tbuckley/cabot-search huggingface dataset:
Abstract 7588: Discovery of NSP-5033: A novel and potent PARP7/12 dual inhibitor
Authors: Qin Chen, Qionglin Huang, Ke Zhang, Yuli Hao, Zixuan Wang, Bing Li
Journal: Cancer Research (2024)

Abstract PARP7 is a mono-ADP-ribosyl transferase that catalyzes the transfer of single units of ADP-ribose onto substrate proteins to regulate their functions. One of its substrates is TANK binding kinases 1 (TBK1), whose MARylation by PARP7 inhibits its activation and thereby represses the type I IFN response to cytosolic nucleic acid. PARP7 is upregulated in many kinds of cancers and acts as a brake in cytosolic nucleic acid sensing, which leads to the suppression of type I IFN signaling and immune response. Therefore, PARP7 is a novel and promising target in cancer immunotherapy. Herein, we describe the discovery of a novel small molecule NSP-5033 as a dual PARP7/PARP12 inhibitor, which potently inhibits PARP7 and PARP12 enzymes with sub-nanomolar and low nanomolar activities, respectively. It displayed potent anti-proliferative activities against a number of cancer cell lines in vitro. NSP-5033 also increased the mRNA level of IFNβ and CXCL10 and stimulated STAT1 phosphorylation, suggesting that it restored the type I IFN response in tumor cells. With excellent ADME and pharmacokinetic properties, NSP-5033 demonstrated potent in vivo efficacy in human lung cancer xenografts with tumor regression and induced antitumor immunity in tumor-bearing immunocompetent mice. NSP-5033 has been nominated as a preclinival candidate for treatment of solid tumors and is undergoing IND-enabling studies. Citation Format: Qin Chen, Qionglin Huang, Ke Zhang, Yuli Hao, Zixuan Wang, Bing Li. Discovery of NSP-5033: A novel and potent PARP7/12 dual 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 7588.
Abstract 7451: Translational models of ovarian cancer-associated cognitive impairment and chemotherapy-induced peripheral neuropathy
Authors: Naomi Lomeli, Donovan Argueta, Diana C. Pearre, Javier Lepe, Kalpna Gupta, Daniela A. Bota
Journal: Cancer Research (2024)

Abstract Cisplatin is widely used to treat ovarian malignancies, and over 70% of ovarian cancer patients report experiencing cancer-related cognitive impairment (CRCI) and chemotherapy-induced peripheral neuropathy (CIPN) during and after chemotherapy treatment. Most pre-clinical CRCI/CIPN studies have been conducted on non-tumor bearing rodents. We developed two novel clinically relevant models of CRCI/CIPN: (1) the ID8 syngeneic mouse model in B6(Cg)-Tyrc-2J/J female mice, and (2) the SKOV3.ip1 ovarian cancer xenograft model in female Cr:NIH-RNU rats. We examined cognitive function and serum cytokine levels with respect to cancer progression and/or in response to cisplatin. B6 female mice were injected with 107 ID8 cells or 0.9% saline, i.p. Mice received cisplatin (2.3 mg/kg/day, i.p.) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) for 5d, followed by 5d of rest for two cycles. RNU rats were injected with 107 SKOV3.ip1 cells or 0.9% saline, i.p. Rats received cisplatin (5 mg/kg, i.p) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) every other week for four cycles. OvT+CIS and OvT+VEH mice and rats showed impairments in novel object recognition (NOR), with discrimination ratios ≤0.5. Cisplatin transiently increased hyperalgesia in OvT+CIS mice, which persisted longitudinally in OvT+VEH mice. Serum cytokine levels were elevated in OvT+VEH mice (IL-2, IL-10, INFγ) and OvT+VEH rats (IL-4, IL-10) compared to OvT+CIS (P&amp;lt;0.05). Ovarian cancer may evoke progressive sensory and neurocognitive deficits and increase systemic pro-inflammatory cytokine levels in the absence of chemotherapy. Future studies will address hyperalgesia and cognitive differences between healthy control and ovarian cancer models +/- cisplatin, and biological mechanisms underlying CRCI and CIPN. Citation Format: Naomi Lomeli, Donovan Argueta, Diana C. Pearre, Javier Lepe, Kalpna Gupta, Daniela A. Bota. Translational models of ovarian cancer-associated cognitive impairment and chemotherapy-induced peripheral neuropathy [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 7451.
Abstract 7445: Association between C-reactive protein and cognitive impairment in IDH-mutant gliomas
Authors: McKenzie C. Kauss, Michelle L. Wright, Dhaivat Raval, Emory Hsieh, Kaitlynn Slattery, Terri S. Armstrong, Tito R. Mendoza, Vivian A. Guedes
Journal: Cancer Research (2024)

Abstract Cognitive impairment is common in primary brain tumor (PBT) patients, as a result of the disease and secondary damage from directed and systemic therapy. Recently, the risk in patients with IDH-mutant gliomas and role of interconnectivity of the tumor with neurons and the tumor microenvironment has heightened interest in exploration of biomarkers of impairment to inform care. Here, we investigate Montreal Cognitive Assessment (MoCA) scores and peripheral blood levels of C-reactive protein (CRP) in a cross-sectional cohort of 47 adult IDH-mutant PBT patients enrolled in a natural history study (NHS, NCT02851706: PI T. Armstrong). MoCA raw scores (range 0-30) were dichotomized (≤ 25 = cognitive dysfunction). Baseline CRP was quantified in banked serum samples in duplicate using (V-Plex/Vascular Injury Panel-2, Meso Scale Discovery [MSD], Rockville, MD) in a QuickPlex SQ 120 instrument (MSD). Lab personnel were blinded to diagnosis and clinical status. To reduce skewness in CRP raw values, we used log transformation. Descriptive statistics, Pearson’s correlation, and logistic regression were conducted using IBM SPSS and SAS Statistics software. The sample was predominately male (62%), white (70%), with high-grade gliomas (III/IV) (68%) and an average age at diagnosis of 36 years (SD: 9; median: 34; range: 20-53). The mean MoCA score was 25 (SD: 5; median: 26; range: 11-30). Dichotomizing MoCA scores showed that less than half (43%) of participants exhibited moderate-severe (≤ 25) cognitive impairment. MoCA binary group was negatively correlated with levels of CRP (r=-0.42, p&amp;lt;.003). The log mean concentration of CRP was higher in participants with cognitive impairment (7.99, SD=0.47 vs 7.57, SD=0.45, p&amp;lt;.003) than those without impairment. Finally, when controlling for age and sex, CRP remained predictive of cognitive impairment (OR 8.18, 95% CI 1.70,39.23). Higher levels of CRP were associated with lower MoCA scores in a cross-sectional sample of patients with IDH-mutant gliomas, suggesting an association between the severity of inflammation and cognitive impairment in IDH-mutant glioma patients. Further analysis in large, more diverse longitudinal cohorts will be needed to validate these findings in this population and compare to those with IDH-WT tumors and develop predictive models to inform biomarker development. Citation Format: McKenzie C. Kauss, Michelle L. Wright, Dhaivat Raval, Emory Hsieh, Kaitlynn Slattery, Terri S. Armstrong, Tito R. Mendoza, Vivian A. Guedes. Association between C-reactive protein and cognitive impairment in IDH-mutant gliomas [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 7445.
Abstract 759: Soy protein diet changes metabolic profile in liver of 7,12-dimethylbenz(<i>α</i>)anthracene (DMBA)-induced mammary tumors in obese zucker rats
Authors: Reza Hakkak, Stepan Melnyk
Journal: Cancer Research (2024)

Abstract Obesity is associated with the risk of certain types of cancers development including breast cancer. Previously, we reported that obesity increased mammary tumor development using obese Zucker rat model. Several studies have shown the health benefit of soy protein consumption. However, the effects of soy protein diet on liver of mammary tumor for oxidative stress and DNA reaction is less known. We used DMBA induced-mammary tumor model to investigate the effects of soy protein diet on pro-oxidative environment and oxidative DNA modification in liver of obese DMBA mammary tumors rats. Female obese zucker rats (n=45) were either fed casein as control (OC; n=20) or soy protein isolate (OS; n=25), received DMBA (65mg/kg BW) at the age 50 days and sacrificed 20 weeks later. We used HPLC-ECD, HPLC-UV and LC-MS techniques for liver metabolic analysis. Comparing liver of OS vs. OC, soy protein 1) decreased the level of Methionine (P&amp;lt;0.02), increased 2) free reduced Homocysteine (P&amp;lt;0.02), 3) S-Adenosylmethionine (SAM, P&amp;lt;0.03), 4) S-Adenosyhomocysteine (SAH, P&amp;lt;0.001) and 5) 5methyl-Cytosine (5mC, P&amp;lt;0.03). Also, soy protein decreased (P&amp;lt;0.003) level of free oxidized Glutathione (GSSG), increased (P&amp;lt;0.02) GSH/GSSG oxidative stress ratio, without any changes a level of free reduced Glutathione (GSH), followed decrease (P&amp;lt;0.04) in liver DNA level of 8-OH-Guanosine (8-OH-G) and level (P&amp;lt;0.02) of 5hmethyl-Cytosine (5hmC). Our results shows soy protein diet capable change liver metabolism: a. Modify a methylation status by increasing levels of SAM (universal methyl group donor) following global liver DNA hypermethylation (5mC), and SAH (methylases inhibitor); b. Alleviate level of oxidative stress in liver by decreasing level of GSSG (not active glutathione), increasing GSH/GSSG ratio (antioxidative capacities), following lower ROS liver DNA damages by decrease levels of 8-OH-G and 5hmC. In conclusion, using obese DMBA-induced mammary tumor Zucker rat model, soy diet making a complex and significantly modification of metabolic conditions in liver affecting both methionine cycle and transsulfuration metabolic pathways. Citation Format: Reza Hakkak, Stepan Melnyk. Soy protein diet changes metabolic profile in liver of 7,12-dimethylbenz(α)anthracene (DMBA)-induced mammary tumors in obese zucker rats [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 759.
Abstract 744: Novel conditionally active biologic (CAB) tetravalent T-cell engagers targeting solid tumors
Authors: Ana Paula Cugnetti, Haizhen Liu, Patricia McNeeley, Charles Xing, Kathryn Woodard, Hwai Chang, Gerhard Frey, William J. Boyle, Jay M. Short
Journal: Cancer Research (2024)

Abstract The use of T-cell engagers (TCEs) has great therapeutic potential in oncology. This potential, however, is diminished due to severe toxicity (cytokine release effects, as well as on-target off-tumor toxicities). We leveraged BioAtla’s Conditionally Active Biologic (CAB) technology (1) to develop bispecific antibodies which have no or very little binding to CD3 and to the tumor target antigen (TAA) in healthy tissue (normal physiological conditions), yet have strong binding in diseased tissues (i.e. tumor microenvironment, TME) derived from glycolytic tumor metabolism, which supports tumor growth (Warburg effect). The conditional activity in the TME is achieved by optimizing the sequences of the binding domains and does not require masking and subsequent activation of the binding domain as used in pro-drugs. We have developed dual-CAB T-cell engagers targeting serval well-established tumor associated antigens. Data demonstrating superior potency with reduced off-target binding through in vitro and in vivo characterization of three new DualCAB TCEs, targeting PSMA, Trop2, and Tissue Factor (TF) will be presented.(1) Chang HW, Frey G, Liu H, Xing C, Steinman L, Boyle WJ and Short, JM Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches. Proc Natl Acad Sci U S A 2021;118. Citation Format: Ana Paula Cugnetti, Haizhen Liu, Patricia McNeeley, Charles Xing, Kathryn Woodard, Hwai Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active biologic (CAB) tetravalent T-cell engagers targeting 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 744.
Abstract 7452: ApoE genotype influences susceptibility to doxorubicin-induced cognitive impairment in juvenile rats
Authors: Chadni Patel, Jeremy Willekens, Frank Diglio, Peter Cole
Journal: Cancer Research (2024)

Abstract Many pediatric cancer survivors experience chemotherapy-induced cognitive impairment (CICI), which negatively impacts the quality of life. Despite extensive research into the multifactorial causes of CICI, there are no FDA approved drugs available to prevent it and the interpatient variability in susceptibility to CICI is not well understood. Among pediatric cancer survivors, those with the E4 allele of Apolipoprotein E (ApoE) are more likely to exhibit cognitive dysfunction than those with the more prevalent ApoE3 allele, suggesting the ApoE4 allele increases susceptibility to CICI. To mimic a curative pediatric treatment regimen, in our experimental model, five-week-old rats homozygous for either human ApoE3 or ApoE4 allele were treated with doxorubicin (DOXO) (2mg/kg/week for 4 weeks) or saline. ApoE4 rats were more likely than ApoE3 rats to exhibit DOXO-induced impairments in visual memory. However, there was no difference between ApoE3 and ApoE4 rats in sensitivity to DOXO-induced spatial memory impairments. Contrast-enhanced magnetic resonance imaging (MRI) was done to evaluate the blood-brain barrier (BBB) integrity because of literature suggesting that the ApoE4 allele contributes to BBB weakness. However, no significant difference was observed in the BBB integrity between ApoE3 and ApoE4 rats. To delve deeper into the neuropathological basis of DOXO-induced cognitive impairment on the ApoE4 allele, ongoing experiments involve immunohistochemical analyses targeting neurogenic changes in neural stem cell proliferation (DCX), neuronal maturation (Syn and PSD95), as well as glial differentiation (Iba1 and GFAP) in brain regions including hippocampus (dentate gyrus) and cortex. Additionally, to determine the effect of DOXO treatment on ApoE4, we are investigating the role of mitogen-activated protein kinase (MAPK) signaling pathways within brain regions pertinent to memory and recognition. In summary, ApoE genotype contributes to differential susceptibility to CICI. Citation Format: Chadni Patel, Jeremy Willekens, Frank Diglio, Peter Cole. ApoE genotype influences susceptibility to doxorubicin-induced cognitive impairment in juvenile rats [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 7452.
Abstract 7585: Targeting of 7 or 24 dehydrocholesterol reductase decreases cancer progression in head and neck cancer
Authors: Bok-Soon Lee, Ji-Hye Choi, Hyo Jeong Kim, Jin Roh, Joselyn Padilla, Kennedy Davis Brock, Jeon Yeob Jang, Hyun Goo Woo, Chul-Ho Kim, Jiyoung Lee
Journal: Cancer Research (2024)

Abstract The elevated expression of cholesterol metabolism has been associated with many cancer including head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanisms between cholesterol biosynthesis and head and neck cancer have not yet been studied. In this study, we identified upregulation of dehydrocholesterol reductase such as DHCR7 or DHCR24 in HNSCC compared with adjacent normal tissues from the same patients using RNA sequencing data. We observed protein expression level of DHCR7 or DHCR24 in head and neck cancer cell lines through Western blotting. We also checked high expression of DHCR7 or DHCR24 in HNSCC tissues from patients using immunohistochemistry assays. Yet, when DHCR7 or DHCR24 was knocked down using siRNA, the viability of HNSCC cells was decreased in MTT assays. In parallel, we adapted small inhibitory drugs; AY9944 for DHCR7 inhibition and Triparanol or SH-42 for DHCR24 inhibition. Treatment of AY9944, Triparanol, or SH-42 also resulted in decreased viability of HNSCC cells. Moreover, when we used a cholesterol blocker, MCD, the cell viability was decreased, whereas the cells overcame cell death by adding the combination of cholesterol and LDL. Taken together, we concluded that head and neck cancer requires DHCR7 and DHCR24 activity involved in cholesterol metabolism for cancer growth. Our data suggest that targeting DHCR7 or DHCR24 using AY9944, Triparanol or SH-42 is one of the potential strategies that will definitely help with cancer treatment for head and neck cancer. Citation Format: Bok-Soon Lee, Ji-Hye Choi, Hyo Jeong Kim, Jin Roh, Joselyn Padilla, Kennedy Davis Brock, Jeon Yeob Jang, Hyun Goo Woo, Chul-Ho Kim, Jiyoung Lee. Targeting of 7 or 24 dehydrocholesterol reductase decreases cancer progression in head and neck 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 7585.
Abstract 1701: ABI1 regulates prostate tumor plasticity through chromatin remodeling and transcriptional regulation
Authors: Leszek Kotula
Journal: Cancer Research (2024)

Abstract Background: Prostate cancer remains a challenging issue affecting men worldwide. In contrast to localized disease, metastatic prostate cancer tumor is incurable. Progression to metastatic disease is characterized by tumor heterogeneity and plasticity regulated by epigenetic changes of tumor cells. While tumor heterogeneity is often associated with gene mutations, tumor plasticity is ascribed to transcriptional regulation and chromatin activity. The latter is modulated by treatment of prostate cancer leading to treatment resistance. Here, we identified a novel mechanism of epigenetic regulation in prostate cancer by an actin regulatory and signaling protein, Abelson Interactor 1 (ABI1). Methods: To demonstrate the ABI1-DNA binding, we employed in vitro binding assays, NMR spectroscopy, and ChIP-seq. from cells expressing alternatively spliced isoforms of ABI1 that contain or lack the DNA binding HHR domain. To determine the ABI1 interactions with several transcriptional factors, we used immunoprecipitation and/or proximity ligation assay (PLA). We used ATAC sequencing to determine the chromatin accessibility in the presence or absence of ABI1 gene. RNA-seq established the activity of transcriptional factors and signaling pathways regulated by ABI1. Results: Using NMR spectroscopy, we established that ABI1 demonstrated DNA binding dependent on the presence of alternatively spliced Exon 4. Exon 4 is located within the homeobox homology region (HHR). The DNA binding activity was confirmed using in vitro binding assays; the assay results confirmed the role of ABI1 HHR. Moreover, cells lacking ABI1 or expressing ABI1 lacking Exon 4 show low accessibility and activity of chromatin. In contrast, cells expressing ABI1 containing Exon 4 show active chromatin. RNA-seq analysis demonstrated that ABI1 regulated transcription in an Exon 4-dependent manner. Conclusions: We uncovered a role of ABI1 in chromatin stability, that is dependent on the presence of the DNA binding region. Notably, ABI1's contribution to transcriptional activity occurs via a transient yet precisely defined interaction between its intrinsically disordered region and DNA. This regulatory control plays a pivotal role in managing tumor plasticity by establishing connections between the actin cytoskeleton, cellular signaling, and transcriptional regulation. Based on these findings, we propose that ABI1 functions as an epigenetic regulator, maintaining transcriptional homeostasis in prostate cancer. Citation Format: Leszek Kotula. ABI1 regulates prostate tumor plasticity through chromatin remodeling and transcriptional regulation [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 1701.
Abstract 1528: Flowcytometric based approach to investigate prostate tumor microenvironment
Authors: karishma sajnani, Sini Eerola, Konsta Kukkonen, Hanna Rauhala, Tapio Visakorpi, Alfonso Urbanucci
Journal: Cancer Research (2024)

Abstract Prostate cancer (PC) and its tumor microenvironment (TME) are heterogenous and evolving along with the treatment patients are exposed to. Modelling of the TME represents an attractive approach to understand how PC evolves and spreads. Flow cytometry is a technique for quantitative measurement of single cell profiling based on the cell surface as well as intracellular markers. We designed a flowcytometric based approach to investigate the interplay between the PC cells and immune cells in a direct coculture. Cells are fluorescently tagged with a cell tracer and the analysis is performed separately on the adherent and non-adherent cells. To optimize the readout method, we investigate the interplay between Jurkat cells and PC cells (LNCaP) as well as immortalized prostate epithelial cell models modified to mimic early events in prostate carcinogenesis (RWPE-1 cells overexpressing androgen receptor, RWPE-1-AR, and having PTEN deletion, RWPE-1-AR-PTENdel).Jurkat (suspension culture) cocultured with LNCaP (adherent culture) exhibited 40% decrease in viability but only 30% of LNCaP dying cell in the floating population compared to LNcaP only which is 60%. When Jurkat were activated using Phorbol 12-myristate 13-acetate (PMA), we observed an increase in LNCaP cell death. Jurkat viability was not impacted in presence of RWPE-1 neither when exposed to RWPE1-AR-PTENdel. In summary our Flowcytometric-based approach will help to understand the interplay between immune cells and prostate cancer cells. Citation Format: karishma sajnani, Sini Eerola, Konsta Kukkonen, Hanna Rauhala, Tapio Visakorpi, Alfonso Urbanucci. Flowcytometric based approach to investigate prostate 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 1528.