bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5994: Neutrophils internalized through LC3-associated phagocytosis trigger tumor ferroptotic cell death in glioblastoma
Authors: Lu Tong Y. , Yee Patricia P. , Chih Stephen Y. , Aregawi Dawit G. , Glantz Michael J. , Zacharia Brad E. , Wang Hong-Gang , Li Wei 
Published: March 2024

Abstract
Necrosis is commonly found in various solid tumors and predicts worse outcome. Chronic ischemia can initiate tumor necrosis, however, how the damaged tissue further expands is unclear. Previous studies found that neutrophils associate with necrosis and could contribute the necrosis development in glioblastoma (GBM) through transferring myeloperoxidase-containing granules into tumor cells and inducing tumor cell ferroptosis. How the neutrophilic granule transfer occurs is unknown. Here, through an unbiased small molecule screen, we found that statins can inhibit the neutrophil-induced tumor cell death through blocking the neutrophilic content transfer into tumor cells. Surprisingly, we found that neutrophils are engulfed by tumor cells before they are fragmented and release the MPO-containing contents in tumor cells. This process is through LC3-associated phagocytosis (LAP) and can be blocked by inhibiting the Vps34-UVRAG-containing PI3K complex. Inhibition of MPO or depletion of Vps34 in an orthotopic xenograft GBM mouse model showed that necrosis formation is reduced, and the tumor-bearing mice can survive longer. Therefore, this study revealed that the neutrophilic granule transfer is through LAP-mediated neutrophil internalization, which then trigger tumor ferroptotic cell death in glioblastoma. Blocking this process may improve prognosis of GBM.
Citation Format: Tong Y. Lu, Patricia P. Yee, Stephen Y. Chih, Dawit G. Aregawi, Michael J. Glantz, Brad E. Zacharia, Hong-Gang Wang, Wei Li. Neutrophils internalized through LC3-associated phagocytosis trigger tumor ferroptotic cell death in glioblastoma [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 5994.
Abstract 6051: Discovery of oral SMARCA2 degraders for the treatment of SMARCA4 mutant tumors
Authors: Clemente Jose C. , Harikrishnan Lal , Knight Steve , Samanta Debangshu , Li Zhenwu , Nagilla Rakesh , Kendsersky Nathan , Joshi Shreyas , Orth Peter , Tudor Matt , Deng Qiaolin , Aguilar-Bonavides Clemente , Behshad Elham , Sui Zhihua , Strickland Corey , Jolivette Larry J. , Mohammad Helai P. 
Published: March 2024

Abstract
The paralog enzymes SMARCA2 and SMARCA4 are mutually exclusive members within the SWI/SNF chromatin remodeling complex. This complex plays a crucial role in governing gene expression by altering the chromatin and rendering it accessible to transcription machinery. The process of chromatin remodeling by the SWI/SNF complex is dependent on ATP hydrolysis. Within the complex, either SMARCA2 or SMARCA4 serves as the sole component capable of catalyzing ATP hydrolysis and are thereby essential to the activity of the complex. SMARCA4 has been found to be mutated in various cancer types, including non-small cell lung carcinoma, colon adenocarcinoma, bladder, and endometrial cancer. In cancer cells where SMARCA4 is deleted, the functionality of the SWI/SNF complex and cell survival is dependent on the presence of SMARCA2, thereby resulting in synthetic lethality if SMARCA2 is depleted. Utilizing in vitro and in vivo model systems we have discovered potent, selective, and orally bioavailable heterobifunctional degraders targeting SMARCA2. Our lead molecules exhibit potent and selective degradation of SMARCA2 (DC50 &lt; 10 nM) with no impact on SMARCA4 (DC50 &gt; 1000 nM). Furthermore, a striking selective activity in proliferation assays was observed with SMARCA4 deleted cells exhibiting gIC50 ranging from 1 -10 nM and SMARCA4 WT cells &gt; 1000 nM. Oral administration in mice harboring human cancer cell line xenografts revealed dose-dependent and selective in vivo degradation of SMARCA2. Degradation of SMARCA2 led to significant anti-tumor activity in SMARCA4 mutant NSCLC xenograft models. Together, these data demonstrate a foundation for the development of a best-in-class degrader for the treatment of SMARCA4 deleted cancers.
Citation Format: Jose C. Clemente, Lal Harikrishnan, Steve Knight, Debangshu Samanta, Zhenwu Li, Rakesh Nagilla, Nathan Kendsersky, Shreyas Joshi, Peter Orth, Matt Tudor, Qiaolin Deng, Clemente Aguilar-Bonavides, Elham Behshad, Zhihua Sui, Corey Strickland, Larry J. Jolivette, Helai P. Mohammad. Discovery of oral SMARCA2 degraders for the treatment of SMARCA4 mutant tumors [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 6051.
Abstract 6066: An inhibitor of deubiquitinating enzyme UCHL5/USP14, VLX1570, enhances the cytotoxic effects of temsirolimus by suppressing PCNA in uuman renal cell carcinoma
Authors: Kuo Kuan-Lin , Chow Po-Ming , Hsu Chen-Hsun , Liao Shih-Ming , Chiu Yen-Ling , Dong Jun-Ren , Ke Tzu-Yao , Huang Kuo-How 
Published: March 2024

Abstract
Renal cell carcinoma (RCC) is a common type of kidney cancer. The overall 5-year survival rate is 74%, but it drops to only 8% for Stage 4 cancers. Several treatments are available for metastatic RCC, including tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors. However, these treatments have limited success. VLX1570 is an inhibitor of deubiquitylating enzymes UCHL5/USP14 that is currently in Phase I clinical trials. It has shown promise in various cancer models, but its effects on RCC have not been reported. This study investigated the impact of UCHL5/USP14 expression on tumor progression and patient survival in a clinical cohort. The results showed that VLX1570 induced apoptosis and cell cycle arrest in RCC cells, leading to reduced cell viability. Additionally, VLX1570 synergized with temsirolimus in vitro, likely by inhibiting PCNA. Moreover, the combination treatment suppressed tumor growth in vivo more effectively than either VLX1570 or temsirolimus alone. These findings suggest that UCHL5/USP14 plays a role in RCC progression and prognosis, making it a promising therapeutic target for overcoming drug resistance in this cancer.
Citation Format: Kuan-Lin Kuo, Po-Ming Chow, Chen-Hsun Hsu, Shih-Ming Liao, Yen-Ling Chiu, Jun-Ren Dong, Tzu-Yao Ke, Kuo-How Huang. An inhibitor of deubiquitinating enzyme UCHL5/USP14, VLX1570, enhances the cytotoxic effects of temsirolimus by suppressing PCNA in uuman renal cell carcinoma [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 6066.
Abstract 6067: Identification of selective CBP degraders with robust preclinical PK, PD, efficacy and safety across solid tumor indications
Authors: Sappal Darshan , Adam Ammar , Ahmad Hafiz , Adams Benjamin , Adhikari Ketaki , Austin Wesley , Bullock Breanna , Bernardo Julie Di , Dixon Thomas , Daniels Danette , Dominici Claudia , Elliot GiNell , Ethell Brian , Gervais Anais , Hossain Md Imran , Huang David , Lahr Dave , Lin Mei Yun , Mayhew David , Mizeracka Karolina , Negretti Solymar , Nguyen Tyler , Prifti Olga , Schiller Shawn , Sherbanee Brenna , Terry David , Ucisik Nihan , Wittenborn Elizabeth , Zhou Qianhe , Zimmerman Mark , La Bonte Laura 
Published: March 2024

Abstract
CREB binding protein (CBP) and E1A binding protein (EP300) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcription factor co-activators. Dysregulation of one or both proteins has been implicated in various cancer types, and functional genomic screens have revealed a bidirectional synthetic lethal relationship between these two paralogs in tumor cells. Due to the high homology between CBP and EP300, identifying selective chemical matter that selectively disrupts the activity of CBP has proven challenging. Small molecule inhibitors targeting the HAT or bromodomain of CBP/EP300 have been developed, however these agents exhibit hematopoietic toxicity resulting from dual inhibition, which limits their therapeutic window. Herein, we describe the PK, PD, and efficacy of selective, potent CBP degraders across various EP300-mutant cancer xenograft models. Our results show deep and sustained CBP degradation, leading to significant tumor growth inhibition in solid tumors. This anti-tumor activity was not associated with significant body weight loss or hematopoietic toxicity. Our CBP-selective protein degraders have the potential to be a first-in-class therapeutic option for patients with tumors harboring EP300 mutations.
Citation Format: Darshan Sappal, Ammar Adam, Hafiz Ahmad, Benjamin Adams, Ketaki Adhikari, Wesley Austin, Breanna Bullock, Julie Di Bernardo, Thomas Dixon, Danette Daniels, Claudia Dominici, GiNell Elliot, Brian Ethell, Anais Gervais, Md Imran Hossain, David Huang, Dave Lahr, Mei Yun Lin, David Mayhew, Karolina Mizeracka, Solymar Negretti, Tyler Nguyen, Olga Prifti, Shawn Schiller, Brenna Sherbanee, David Terry, Nihan Ucisik, Elizabeth Wittenborn, Qianhe Zhou, Mark Zimmerman, Laura La Bonte. Identification of selective CBP degraders with robust preclinical PK, PD, efficacy and safety across solid tumor indications [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 6067.
Abstract 6107: Survival differences by socioeconomic status in Merkel cell carcinoma: A retrospective analysis using the National Cancer Database
Authors: Chang Rachel C. , Brunsgaard Elise K. , Reid David 
Published: March 2024

Abstract
Introduction: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer whose incidence and survival outcomes demonstrate disparities based on patients’ socioeconomic status (SES). This study aims to evaluate the impact of SES on MCC diagnosis age, comorbidity burden, treatment modalities, and survival outcomes using the National Cancer Database.
Methods: We conducted a retrospective analysis of 9742 patients diagnosed with MCC from 2016 to 2020 in the United States. To assess how socioeconomic status influences outcomes, a composite score was created by adding income and education quartile assignments (1, 2, 3, 4), to create new composite SES quartiles of 2-3, 4-5, 6-7, and 8. Patients were stratified into quartiles based on their SES (lowest Q1 to highest Q4). Binomial test was performed for categorical variables and ANOVA was performed for continuous. Survival differences were examined with Cox proportional hazards models and Kaplan-Meier curves.
Results: Patients with lower SES presented with MCC at younger ages, with the average age of patients in the lowest SES Q1 being 73.8 years (95% CI 73.15-74.35) and the highest SES Q4 being 75.0 years (95% CI 74.48-75.46). Patients in SES Q1 also had higher Charson-Deyo scores, indicating more comorbidities than patients in SES Q4 (8.41% vs 5.8%, p &lt; 0.001). They were also more likely to have advanced stage 4 MCC (9.67% vs 7.79%, p &lt; 0.01) compared to patients in SES Q4. When treated with surgery, patients in SES Q1 were more likely to be treated with local tumor excision (14.39% vs 10.83%, p &lt; 0.001) whereas patients in SES Q4 were more likely treated with Mohs surgery (5.02% vs 3.56%, p &lt; 0.01). Survival probabilities for patients SES Q1 were worse at 1 year (82.99% vs 85.81%, p&lt;0.001), 3 years (61.18% vs 68.49%, p &lt; 0.001) and 5 years (45.99% vs 55.09%, p &lt; 0.001) compared to patients in SES Q4.
Conclusion: This study highlights disparities in age at diagnosis, comorbidities, treatment, and survival outcomes in MCC patients based on SES. Patients in lower SES quartiles are diagnosed younger, bear higher comorbidity burdens, and have worse rates of survival.
Citation Format: Rachel C. Chang, Elise K. Brunsgaard, David Reid. Survival differences by socioeconomic status in Merkel cell carcinoma: A retrospective analysis using the National Cancer 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 6107.
Abstract 611: Discovery of LNX231, a multi-kinase inhibitor mainly target FLT3 with robust in vivo efficacy in FLT3 mutant AML models
Authors: Zhao Lizhi , Hao Guizhou , Deng Rong , Zhang Naihua , Yao Jingchun , Zhu Anguo , Li Guangyan , Wang Enli , Li Zhenyu , Liu Zhong , Zhang Guimin 
Published: March 2024

Abstract
LNX231 is a multi-kinase inhibitor mainly target FLT3, which could both directly kill cancer cells and promote tumor immunity. LNX231 potently inhibits FLT3 activity in biochemical assay, with a 50% inhibitory concentration (IC50) of 3.5 nM, significantly inhibits FLT3-D835Y and FLT3 ITD, the values of IC50 are 20 nM and 4.4 nM. LNX231 inhibits the proliferation of FLT3 mutant AML cell lines via RAS-MARK and JAK-STAT pathway. LNX231 significantly decreases the phosphorylation of STAT5 and ERK in MV-4-11 cells at the high concentration, but has no effect on the phosphorylation of FLT3 and AKT. LNX231 significantly decreases the phosphorylation of FLT3, STAT5 and ERK in MOLM-13 cells at the high concentration, but has no effect on the phosphorylation of AKT. In FLT3 mutated AML models, LNX231 induced sustained tumor shrinkage as a single agent and was well tolerated. At the same dose, LNX231 was more potent than the FDA-approved drug Gilteritinib. In the MC38 tumor-bearing model, the efficacy of LNX231 was better than Sunitinib and Lenvatinib. LNX231 has good oral bioavailability in different species, such as mouse, rat, dog and monkey. DMPK data predicted oral QD dosing in human. It also showed excellent ADMET profile as a pre-clinical candidate. Safety tolerability studies were conducted in mice and dogs. LNX231 has low cardiotoxicity (IC50 of hERG is 25.84 µM) and 5-6 times safety window. In conclusion, we discovered LNX231 as a multi-kinase inhibitor for FLT3 mutated AML.
Citation Format: Lizhi Zhao, Guizhou Hao, Rong Deng, Naihua Zhang, Jingchun Yao, Anguo Zhu, Guangyan Li, Enli Wang, Zhenyu Li, Zhong Liu, Guimin Zhang. Discovery of LNX231, a multi-kinase inhibitor mainly target FLT3 with robust in vivo efficacy in FLT3 mutant AML 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 611.
Abstract 6159: Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease
Authors: Ahmed Md Shakir Uddin , Dorsey Tiffany , Ambs Stefan 
Published: March 2024

Abstract
Prostate cancer is a leading cause of cancer-related deaths among men in the United States and affects African American (AA) men more so than other men. We and others previously described a distinct tumor immunobiology in AA prostate cancer patients. Furthermore, we discovered a serum proteome-defined suppression of tumor immunity signature that is prevalent among these patients and associated with lethal prostate cancer. In the current study, we sought to investigate the composition of circulating peripheral blood mononuclear cells (PBMCs) in AA and European American (EA) prostate cancer patients and their association with patient group and lethal prostate cancer. We obtained high-quality RNA-sequencing data for 277336 single cells representing circulating PBMCs from 59 AA and EA men. In the analysis, being an AA patients associated with an increased abundance of exhausted T cells, higher numbers of plasma B cells and CD16+ monocytes. Gene signatures indicative of T cell exhaustion and Treg activity were generally elevated in AA PBMCs while T cell effector function features were decreased. Within the overall cell population, interferon gene signatures were robustly elevated in AA than EA patients. This gene signature pattern that we observed in AA patients also associated with lethal prostate cancer, namely the T cell exhaustion, Treg activity and elevated interferon signaling gene signatures, may contribute to immune dysfunction and immune injury; pointing to potential clinical implications. Lastly, the interferon-induced transmembrane protein (IFITM3), interferon alpha inducible protein (IFI6), cysteine rich protein-1 (CRIP1), and the RAC family small GTPase2 (RAC2) were notably upregulated in AA patient-derived immune cells. In summary, we show that circulating immune cell populations and the associated gene signatures differ between men of African and European descent. Those elevated in AA patients correlated with lethal prostate cancer.
Citation Format: Md Shakir Uddin Ahmed, Tiffany Dorsey, Stefan Ambs. Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease [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 6159.
Abstract 6262: Optimal cut-off age for AJCC staging system in Middle Eastern patients with differentiated thyroid cancer
Authors: Parvathareddy Sandeep K. , Siraj Abdul K. , Annaiyappanaidu Padmanaban , Ahmed Saeeda O. , Siraj Nabil , Qadri Zeeshan , Azam Saud , Al-Kuraya Khawla S. 
Published: March 2024

Abstract
Background: Differentiated Thyroid Cancer (DTC) has an indolent nature and generally has favorable prognosis. AJCC TNM classification is the most adopted system to evaluate the biological behavior of DTC. Age cut-off of 55 years has been included in the eighth edition of TNM staging system since it led to better prediction of disease specific survival (DSS) of patients with DTC. However, optimal age cut-off in DTC patients from Middle Eastern ethnicity has not been fully explored. We evaluated the optimal age cut-off for the TNM staging system to predict DSS in Middle Eastern patients with DTC.
Methods: We retrospectively analyzed a large cohort of 1721 adult DTC patients who underwent surgery between 1990 to 2018. The optimal age cut-off value was determined using several age cut-offs (between 20 and 85 years) to assess DSS. Harrel’s C-Index, Akaike information criterion (AIC) and Bayesian Information Criterion (BIC) were used to assess the statistical model performance of the TNM staging system (eighth edition), with different age cut-offs for prediction of DSS. The proportion of variation explained (PVE) was also calculated to compare predictability of DSS in patients with DTC.
Results: The median age of patients at diagnosis was 39.9 years (IQR 31.0 - 51.7 years) and 75.5% (1299/1721) were female. Median follow up was 9.3 years and 10 years DSS was 97.1%. For DTC overall, an age cut-off of 50 years had the best statistical model performance. On receiver operating characteristic curve analysis, the optimal age cut-off for prediction of DSS was 50.5 years (area under the curve = 0.872, p &lt; 0.0001).
Conclusion: In this large cohort of Middle Eastern DTC patients, an age cut-off of 50 years was more appropriate for TNM staging to achieve better predictability for DSS. Therefore, implementation of different age cut-off for DTC in Middle Eastern patients could improve the predictive value for TNM staging system, and allow for better therapeutic and surveillance approach for these patients.
Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Saeeda O. Ahmed, Nabil Siraj, Zeeshan Qadri, Saud Azam, Khawla S. Al-Kuraya. Optimal cut-off age for AJCC staging system in Middle Eastern patients with differentiated thyroid 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 6262.
Abstract 6269: Assessment of new generation endocrine therapies for the treatment of breast to bone metastasis
Authors: Zboril Emily Kate , Altman Julia E. , Hairr Nicole S. , Myrick Rachel K. , Olex Amy L. , Dozmorov Mikhail G. , Harrell J. Chuck 
Published: March 2024

Abstract
Estrogen receptor (ER) signaling is the main driver of tumorigenesis in ER+ breast cancers by inducing proliferation and survival through genomic and non-genomic means, therefore inhibition of ER signaling has been a mainstay of treatment for decades. Roughly 30 percent of patients will develop treatment-refractory recurrence or metastasis within their lifetime, which may include metastasis to the bone, lung, liver, and brain. Although advances in treatment approaches have prolonged average progression free survival, metastatic breast cancer remains incurable. A new endocrine therapy, Elacestrant, has been approved by the FDA for the treatment of ER+, ESR1-mutant advanced or metastatic breast cancer. The mechanism of action of Elacestrant involves both degradation of ER and modulation of ER signaling through non-degradative means. The central hypothesis of this study was that Elacestrant may prolong progression free survival in animal models of breast to bone metastasis, because modulation of ER in the bone would decrease the incidence of osteoporosis which is induced by other endocrine therapies. However, we discovered that prolonged Elacestrant treatment induces destruction of the trabecular bone structure and increased adipocyte mass within the bone, consistent with an osteoporotic phenotype. Ongoing studies will seek to determine if other endocrine therapies will provide better protection to the bone architecture while reducing metastatic burden in animal models. Additionally, we will evaluate organotropic efficacy of new endocrine therapies on multi-organ metastasis to determine if utility is contingent upon the metastatic site.
Citation Format: Emily Kate Zboril, Julia E. Altman, Nicole S. Hairr, Rachel K. Myrick, Amy L. Olex, Mikhail G. Dozmorov, J. Chuck Harrell. Assessment of new generation endocrine therapies for the treatment of breast to bone metastasis [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 6269.