tbuckley/cabot-search huggingface dataset:
Abstract 7468: Development of a high complexity flow cytometry panel to assess minimum residual disease in acute myeloid leukemia
Authors: Jessica Pearl, Elena Bruni, Haoting Hsu, Brandon Walling, Karin Abarca-Heidemann
Journal: Cancer Research (2024)

Abstract Acute Myeloid Leukemia (AML) is a highly heterogeneous disease with a diverse range of abnormal myeloid subpopulations resulting in challenges in clinical diagnosis and treatment. Many methods such as flow cytometry are used to provide precise information for risk stratification and treatment methods. Flow cytometry utilizes the expression patterns of cellular markers to characterize the high diversity in AML subpopulations with high sensitivity and specificity. This coupled with rapid analysis timelines allows for flow cytometry to be an excellent tool for the identification of AML lineage and progression through both phenotypic analysis and difference from normal. As AML lineage and disease progression are predictors of residual disease and relapse; the need for effective and accurate characterization of AML populations is critical. Here, Champions Oncology has developed a high-complexity 18-color flow cytometry panel to identify AML subpopulations at high resolution. We have characterized AML samples to evaluate the expression of phenotypic markers and their heterogeneity. Utilizing primary AML samples, we have evaluated the stability of AML subpopulations to understand how delayed analysis, such as what is seen in clinical trials, may impact marker expression and observed key populations were stable for up to 72 hours after collection. In addition to stability, understanding the lower limits of detection is critical for AML patients, particularly for minimum residual disease and relapse screening. The use of a flow cytometric panel again provides an excellent tool for these tests due to the single cell nature that allows for the interrogation of individual populations with primary AML subpopulations detected at a range of 10−3 to 10−4. Finally, with hundreds of never-passaged AML models characterized and cryopreserved by both flow cytometry and sequencing at Champions Oncology, we investigated how the cryopreservation processes impacted the expression of AML subpopulations. We have observed similar expression and detection of AML populations following cryopreservation indicating that these models can be utilized as an excellent tool for further studies. Collectively, our data indicates that the panel developed at Champions Oncology provides robust data analysis of AML subpopulations and can be an excellent tool for the tracking of AML disease progression in the clinic. Citation Format: Jessica Pearl, Elena Bruni, Haoting Hsu, Brandon Walling, Karin Abarca-Heidemann. Development of a high complexity flow cytometry panel to assess minimum residual disease in acute myeloid leukemia [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 7468.
Abstract 1029: Role of <i>PCDHGA12</i>/<i>PRRX1</i> methylation for the diagnosis of lung cancer using bronchial washing fluid
Authors: Ji Woong Son, Tae Jeong Oh, Minheyok Lee, Chang Ryul Park, Sungwhan An
Journal: Cancer Research (2024)

Abstract Bronchoscopy is a frequently used initial diagnostic procedure for patients with suspected lung cancer (LC). Cytological examinations of bronchial washing (BW) samples, obtained during bronchoscopy, often yield inconclusive results in the diagnosis of LC. Aberrant DNA methylation has previously been shown to be a useful biomarker for LC. DNA methylation analysis in BW specimens could serve as a valuable clinical adjunct to cytology. In this study, to identify potential methylation biomarkers for LC, methylation microarray analyses were performed on primary tumors and compared with adjacent non-tumor tissues of 13 patients with LC at various stages (I - IV). A stepwise validation process using bisulfite-pyrosequencing of cell lines and tissues identified six methylated genes (ADAMTS20, FOXC2, NKX2-5, OLIG3, PCDHGA12, and PRRX1) associated with LC. To assess methylation in BW samples, a highly sensitive and accurate 3-plex Linear Target Enrichment (LTE)-quantitative methylation-specific PCR (qMSP) in a single closed tube was developed. Clinical validation was performed using BW samples from patients with LC (n = 68) and non-LC (benign) (n = 33) and identified PCDHGA12 and PRRX1 methylation as the best performing marker combination for detecting LC. The 2-marker combination exhibited a sensitivity of 82.4% and a specificity of 87.9%, with an area under the curve of 0.891. Notably, its sensitivity was 100% for small cell LC. The 2-marker combination had a positive predictive value of 93.3% and a negative predictive value of 70.7%. Its sensitivity outperformed cytology. The methylation status of the 2-marker showed no correlation with gender, age or stage, but was associated with tumor location and histology. In conclusion, we identified PCDHGA12 and PRRX1 methylation as high potential biomarkers for LC diagnosis. This study shows that these biomarkers could be used as a diagnostic adjunct to cytology in the clinical practice for diagnosing LC in BW specimens. Citation Format: Ji Woong Son, Tae Jeong Oh, Minheyok Lee, Chang Ryul Park, Sungwhan An. Role of PCDHGA12/PRRX1 methylation for the diagnosis of lung cancer using bronchial washing fluid [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 1029.
Abstract 1374: Targeting CD47/SIRPɑ axis in urologic cancer triggers enhanced phagocytosis of tumor cell and induces tumor growth inhibition
Authors: Fan Shen, Monali Praharaj, Alex J. Lee, Thomas R. Nirschl, Xiaoxu Wang
Journal: Cancer Research (2024)

Abstract Signal regulatory protein-α (SIRPα; CD172a or SHPS-1) is a transmembrane molecule that highly expressed on myeloid population. Binding of CD47 (integrin-associated protein, IAP) to SIRPα inhibits phagocytosis in macrophages, which acts as a mechanism of maintaining homeostasis. Tumor cells however, often time upregulate CD47 to evade immune response. Using publicly available dataset, we found that human prostate cancer cells upregulate expression of both CD47 and calreticulin, a “eat me” signal when engaged with Low density lipoprotein receptor-related protein 1 (LRP1). In addition, macrophages, monocytes and dendritic cells in human prostate cancer do have relatively high level of SIRPɑ and LRP1 expression. This finding provides the rationale of targeting CD47/SIRPɑ axis in prostate cancer to shift the balance between pro-phagocytosis and anti-phagocytosis signaling. We then moved to RM1 and B6Cap, two syngeneic prostate cancer models in immunocompetent mice. Significant tumor growth inhibition was seen in both models with anti SIRPɑ blocking antibody. Furthermore, we observed in vitro that CD47 or SIRPɑ blockage led to enhanced PC3 cell line phagocytosis by human monocyte derived macrophages (HMDMs). Same finding was found using mouse bone marrow derived macrophages (BMDMs). We then utilized ovalbumin expressing MB49 bladder cancer cell line and cocultured those with BMDMs. CD8+ T cell from OT1 mice exhibited higher expression of activation makers when cocultured BMDMs treated by either anti CD47 or SIRPɑ antibody, indicating that enhanced phagocytosis subsequently increases antigen cross presentation in macrophages. In summary, we identified that CD47 is overexpressed in human prostate cancer; blocking CD47/SIRPɑ did inhibit tumor growth through enhanced phagocytosis and antigen presentation. Citation Format: Fan Shen, Monali Praharaj, Alex J. Lee, Thomas R. Nirschl, Xiaoxu Wang. Targeting CD47/SIRPɑ axis in urologic cancer triggers enhanced phagocytosis of tumor cell and induces tumor growth inhibition [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 1374.
Abstract 1007: Breast cancer related lymphedema patient characteristics and treatment patterns in a Hispanic majority population
Authors: Sarah A. Shaker, Lauren P. Rahman, Marcela Mazo Canola
Journal: Cancer Research (2024)

Abstract Background: Studies have shown an increased risk of Breast Cancer Related Lymphedema (BCRL) in Hispanic populations, however there are limited studies examining factors specific to BCRL in this minority population. This retrospective study aims to characterize and analyze treatment and demographic related factors associated with BCRL in the Hispanic majority population of San Antonio. Methods: This is a retrospective, single institution study of patients with BCRL between 2017-2020 at Mays Cancer Center in San Antonio, Texas, a city with a majority minority Hispanic population.Results: 110 subjects with BCRL were identified with a median age of 62 years old. 52.7% were Hispanic while 47.3% were non-Hispanic. The median BMI was 31 with over 75% of subjects with BCRL categorized with BMIs of overweight or obese. 89.1% received some form of chemotherapy, whether neoadjuvant or adjuvant, and 80.9% were exposed to some form of taxane. The majority underwent more invasive procedures and surgeries: 69.1% had axillary lymph node dissection and 71.2% underwent mastectomy. The median number of lymph nodes removed were 12. 62.7% of BCRL patients were exposed to nodal radiation. Regarding BCRL severity, 29.4% were classified as grade 1 while 11% classified as grade 3. Of note, there was a statistically significant correlation between more severe lymphedema (grade 2 and 3) and use of chemotherapy (P-value = 0.04.)Conclusion: The demographic composition of patients with BCRL closely mirrors the ethnically diverse population of San Antonio, with a large Hispanic predominance. Within this cohort of patients of BCRL, a large portion demonstrated factors of elevated BMI, more invasive surgical interventions, and exposure to chemotherapy, specifically taxane. The examination of these factors in a Hispanic-centric urban setting such as San Antonio offers crucial insight into a patient population at heightened risk for developing BCRL. Citation Format: Sarah A. Shaker, Lauren P. Rahman, Marcela Mazo Canola. Breast cancer related lymphedema patient characteristics and treatment patterns in a Hispanic majority population [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 1007.
Abstract 1087: Synergistic mechanisms against pediatric bone sarcoma models: Trabectedin enhances oncolytic virotherapy intratumoral spread and antitumor immune activation
Authors: Emily Ringwalt, Mark Currier, Andrea Glaspell, Matthew V. Cannon, Chun-Yu Chen, Amy C. Gross, Maren Cam, Pin-Yi Wang, Ryan D. Roberts, Timothy P. Cripe
Journal: Cancer Research (2024)

Abstract Osteosarcoma and Ewing sarcoma are the most common pediatric bone malignancies and, despite decades of research, efforts to treat patients with advanced disease remain dismal. To address this inadequacy, we leverage oncolytic herpes simplex virotherapy as a double-edged attack against tumors through 1) tumor cell-specific lysis and 2) antitumor immune stimulation. However, previous trials of oncolytic herpes simplex virotherapy in pediatric sarcomas displayed limited responses, likely due to the observed presence of immunosuppressive monocytes and macrophages. To improve efficacy, we combined oncolytic herpes simplex virotherapy with trabectedin, an FDA-approved DNA-binding agent known to disrupt gene expression and deplete monocytes and macrophages. Surprisingly, we found that the efficacy of this combination far surpassed our predictions, inducing complete and partial regressions in multiple models of Ewing sarcoma and osteosarcoma. To explore potential mechanisms driving this high degree of synergy, we performed single cell RNA sequencing on tumors of mice treated with monotherapy or combination therapy. Interestingly, trabectedin synergized with the oncolytic virotherapy through two unexpected mechanisms. Our analysis revealed that trabectedin increased intratumoral oncolytic virus spread by disrupting expression of the intrinsic antiviral response in human Ewing sarcoma cells. Additionally, trabectedin not only reduced immunosuppressive macrophages but also stimulated cytotoxic granzyme expression in infiltrating T and NK cells in immunocompetent osteosarcoma models. These effector NK and T cells were necessary for the regressions of osteosarcoma allografts treated with trabectedin and oncolytic virotherapy. Thus, trabectedin enhanced both the oncolytic effect of herpes simplex virotherapy and the effector function of cytotoxic lymphocytes that become activated in response to the virus. The combination of trabectedin and oncolytic herpes simplex virotherapy offers the potential to unite these mechanisms against bone tumors to achieve better outcomes for children. Citation Format: Emily Ringwalt, Mark Currier, Andrea Glaspell, Matthew V. Cannon, Chun-Yu Chen, Amy C. Gross, Maren Cam, Pin-Yi Wang, Ryan D. Roberts, Timothy P. Cripe. Synergistic mechanisms against pediatric bone sarcoma models: Trabectedin enhances oncolytic virotherapy intratumoral spread and antitumor immune activation [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 1087.
Abstract 7460: Characterizing the role of PCBP1 in the activation of the cGAS-STING/type I Interferon axis to promote anti-tumor immunity
Authors: Cécile Fréreux, Paramita Chakraborty, Annamarie C. Dalton, Breege V. Howley, Bryan Granger, Joseph A. Karam, Silvia G. Vaena, Martin J. Romeo, Philip H. Howe
Journal: Cancer Research (2024)

Abstract The emergence of immunotherapies has encouraged the need to better understand the molecular mechanisms that modulate the tumor immune microenvironment to kill cancer cells as well as the strategies used by cancer cells to evade the immune system. In several cancer types, the Poly(rC) Binding Protein 1 (PCBP1) has shown to have tumor suppressive effects, however its function in regulating the tumor immune environment remains unclear. To investigate this in the context of breast cancer, we established a CRISPR-Cas9-medited knock-out of PCBP1 in a Py8119 murine breast cancer cell line. PCBP1−/− cells revealed a decrease in the activation of the cGAS-STING pathway and is associated with lower levels of type I interferons (IFNs) and Interferon Stimulated Genes’ (ISGs) expression. The cGAS-STING pathway plays an important role in innate immunity as it fights pathogenic infections and tumorigenesis through the production of type I IFN and ISGs. It also promotes the priming and infiltration of T cells at the tumor site to fight cancer cells. Our results suggested that PCBP1 is acting on the activation of the cGAS-STING pathway and could further modulate the tumor immune microenvironment. We then confirmed our results in vivo by establishing a tumorigenic C57BL/6 PyMT transgenic mouse model with conditional knockout for PCBP1 in mammary cells. Our data demonstrate that PCBP1−/− PyMT mice have higher tumor burdens compared to PCBP1+/+ PyMT mice and also show a decreased ISGs’ signature by RNA-sequencing, qPCR and western blot, as previously observed in vitro in the Py8119 PCBP1−/− cell line. Additional single nuclei RNA-sequencing analyses confirmed that this downregulation of ISGs is observed in mammary cancer cells where PCBP1 is knocked-out. Strikingly, IHC and flow cytometry analyses of PCBP1−/− tumors isolated from these mice also revealed a decrease in CD8+ T-cells. Therefore, PCBP1 silencing may promote tumor growth by impairing the activation of the cGAS-STING/IFN-I/ISGs axis, which may contribute to the decrease in CD8+ T-cells’ infiltration at the tumor site. Additionally, we are further investigating the molecular mechanisms mediated by PCBP1 that trigger this activation of the cGAS-STING pathway. Citation Format: Cécile Fréreux, Paramita Chakraborty, Annamarie C. Dalton, Breege V. Howley, Bryan Granger, Joseph A. Karam, Silvia G. Vaena, Martin J. Romeo, Philip H. Howe. Characterizing the role of PCBP1 in the activation of the cGAS-STING/type I Interferon axis to promote anti-tumor immunity [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 7460.
Abstract 3139: BL-M11D1, a novel CD33-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation
Authors: Weili Wan, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Ruigang Li, Jahan Salar Khalili, Xiao Sa, Yongqi Yan, Xuejiao Shen, Yi Zhu
Journal: Cancer Research (2024)

Abstract CD33, is a transmembrane receptor expressed on cells of myeloid lineage. It is therapeutically targeted in cancer due to overexpression broadly among hematopoietic malignancies including AML. To develop a promising therapeutic anti-tumor agent, we generated BL-M11D1, a CD33-Ed-04 ADC. It is built on gemtuzumab, a specific monoclonal antibody against CD33, having a wt Fc that can mediate ADCC in vitro. BL-M11D1 is composed of gemtuzumab, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04). The novel Ed-04 is a derivative of the alkaloid camptothecin and mediates cell cycle arrest at the S phase and subsequent apoptosis. BL-M11D1 achieves a high drug-to-antibody-ratio (DAR=10) with a highly stable linker and is readily internalized and trafficked to lysosomal cellular compartments. The antitumor efficacy of BL-M11D1 was evaluated in xenograft tumor models. BL-M11D1 exhibited strong tumor inhibition capacity toward the human hematopoietic malignancies engrafted xenograft models. In summary, these studies suggest BL-M11D1, a novel CD33-targeting ADC, is potentially efficacious in the treatment of CD33-expressing disease. The clinical phase I trial is being undertaken to evaluate safety, dosing and observations of preliminary signs of efficacy. Citation Format: Weili Wan, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Ruigang Li, Jahan Salar Khalili, Xiao Sa, Yongqi Yan, Xuejiao Shen, Yi Zhu. BL-M11D1, a novel CD33-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation [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 3139.
Abstract 3140: BL-M05D1, a novel claudin 18.2-targeting ADC, demonstrates specific potent anti-tumor efficacy in preclinical evaluation
Authors: Weili Wan, Kelcey Dinkel, Austin Sanford, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Ruigang Li, Jahan Salar Khalili, Xiao Sa, Yongqi Yan, Xuejiao Shen, Yi Zhu
Journal: Cancer Research (2024)

Abstract Claudin 18.2, is a member of the tight junction protein family, and an isoform of claudin18. It is therapeutically targeted in cancer due to its limited expression in normal tissue and prevalent expression in a variety of human carcinomas. To develop a promising therapeutic anti-tumor agent, we generated BL-M05D1, an anti-Claudin 18.2-Ed-04 ADC. It is comprised of a novel, specific monoclonal antibody against Claudin 18.2 (5103F3), having a wt Fc that can mediate ADCC and CDC in vitro. BL-M05D1 is composed of (5103F3), a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04). The novel Ed-04 is a derivative of the alkaloid camptothecin and mediates cell cycle arrest at the S phase and subsequent apoptosis. BL-M05D1 achieves a high drug-to-antibody-ratio (DAR=8) with a highly stable linker and is readily internalized and trafficked to lysosomal cellular compartments. The antitumor efficacy of BL-M05D1 was evaluated in xenograft tumor models. BL-M05D1 exhibited strong tumor inhibition capacity toward the human gastric cancer cell MKN-45-Claudin18.2 (#C11D) xenograft model, and human pancreatic cancer cell Patu8988s-Claudin18.2 (#C7G) xenograft model. In summary, these studies suggest BL-M05D1, a novel Claudin 18.2-targeting ADC, is potentially efficacious in the treatment of Claudin 18.2-expressing carcinomas. The clinical phase I is being undertaken to evaluate safety, dosing and observations of preliminary signs of efficacy. Citation Format: Weili Wan, Kelcey Dinkel, Austin Sanford, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Ruigang Li, Jahan Salar Khalili, Xiao Sa, Yongqi Yan, Xuejiao Shen, Yi Zhu. BL-M05D1, a novel claudin 18.2-targeting ADC, demonstrates specific potent anti-tumor efficacy in preclinical evaluation [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 3140.
Abstract 6630: Non-cell-autonomous cancer progression from chromosomal instability
Authors: Jun Li, Melissa Hubisz, Ethan Earlie, Mercedes Duran, Christy Hong, Austin Varela, Emanuele Lettera, Matthew Deyell, Bernardo Tavora, Jonathan Havel, Phyu Su, Amit Dipak Amin, Karolina Budre, Erina Kamiya, Julie-Ann Cavallo, Christopher Garris, Simon Powell, Jorge Reis-Filho, Hannah Wen, Sarah Bettigole, Atif Khan, Benjamin Izar, Eileen Parkes, Ashley Laughney, Samuel Bakhoum
Journal: Cancer Research (2024)

Abstract Chromosomal instability (CIN) is a driver of cancer metastasis, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing—a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell-cell interactions from single-cell transcriptomic data—we show that CIN-induced chronic activation of the cGAS-STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumor microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signaling abrogates CIN-dependent effects on the tumor microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumor cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signaling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumors spurred by CIN-induced inflammation. Citation Format: Jun Li, Melissa Hubisz, Ethan Earlie, Mercedes Duran, Christy Hong, Austin Varela, Emanuele Lettera, Matthew Deyell, Bernardo Tavora, Jonathan Havel, Phyu Su, Amit Dipak Amin, Karolina Budre, Erina Kamiya, Julie-Ann Cavallo, Christopher Garris, Simon Powell, Jorge Reis-Filho, Hannah Wen, Sarah Bettigole, Atif Khan, Benjamin Izar, Eileen Parkes, Ashley Laughney, Samuel Bakhoum. Non-cell-autonomous cancer progression from chromosomal instability [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 6630.