tbuckley/cabot-search huggingface dataset:
Abstract 4029: HPK1 inhibitor reinvigorates exhausted tumor-infiltrating CD8 T cells and synergizes with anti-PD-1 blockade in gynecologic malignancies
Authors: Junsik Park, Yong Jae Lee, Sunghoon Kim, Seungmook Lim, A Yeong Park, Jamie Jae Eun Kim, Jinhwa Lee, Sang Wun Kim, Su-Hyung Park, Jung-Yun Lee
Journal: Cancer Research (2024)

Abstract HPK1 (Hematopoietic Progenitor Kinase 1) is a negative intracellular immune checkpoint that interferes with the priming and activation of T cells. In recent years, several HPK1 inhibitors have been discovered as novel immune-oncology drugs with promising potential to improve anti-tumor immune responses. However, there has been no study showing the effects and potential application of HPK1 in gynecologic malignancies. Therefore, we investigated the expression and role of HPK1 in tumor-infiltrating CD8 T cells (CD8 TILs) and how the selective small molecule kinase inhibitor, FB849, affected the reinvigoration of exhausted CD8 TILs in gynecologic cancers. We isolated TILs from patients with newly diagnosed endometrial (n=53) and ovarian cancer (n=46). The immunological properties and HPK1 signaling pathway of CD8 TILs were explored using flow cytometry. TILs were in vitro stimulated with anti-CD3 in the presence of FB849 and/or anti-PD-1, and their proliferation was assessed. We observed that HPK1 marked severely exhausted PD-1+CD8 TILs, and high HPK1 expressers had more exhausted PD-1+CD8 TILs compared to low HPK1 expressers. In addition, FB849 could successfully restore the effector function of exhausted CD8 TILs. In particular, the reinvigorating capacity of FB849 was negatively correlated with phosphorylated SLP76+PD-1+CD8 TILs in endometrial cancer. In addition, FB849 further enhanced anti-PD-1-mediated reinvigoration of CD8 TILs in endometrial cancer. However, there was no synergistic effect of FB849 + anti-PD-1 in terms of proliferative capacity in ovarian cancer. Overall, the results of our present study provide a rationale for clinical trials investigating the anti-tumor efficacy of FB849 ± anti-PD-1 tailored to the respective properties of gynecologic malignancies. Citation Format: Junsik Park, Yong Jae Lee, Sunghoon Kim, Seungmook Lim, A Yeong Park, Jamie Jae Eun Kim, Jinhwa Lee, Sang Wun Kim, Su-Hyung Park, Jung-Yun Lee. HPK1 inhibitor reinvigorates exhausted tumor-infiltrating CD8 T cells and synergizes with anti-PD-1 blockade in gynecologic malignancies [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 4029.
Abstract 5912: Rational design of a small-molecule inhibitor targeting the allosteric site of sos1 in oncogenic k-ras pancreatic cancer
Authors: Xin Duan, Chris R Evelyn, Jacek Biesiada, James F Johnson, William L. Seibel, Jaroslaw Meller, Yi Zheng
Journal: Cancer Research (2024)

Abstract Oncogenic Kras signaling is a key therapeutic target in human cancers. Ras activation is catalyzed by guanine nucleotide exchange factors (GEFs), of which SOS1 is a major player that transduces receptor tyrosine kinase signaling to Ras. In addition to recently devised oncogenic Kras targeting small molecule inhibitors, disrupting the catalytic interaction between Ras and SOS1 has emerged as an attractive therapeutic strategy in working synergistically with Kras inhibitors and overcoming resistance. Previous studies have demonstrated an active “feed forward” loop of active Kras binding to the allosteric site of SOS1 that further stimulates SOS1 catalytic activation of wild type H/N/Kras, which is required for oncogenic Kras driven tumorigenesis. Here we have developed a rational approach that combines virtual screening with experimental screening to identify small molecule inhibitors that target the allosteric site of SOS1 to suppress oncogenic Kras mediated SOS1-regulated wild-type Ras activities. Unlike SOS1 catalytic site inhibitors which can have significant toxicity due to their ability to inhibit normal Ras signaling function, the lead SOS1 allosteric inhibitors developed in our laboratory binds to the allosteric site of SOS1 and blocks active Ras interaction with SOS1: we found these inhibitors can competitively suppresses SOS1-Ras interaction at the SOS1 allosteric site and dose-dependently inhibits the feed-forward SOS1 GEF activity. Mutagenesis and structure-activity relationship studies mapped the site of action to the SOS1 allosteric site, and preliminarily defined the chemical moieties in the inhibitor essential for the activity. The inhibitor showed dose-dependent and selective efficacy in inhibiting WT Ras activity, downstream signaling activities, and associated cell proliferation in KRAS mutation cells but not KRAS wild-type cells. Compared to the SOS1 catalytic inhibitor, BI3406, our inhibitors showed better selectivity for KRAS mutant pancreatic cancer cells vs. WT KRAS cells. These studies establish a proof of principle for the rational design of small molecule inhibitors targeting an oncogenic Kras specific allosteric site of SOS1 and provide a novel therapeutic concept to target KRAS-driven tumors more effectively. Citation Format: Xin Duan, Chris R Evelyn, Jacek Biesiada, James F Johnson, William L. Seibel, Jaroslaw Meller, Yi Zheng. Rational design of a small-molecule inhibitor targeting the allosteric site of sos1 in oncogenic k-ras pancreatic 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 5912.
Abstract 6114: Trends in hematological cancer subtype mortality by educational attainment and sex in the United States, 2000-2020
Authors: Emily C. Marlow, Farhad Islami, Ahmedin Jemal
Journal: Cancer Research (2024)

Abstract Objective: To examine mortality trends for hematological cancer subtypes (leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and myeloma) by educational attainment and sex in the United States. Methods: Using data on 1,082,234 U.S. deaths from 2000-2020, age-standardized death rates were calculated by sex and educational attainment (high school/GED or less, some college, and 4 years of college or more). Annual percentage change (APC) and 95% confidence intervals (CI) for mortality rates were generated using Joinpoint regression. Results: For all hematological cancer subtypes, mortality rates were largest among males and those with the least education for all study years. In general, decreasing trends were observed in recent years for non-Hodgkin’s lymphoma, myeloma, and leukemia mortality rates. Non-Hodgkin’s lymphoma mortality rates, for example, decreased among males and females in 2009-2020 (APC: -2.0%; 95%CI: -2.4%, -1.5% and APC: -2.8%; 95%CI -3.2%, -2.3%). As another example, non-Hodgkin’s lymphoma mortality rates among most educated males decreased in 2000-2012 (APC: -1.8%; 95%CI: -2.2%, -1.3%) followed by a steeper decline in 2012-2020 (APC: -3.7%; 95%CI: -4.4%, -2.9%); a similar pattern was observed among most educated females (APC: -1.6%; 95%CI: -2.2%, -1.0% in 2000-2011 and APC: -4.1%; 95%CI: -4.9%, -3.4% in 2011-2020). Trends in Hodgkin’s lymphoma death rates however differed by educational attainment. For example, mortality rates among least educated males increased in 2000-2009 (APC: 1.7%; 95%CI: 0.8%, 2.5%) and remained unchanged in 2009-2020 (APC: -0.3%; 95%CI: -0.9%, 0.3%). Rates among least educated females also increased in 2000-2020 (APC: 0.4%; 95%CI: 0.1%, 0.7%). In contrast, mortality rates declined for most educated males from 2010-2020 (APC: -1.9%; 95%CI: -2.6%, -1.2%) and most educated females from 2011-2020 (APC: -3.5%; 95%CI: -4.8%, -2.2%). Conclusion: Hematological cancer mortality rates were highest among males and those with least education. In general, mortality rates have declined in recent years for non-Hodgkin’s lymphoma, myeloma, and leukemia for males and females among all educational attainment groups, while Hodgkin’s lymphoma has shown a slight increasing trend among least educated males and females. Citation Format: Emily C. Marlow, Farhad Islami, Ahmedin Jemal. Trends in hematological cancer subtype mortality by educational attainment and sex in the United States, 2000-2020 [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 6114.
Abstract 2896: Elucidating the role of transglutaminase 2 (TGM2) in pancreatic ductal adenocarcinoma pathogenesis and its therapeutic implications
Authors: Polina Wright, Azeddine Atfi
Journal: Cancer Research (2024)

Abstract Pancreatic cancer remains one of the deadliest malignancies, with limited therapeutic options and a poor prognosis due to delayed symptom presentation and disease detection. Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 8%, predominantly attributed to oncogenic KRAS mutations and loss-of-function mutations in TP53, SMAD4, and P16. Our lab is interested in studying Transglutaminase 2 (TGM2), a multifunctional enzyme involved in protein cross-linking and cellular signaling, because it is highly correlated with cancer cell survival, malignancy, metastasis, and treatment resistance. Clinically, overexpression of TGM2 is associated with poorer survival in patients with Pancreatic Ductal Adenocarcinoma so it is imperative to understand the mechanism of its action in disease progression. To elucidate the role of TGM2 in PDAC, we studied the targeted deletion of TGM2 in the context of a mouse model of PDAC and saw a significant reduction in PDAC incidence and precursor lesion formation, suggesting that TGM2 has a role in the tumor microenvironment. Using single cell sequencing, we found TGM2 levels to be elevated in certain cell populations, specifically endothelial cells and cancer cells. We discovered high TGM2 levels in TIE2-GFP mouse vessels and subsequently found high TGM2 levels in patient tumor vasculature. Further studies aim to conditionally ablate TGM2 in endothelial cells to assess its mechanistic involvement in PDAC initiation and progression. Additionally, we are studying concurrent conditional TGM2 and SMAD4 deletions in mice to investigate pancreatic cancer precursor lesion formation and are further evaluating the protective mechanisms of a TGM2 deletion in a more aggressive mouse model of PDAC. Our preliminary findings substantiate TGM2 as a critical player in PDAC pathogenesis, opening avenues for targeted therapeutics to ultimately improve patient prognosis. Citation Format: Polina Wright, Azeddine Atfi. Elucidating the role of transglutaminase 2 (TGM2) in pancreatic ductal adenocarcinoma pathogenesis and its therapeutic implications [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 2896.
Abstract 5871: Unveiling mechanisms of CDK4/6 inhibitor resistance in ER+ breast cancer models with acquired resistance
Authors: Bin Li, Gaoxiang Liu, Ting Ni, Wenting Shi, Qingyang Gu
Journal: Cancer Research (2024)

Abstract Introduction: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including palbociclib, ribociclib, and abemaciclib, have revolutionized the treatment of estrogen receptor-positive (ER+) breast cancer. However, the development of resistance to these inhibitors poses a formidable challenge in the clinical management of ER+ breast cancer. This study aims to explore the common resistance mechanisms in three CDK4/6 inhibitor-resistant models induced by chronic exposure to these agents. Methods: We developed models of resistance to palbociclib, ribociclib, and abemaciclib by repeatedly exposing murine xenografts to these CDK4/6 inhibitors. Resistance was confirmed through cell viability assays and in vivo tumorigenesis studies. The tumors were sequenced using NGS analyses, and genes of interest were validated through Western blotting and qPCR. Results: In all resistant models, we identified a common resistant mechanism via NGS analyses, which was characterized by the overexpression of the FAT1, CCNE1, and AR genes. The upregulation of these genes at mRNA and protein levels was confirmed by qPCR analyses and western blotting, respectively. Our data indicate that upregulation of FAT1, CCNE1, and AR genes may play a critical role in mediating resistance to CDK4/6 inhibitors, namely palbociclib, ribociclib, and abemaciclib. Conclusion: Our investigation uncovered a shared mechanism, characterized by the overexpression of FAT1, CCNE1, and AR genes, that underlay CDK4/6 inhibitors-induced drug resistance in ER+ breast cancer. These findings shed light on the shared pathways that drive CDK4/6 inhibitor resistance and provide insights into potential therapeutic targets for overcoming this resistance in breast cancer patients. Understanding these mechanisms is crucial for the development of more effective treatment strategies for CDK4/6 inhibitor-resistant cancers. Citation Format: Bin Li, Gaoxiang Liu, Ting Ni, Wenting Shi, Qingyang Gu. Unveiling mechanisms of CDK4/6 inhibitor resistance in ER+ breast cancer models with acquired resistance [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 5871.
Abstract 7356: 3 UTR variations in esophageal squamous cell carcinoma in African Americans
Authors: Ceyda Erkizan, Robert Wadleigh
Journal: Cancer Research (2024)

Abstract Esophageal squamous cell carcinoma (ESCC) predominantly affects African Americans (AA). Esophageal Cancer (EC) consists of two major histological subtypes: esophageal adenocarcinoma and squamous cell carcinoma. ESCC ranks among the most lethal cancers and is particularly aggressive among AA, comprising about 75% of total ESCC patients. The 5-year survival rate for localized EC in AA patients is 25%; in contrast, the survival rate for EC patients of Caucasian origin is 48%. However, for metastatic disease, the survival rate decreases dramatically to 5% regardless of race. To conduct an extensive mutation screening, we performed whole exome sequencing (WES) in 10 paired AA ESCC and control tissues. Mutations included nonsynonymous mutations in multiple genes and copy number variations. Here, we report on further analysis of the WES data to identify 3 UTR noncoding region alterations, comprising the highest proportion of noncoding variations. Whole exome sequencing was performed using Agilent SureSelect XT Human All Exon V6 + UTR kit on matched normal-tumor samples from 10 AA patients (nine males and one female) with advanced-stage ESCC. The ages of patients ranged from 53 to 80 years. All patients, except for one, reported tobacco use and alcohol consumption. Our analysis yielded 5378 variants in noncoding regions in our cohort. The most variations were found in the 3UTR location, with 46% of all noncoding variations. In our dataset, variations in the 3UTR region of 48 genes were predicted by CScape to assert an oncogenic effect. The highest ten oncogenic predictive scores are for ETV1, FOXO3, MSI2, TCF7L2, KAT6A, FOXO1, IRF4, TRIM24, ELK4, and FGFR1 genes. Approximately 2500 genes having 3’UTR variations are over-presented in intracellular signaling and cell-cell communications, transcriptional regulation of pluripotent stem cells by OCT4, SOX2, NANOG, generic RNA polymerase II transcription, RHO GTPase cycle, and regulation of cytoskeletal remodeling. The combined effects of noncoding and coding region mutations may largely impact poor prognosis in AA with ESCC and yield targets for developing candidate therapeutics. Citation Format: Ceyda Erkizan, Robert Wadleigh. 3 UTR variations in esophageal squamous cell carcinoma in African Americans [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 7356.
Abstract 4028: Inhibition of IL25 IL17RA improves immune related adverse events of checkpoint inhibitors and reveals antitumor activity
Authors: Xizi Hu, Shoiab Bukhari, Carly Tymm, Kieran Adam, Shalom Lerrer, Brian Henick, Robert Winchester, Adam Mor
Journal: Cancer Research (2024)

Abstract Immune checkpoint inhibitors (ICI) have improved outcomes and extended patient survival in several tumor types. However, ICI often induces immune-related adverse events (irAEs) that warrant therapy cessation, thereby limiting the overall effectiveness of this class of therapeutic agents. Currently, available therapies used to treat irAEs might also blunt the antitumor activity of the ICI themselves. Therefore, there is an urgent need to identify treatments that have the potential to be administered alongside ICI to optimize their use. Using a translationally relevant murine model of anti-PD-1 and anti-CTLA-4 antibodies-induced irAEs, we compared the safety and efficacy of prednisolone, anti-IL-6, anti-TNFɑ, anti-IL-25 (IL-17E), and anti-IL-17RA (the receptor for IL-25) administration to prevent irAEs and to reduce tumor size. While all interventions were adequate to inhibit the onset of irAEs pneumonitis and hepatitis, treatment with anti-IL-25 or anti-IL-17RA antibodies also exerted significant additional antitumor activity. Mechanistically, IL-25/IL-17RA blockade reduced the number of organ-infiltrating lymphocytes. These findings suggest that IL-25/IL-17RA may serve as an additional target when treating ICI-responsive tumors, allowing for better tumor control while suppressing immune-related toxicities. Citation Format: Xizi Hu, Shoiab Bukhari, Carly Tymm, Kieran Adam, Shalom Lerrer, Brian Henick, Robert Winchester, Adam Mor. Inhibition of IL25 IL17RA improves immune related adverse events of checkpoint inhibitors and reveals antitumor activity [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 4028.
Abstract 4189: BALB/c-hIL12RB1/hIL12RB2: A robust model for preclinical research in human IL-12 therapy
Authors: Yuan Fang, Huiyi Wang, Jun Xing, Lu Yang, Jing Zhao, Xiang Gao, Cunxiang Ju
Journal: Cancer Research (2024)

Abstract Interleukin-12 (IL-12) is a multifaceted cytokine primarily produced by antigen-activated dendritic cells, macrophages, and neutrophils. Its receptor is a composite of IL12RB1 and IL12RB2, and the union of these two subunits forms a high-affinity receptor complex proficient in mediating IL-12 signaling. As a pivotal regulator of innate and adaptive immunity, IL-12 plays a crucial role in steering the differentiation of naïve T cells into Th1 cells. It is renowned as a T cell stimulatory factor, fostering T cell proliferation. Furthermore, IL-12 has the capacity to augment the activation of cytotoxic lymphocytes and natural killer cells (NK), thereby enhancing interferon (IFN-γ) production. Empirical evidence consistently demonstrates that IL-12 synergistically exerts anti-tumor effects in conjunction with various immune cells, such as T cells and NK cells. Its effectiveness in preclinical studies has solidified IL-12 as an appealing drug target, leading to the development of activating antibodies, therapeutic IL-12 proteins, and tumor vaccines as potential treatments. To delve deeper into the functionality and therapeutic potential of IL-12, we have engineered a humanized mouse model, known as BALB/c-hIL12RB1/hIL12RB2. Notably, this model fully preserves the intracellular domains of mouse IL12RB1 and IL12RB2 proteins, ensuring the normal propagation of intracellular signaling. It also effectively expresses human IL12RB1 and IL12RB2. In vitro functional validation experiments have verified that BALB/c-hIL12RB1/hIL12RB2 mice can proficiently generate IFN-γ when induced by human IL-12. Furthermore, in vivo efficacy experiments have yielded compelling results. Intratumoral administration of human IL-12 mRNA in BALB/c-hIL12RB1/hIL12RB2 mice led to a significant suppression in the growth of CT26 tumors, culminating in complete tumor regression. Subsequent rechallenge experiments conducted after the discontinuation of treatment revealed no tumor recurrence, signifying the enduring inhibitory effect of hIL12 mRNA on mouse tumors. In conclusion, the development of BALB/c-hIL12RB1/hIL12RB2 mice stands as a robust model for advancing preclinical research in the realm of human IL-12 therapy. Citation Format: Yuan Fang, Huiyi Wang, Jun Xing, Lu Yang, Jing Zhao, Xiang Gao, Cunxiang Ju. BALB/c-hIL12RB1/hIL12RB2: A robust model for preclinical research in human IL-12 therapy [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 4189.