bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2097: ABT co-dose accelerated target validation with a fit-for-purpose HPK1 inhibitor tool
Authors: Methot Joey L. , Chen Joanna L. , Yu Elsie , Otte Ryan D. , Xu Haiyan , Xu Zangwei , Lacey Brian , Laskey Jason , Mcleod Robbie , Smith Dustin , Pasternak Alexander 
Published: March 2024

Abstract
Target validation can be challenging when mouse efficacy studies require achieving a high therapeutic exposure of a tool compound, ideally with a low peak-to-trough (P/T) ratio to avoid Cmax-induced toxicity. Herein, we describe the daily co-administration of the CYP inhibitor aminobenzotriazole (ABT) as a well-tolerated PK enhancer for medium-term efficacy studies in mice, enabling faster decision-making in the early space with imperfect tools. Genetic studies in mice have suggested that HPK1 inhibition would lead to enhanced effector T-cell function, decreased tumor growth and enhanced αPD-L1 efficacy. However, it remains unknown whether immune activation by pharmacological inhibition of HPK1 will recapitulate the genetic deletions. We developed a fit for purpose tool compound with picomolar HPK1 potency, excellent kinome selectivity (98% &gt;100x, ATP-Km corrected), dose-dependent inhibition of pSLP76, sustained IL2 elevation in PBMCs, and IL6/TNFa elevation in dendritic cells. The mouse PK for this tool was inadequate, having a low exposure (AUC 16 uM-hr at 100 mg/kg po) and a high P/T ratio of 13 that could lead to an erosion of kinome selectivity in vivo; complicating efficacy interpretation and limiting overall tolerability. However, when co-dosed with ABT (50 mg/kg po 2 h prior to the HPK1 inhibitor), improved exposure of our tool was achieved (AUC 63 uM-hr at 100 mg/kg po), 90% inhibition of pSLP76 was maintained at C(trough), and the P/T ratio was reduced to 3 to avoid Cmax-induced toxicity. The inhibitor was well-tolerated co-dosed with ABT for three weeks in mice, enabling studies sooner to probe HPK1 pharmacological inhibition in cancer immunotherapy as a monotherapy as well as in combination with a mouse anti-PD-1 antibody.
Citation Format: Joey L. Methot, Joanna L. Chen, Elsie Yu, Ryan D. Otte, Haiyan Xu, Zangwei Xu, Brian Lacey, Jason Laskey, Robbie Mcleod, Dustin Smith, Alexander Pasternak. ABT co-dose accelerated target validation with a fit-for-purpose HPK1 inhibitor tool [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 2097.
Abstract 210: Carcinogenic influence of e-cigarette aerosols on breast and lung cancer models
Authors: Begum Rizwana , Thota Shilpa , Chintala Naveen , Sapkota Biplov , Pandit Abhishek , Francis Joseph 
Published: March 2024

Abstract
Background and Purpose: With the rising popularity of E-cigarettes among the youth, there is an urgent need to understand their long-term health implications, particularly the potential for carcinogenesis. Although tobacco smoking is established as a major cancer risk factor, the carcinogenic potential of E-cigarettes remains underexplored. Given that metastatic cancer accounts for most cancer-related deaths in the United States, elucidating the biological impacts of E-cigarette aerosols on cancer progression is critical for developing effective interventions. This study aims to address this critical gap by exploring the effects of E-cigarette aerosols on cellular models pertinent to breast and lung cancer.
Methods: Mouse breast epithelial cells (HC11), triple-negative breast cancer cells (4T1), and human lung adenocarcinoma cells (Calu-3) were exposed to E-cigarette aerosol at the air-liquid interface for one hour, followed by a 24-hour recovery period.
Results: Our study revealed that E-cigarette aerosols with mint flavor induce epithelial-to-mesenchymal transition (EMT) in both normal mammary epithelial and breast cancer cells. Furthermore, we also observed activation of the TGF pathway and an increased expression of stemness-related markers (OCT4, SOX2, NANOG, KLF4, and c-MYC) in 4T1 cells exposed to mint and menthol-flavored E-cigarette aerosols in both 2D and 3D cell culture environments. Microscopic examination at a 10X magnification level revealed that 4T1 and Calu-3 cells exposed to menthol-flavored E-cigarette aerosols exhibited signs of cellular disassociation and detachment whereas the control cells maintained discoidal aggregate morphology.
Conclusion: The data presented here illuminate a potential link between E-cigarette use and carcinogenic processes, challenging the notion of E-cigarettes as a safe smoking alternative. This research is of paramount importance to cancer research as it unveils possible new avenues for tumor progression, emphasizing the necessity for a critical evaluation of E-cigarette products.
Citation Format: Rizwana Begum, Shilpa Thota, Naveen Chintala, Biplov Sapkota, Abhishek Pandit, Joseph Francis. Carcinogenic influence of e-cigarette aerosols on breast and lung cancer 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 210.
Abstract 2102: Understanding the mechanism of action of rigosertib in recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma through single cellanalysis
Authors: South Andrew P. , Han Suhao , Fortina Paolo 
Published: March 2024

Abstract
The allosteric inhibitor rigosertib (an experimental therapeutic) was previously identified as an effective inducer of G2M arrest and apoptosis in squamous cell carcinoma (SCC) keratinocytes isolated from patients with the rare genetic disease recessive dystrophic epidermolysis bullosa (RDEB), both in vitro and in vivo. Early clinical trial data treating RDEB-associated SCC with rigosertib has shown remarkable efficacy in a sub-set of patients and understanding the mechanism of action of rigosertib in this lethal cancer would provide rationale for patient stratification. Multiple mechanisms of action were previously attributed to rigosertib, including polo-like kinase-1 (PLK1), PI3-kinase, activated RAS and microtubule polymerization inhibition. Our published data comparing PLK1 siRNA with PI3-Kinase inhibitors, MAPK inhibitors and microtubule disruption favored PLK1 as a mechanism of action without definitive conclusion. We therefore sought to determine the mechanism of action using transcriptomic profiling. Flow cytometry experiments identified three main categories of time to increase G2M in nine separate RDEB SCC keratinocyte populations in culture ranging from 1 to 6 hours after exposure to 1uM rigosertib. Bulk-RNA sequencing of representative populations from time to G2M groupings failed to identify consistent transcriptional change after exposure to rigosertib. However, single cell sequencing was able to identify increases in sub-populations of cells associated with G2M as well as transient emergence of unique populations that were specific to individual patient populations after exposure to rigosertib in culture. Of note a transient population of RDEB SCC keratinocytes only present after 1 hour of exposure to rigosertib was characterized by increased expression of the potassium regulator KCNRG which has previously been associated with apoptosis in chronic lymphocytic leukemia. Ongoing work is determining the role this gene may play in the mechanism of apoptosis induction in RDEB SCC keratinocytes after exposure to rigosertib.
Citation Format: Andrew P. South, Suhao Han, Paolo Fortina. Understanding the mechanism of action of rigosertib in recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma through single cellanalysis [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 2102.
Abstract 2157: Evaluating cervical and lung cancer risk among Hispanic and Non-Hispanic Black women in three urban Texas counties
Authors: Chu Megan L. , Jayesh Irene E. 
Published: March 2024

Abstract
This study examines if there is a statistically significant difference in the risk of being diagnosed with cervical and lung cancer between Hispanic and Non-Hispanic Black (NHB) women in Tarrant, Dallas, and Bexar county.
Pulling from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program, 2000-2020 trends in cancer diagnosis were measured by age-adjusted annual percent change (APC). Data was sorted by county and race/ethnicity and statistically insignificant measures were removed. APC measures were ranked relative to counties across Texas and the US. APC measures with 95% confidence intervals for Hispanic and NHB women in Tarrant, Dallas, and Bexar county were compared for a significant difference. Results from a previous study indicated that the slowest decreases in cervical cancer rates are found among Hispanic and African-American women in Tarrant and Dallas County. We built upon this study to assess if there was a statistically significant difference in the risk of developing cervical and lung cancer between these two groups. In Tarrant County (TC), the cervical cancer APC of Hispanic women was -1.8 [-3.4,0.1] and NHB women was -1.2 [-3.7, 1.3]. In Dallas County, the cervical cancer APC of Hispanic women was -2.1 [-3.4, -0.8] and NHB women was -1.8 [-3, -0.5]. This indicates that for both cities, Hispanic women saw a greater decrease in the APC in cervical cancer rates than NHB women.
In Tarrant County (TC), the lung cancer APC of Hispanic women was -2.7 [-4.5, -0.9] and NHB women was -2.1[-3.1, -1.1]. In Dallas County, the lung cancer APC of Hispanic women was -2.3 [-4.2, -0.4] and NHB women was -1.8 [-2.5, -1]. This indicates that for both cities, while Hispanic women saw a greater decrease in the APC in lung cancer rates than NHB women, the decrease is not statistically significant due to the overlap of the confidence intervals. Even though the confidence interval (CI) overlaps indicates insignificance, the APC can still provide valuable information regarding diagnostic trends seen in urban cities. The results showed that there is no significant difference between these two groups, suggesting that other county-level factors may play a role in diagnostic disparities seen between these two racial groups.
Citation Format: Megan L. Chu, Irene E. Jayesh. Evaluating cervical and lung cancer risk among Hispanic and Non-Hispanic Black women in three urban Texas counties [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 2157.
Abstract 22: Development and characterization of human tumor specific cytotoxic lymphocytes for preclinical drug development
Authors: Rohleff Ina , Gröne Lea , Lashuk Kanstantsin , Schueler Julia B. 
Published: March 2024

Abstract
Heterogeneity within a tumor allows it to better adapt to changing conditions and can have therefore a negative impact on a patient’s prognosis, response to treatment and overall health. Breast cancer is a highly heterogeneous disease caused by distinct genetic mutations in mammary epithelial cells, resulting in significantly different forms of the disease and a need for highly personalized treatment schemes for patients. Hence, it is important to develop and improve (immuno)therapies for breast cancer patients. Adoptive T-cell therapy with autologous CD8+ cytotoxic T cell lymphocytes (CTL) is a promising method that has already shown promising effects in melanoma patients. Unfortunately, there is almost no information about the use in breast cancer patients. We developed an in vitro protocol to generate tumor-specific CTLs by priming on HER2+ breast cancer cell lines JIMT-1 and SKBR-3. Subsequently, these primed CTLs were tested in 2D and 3D immune cell killing assays in a life cell imaging device in combination with an endpoint viability assay. The activity was compared with unspecific CD8+T cells activated by phytohemagglutinin (PHA) or αCD2/αCD3/αCD28, HER2-peptide specific T cells and HER2-CAR T cells serving as a positive control. We investigated the feasibility to freeze CTLs for use in subsequent studies and validated the relevance of HER2 as the main druggable target in the tumor lines using an siRNA approach. The CTLs were most effective on JIMT-1 in a 3D setting, whereas the SKBR-3 CTLs displayed similar activity in 2D and in 3D. The respective CTLs were tumor line specific, as SKBR-3 CTLs did not kill efficiently the JIMT-1 cells and vice versa. The same CTLs displayed the same efficacy pattern after thawing but less pronounced. Thus, within one experimental set-up it is recommended to use either one. The Her2 knockdown in the target cells reduced the killing activity of the CTLs slightly. However, this effect was not statistically significant proving the importance of CTLs as treatment option as well as neoantigens as targets in drug development. In summary, the CTLs proved to capture the respective tumor heterogeneity showing high killing rates in both SK-BR3 and JIMT-1 being more active than HER2-peptide specific T cells. The availability of CTLs in a preclinical setting facilitates screening approaches for combinational studies. Beyond that they can serve as starting material to develop cancer vaccines and identify highly immunogenic neoantigens.
Citation Format: Ina Rohleff, Lea Gröne, Kanstantsin Lashuk, Julia B. Schueler. Development and characterization of human tumor specific cytotoxic lymphocytes for preclinical drug development [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 22.
Abstract 2243: A multi-ethnic population-based pilot study of multiple myeloma disparities
Authors: Rolon Angelica M. , Vang April P. , Quino J. Elizabeth , Estrada Ana , Stewart Eric , Cress Rosemary D. , Carvajal-Carmona Luis , Arana Alexa Morales 
Published: March 2024

Abstract
To understand multiple myeloma (MM) disparities we established the Precision MEDicine, EqUity and Disparities Research in MultipLe MyeLomA (MEDULLA) study, a population-based study in California. Our study contacted, via the Cancer Registry of Greater California (CRGC), 100 adult MM patients from four racial/ethnic groups: Non-Hispanic Black (NHB), Non-Hispanic White (NHW), Latinos, and Asians. Data collection included variables reported to the CRGC, a self-administered survey, and biospecimen saliva collection. The survey focused on demographics, risk factors, cancer treatment, family history, quality of life, and social determinants of health. Of the 400 MM patients, we had 95 patients who responded to the survey, giving a response rate of 24%. 44% of those who responded were NHW, 21% NHB, 19% Latinos, and 16% Asians. Those that provided a response tend to be living in a census tract location with lower proportions of poverty (p=0.0004), higher proportion of adults ages 25 years or over with a college degree (p=0.0011), higher median household income (p=0.0048), lower proportion of adults ages 25 years or over without a high school diploma (p&lt;0.0001), and a lower proportion of individuals ages 16 or over who are unemployed (p&lt;0.006). All respondents also have a lower comorbidity count and expressed being in good health. For minorities, we identified a trend where a higher response rate is seen if they live in an area where median household income is higher (p=0.0108). For every 1% increase in poverty rates, NHW living in such neighborhoods were 3% less likely to respond to the survey (p=0.04). For every 10% increase in the proportion of individuals having a college degree, response rate increased by 1.17 for minorities in that neighborhood (p=0.07). Minorities living in neighborhoods with high proportions of adults without a high school diploma and high unemployment rates are less likely to respond (p=0.02 and p=0.047, respectively). In conclusion, we found significantly lower participation rates among minority groups, with socio-economic factors affecting response rates. Our findings, therefore, suggest that future studies must develop improved community-focused and culturally tailored strategies to engage and meaningfully understand MM etiology and survivorship in such populations.
Citation Format: Angelica M. Rolon, April P. Vang, J. Elizabeth Quino, Ana Estrada, Eric Stewart, Rosemary D. Cress, Luis Carvajal-Carmona, Alexa Morales Arana. A multi-ethnic population-based pilot study of multiple myeloma disparities [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 2243.
Abstract 226: Effect of MCL-1 inhibitor on organoids derived from cholangiocarcinoma patients with IDH1 mutation
Authors: Suzuki Shiho , Matsuzaki Juntaro , Muramatsu Toshihide , Kanai Yae , Saito Yoshimasa 
Published: March 2024

Abstract
Cholangiocarcinomas are highly aggressive malignancies with a poor prognosis. The global incidence of cholangiocarcinoma patients appears to be on the rise. While surgical resection remains the curative option for cholangiocarcinoma patients, the majority of cases are diagnosed at an advanced stage, resulting in poor outcomes. Patients with inoperable cholangiocarcinomas typically undergo chemotherapy regimens, including Gemcitabine, but their efficacy is limited, leading to low 5-year survival rates. Recent advancements in organoid culture technology allow for the in vitro replication of tissue structures by culturing tissue stem cells in three dimensions, offering great promise for personalized medicine. Utilizing patient-derived organoids has proven effective in predicting the outcomes of therapeutic drugs. We have successfully established organoids using cancer tissue derived from cholangiocarcinoma patients, and stably culturing and maintaining them, promoting their application to personalized medicine (Saito Y et al. Cell Rep. 27, 1265, 2019, Saito Y et al. Cancer Cell 40, 226, 2022). IDH1 mutations have been identified in approximately 15% of intrahepatic cholangiocarcinomas and are known to convert α-ketoglutarate (α-KG) in the TCA cycle to produce 2-hydroxyglutarate (2-HG), which is observed in gliomas and acute myeloid leukemia. 2-HG acts as an antagonist to α-KG-dependent dioxygenases, promoting cancer development. This study aims to develop a novel treatment for cholangiocarcinomas with IDH1 mutations. Metabolomic analysis of patient-derived cholangiocarcinoma organoids revealed 2-HG accumulation and reduced ATP production in IDH1-mutated cholangiocarcinoma organoids compared to IDH1 wild-type cholangiocarcinoma organoids. This may suppress the protein synthesis of MCL-1 and mTOR signaling through the activation of AMPK kinase, suggesting that further inhibition of MCL-1 could be lethal in IDH1-mutated cholangiocarcinoma organoids. Indeed, exposure to S63845, an MCL-1 inhibitor, significantly inhibited cell proliferation in IDH1-mutated cholangiocarcinoma organoids, unlike in IDH1 wild-type cholangiocarcinoma organoids. Furthermore, the combination of MCL-1 inhibitor and BCL-XL inhibitor demonstrated a synergistic and potent growth inhibitory effect on cholangiocarcinoma organoids. These findings indicate that the MCL-1 inhibitor holds promise as a new therapeutic agent for cholangiocarcinoma patients with IDH1 mutations.
Citation Format: Shiho Suzuki, Juntaro Matsuzaki, Toshihide Muramatsu, Yae Kanai, Yoshimasa Saito. Effect of MCL-1 inhibitor on organoids derived from cholangiocarcinoma patients with IDH1 mutation [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 226.
Abstract 2285: Mass spectrometry-based proteomics profiling reveals differential proteome composition in tumor and normal tissues, with implications for normalization
Authors: Zheng Ying , Olita Lindsay , Nivens McIver , Chiang Abby , Ahuja Shreya , Glover Matthew , Bullen John , Hurt Elaine , Zhong Wenyan 
Published: March 2024

Abstract
The composition of the proteome varies significantly across different tissues and disease states creating a challenge of how best to compare expression levels of each protein across these tissue types. Traditionally, a median approach to normalization has been used, but this could obscure meaningful biological differences between tissues. Here, we present a quantitative proteomic study analyzing proteome composition across tumor and normal tissues in order to assess normalization methods. Human proteomes covering 7 cancer indications (244 samples) and 12 normal tissue organs (370 samples) were analyzed by data-independent acquisition mass spectrometry. On average, over 8,000 proteins were quantified across the study cohorts. Comparison of proteomes revealed an average of 11.4% higher protein identification in tumors compared to matched normal tissues (6 tumor types all p&lt;0.003). Tissue origin strongly influenced proteome composition, most notably in bone marrow, while cancer tissues displayed less proteomic composition variation than normal tissues. Compared to global median normalization, riBAQ and tissue-specific quantile normalization reduced technical variances while maintaining biological differences between tissue types. By revealing tissue-specific proteome signatures as well as systemic proteomic alterations in tumors, this study lays the groundwork for appropriate comparative approaches accounting for tissue origins, and establishes a framework for discovery of tissue-specific biomarkers, which may facilitate the development of novel diagnostic and prognostic tests, and guide therapeutic interventions for cancer.
Citation Format: Ying Zheng, Lindsay Olita, McIver Nivens, Abby Chiang, Shreya Ahuja, Matthew Glover, John Bullen, Elaine Hurt, Wenyan Zhong. Mass spectrometry-based proteomics profiling reveals differential proteome composition in tumor and normal tissues, with implications for normalization [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 2285.