bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 57: Ibrutinib improves chimeric antigen receptor T cell control of leukemia by inhibiting myeloid-derived suppressor cells
Authors: Frost Benjamin F. , Shestova Olga , Shen Feng , Sharpe Chia , Byrd John C. , Gill Saar I. 
Published: March 2024

Abstract
Background: In patients with chronic lymphocytic leukemia (CLL), we and others have shown that the addition of the BTK inhibitor ibrutinib to CART cells increases the rates of durable complete responses. The mechanism for this remains unknown. Lymphodepletion (LD) is considered critical for CART cell therapy success, yet emergency myelopoiesis during recovery from LD may induce a surge of myeloid-derived suppressor cells (MDSC), particularly in patients with advanced cancer. BTK inhibition has been shown to inhibit MDSC function in vitro. We therefore hypothesized that administration of ibrutinib during and following LD could reduce MDSC-mediated suppression of CART cells and thereby improve CART cell outcomes.
Methods: To explore the effects of ibrutinib on human MDSCs, we engineered suppressive monocytes through in vitro culture of CD14+ cells in the presence of IL-6 and GM-CSF. We added ibrutinib to the culture on Days 0-4 and compared the ability of the monocytes to inhibit proliferation of human CAR-T cells. To model CLL treatment with CART in immunocompetent mice, we used the Em-TCL1 adaptive transfer model of CLL. Mice were treated with ibrutinib (I), cyclophosphamide and fludarabine (FC), or ibrutinib + FC (FC+I). MDSCs were isolated from these mice for in vitro function studies. In subsequent experiments mice were also treated with syngeneic CART19 with or without FC or FC+I.
Results: In vitro generated human MDSC suppressed CART19 function, and this was prevented by pre-treatment of MDSC with ibrutinib. Myeloid cells from the spleens of CLL-bearing mice inhibited syngeneic CART19 function ex vivo regardless of treatment with FC or I alone, but myeloid cells harvested from CLL-bearing mice treated with FC+I lost suppressive function. Finally, mice treated with CART19 after a LD regimen resembling that in our recently reported clinical trial (FC+I) showed a survival advantage over all other groups.
Conclusions: BTK inhibition with ibrutinib prevents myeloid cell suppression of CART cells in vitro in human and murine systems. When combined with lymphodepleting chemotherapy (FC), ibrutinib enhances CART cell control of CLL in vivo, possibly by preventing MDSC-mediated suppression of CART cells.
Citation Format: Benjamin F. Frost, Olga Shestova, Feng Shen, Chia Sharpe, John C. Byrd, Saar I. Gill. Ibrutinib improves chimeric antigen receptor T cell control of leukemia by inhibiting myeloid-derived suppressor cells [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 57.
Abstract 5727: ISM9682A, a novel and potent KIF18A inhibitor, shows robust antitumor effects against chromosomally unstable cancers
Authors: Zhang Jie , Gao Feng , Zhu Wei , Xu Chenxi , Ding Xiaoyu , Shang Jing , Qiao Junwen , Chen Shan , Cai Xin , Ding Xiao , Bavadekar Supriya , Rao Sujata , Zhang Man , Ren Feng , Zhavoronkov Alex 
Published: March 2024

Abstract
KIF18A belongs to the kinesin-8 subfamily and is a plus-end-directed motor, which regulates kinetochore microtubules dynamics to control mitotic chromosome alignment and spindle tension. Studies have shown that genetic depletion or pharmacological inhibition of KIF18A is a promising therapeutic approach for cancers, exhibiting high chromosomal instability (CIN-high), without having a significant impact on the normal division of euploid cells. Here, we report the discovery and preclinical evaluation of ISM9682A, a novel KIF18A inhibitor with excellent potency and high selectivity. ISM9682A is a potent KIF18A inhibitor with a single-digit nanomolar IC50 value and exhibits high selectivity over other kinesin family members. In addition, ISM9682A demonstrated excellent monotherapy anti-proliferative activity, with single-digit nanomolar IC50 values, in high-grade serous ovarian carcinoma (HGSOC) as well as in triple-negative breast cancer (TNBC) aneuploid cell lines with p53 mutation. Notably, ISM9682A exhibited a prolonged drug-target residence time indicated by both enzymatic and cellular assays. Consistent with the in vitro findings, ISM9682A displayed significant anti-tumor efficacy with a robust pharmacodynamic response (pH3, mitotic marker; γH2AX, DNA damage marker) in OVCAR3 and HCC1806 CDX models in a dose-dependent manner. In addition to its robust biological potency and high selectivity, ISM9682A exhibits favorable drug-like properties, including desirable in vitro ADMET characteristics and excellent in vivo exposure, clearance, as well as good oral bioavailability across multiple preclinical species. Collectively, these findings highlight the potential of ISM9682A as a novel and highly potent KIF18A inhibitor for the treatment of CIN-high cancers.
Citation Format: Jie Zhang, Feng Gao, Wei Zhu, Chenxi Xu, Xiaoyu Ding, Jing Shang, Junwen Qiao, Shan Chen, Xin Cai, Xiao Ding, Supriya Bavadekar, Sujata Rao, Man Zhang, Feng Ren, Alex Zhavoronkov. ISM9682A, a novel and potent KIF18A inhibitor, shows robust antitumor effects against chromosomally unstable cancers [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 5727.
Abstract 5746: Tris(4-methoxyphenyl) methanol conjugates of triptorelin as cell-penetrating anti-cancer prodrugs
Authors: Beni Ryan , Boadi William , Alnakhli Jawzah , Alhamed Samiyah 
Published: March 2024

Abstract
Triptorelin® (TRP) is an anti-cancer drug used for the treatment of a wide range of hormone-responsive cancers, including prostate cancer. The increase in testosterone levels, known as the flare effect, is a major side effect of cancer chemotherapy when TRP is used in a combination regimen. Reports indicate that enhancing the cellular uptake and retention of TRP can improve its biological activity. In this study, TRP conjugates of tris(4-methoxyphenyl) methanol derivatives (TPMs) with optimized hydrophobicity were synthesized by reacting 2-substituted methoxybenzenes with 1,3,5-trioxane, followed by conjugation with TRP and sebacic acid to produce TRP-TPMs derivatives. The hydrophobicity of TRP was optimized by using the appropriate hydrophobic linker attached to the respective TPM to improve cellular uptake. The aim of the current studies was to evaluate the respective antiproliferative effects of the newly synthesized TRP-TPMs, physical mixtures of TPMs and TRP using different cell lines. Our hypothesis was that exposure of cells to TRP-TPMs derivatives can enhance the antiproliferative activities in cells in comparison to respective the physical mixtures and TRP. Antiproliferative studies in human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse preadipocytes (3T3-L1) were carried out following exposure to the respective compounds. Our findings indicate that TRP-TPMs conjugates, at a concentration of 50 µM, significantly inhibited cell proliferation in CCRF-CEM, SK-OV-3, and 3T3-L1 cells by 21-37%, 24-73%, and 37-56%, respectively, following 72-hour incubation in comparison to the respective physical mixtures and TRP. Conjugation of TRP with the respective derivative of TPMs enhanced antiproliferative activities in all the cells (with no significant differences in cytotoxicity) compared to the physical mixtures of TPMs and TRP. The findings in the current studies suggest that TRP-TPMs can be used as potential prodrugs, to enhance the cells biological activity, and cellular uptake of TRP.
Citation Format: Ryan Beni, William Boadi, Jawzah Alnakhli, Samiyah Alhamed. Tris(4-methoxyphenyl) methanol conjugates of triptorelin as cell-penetrating anti-cancer prodrugs [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 5746.
Abstract 5751: Ultrasound responsive injectable hydrogels for on-demand drug delivery
Authors: Xiang Li , Sener Gulsu , Yildirim Adem 
Published: March 2024

Abstract
In this work, we developed ultrasound-responsive and injectable hydrogels for local and on-demand release of chemotherapeutics to solid tumors. Injectable hydrogels were prepared by using a zwitterionic monomer, sulfobetaine methacrylate (SBMA), without using any crosslinker. Gelation was performed at -20 oC using APS/TEMED as initiator, allowing the formation of strong electrostatic interactions between poly(SBMA) chains to physically crosslink the hydrogels. Monomer and initiator concentrations were carefully optimized to achieve injectable hydrogels with mechanical and thermal stability. To render ultrasound responsivity to the hydrogels, we loaded the hydrogels with hydrophobically (dodecyl) modified mesoporous silica nanoparticles (hMSNs) with sizes around 50 nm. When insonated with low-intensity focused ultrasound (LIUS), the hMSNs incept acoustic cavitation (i.e., growth and collapse of microsized bubbles), which in turn generates mechanical effects in the hydrogels such as shock waves or water jets. We found that loading the hydrogels with hMSN did not affect their injectability, and they remained mechanically stable at 37 °C for more than a week. hMSN-loaded hydrogels demonstrated strong ultrasound responsivity even at low particle concentrations (0.1 mg/mL) and ultrasound powers (25 W, 0.02% duty cycle). Finally, we loaded the hydrogels with a chemotherapy drug, doxorubicin (DOX, 0.2 mg/mL). DOX-loaded hydrogels demonstrated minimal release without LIUS treatment (&lt;20% in a day). Application of LIUS (150 W, 1% duty cycle) for 5 min resulted in almost complete mechanical disintegration of the hydrogels, resulting in a burst DOX release. We also showed that the amount of released DOX could be controlled by tuning the LUIS power and its duration. In summary, we developed injectable hydrogels with strong ultrasound responsivity. These hydrogels hold great promise for local and on-demand drug delivery to solid tumors, which is currently under investigation in our laboratory.
Citation Format: Li Xiang, Gulsu Sener, Adem Yildirim. Ultrasound responsive injectable hydrogels for on-demand drug delivery [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 5751.
Abstract 5754: Targeting miR-92b with peptide-modified liposomes for glioblastoma treatment
Authors: Sánchez-Álvarez Annelis Odette , Valiyeva Fatima , Vivas-Mejia Pablo E. 
Published: March 2024

Abstract
Focusing on enhancing drug delivery to the brain, we aim to optimize a nanocarrier system with a specific focus on glioblastoma (GBM). This involves the utilization of spherical nucleic acids (SNAs) enclosed in peptide-modified liposomes, a configuration previously proven to effectively penetrate the blood-brain barrier (BBB) in a GBM mouse model. Our objective is to enhance the nanocarrier's treatment load by optimizing the attachment of oligonucleotide-modified gold nanoparticles (OMI) to the SNAs. MicroRNAs (miRNAs) play crucial roles in GBM pathogenesis, with miR-92b identified as overexpressed in various cancers, including GBM. Previous research from our lab implicated miR-92b in targeting proteins (FBXW7 & SKP2) in the ubiquitination pathway. RNA sequencing confirmed the significance of these pathways. RNA sequencing of miR-92b inhibition in the U87 GBM cell line revealed impacts on cell cycle, apoptosis, DNA repair, and multiple cancer-related pathways. We successfully modified the gold nanoparticle size from 15 nm to 5 nm, increasing the surface area and improving OMI attachment efficiency from less than 5% to 50%. This alteration significantly enhances drug loading in the nanocarrier, providing a promising platform for clinical applications. Characterization of the optimized peptide-modified liposomes reassured the retention and potential improvement of original features related to nanoparticle size and internalization in cell cultures. Future in vivo experiments, utilizing a GBM mouse model, will assess the therapeutic effect of inhibiting miR-92b using peptide-modified liposomes as a drug delivery system. Our multifaceted approach, involving nanocarrier optimization and miR-92b inhibition, holds promise for developing an effective treatment strategy against GBM. The presented results highlight the potential translational impact of our research in addressing the challenges associated with GBM therapy.
Citation Format: Annelis Odette Sánchez-Álvarez, Fatima Valiyeva, Pablo E. Vivas-Mejia. Targeting miR-92b with peptide-modified liposomes for glioblastoma treatment [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 5754.
Abstract 5766: Fungal genomes in drug discovery: Application of CETSA to study the mechanism of action of brefeldin A
Authors: Friman Tomas , Fontaine Benjamin M. , Chernobrovkin Alexey , Molina Daniel Martinez , Brehmer Victoria , Lundgren Stina , Castaldi Paola M. , Verdine Gregory L. 
Published: March 2024

Abstract
Fungal genomes encode a vast collection of chemical diversity that has evolved over millions of years to engage specific targets and modulate diverse biological processes. These Genetically Encoded small Molecules (GEMs) constitute a largely untapped source of potential therapeutics. Although fungal GEMs such as cyclosporine, lovastatin, and penicillin have revolutionized modern medicine, these GEMs were discovered serendipitously through bioactivity-guided fractionation of fungal extracts. LifeMine is redefining GEM discovery through the deployment of proprietary genomic search algorithms that enable GEM target prediction a priori. Our strategy facilitates focused search-and-retrieval campaigns to rationally discover molecules selected by Nature to modulate the desired target protein. These GEM drug leads often exhibit unique structural and mechanistic features, necessitating comprehensive deconvolution of the human target profile and mechanism of action during the development process from GEM to clinical candidate. As a proof-of-concept study, we leveraged CETSA Explore to study the biological mechanism of the fungal polyketide lactone Brefeldin A (BFA) in human THP-1 cells. This GEM, originally isolated from the filamentous fungus Penicillium brefeldianis, inhibits protein trafficking between the endoplasmic reticulum and the Golgi complex, eliciting antiviral, antifungal, and anticancer activity. Our CETSA profiling study confirmed the Golgi-associated guanine nucleotide exchange factor GBF1 as the primary target of BFA, validating the established mechanism of this GEM as an inhibitor of GBF1-mediated activation of the small GTPase ARF1. These results demonstrate the utility of integrating the LifeMine GEM discovery engine with downstream proteomic profiling technologies to facilitate the mechanistic characterization of fungal GEMs en route to novel therapeutics.
Citation Format: Tomas Friman, Benjamin M. Fontaine, Alexey Chernobrovkin, Daniel Martinez Molina, Victoria Brehmer, Stina Lundgren, Paola M. Castaldi, Gregory L. Verdine. Fungal genomes in drug discovery: Application of CETSA to study the mechanism of action of brefeldin A [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 5766.
Abstract 5767: DNA binding mechanism of prostate cancer target ONECUT2
Authors: Chatterjee Avradip , Gallent Brad , Katiki Madhusudhanarao , Qian Chen , Harter Matthew R. , Freeman Michael R. , Murali Ramachandran 
Published: March 2024

Abstract
Transcription factors (TF) are essential determinants of gene regulation and their aberrant expression frequently drive cancers. The binding of TFs to cognate DNA is central to their role in gene regulation. An understanding of their DNA binding mechanism is, therefore, of fundamental and therapeutic relevance. Generally, TFs bind DNA through defined DNA binding domains. The CUT and homeodomain are two such evolutionarily conserved elements found paired in multiple transcription factor families including ONECUT (OC), POU, CUX and SATB. However, the mechanism of cross-talk between the CUT and homeodomain to coordinatedly bind DNA remains unknown. Here, we report an integrative DNA binding analyses of the transcription factor OC2, a promising target for treatment of aggressive prostate cancer. We demonstrate that the homeodomain of OC2 thermodynamically stabilizes the DNA binding through allosteric modulation of CUT. The binding energetics is further dependent on base interactions by evolutionarily conserved amino acids in both CUT and homeodomain. In addition, we have discovered a unique arginine pair in the homeodomain, conserved within the ONECUT family, but not across POU and SATB families. We show that one arginine of this pair binds distinctly to DNA in respective complexes formed by OC2 and OC1. Notably, the above base-interactions are crucial for OC2-driven disease progression in a prostate cancer cell-line model. Taken together, our studies show that base-interactions by the evolutionarily conserved residues determine the basic DNA binding functionality through establishing favorable thermodynamics, while interactions by the arginine motif impart family-specific attributes. These findings also establish the homeodomain as a key regulator of DNA binding by OC2 and provide a mechanism for cooperative DNA binding by the CUT-homeodomain module in general. Importantly, these insights reveal vulnerabilities for therapeutic targeting of OC2.
Citation Format: Avradip Chatterjee, Brad Gallent, Madhusudhanarao Katiki, Chen Qian, Matthew R. Harter, Michael R. Freeman, Ramachandran Murali. DNA binding mechanism of prostate cancer target ONECUT2 [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 5767.
Abstract 5770: Inhibition of KRAS G12D mutant with small molecules
Authors: Lee Dae-Hee , Lee Ji Yoon 
Published: March 2024

Abstract
Background: RAS mutations are occurring at a high rate in colorectal cancer, lung cancer, and pancreatic cancer. RAS is family of small GTPase proteins with important roles in cell growth, differentiation, proliferation, and survival. There are three types of RAS genes: HRAS, KRAS, and NRAS. The The RAS gene is the most commonly found oncogene in human cancer. KRAS exhibits a highest mutation rate compared to those of HRAS and NRAS in various cancer types.
Methods: Colorectal cell line LIM1215, SW48 and NSCLC cell line NCI-H1975, NCI-H838 were used for MTT assays. Apoptosis assay was performed using the annexin V-FITC apoptosis detection kit (BioBud, Cat. LS-02-100). Colony forming assay was performed with 6-well culture plates by seeding 500 cells/well. The expression levels of proteins involved in Q2a-induced signaling pathway were determined by Western blot. In vivo study was performed with tumor xenografts. HT-29 cells were implanted into the right flank of 5-week-old BALB/c nude mice. Tumor size was determined by measuring the diameter (width, length) of the tumor every two days with a digital caliper. All group mice sacrificed at day 19.
Results: Patients with cancer involving KRAS mutations are resistant to therapeutics that target epidermal growth factor receptor and show poor outcomes. In addition, effective treatments that target G12D in KRAS have not been developed. Thus, therapeutic agents targeting the G12D mutation in KRAS are needed. In this study, we identified the Q2a compound, a quinazoline-based derivative that specifically acts on the KRAS G12D mutation. This compound induced cell apoptosis by reducing phosphorylation of AKT in the PI3K pathway downstream of KRAS. Q2a compound specifically inhibited the growth of KRAS G12D mutant cells. In addition, cells with the KRAS G12D mutation were more sensitive to Q2a compound compared to the sensitivity of wild-type cells and those with other KRAS mutations, resulting in apoptosis. Treatment with the Q2a compound also decreased C-RAF phosphorylation in the MAPK pathway, which is downstream of KRAS. In KRAS G12D-mutated colorectal cancer xenografts, Q2a compound inhibited tumor production without significant liver toxicity.
Conclusion: Q2a compounds show potential as therapeutic agents that target KRAS G12D mutations in colorectal and pancreatic cancers.
Kyewords: Anti-Cancer Drug, KRAS G12D Mutant, apoptosis, colon cancerJi Yoon Lee, Dae-Hee Lee*Department of Marine Bio Food Science, Gangneung-Wonju national University
Citation Format: Dae-Hee Lee, Ji Yoon Lee. Inhibition of KRAS G12D mutant with small molecules [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 5770.