tbuckley/cabot-search huggingface dataset:
Abstract 1493: Secretory function of neuroendocrine-like prostate cancer cell enhances therapy resistance and metastatic potential of adjacent adenocarcinoma
Authors: Juhi Mishra, Sanika Bodas, Sreyashi Bhattacharya, Dipanwita Das, Sheeraz UnNazir, Samikshan Dutta, Kaustubh Datta
Journal: Cancer Research (2024)

Abstract Background: Castration-resistant prostate cancer (CRPC) is advanced non curable disease associated with poor prognosis and survival n patients. Androgen receptor pathway inhibitors (ARSIs) are used to treat advanced prostate cancer, but in majority of patients it progresses by developing resistance to AR-directed therapies and is referred to as CRPC. Adenocarcinoma cells in CRPC tumor often undergoes lineage switch and become neuroendocrine-like cancer cells (NEPC) with small-cell histology, characterized by the loss of Tp53 and Rb1 genes. NEPC cells are frequently present as scattered foci along with prostatic adenocarcinomas and are secretory in nature. Objective: The primary objective is to determine how these NEPC cells influence surrounding adenocarcinoma and aids in disease progression. Methods: We performed Mass spec and cytokine array experiments from NEPC conditioned media to determine its secretory phenotype. We orthotopically implanted NEPC and adeno cells in the nude mice and performed colony formation assay on flow sorted adeno cells from the tumor. We also checked the effect of NEPC on the adeno cells and TME components. Results: Our analysis of the RNA-seq data from SU2C-PCF cohort and NE-like cells revealed that functions related to secretion were significantly enriched in NE-like PCa. NE-like cells gain the ability to secrete neuropeptides, growth factors, and cytokines to establish cell-cell communication. This secretory function is tightly regulated by the Neuropilin2 (NRP2) axis. We studied for the effect of NE-like cells on the adenocarcinoma cells in the mice tumor model and found that the presence of NE-like cells facilitated the adenocarcinoma cells to acquire aggressive characteristics. This could be due to both direct and/or through the modulation of the tumor microenvironment (TME). The direct effect could be by enhancing the therapy resistant ability of the surrounding adenocarcinoma, and the indirect effect is through the tumor microenvironment especially through neurons and macrophages that promote metastatic potential. Conclusions: Overall, our results prove that NE-like cancer cells influence the adjacent adenocarcinoma cells directly by making them resistant to treatment and indirectly make them more metastatic by utilizing macrophage-neuron axis. Citation Format: Juhi Mishra, Sanika Bodas, Sreyashi Bhattacharya, Dipanwita Das, Sheeraz UnNazir, Samikshan Dutta, Kaustubh Datta. Secretory function of neuroendocrine-like prostate cancer cell enhances therapy resistance and metastatic potential of adjacent adenocarcinoma [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 1493.
Abstract 294: The HOXB7 protein promotes breast cancer cell growth through activation of the CCL5/CCR5 pathway in the crosstalk of adipocyte
Authors: Ahone Gina Akume, Kideok Jin
Journal: Cancer Research (2024)

Abstract Homeobox genes are regulatory genes that encode nuclear proteins acting as transcription factors during normal development and differentiation. One such gene, HOXB7, plays a role in various developmental processes, including hematopoietic differentiation, lymphoid development, and mammary gland development. However, the role of HOX genes in breast cancer development remains largely unexplored. Our previous studies revealed that HOXB7 expression was significantly elevated in primary cancer and distant metastasis. HOXB7 overexpression promoted cell proliferation in SKBR3 breast cancer cells, leading to robustly vascularized xenografts in immunodeficient mice. Furthermore, HOXB7 enhanced tumor growth through TGF beta signaling and recruitment of macrophages, indicating the role of HOXB7 in the crosstalk of stromal components. We found evidence that HOXB7 overexpression in ER+ breast cancer cells promotes tumor cell growth through increased expression and signaling of CCL5/CCR5 in crosstalk with adipocytes. By screening secreted factors in adipocytes induced by TCM of MCF-7-HOXB7 cells, it was also found that CCL5 is highly expressed in HOXB7-overexpressing MCF-7 cells. The CCR5 inhibitor, maraviroc, sensitized MCF-7-HOXB7 cells compared to control cells. These findings suggest that blocking the interaction between CCL5 and CCR5 signaling significantly inhibits ER+ breast cancer with HOXB7 overexpression. We aim to further investigate if HOXB7 overexpression in ER+ breast cancer cells promotes tumor cell growth through increased expression and signaling of CCL5/CCR5 in crosstalk with adipocytes and the role of CCL5 in breast cancer cell growth and migration. Citation Format: Ahone Gina Akume, Kideok Jin. The HOXB7 protein promotes breast cancer cell growth through activation of the CCL5/CCR5 pathway in the crosstalk of adipocyte [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 294.
Abstract 1886: BRY812, an anti-LIV-1 antibody drug conjugate with novel conjugation method for cancer therapeutics
Authors: Xiaobei Zhao, Jie Zhu, Yaqiong Zhou, Jing Li, Lei Nie, Haibin Wang, Gang Chen
Journal: Cancer Research (2024)

Abstract LIV-1, also known as SLC39A6 or ZIP6, belongs to the zinc transporter family and was initially identified as an estrogen-inducible gene in breast cancer. Immunohistochemical (IHC) analysis have revealed escalated LIV-1 expression in estrogen receptor-positive (ER+), hormone-treated tumors (both primary and metastatic sites) as well as ER-/PR-/Her2- (triple-negative) breast cancers. Notably, healthy human tissues exhibit limited LIV-1 expression, primarily in hormone regulated organs (prostate, uterus, and breast). The escalated expression of LIV-1 in breast and prostate cancer, as well as melanoma and other tumors, positions LIV-1 as an excellent target for ADC therapeutics. BRY812 is a monomethyl auristatin E (MMAE)-conjugated humanized IgG1 ADC against LIV-1. With Bioray’s irreversible conjugation method CysLinkTM, BRY812 enables superior in vivo stability and eliminates off-target payload migration. The PK studies in rat and monkey demonstrated that the free MMAE released from ADC is 1 to 2 logs lower compared with approved ADCs prepared by the standard conjugation method. BRY812 is well tolerated in cynomolgus monkeys with repeated doses. With best-in-class anti-tumor efficacy in various models, BRY812 demonstrated a wider therapeutic window for cancer treatment. BRY812 is currently in Phase Ia dose escalation stage clinical trial to explore the maximum tolerate dosage (MTD) from 0.25 to 3.6 mg/kg Q3W in patients with advanced malignancies. Citation Format: Xiaobei Zhao, Jie Zhu, Yaqiong Zhou, Jing Li, Lei Nie, Haibin Wang, Gang Chen. BRY812, an anti-LIV-1 antibody drug conjugate with novel conjugation method for cancer therapeutics [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 1886.
Abstract 1313: Racial disparities in colorectal cancer incidence across US ethnic groups: A comprehensive analysis
Authors: Anathbandhu Chaudhuri, Rosianna Gray
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) ranks as the third most prevalent global cancer and the fourth leading cause of cancer-related deaths. Racial disparities in CRC within the United States pose a significant public health concern, affecting incidence, mortality rates, and screening rates. This study investigates the impact of racial disparities on CRC incidence across various US states, utilizing CRC data from the National Cancer Institute (NCI) at the Centers for Disease Control and Prevention (CDC). Analysis with GraphPad Prism 5 software and Student's t-test reveals a consistent trend of higher CRC incidence in males compared to females, irrespective of ethnicity. Notably, the Black and American Indian ethnic groups demonstrate the highest CRC incidences among all races, especially in individuals aged 65 and above. Certain states, including Iowa and Mississippi for Black populations, and Alaska, Minnesota, Montana, Oklahoma, and South Dakota for American Indian populations, exhibit significantly elevated CRC incidences compared to the national average. County-specific analysis in Alabama reveals varying CRC incidence rates across ethnic groups, with higher rates in specific counties, such as Clarke County for Black males. Limited reports for American Indian, Asian Pacific, and Hispanic ethnic groups indicate potential disparities in access to testing, awareness, and funding for CRC detection and prevention. This study concludes that Black and American Indian males and females experience a higher incidence of colorectal cancer, possibly influenced by genetic factors or other variables contributing to CRC development. The observed disparities are multifaceted, arising from a combination of social, economic, and healthcare system factors. Addressing these complexities is crucial for mitigating CRC disparities and promoting equitable healthcare access and outcomes. Additional research, including molecular screening studies, is essential to substantiate disparities in cancer-related health and enhance public health and cancer awareness within the community. Key Words: Cancer, Colorectal Cancer, Health Care, Racial Disparities Citation Format: Anathbandhu Chaudhuri, Rosianna Gray. Racial disparities in colorectal cancer incidence across US ethnic groups: A comprehensive analysis [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 1313.
Abstract 2929: Multiplexed somatic genome editing to model and investigate advanced colorectal cancer
Authors: Manuel Mastel, Rene Jackstadt, Jasmin Meier, Gabriele Diamante
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is among the deadliest cancers worldwide, with advanced CRC being the leading cause of death. For the development of novel therapy options, it is crucial to investigate mechanisms of advanced CRC in a bona fide way. However, little is known about the impact of distinct genomic alterations on cancer progression. The assessment of the function and role of the putative drivers in tumor progression via sequencing data remains challenging, due to the complexity and possible combinations of the candidates. Hence, genetically engineered mouse models (GEMMs) represent the mainstay for the investigation of the role of oncogenes and tumor suppressor genes in cancer progression. However, particularly in CRC, they are limited by imprecise modeling of cancer-associated changes, challenging scalability, and development of tumors in anatomically incorrect places. To tackle these issues, we developed SOmatic CRISPR-mediated genome Alterations of Tumor suppressors with Exploratory single cell Sequencing (SOCRATES) to analyze advanced CRC. We multiplexed CRISPR-Cas systems, packaged them into lentiviral particles, and delivered them to enterocytes via colonoscopy-guided submucosal injection. With this innovative approach, SOCRATES enables rapid and direct in vivo genome engineering for the modeling of advanced CRC with distinct mutational patterns and the investigation of the cancer cell states and tumor microenvironment (TME) upon editing the genes of interest. Similar to the Greek philosopher Socrates, who established a form of argumentized dialogue between individuals, SOCRATES facilitates the understanding of previously undiscovered communication between cancer cells and TME. We analyzed the influence of the most recurrent tumor suppressor mutations (Fbxw7, Ptprt, Arid1a, Atrx, Atm, Smad4, Pten) on the cancer cell state and TME in advanced CRC. Further, we created a TS-TME interaction atlas and revealed novel mechanistic insights into how the TS mutations rewire cell states and cell-cell communications. With this generated knowledge, SOCRATES will contribute to our understanding of complex tumor ecosystems and foster the improvement of diagnostic and therapeutic approaches. Citation Format: Manuel Mastel, Rene Jackstadt, Jasmin Meier, Gabriele Diamante. Multiplexed somatic genome editing to model and investigate advanced colorectal 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 2929.
Abstract 2503: The role of APOBEC in early stage-<i>EGFR</i> mutant non-small cell lung cancer
Authors: Hyun Ae Jung, Jinyeong Lim, Yoon-La Choi, Sehhoon Park, Jong-Mu Sun, Myung-Ju Ahn, Se-Hoon Lee
Journal: Cancer Research (2024)

Abstract Background: The APOBEC family of zinc-coordinating enzymes converts cytosines to uracils in single-strand DNA. APOBEC plays a crucial role in the mutation process of non-small cell lung cancer (NSCLC) and is essential for both adaptive and innate immune responses. This study aims to evaluate the role of the APOBEC mutation signature in early-stage non-small cell lung cancer (NSCLC). Methods: We conducted whole-exome sequencing and whole-transcriptome sequencing using fresh tissue or formalin-fixed paraffin-embedded samples from 100 patients diagnosed with pathologic stage II-IIIA non-squamous NSCLC, all of whom underwent complete resection between January 2014 and December 2020 at Samsung Medical Center. This study aimed to assess the impact of APOBEC enrichment on disease-free survival (DFS), progression-free survival (PFS) of EGFR-TKI, and overall survival following recurrence. Results: Median follow-up duration was 58.2 months (range, 11.3-141.1). Of the patients, 74% were never-smokers, and 52% had stage III disease. Among the 100 patients, 18 (18%) exhibited APOBEC enrichment (≥ 2). The median RFS was 25.2 months (95% CI, 17.3-33.2). Notably, APOBEC enrichment did not show a significant association with DFS (P=0.14). Among the 76 patients who experienced radiological recurrence, 69 received EGFR-TKI as first-line treatment. The median PFS for EGFR-TKI was 22.9 months (95% CI, 13.0-32.8). However, within this group, patients with APOBEC enrichment showed a shorter PFS compared to those without APOBEC enrichment (8.1 months vs. 24.6 months, P=0.014). In multivariate analysis, poor PFS of EGFR-TKI was associated with the type of EGFR mutation (L858R vs. exon 19 deletion, HR=1.9, P=0.04), TP53 mutation (mutation vs. wild type, HR=2.1, P=0.03), and APOBEC enrichment (≥ 2 vs. &amp;lt;2, HR=2.2, P=0.02). Overall survival from the starting EGFR-TKI was 61.1 months and 21.7 months for patients with APOBEC enrichment or patients without APOBEC enrichment, respectively (P=0.027). Conclusions: APOBEC mutation signature may be presented at initial diagnosis of early-stage EGFR mutant NSCLC and it was associated with poor PFS of EGFR-TKI and overall survival. Citation Format: Hyun Ae Jung, Jinyeong Lim, Yoon-La Choi, Sehhoon Park, Jong-Mu Sun, Myung-Ju Ahn, Se-Hoon Lee. The role of APOBEC in early stage-EGFR mutant non-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 2503.
Abstract 2153: The impact of socioeconomic and racial segregation on cancer stage at diagnosis, treatment and mortality among patients with small cell lung cancer
Authors: Bayu B. Bekele, Min Lian, Ying Liu
Journal: Cancer Research (2024)

Abstract Background: Although studies have revealed the adverse impact of residential segregation on early detection, treatment, and survival of non-small cell lung cancer―a predominant type of lung cancers, it remains unknown regarding the role of residential segregation in treatment and outcomes of small cell lung cancer (SCLC)―a rare type of lung cancer characterized by rapid growth and poor prognosis. Therefore, we examined the associations of racialized socioeconomic segregation with risks of extensive-stage diagnosis, non-adherence to guideline-recommended treatment, and mortality among non-Hispanic White (NHW) and non-Hispanic Black (NHB) patients with SCLC. Methods: This population-based retrospective cohort study included patients who were diagnosed with SCLC as a first primary malignancy at age 20 and older between January 2007 and December 2015, followed through December 2016, and identified from the Surveillance, Epidemiology, and End Results. County-level racialized socioeconomic segregation was measured using the Index of Concentration at the Extremes (ICE). Multilevel logistic regression accounting for county-level clustering was used to estimate odds ratios (ORs) for extensive-stage diagnosis and non-adherence to guideline-recommended treatment. Hazard ratios (HRs) for lung cancer-specific mortality and all-cause mortality were computed using multilevel Cox regression. Results: Among 38,393 patients, 90.1% were NHW and 9.9% were NHB. Patients dwelling in the counties with the highest concentration of low-income NHB households (highest ICE quartile) had higher risks of non-adherence to guideline-recommended treatment (OR=1.23, 95% CI: 1.08-1.40; Ptrend &amp;lt;0.01), lung cancer-specific mortality (HR=1.08, 95% CI: 1.04-1.12; Ptrend &amp;lt;0.01), and all-cause mortality (HR=1.13, 95% CI: 1.09-1.17; Ptrend &amp;lt;0.0001) as compared with patients dwelling in the counties with the highest concentration of high-income NHW households (lowest ICE quartile). These associations were comparable between NHB and NHW patients. Racialized economic segregation was not significantly associated with extensive-stage diagnosis. Conclusions: Residing in the segregated, low-income NHB counties had adverse impacts on stage-appropriate treatment for SCLC and survival outcomes. Future research on the pathway(s) linking residential segregation to SCLC treatment underutilization and poor outcomes is warranted. Citation Format: Bayu B. Bekele, Min Lian, Ying Liu. The impact of socioeconomic and racial segregation on cancer stage at diagnosis, treatment and mortality among patients with 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 2153.
Abstract 1881: Screening of Rac1 and Cdc42 inhibitors as anti-metastatic compounds
Authors: Jessica Colón González, María C. Santa María Fuentes, Cornelis Vlaar, Suranganie Dharmawardhane
Journal: Cancer Research (2024)

Abstract Metastasis is responsible for &amp;gt;90% of cancer-related deaths and is a key cause of failure of cancer therapy. The development of effective targeted therapy to prevent and treat metastasis has been challenging. Homologous Rho GTPases Rac and Cdc42 are viable metastasis targets because they have a crucial role in the signaling pathways that regulate cell survival, proliferation, and migration, so dysregulation of these proteins leads to cancer progression and metastasis of diverse cancer types. Therefore, targeting these regulatory proteins results in anticancer and antimetastatic activity, as observed with our dual Rac/Cdc42 inhibitor, MBQ-167, in triple-negative breast cancer. MBQ-167 has an IC50 of ~100nM for Rac and Cdc42 activation inhibition and a GI50 of 130nM. MBQ-167 inhibits the binding of guanine nucleotides to Rac and Cdc42 with similar efficacy. The purpose of this study was to identify MBQ-167 derivatives with similar or greater efficacy and specificity, with a range of inhibitory mechanisms, that may be specific to the different guanine nucleotide exchange factors expressed in distinct cancer cell types. Currently, over 30 different compounds with potential Rac1 and Cdc42 inhibitory activity are being evaluated. So far, some of the evaluated compounds have shown comparable GI50 values to MBQ-167 in metastatic breast cancer cell lines. From this screening, CPV-337 was selected as a compound with a GI50 of ~55nM and ~70% Rac activation inhibition at 50nM, therefore being 2X more effective than our leading compound MBQ-167. However, evaluation of CPV-337 in the viability of the MCF-10 non-tumorigenic epithelial cell line demonstrated a GI50 of ~63nM, which is similar to that of breast cancer cells. Therefore, CPV-337 may have cytotoxic effects on breast cancer. We are continuing to screen the library of MBQ-167 derivatives in breast, pancreatic, lung, and prostate cancer cell lines. Citation Format: Jessica Colón González, María C. Santa María Fuentes, Cornelis Vlaar, Suranganie Dharmawardhane. Screening of Rac1 and Cdc42 inhibitors as anti-metastatic compounds [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 1881.