially for the triple-negative subtype. The weak responsiveness is attributed to tumor intrinsic as well as tumor extrinsic factors, suggesting a need for novel approaches. We have used the CRISPR Cas9 kinome knockout library consisting of 763 kinase genes to identify tumor intrinsic kinase conferring resistance to anti-PD-1 immune checkpoint blockade and identified the CDC42BPB kinase as a potential target to overcome the resistance to anti-PD-1 immunotherapy. We found that CDC42BPB is highly expressed in breast cancer patients who are non-responsive to immunotherapy. Importantly, a small molecule pharmacological inhibitor, BDP5290, which targets CDC42BPB synergized with anti-PD-1 and enhanced tumor cell killing by promoting T-cell proliferation in both in vitro and in vivo assays. Moreover, anti-PD-1 resistant breast cancer cells showed higher expression of CDC42BPB, and its inhibition rendered the resistant cells more susceptible to T cell killing in the presence of anti-PD-1. We also found that CDC42BPB phosphorylated AURKA which in turn upregulated PD-L1 through cMYC. Our results have revealed a robust link between tumor intrinsic kinase and immunotherapy resistance and provided a rationale for a novel combination therapy of CDC42BPB inhibition and anti-PD-1 immunotherapy for breast cancer.
Citation Format: Ravindra Pramod Deshpande, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, John Hunting, Jimmy Ruiz, Wencheng Li, Kounosuke Watabe. Tumor intrinsic CDC42BPB confers resistance to anti-PD-1 immune checkpoint blockade 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 7514.
Abstract 7569: Characterizing pathways for metastasis of retinoblastoma in forebrain organoids
Authors: Shtanko Yulia , Rodriguez Sara , Schachner Benjamin , Adis Emily , McLaughlin Samantha , Borges Sebastian , Dollar James , Zuniga Ashley , Quintana Gabriela , Lopez Sofia , Owens Dawn , Moulin Chloe , Braun Steffanie , Yenisehirli Gulum , Pelaez Daniel , Harbour J. William , Kurtenbach Stefan 
Published: March 2024

Abstract
Retinoblastoma (Rb) is a childhood cancer of the eye, which usually presents in children under the age of five. When detected early, Rb has favorable prognosis in developed countries, but metastasis into the central nervous system (CNS) through the optic nerve correlate with a high mortality rate. Even if detected early, the available harsh and unspecific treatments can cause serious side effects, and enucleations are still performed frequently. There is still uncertainty regarding the mechanism for metastasis into the central nervous system. We performed bioinformatic analysis of single cell sequencing data for retinoblastoma, retinal tissues, optic nerve, and brain, to identify potential pathways and cell-cell communications fostering Rb invasion into the optic nerve and brain. Our analysis revealed several potential metastatic drivers, including immune modulation involving MIF, secreted by the Rb cells, as well as cell-adhesion pathways promoting a change in cellular phenotype. Given that animal models do not faithfully recapitulate human Rb initiation and progression, we developed a novel human iPSC-derived forebrain organoid model to investigate mechanisms of Rb CNS metastasis. Microinjections of GFP-labelled Rb cells allow to track growth and spread. In this fully human model including microglial cells, we can, for the first time, study the Rb forebrain interactions and pathways involved. RNA-seq analysis of Rb cells growing in forebrain organoids shows increased activity in neuron projection development and neuron migration, overlapping with the observed phenotype switch of invading Rb. Together, we present a novel iPSC-derived human forebrain model to monitor growth and spread of metastatic Rb, and describe new pathways involved in invading and metastasizing Rb.
Citation Format: Yulia Shtanko, Sara Rodriguez, Benjamin Schachner, Emily Adis, Samantha McLaughlin, Sebastian Borges, James Dollar, Ashley Zuniga, Gabriela Quintana, Sofia Lopez, Dawn Owens, Chloe Moulin, Steffanie Braun, Gulum Yenisehirli, Daniel Pelaez, J. William Harbour, Stefan Kurtenbach. Characterizing pathways for metastasis of retinoblastoma in forebrain organoids [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 7569.
Abstract 7611: Circulating blood RNAseq detects activation of immune system and predicts response to immunotherapy in bladder cancer
Authors: Richard Corentin , Chevrier Sandy , Marabelle Aurélien , Boidot Romain 
Published: March 2024

Abstract
Background: Anti-PD(L)1 immunotherapies have revolutionized oncology by getting durable tumor responses in advanced cancers. Nevertheless, currently approved biomarkers (PD-L1, MSI, TMB) have suboptimal positive/negative predictive values for tumor responses and survival.
Aims & Methods: We sought to assess the value of gene expression on circulating blood to predict responses to immunotherapy. We performed total paired-end RNAseq at 20-million reads and analyzed differential gene expressions according to cancer outcomes on baseline frozen whole blood from a cohort of 186 patients prospectively enrolled in the IOPREDI study, a French ancillary cohort of the international multi-center STRONG Phase III trial testing the anti-PD-L1 durvalumab in advanced bladder cancers (NCT03084471).
Results: One hundred and sixty four out of the 186 baseline samples generated valuable blood transcriptome data. Thanks to mathematical corrections, all samples were normalized, and the analysis was possible without introducing any bias despite the sample origin from 16 enrolling sites. We first observed that patients with a complete or partial response or a stable disease overexpressed 19 genes, 5 of which are markers of immune cell activation: CXCL8, EOMES, GBP5, GZMA, and GZMH. Conversely, patients with a progressive disease overexpressed 11 genes including CD177, a marker of neutrophil cells, recently associated to immunotherapy resistance. Next, patients with a PFS &gt; 3 months showed an overexpression of 25 genes associated with immune cells activation such as CD8A, CXCL8, EOMES, FASLG, GZM genes, whereas patients with a shorter PFS highly expressed genes of immune cell inhibition: CD177, CD300LG, CD99, and CST7. Finally, patients with an OS &gt; 7 months had also a higher expression of the same previous genes completed with 6 other genes, still indicators of immunity activation (CD3D, CD3E, CD3G, GZMM, IL2RB, and PTGDS).
Conclusion: Total RNAseq from RNA directly extracted from whole blood can detect baseline activation of T-cells in patients who will subsequently benefit from anti-PD-L1 immunotherapy. This work shows that RNAseq can detect an immune activation state in circulating blood without specific cell selection. This technique could be used in clinical trials to select for patients prone to benefit from cancer immunotherapies.
Citation Format: Corentin Richard, Sandy Chevrier, Aurélien Marabelle, Romain Boidot. Circulating blood RNAseq detects activation of immune system and predicts response to immunotherapy in bladder 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 7611.
Abstract 7621: Serum albumin and derived neutrophil-to-lymphocyte ratio are potential predictive biomarkers for immune checkpoint inhibitors in small cell lung cancer
Authors: Kuang Zhanpeng , Miao Jessica , Zhang Xiaoli 
Published: March 2024

Abstract
Background: Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of small cell lung cancer (SCLC), but only a minority of patients benefit from this therapy. Therefore, it is critical to identify potential risk factors that could predict the efficacy of ICI treatment in SCLC patients and identify patient subgroups who may benefit the most from ICI therapy.
Methods: Our study included a total of 183 SCLC patients who had received at least one dose of ICI treatment. We utilized both logistic regression and Cox proportional hazard regression to evaluate whether various patient clinical factors and serum biomarkers, could serve as predictors of patient response to treatment and overall survival (OS) during ICI therapy.
Results: Logistic regression showed that patients with a history of surgery (p=0.003, OR 9.06, 95% CI: (2.17, 37.9)) and no metastasis (p=0.008, OR 7.82, 95% CI: (1.73, 35.4)) exhibited a higher odds of response to ICI treatment. Cox regression analyses demonstrated that pretreatment blood albumin (p=0.003, HR 1.72, 95% CI: (1.21, 2.45)) and derived neutrophil to lymphocyte ratio (dNLR) (p=0.003, HR 1.71, 95% CI: (1.20-2.44)) were independent predictors for OS in SCLC patients. By establishing a pre-treatment prognostic scoring system based on baseline albumin and dNLR, we found that patients with high albumin and low dNLR exhibited a significantly better prognosis than those with low albumin and high dNLR in both the full (P&lt;.0001, HR 0.33, 95% CI: 0.20-0.55) and the metastatic cohort (P&lt;.0001, HR 0.28, 95% CI: 0.15-0.51). The better prognostic group also had younger age, higher BMI and lower systemic inflammatory biomarker values than the unfavorable group (P&lt;.0001).
Conclusion: Our data reveals the significant role of metastasis status and treatment history in predicting the initial response of SCLC patients to ICI treatment. However, baseline serum albumin and dNLR provide a more precise prognostic prediction for patient OS. The scoring system based on albumin and dNLR enhances the ability to stratify patient prognosis and holds the potential to guide clinical decision-making for SCLC patients undergoing ICI therapy.
Citation Format: Zhanpeng Kuang, Jessica Miao, Xiaoli Zhang. Serum albumin and derived neutrophil-to-lymphocyte ratio are potential predictive biomarkers for immune checkpoint inhibitors in small cell lung 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 7621.
Abstract 7623: Biomarker study to personalized neoadjuvant chemotherapy using preoperative gastric cancer specimens of biopsy from the COMPASS trial, a phase II randmazed controlled trial
Authors: Oshima Takashi 
Published: March 2024

Abstract
Background and Aim: The results of COMPASS, a randomized phase II trial, suggest that preoperative adjuvant chemotherapy (NAC) regimen or course for locally advanced gastric cancer (GC) does not affect overall survival (OS). However, we hypothesized that some NAC regimens may be more effective for OS on a case-by-case basis. Furthermore, we searched for biomarkers, assuming that further improvement in the outcome of locally advanced GC could be expected if appropriate NAC regimens could be selected using biomarkers before treatment initiation.
Materials and Methods: RNA was extracted from endoscopic biopsy specimens of primary tumors collected prior to NAC administration in COMPASS patients, and real-time polymerase chain reaction (PCR) of 127 genes was performed to identify genes with significant (P &lt; 0.05) interaction P values for survival with each regimen and stratified OS with each regimen. Genes were identified and biomarkers were searched at the protein level using immunohistochemical analysis.
Results: The THBS1, MSI1, and IGF2BP3 genes were identified as genes whose expression levels significantly (P &lt; 0.05) stratified survival for each regimen and had significant (P &lt; 0.05) interaction P values. Furthermore, a strong correlation was observed between each gene and THBS1, MSI1, and IGF2BP protein expression by immunohistochemical analysis, confirming that protein expression levels by immunohistochemical analysis are also useful as biomarkers.
Conclusion: Using endoscopic biopsy specimens prior to NAC for locally advanced GC, biomarkers were identified to select NAC regimens over predicted OS. The results of this study may guide the conduct of clinical trials of individualized treatment of NAC using biomarkers.
Citation Format: Takashi Oshima. Biomarker study to personalized neoadjuvant chemotherapy using preoperative gastric cancer specimens of biopsy from the COMPASS trial, a phase II randmazed controlled trial [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 7623.
Abstract 7629: Association between COMT expression and therapeutic efficacy of androgen receptor-axis targeted in prostate cancer
Authors: Maekawa Shigekatsu , Takata Ryo , Shiomi Ei , Ikarashi Daiki , Matsuura Tomohiko , Kato Renpei , Kanehira Mitsugu , Sugimura Jun , Obara Wataru 
Published: March 2024

Abstract
Background: The enzyme of catechol-O-methyltransferase (COMT) inhibits the proliferation of prostate cancer (PCa). There has been no obvious biomarker that contributes to the selection of a therapeutic agent among new-generation androgen receptor-axis targeted (ARAT) therapy, such as abiraterone (ABI) or enzalutamide (ENZ). We aimed to assess the possibility of using COMT expression as a biomarker for PCa progression and the criteria for selecting ABI or ENZ.
Methods: We retrospectively evaluated 60 patients with PCa treated with ABI or ENZ via needle biopsy or radical prostatectomy. Immunostaining of COMT was performed using formalin-fixed, paraffin-embedded blocks obtained from the initial prostate biopsy for diagnosis or prostatectomy. Immunostaining evaluations were scored by immunostaining intensity (0-3) and staining area (0-3), and the total score ≥4 was defined as "high expression" and the total score &lt;4 was defined as "low expression.” The associations between COMT expression levels and clinical outcomes, including the duration of ENZ or ABI response, were also assessed.
Results: Of the 60 cases, nine (15%) showed low expression of COMT. Overall survival was significantly shorter in patients with lower COMT expression (hazard ratio [HR] = 0.24, 95% confidence interval [CI] 0.07-0.83, P= 0.024). When ENZ was administered as the first ARAT, progression-free survival (PFS) was significantly different between patients with COMT expression scores &lt;4 and ≥4 (median 5.9 and 23.3 months, respectively). However, when ABI was administered as the first ARAT, there was no significant difference in the PFS of ARAT between COMT expression scores &lt;4 and ≥4.
Conclusion: Patients with lower COMT expression have a significantly poorer prognosis for PCa. In addition, PFS after ENZ administration, as the first ARAT, correlated with COMT expression levels. To our knowledge, this is the first report of an association between COMT expression and the duration of ARAT.
Citation Format: Shigekatsu Maekawa, Ryo Takata, Ei Shiomi, Daiki Ikarashi, Tomohiko Matsuura, Renpei Kato, Mitsugu Kanehira, Jun Sugimura, Wataru Obara. Association between COMT expression and therapeutic efficacy of androgen receptor-axis targeted in prostate 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 7629.
Abstract 766: Effects of supplemental calcium and vitamin D on circulating biomarkers of gut barrier function in colorectal adenoma patients: A randomized controlled trial
Authors: Lee Sangji , Fedirko Veronika , Bostick Roberd M. , Pearce Bradley , Barry Elizabeth L. , Rutherford Robin E. , Seabrook March E. 
Published: March 2024

Abstract
Introduction: Recent experimental evidence shows that intestinal barrier disruption initiates colon inflammation, which may promote colorectal carcinogenesis. In experimental models, vitamin D and calcium improved gut barrier function; however, this has not been assessed in humans.
Method: To test the effects of supplemental calcium and vitamin D3 on circulating biomarkers of intestinal mucosal damage (intestinal fatty-acid binding protein, IFABP) and exposure to bacterial products due to impaired gut barrier (lipopolysaccharide-binding protein, LBP), we conducted an “adjunct biomarker study” to a larger 11-center, randomized, placebo-controlled, partial 2 × 2 factorial chemoprevention clinical trial, the Vitamin D/Calcium Polyp Prevention Study. Participants were randomized into four different treatment groups: placebo, 1,200 mg/day calcium, 1,000 IU/day vitamin D3, and 1,200 mg/day calcium plus 1,000 IU/day vitamin D3. Circulating concentrations of LBP and IFABP were measured at baseline and 1-year follow-up using the Meso Scale Discovery electrochemiluminescence assays in a subset of 118 participants included in the adjunct biomarker study.
Result: Following one year of vitamin D3 treatment, in the vitamin D3 plus calcium and vitamin D3 groups versus placebo and calcium groups, LBP decreased 10% (316 ng/ml; P=0.23) and IFABP 18% (77 ng/ml; P=0.06). A similar decrease of 20% (P=0.10) was observed for IFABP, but not LBP, in the vitamin D3 plus calcium versus the calcium group. There were no appreciable biomarker changes with calcium treatment. In stratified analyses, we found possible effect modifications by baseline serum 25-OH-vitamin D, total calcium intake, body mass index, and interleukin 6 (IL-6) concentration on estimated vitamin D3 treatment effects on LBP and/or IFABP.
Conclusion: These preliminary results are consistent with vitamin D’s potential protective effects on intestinal mucosal barrier and support further research of vitamin D against gut barrier disruption and colorectal neoplasms.
Citation Format: Sangji Lee, Veronika Fedirko, Roberd M. Bostick, Bradley Pearce, Elizabeth L. Barry, Robin E. Rutherford, March E. Seabrook. Effects of supplemental calcium and vitamin D on circulating biomarkers of gut barrier function in colorectal adenoma patients: A randomized controlled trial [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 766.
Abstract 769: Incorporating a cross-ancestry polygenic risk score into a clinical model improved breast cancer risk prediction in women with pathogenic variants
Authors: Tshiaba Placede , Sun Monika , Ratman Dariusz , Weitzel Jeffrey N. , Shah Premal , Rabinowitz Matthew , Kumar Akash , Im Kate 
Published: March 2024

Abstract
Introduction. We previously developed and validated a cross-ancestry polygenic risk score (caPRS) to predict risk of developing breast cancer (BC) in women who do not carry pathogenic variants (PVs) in BC susceptibility genes. Here we aimed to expand upon that study by integrating the caPRS with the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model to combine the effects of genetic and clinical factors in carriers of PVs in BRCA1, BRCA2, PALB2, CHEK2 and ATM.
Methods. We explored the association of caPRS among 12,525 women from the UK Biobank and the Consortium of Investigators of Modifiers of BRCA1/2. The effect size of the caPRS was evaluated separately for individuals carrying PVs in BRCA1, BRCA2, CHEK2, ATM and PALB2. We used a logistic regression model adjusted for age, first-degree BC family history (FHx) and cohort for BRCA1 and BRCA2 to examine the association of the caPRS with BC. The effect sizes were expressed as standardized odds ratios (ORs) with 95% confidence intervals (CIs). The estimated absolute risks to age 80 of developing BC were calculated for unaffected women by combining the caPRS-based risk with gene-specific clinical risk estimates from the BOADICEA model based on U.S. incidences.
Results. The caPRS was significantly associated with BC risk across all PV carrier groups. Using BOADICEA alone, the estimated absolute BC risk by age 80 for an average unaffected 20-year-old female in the U.S. with an unknown FHx ranged from 23.8% for CHEK2 carriers to 79.4% for BRCA2 carriers. Integration of caPRS into BOADICEA, yielded the distribution of risk for each gene. (Table)
Gene N OR per SD (95% CI) Absolute risk by BOADICEA Median absolute risk by BOADICEA + caPRS (Range) ATM 2,037 1.46 (1.25 - 1.71) 24.9% 27.1% (0.1 - 70.5) BRCA1 5,794 1.24 (1.18 - 1.31) 76.1% 75.6% (55.6 - 87.7) BRCA2 4,018 1.40 (1.31 - 1.49) 79.4% 78.7% (45.2 - 92.1) CHEK2 372 1.88 (1.41 - 2.55) 23.8% 28.2% (0.0 - 78.4) PALB2 304 1.81 (1.37 - 2.43) 53.9% 56.3% (2.9 - 90.9)
Conclusions. The caPRS significantly modified BC risk for carriers of PVs and could help tailor guidelines for women with PVs, particularly in moderate penetrance genes. More data is needed to increase the precision and reach of risk assessment in diverse populations.
Citation Format: Placede Tshiaba, Monika Sun, Dariusz Ratman, Jeffrey N. Weitzel, Premal Shah, Matthew Rabinowitz, Akash Kumar, Kate Im. Incorporating a cross-ancestry polygenic risk score into a clinical model improved breast cancer risk prediction in women with pathogenic variants [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 769.