tbuckley/cabot-search huggingface dataset:
Abstract 3438: Associations between estimated endotoxin exposure and circulating immunological markers among male farmers
Authors: Somayina C. Ezennia, Laura E. Beane-Freeman, Vicky C. Chang, Shuai Xie, Gabriella Andreotti, Melissa C. Friesen, Jonathan N. Hofmann
Journal: Cancer Research (2024)

Abstract Occupational exposure to endotoxin has been associated with reduced lung cancer risk. Farmers who perform certain tasks (e.g., raising hogs) can be highly exposed to endotoxin. The mechanisms through which endotoxin could confer a lower risk of lung cancer, while likely to be immune mediated, are not clear. To address this gap, we evaluated associations between estimated endotoxin exposure and circulating immunologic markers among male farmers in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study. Our investigation included 122 non-smoking farmers from Iowa, oversampling those raising hogs (n=61). We evaluated 58 serologic markers, including some linked to lung cancer, that were measured using multiplex bead-based assays. Based on an algorithm linking personal air measurements in BEEA and published data to reported farming tasks, we estimated cumulative endotoxin exposure in the last 30 days and 12 months before sample collection. We used multivariable linear regression to estimate geometric mean ratios of immune markers across exposure quartiles, overall and by season of sample collection. Higher endotoxin exposure in the last 30 days was associated with increased levels of FGF-2, MIP-3A/CCL20, and sIL-4R (Ptrend ≤ 0.02), and with decreased levels of MDC/CCL22 (Ptrend = 0.02). In analyses stratified by season, the positive associations with FGF-2 and MIP-3A/CCL20 were most apparent in the winter (Ptrend = 0.002 and 0.03, respectively); we also observed an inverse association with sCD27 levels in the summer (Ptrend = 0.03). Similar patterns were observed for endotoxin exposure in the last 12 months. This study is the first to use novel algorithm-based endotoxin exposure estimates to evaluate associations with intermediate lung cancer-related markers. Several markers were associated with endotoxin levels in an exposure-response manner. Our findings suggest possible biological mechanisms through which endotoxin may reduce risk of lung cancer. Table 1. Associations between estimated endotoxin exposure in the last 30 days and selected serum im Citation Format: Somayina C. Ezennia, Laura E. Beane-Freeman, Vicky C. Chang, Shuai Xie, Gabriella Andreotti, Melissa C. Friesen, Jonathan N. Hofmann. Associations between estimated endotoxin exposure and circulating immunological markers among male farmers [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 3438.
Abstract 6626: Functional and molecular interrogation of a high-plasticity cell state in lung cancer
Authors: Jason Earl Chan, Chun-Hao Pan, Carleigh Sussman, Hannah Styers, Emma Brown, Griffin Hartmann, Brigita Meškauskaitė, Melissa Blum, Selena Ding, Stefan Torborg, Zhuxuan Li, Simon Joost, Eliud Rivas-Hernandez, Thomas Norman, Ronan Chaligne, Yan Yan, Tuomas Tammela
Journal: Cancer Research (2024)

Abstract Despite recent advancements in lung adenocarcinoma (LUAD) treatment, mortality remains high. Thus, a need exists for novel therapeutic concepts to enhance treatment efficacy and improve patient survival. Cancer cell plasticity, the capacity for cancer cells to differentiate and adapt to cell-extrinsic pressures, drives LUAD progression and enables treatment resistance. We discovered a molecularly distinct "high-plasticity cell state" (HPCS), which emerges during the initial stages of tumor development and is maintained in established tumors, comprising 10-15% of the cancer cell pool. We hypothesized that the HPCS is critical for tumor progression and drug resistance. To functionally interrogate this cell state, we engineered a novel genetic system that enables both in situ ablation (via a suicide gene) and longitudinal lineage tracing (via secreted luciferases) of the HPCS in an autochthonous genetically engineered mouse LUAD model. Lineage-tracing revealed the HPCS harbors high differentiation potential (plasticity) and growth potential in situ. Strikingly, ablation of the HPCS led to robust tumor regression and growth suppression. Motivated by these findings, we sought to identify molecular drivers of the HPCS using an in vivo multiplexed gene perturbation approach coupled to single-cell RNA sequencing. This effort led to the identification of central transcriptional plasticity drivers. This study motivates the therapeutic targeting of the HPCS in lung cancer and uncovers candidate targets. Citation Format: Jason Earl Chan, Chun-Hao Pan, Carleigh Sussman, Hannah Styers, Emma Brown, Griffin Hartmann, Brigita Meškauskaitė, Melissa Blum, Selena Ding, Stefan Torborg, Zhuxuan Li, Simon Joost, Eliud Rivas-Hernandez, Thomas Norman, Ronan Chaligne, Yan Yan, Tuomas Tammela. Functional and molecular interrogation of a high-plasticity cell state in 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 6626.
Abstract 6598: Inhibition of cGAS as a strategy to restore anti-tumor immunity response to STING agonist in chromosomally unstable tumors
Authors: Christy Hong, Lindsay Caprio, Mercedes Duran, Meri Rogava, Hsiang-His Ling, Sreeharsha Gurrapu, Leon Ebel, Melody Di Bona, Benjamin Izar, Samuel F. Bakhoum
Journal: Cancer Research (2024)

Abstract The activation of STING (stimulator of interferon genes) has been widely shown to induce signaling pathways, triggering type I interferon and ultimately generating anti-tumor immunity. Whereas initial preclinical studies on STING agonists exhibited boost in anti-tumor response, clinical trials combining STING agonist and immune checkpoint blockade agent PD-1 reported that only small subset of patients benefited from the treatment. This study highlights a potential key mechanism underlying the lack of benefit from STING agonist observed in most clinical trial patients. We reveal a phenomenon known as chromosomal instability (CIN), characterized by persistent chromosome segregation errors over multiple rounds of mitosis, drives chronic activation of cGAS (cyclic GMP‒AMP synthase) through continuously supplying its substrate in the form of micronuclei. Chronic activation of cGAS stimulates degradation of its downstream target STING in a feedback-loop manner. This consequently attenuates type I interferon signaling upon STING activation, blunting its anti-tumor response. Remarkably, we show suppression of CIN, achieved through introduction of mitotic centromere-associated kinesin (MCAK), or inhibition of cGAS activity, either by pharmacological agent or total genetic ablation of cGAS using CRISPR-Cas9, restores type I interferon production and anti-tumor immunity upon the administration of STING agonist, MSA-2 in four of the five advanced tumor models. Furthermore, we show this restoration of type I interferon signaling and anti-tumor immunity is cancer cell STING-dependent as genetic deletion of STING in the tumor cells nullifies this effect. In summary, we provide a mechanistic insight underlying the limited anti-tumor response observed in STING agonist trials and propose potential strategies, through finetuning of CIN level or inhibition of cGAS activity, to illicit stronger anti-tumor immunity in combination with STING agonist treatment. Citation Format: Christy Hong, Lindsay Caprio, Mercedes Duran, Meri Rogava, Hsiang-His Ling, Sreeharsha Gurrapu, Leon Ebel, Melody Di Bona, Benjamin Izar, Samuel F. Bakhoum. Inhibition of cGAS as a strategy to restore anti-tumor immunity response to STING agonist in chromosomally unstable 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 6598.
Abstract 6624: MYC promotes lobuloalveologenesis and mammary tumorigenesis in male mice
Authors: Emilia M. Pulver, Eline van der Burg, Anne Paulien Drenth, Julia Yemelyanenko, Nils Ravensbergen, Roebi de Bruijn, Sjoerd Klarenbeek, Ji-Ying Song, Manon Boeije, Bjørn Siteur, Natalie Proost, Colinda Scheele, Peter Bouwman, Jos Jonkers
Journal: Cancer Research (2024)

Abstract Male breast cancer is a rare disease that is largely overlooked and clinically regarded to recapitulate female breast cancer biology. The worse overall outcome for male patients compared to females, however, underscores inadequate disease management and a sex-based divergence in disease biology. To gain more insight into male breast biology and pathology, we used mouse models of triple-negative breast cancer and 3D whole-mount confocal imaging techniques to evaluate both in vivo and ex vivo mammary gland development, tumor formation, and hormone signaling dependence. Our results show that Myc overexpression in collaboration with Trp53 deficiency drives mammary tumorigenesis in male mice. We show that MYC overexpression promotes estrogen-independent formation of lobuloalveolar structures, which progress into tumors with a similar histology and immune landscape as female mammary tumors but with significantly more genomic instability. In female mice, MYC overexpression bypasses the dependency on paracrine estrogen signaling in mammary tumorigenesis. These data provide robust evidence that MYC overrides mammary tumor estrogen dependence and abolishes the tumor-preventive effect of a low-estrogen environment. Supporting this notion, in vitro experiments in human female breast cancer cell lines indicate that MYC overexpression may functionally contribute to endocrine therapy resistance and therefore could possibly serve as a prognostic biomarker or clinically targetable pathway for treating both male and female breast cancers. Collectively, this preclinical work presents new insights into male mammary gland biology and mechanisms of cancer progression that might translate to a broader range of breast cancers in the clinic. Citation Format: Emilia M. Pulver, Eline van der Burg, Anne Paulien Drenth, Julia Yemelyanenko, Nils Ravensbergen, Roebi de Bruijn, Sjoerd Klarenbeek, Ji-Ying Song, Manon Boeije, Bjørn Siteur, Natalie Proost, Colinda Scheele, Peter Bouwman, Jos Jonkers. MYC promotes lobuloalveologenesis and mammary tumorigenesis in male mice [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 6624.
Abstract 163: Role of macrophages in the development of ovarian cancer stem-like cells during chemotherapy
Authors: Luisjesus S. Cruz, Denay Stevenson, Mikella Robinson, Steffy Mathew, Isabella Amador, Gregory Jordan, Carrie D. House
Journal: Cancer Research (2024)

Abstract Ovarian cancer is a poorly understood disease with 75% death rate when identified after metastasis. Drug resistance and tumor recurrence are likely due to cancer stem-like cells (CSCs) that evade chemotherapy and induce relapse with phenotypes that are distinct from bulk tumor cells. It remains unclear how CSCs facilitate relapse and what role the tumor microenvironment (TME) plays in this process. Our preliminary data show that a secreted cytokine, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and its receptor Fn14 are overexpressed in ovarian tumors and increase after chemotherapy. TWEAK is a strong inducer of stem cell features and enhances survival of CSCs during chemotherapy exposure. The source of TWEAK has not been clarified, although clinical data from human ovarian tumors show that TWEAK mRNA was primarily observed in a subset of infiltrating immune cells known as tumor associated macrophages (TAMs). When we evaluated TWEAK expression in cells found in the ovarian TME, including PBMC and THP-1-derived macrophages, IMR-90 activated fibroblasts, and ovarian cancer cell lines, we found that PBMC macrophages were the primary source of TWEAK production. Since cytotoxic chemotherapy can enrich for different TAM populations, we propose that TWEAK producing TAMs support CSC survival and expansion and contribute to the high rate of relapse in ovarian cancer patients. We further found that treatment with a small molecule inhibitor of TAM polarization leads to decreased TWEAK production, fewer CSCs, and prolonged remission in mouse models of ovarian cancer relapse as compared to vehicle. Currently we are testing whether knockout of Fn14 in ovarian cancer cells co-cultured with TAMs reduces stem cell features dependent on TWEAK-Fn14 signaling. Identification of immune populations responsible for TWEAK production could lead to new therapeutic strategies for patients with high rates of relapse. Citation Format: Luisjesus S. Cruz, Denay Stevenson, Mikella Robinson, Steffy Mathew, Isabella Amador, Gregory Jordan, Carrie D. House. Role of macrophages in the development of ovarian cancer stem-like cells during chemotherapy [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 163.
Abstract 1961: Discovery of a highly potent and brain penetrant fourth generation EGFR tyrosine kinase inhibitor
Authors: sanjeev kumar, junmei wang, wenqian li, weitao pan, zhiming wen, Kuo-Long yu, Genshi Zhao, tinggui yin
Journal: Cancer Research (2024)

Abstract Third generation EGFR tyrosine kinase inhibitors (TKIs) such as Osimertinib have emerged as first-line standard of care therapy to treat non-small cell lung cancer (NSCLC) patients with activating EGFR mutations (del19, L858R or T790M). However, within 12 to 18 months following treatment, 15-20% of the patients develop C797S mutation, which drives resistance to these drugs; with the progression of disease brain metastasis is observed in 40-70% of the EGFRm+ NSCLC patients. Here, we report a highly potent and brain penetrant fourth generation EGFR-TKI ACE-34237307, designed to overcome C797S mutation (del19/C797S and L858R/C797S), and common single point mutations (del19 and L858R). ACE-34237307 is also designed to potently inhibit the more prevalent non-canonical EGFR mutations such as G719S and L861Q. ACE-34237307 showed robust anti-proliferative activity against EGFR double mutations in Ba/F3 (EGFR-del19/C797S and EGFR-L858R/C797S) cell lines with IC50 values of 0.1 and 0.23 nM, respectively. In phospho-EGFR assay, ACE-34237307 demonstrates over 79-fold selectivity against A431 (EGFR-WT) cell line when compared to PC-9 (EGFR-del 19) cell line. ACE-34237307 is highly brain penetrant with B/P ratio of 2.3 in rat and 1.2 in mouse. It has an excellent pharmacokinetic profile in rat, mouse and dog with good bioavailability, a flat PK curve and reduced Cmax, which will translate to a better safety profile. The in vivo anti-tumor efficacy was evaluated in Osimertinib resistant double mutant Ba/F3-EGFR-del19/C797S and L858R/C797S as well as del19 and L858R single mutant xenograft models. It has been shown that ACE-34237307 at doses of ≥ 0.6 mg/kg induces complete tumor regression or eradication in all tumor models tested. In brain tumor models with Ba/F3 (EGFR-del19/C797S) and PC-9 (EGFR-del19), ACE-34237307 showed complete inhibition or eradication of brain tumors and drastically extended animal survival at ≥ 0.6 mg/kg. In summary, ACE-34237307 is a potent fourth generation EGFR-TKI with high WT selectivity, excellent brain penetration, highly favorable DMPK profile, outstanding in vivo efficacy in subcutaneous and brain tumor models and low projected human dose amenable to QD dosing. Citation Format: sanjeev kumar, junmei wang, wenqian li, weitao pan, zhiming wen, Kuo-Long yu, Genshi Zhao, tinggui yin. Discovery of a highly potent and brain penetrant fourth generation EGFR tyrosine kinase inhibitor [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 1961.
Abstract 1965: 3HP-2827-high selective inhibitor of FGFR2, a best-in-class therapy for FGFR2-driven solid tumors
Authors: Susan S. Liu-Chen, Jufang Lin, Jingyu Hu, Yanchao Liu, Weibo Zhang, Zhixiong Zhang, Yan Ding, Jinqiu Liu, Kevin Chen, Shaojing Hu
Journal: Cancer Research (2024)

Abstract FDA-approved pan-FGFR inhibitors bring encouraging results in solid tumors. However, resistance mechanisms and side effect profiles may limit their clinical utility. We designed 3HP-2827, a highly selective and potent small molecule inhibitor of FGFR2, to treat solid tumors harboring FGFR2 alterations, including amplifications, mutations, and fusions to overcome these limitations. 3HP-2827 inhibits FGFR2 enzyme activity with more than 1623-fold selectivity over FGFR1 and FGFR3. 3HP-2827 inhibits cell proliferation with IC50 &amp;lt;10 nM and 30 nM in FGFR2 amplified and FGFR2-mutant cancer cell lines, respectively. 3HP-2827 demonstrates high kinome selectivity for FGFR2 against a panel of 485 human kinases, resulting in 90.1% inhibition of FGFR2, and no other kinases showed greater than 75% inhibition. 3HP-2827 leads only modest activity at 10 µM against PDE4D2 and LCK in 44 distinct common adverse drug reaction targets, supporting its high degree of safety. 3HP-2827 also demonstrates a dose-dependent inhibition of phosphorylation of FGFR2 and FGFR2 signaling pathway nodes, including ERK and AKT, in the FGFR2-dependent cancer cell line. In vivo, 3HP-2827 demonstrates potent antitumor activity in cell- and patient-derived xenograft mouse models, including FGFR2-amplified gastric cancer, FGFR2-mutant (N549K) endometrial cancer, FGFR2 fusion ICC and gastric cancers. Strikingly, 3HP-2827 demonstrates superior activity in patient-derived ICC and gastric cancer, cell-derived endometrial cancer (CDX) in tumor and pFGFR2 inhibitions. In the ICC PDX model, 3HP-2827 also induces the regression of pemigatinib-resistant tumors. 3HP-2827 is well tolerated in the toxicology studies, and no hyperphosphatemia or tissue mineralization is observed at 150 mg/kg/kg/day in rats and 120 mg/kg/day in dogs. The data support that 3HP-2827, a potential to be a best-in-class selective FGFR2 inhibitor, will be studying clinically at the beginning of 2024. Citation Format: Susan S. Liu-Chen, Jufang Lin, Jingyu Hu, Yanchao Liu, Weibo Zhang, Zhixiong Zhang, Yan Ding, Jinqiu Liu, Kevin Chen, Shaojing Hu. 3HP-2827-high selective inhibitor of FGFR2, a best-in-class therapy for FGFR2-driven solid 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 1965.
Abstract 4757: Combining PARP inhibitor with TACC3 inhibition overcomes PARP inhibitor resistance in ovarian cancer
Authors: Yu Wu, Qilong Wang, Chaolin Deng, Mo Li, Yinan Xiao
Journal: Cancer Research (2024)

Abstract The treatment of ovarian cancer (OC) presents a significant challenge due to the emergence of resistance to poly (ADP-ribose) polymerase inhibitors (PARPi). Transforming acidic coiled coil containing protein 3 (TACC3) belongs to the TACC family, characterized by its coiled-coil domains. TACC3 plays a crucial role in cell division, particularly in the formation and stability of the mitotic spindle, which is essential for proper chromosome segregation. Mutations or changes in TACC3 have been associated with various cancers, making it an increasingly attractive target for anticancer therapy in recent years. Here, we demonstrated a significant upregulation of TACC3 in OC, correlating with adverse clinical outcomes. Notably, PARPi-resistant OC cells exhibited a marked sensitivity to TACC3 inhibition. This was evidenced by the induction of spindle defects and mitotic catastrophe in PARPi-resistant cells upon TACC3 suppression, achieved either genetically or pharmacologically. Moreover, we explored the therapeutic efficacy of combining TACC3 inhibitor with PARPi, specifically BO-264 with olaparib or niraparib. This combination exhibited a synergistic effect, markedly reducing cell viability in vitro and tumor growth in PARPi-resistant tumor xenograft models. Our study suggests a promising new method for treating ovarian cancer, especially for those resistant to current PARPi treatments, by simultaneously targeting TACC3 and PARPi, enhancing treatment efficacy and potentially improving patient outcomes. Citation Format: Yu Wu, Qilong Wang, Chaolin Deng, Mo Li, Yinan Xiao. Combining PARP inhibitor with TACC3 inhibition overcomes PARP inhibitor resistance in ovarian 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 4757.
Abstract 4164: Hybrid photoacoustic imaging and fast ultrasound localization microscopy to probe the tumor microenvironment
Authors: Shensheng Zhao, Sayantani Basu, Roy H. Campbell, Yang Zhao, Yun-Sheng Chen
Journal: Cancer Research (2024)

Abstract Photoacoustic (PA) imaging can map the physiological conditions of tissues and track the biodistribution of contrast agents. Ultrasound localization microscopy (ULM) with microbubbles provides deep-tissue super-resolution blood vessel images and blood velocity maps. The integration of these techniques offers a potential tool for oncological applications, such as visualizing tumor hypoxia and vasculature. Additionally, because PA imaging and ULM can share the same ultrasound detector and data-acquisition system, PA images can seamlessly fuse with ULM images without requiring post co-registration processing. However, the acquisition time of ULM is considerably longer (several minutes per frame) compared to PA imaging (10 milliseconds to 100 milliseconds per frame), limiting the simultaneous acquisition of the two imaging modalities. To address this issue, we developed a deep learning model based on U-Net to accelerate the frame rate of ULM using information from sparse microbubble locations and power Doppler images. By enabling fast ULM acquisition, we developed an interleaved PA/fast ULM imaging technique to simultaneously capture photoacoustic and ULM images. Our experiments demonstrated up to a 16 times improvement in acquisition speed with U-Net, utilizing in vivo mouse brain and skin tumor data. The hybrid imaging sequence achieved super-resolution vascular and tissue oxygenation imaging with less than 2 seconds of acquisition time per frame in vivo. The implementation of this rapid dual imaging scheme enables the longitudinal monitoring of 3D tumor microvasculature and hypoxia conditions using a common linear ultrasound transducer. We monitored tumor growth of epidermoid carcinoma (A431) in a mouse model from Day 7 to Day 17 of tumor implantation, and the results reveal a significant decrease in tumor vasculature density and oxygen saturation as the tumor grew larger over time. The results indicate a positive relationship between oxygen saturation and vessel density. Our findings showcase the potential of this innovative technique for advancing deep tissue, high-resolution, multi-biological parameters imaging in oncological research. Citation Format: Shensheng Zhao, Sayantani Basu, Roy H. Campbell, Yang Zhao, Yun-Sheng Chen. Hybrid photoacoustic imaging and fast ultrasound localization microscopy to probe the tumor microenvironment [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 4164.