bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A053: The dual BRG1/BRM (SMARCA4/2) inhibitor FHD-286 induces functional differentiation and splicing defects in preclinical models of acute myeloid leukemia (AML)
Authors: Gartin Ashley K. , Mayhew David N. , Lahr David L. , Elliott GiNell , Gandevia Heena , Wilson Molly M. , Centore Richard , Collins Mike , Thomsen Astrid , Piel Jessica , Sandoval Gabriel J. , Hentemann Martin 
Published: December 2023

Abstract
The BRG/BRM associated factor (BAF) complex is a chromatin remodeler critical for maintenance of cell viability in many cancers. This includes acute myeloid leukemia (AML), where BAF maintains the stem-like transcriptional state of blast cells. FHD-286 is a dual inhibitor of the BAF ATPase subunits BRG1 and BRM and is currently being investigated in relapsed or refractory AML and myelodysplastic syndrome. We have shown previously that FHD-286 induces the expression of the myeloid differentiation marker CD11b in preclinical models after treatment with sub-cytoreductive doses at long timepoints. Here we further characterized the differentiation phenotype induced by low-dose FHD-286 in AML cell lines through RNA-seq and a genome-wide CRISPR-Cas9 knockout screen. These datasets and mechanistic follow-up studies suggested AML cell lines treated with FHD-286 can functionally differentiate to gain the ability to produce superoxide anion and perform phagocytosis. We also found that FHD-286 treatment disrupts mRNA splicing and that this is a likely contributor to AML cell growth defects induced by BRG1/BRM inhibition. This study suggests multiple mechanisms by which FHD-286 is able to disrupt the stem-like transcriptional state of AML blasts to cause differentiation and ultimately cell death.
Citation Format: Ashley K. Gartin, David N. Mayhew, David L. Lahr, GiNell Elliott, Heena Gandevia, Molly M. Wilson, Richard Centore, Mike Collins, Astrid Thomsen, Jessica Piel, Gabriel J. Sandoval, Martin Hentemann. The dual BRG1/BRM (SMARCA4/2) inhibitor FHD-286 induces functional differentiation and splicing defects in preclinical models of acute myeloid leukemia (AML) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A053.
Abstract A055: Discovery of a novel, highly potent VHL-recruiting EZH2 PROTAC degrader targeting MLL-r AML
Authors: Velez Julia , Yu Xufen , Dale Brandon , Park Kwang-Su , Ümit Kaniskan H. , Jin Jian 
Published: December 2023

Abstract
Mutated or overexpressed Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), has been implicated in numerous cancers, including breast, leukemia, and lung. Through its methyltransferase activity, EZH2 tri-methylates H3K27 to repress transcription. In addition to its enzymatic activity, recent studies have highlighted non-enzymatic oncogenic functions of EZH2 that limit the efficacy of enzymatic inhibitors. Therefore, alternative therapeutic strategies such as proteolysis targeting chimera (PROTAC) degraders that suppress both enzymatic and non-enzymatic activity have been developed. PROTACs are heterobifunctional molecules consisting of a protein of interest (POI) binder linked to an E3-ligase ligand. The manufactured proximity between the POI and the recruited E3-ligase complex initiates ubiquitination of the POI, resulting in its degradation via the 26S proteasome. EZH2 exhibits enzymatic and non-enzymatic oncogenic activity in various cancers including MLL1-rearranged acute myeloid leukemia (MLL-r AML) and triple negative breast cancer (TNBC). Here we present MS8847, a novel VHL-recruiting EZH2 PROTAC degrader. In MLL-r AML cells, MS8847 induces potent EZH2 degradation in a ubiquitin proteasome-, time- and concentration-dependent manner. Compared to the previously published EZH2-targeting PROTAC degraders (MS8815, YM281, U3i, and E7) and parent inhibitor, Tazemetostat, MS8847 displays superior EZH2 degradation and cell growth inhibition in MLL-r AML cell lines dependent on both enzymatic and non-enzymatic EZH2 activity. MS8847 also induces EZH2 degradation and cell growth inhibition in TNBC cell lines. Moreover, MS8847 has a favorable PK profile making it suitable for in vivo studies. Together, MS8847 offers an improved VHL-recruiting EZH2 PROTAC degrader with potential as an effective therapeutic agent to treat EZH2-dependent cancers.
Citation Format: Julia Velez, Xufen Yu, Brandon Dale, Kwang-Su Park, H. Ümit Kaniskan, Jian Jin. Discovery of a novel, highly potent VHL-recruiting EZH2 PROTAC degrader targeting MLL-r AML [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A055.
Abstract A059: Small molecule microarray lysate screen identifies bromodomain ligands that target the MYC transcription regulatory network
Authors: Cohen Emily B , Ma Zhihua , Glore Wayne L , Volkov Oleg A , Liang Tong , Obholzer Nikolaus D , Clay Andrew C , Pingili Mulini Reddy , Zheng Yupeng , Li Jun , Wang Shi Yun , Chen Tom , Freeman David B , Gao Hua , Zhou Minyun , Cheung Priscilla , Hopkins Tamara D , Pop Marius S , Dinsmore Christopher J , Trotter B. Wesley , Lin Charles Y , Rahl Peter B 
Published: December 2023

Abstract
MYC is the most frequently amplified gene in human cancers and one of the most sought-after drug targets for cancer therapy. Its function as a transcription factor is essential for its oncogenic potential. However, development of small molecules that target oncogenic MYC function in cells has been intractable due to its lack of known ligand binding sites. To overcome these structural challenges, we leveraged Kronos Bio’s small molecule microarray (SMM) screening platform to identify small molecules that can bind to MYC transcriptional complexes in cell lysates from cancer cells with deregulated MYC function. Unbiased transcriptional signature-based profiling identified multiple SMM hits that modulated the MYC transcription regulatory network (TRN) in MYC-dependent cancer cell lines. One of the SMM hits mimicked signature changes due to MYC loss of function, which were also similar to signature changes effected by BET bromodomain inhibitors. Biochemical, biophysical, and structural analyses found that the SMM hit could directly engage with BET bromodomains in purified systems. Cell-based proximity labeling demonstrated binding to BET proteins in live cells, and comparative pharmacology approaches suggested that the BET protein engagement was likely driving the observed gene expression changes. These results demonstrate the utility of the SMM platform in identifying ligands that modulate transcription factor TRNs through binding to critical cofactors.
Citation Format: Emily B Cohen, Zhihua Ma, Wayne L Glore, Oleg A Volkov, Tong Liang, Nikolaus D Obholzer, Andrew C Clay, Mulini Reddy Pingili, Yupeng Zheng, Jun Li, Shi Yun Wang, Tom Chen, David B Freeman, Hua Gao, Minyun Zhou, Priscilla Cheung, Tamara D Hopkins, Marius S Pop, Christopher J Dinsmore, B. Wesley Trotter, Charles Y Lin, Peter B Rahl. Small molecule microarray lysate screen identifies bromodomain ligands that target the MYC transcription regulatory network [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A059.
Abstract A079: FHD286 is a BRG1/BRM ATPase inhibitor showing efficacy in NSCLC models and is applicable to NSCLC patients both as a single agent treatment and in combination with current standards of care
Authors: Mikse Oliver , Adam Ammar , Elliott GiNell , Lahr Dave , Amaral Victoria , Viswanathan Priyadharshini , Johannessen Liv , Ahmad Hafiz , Wan Jessica , Bellon Steven , Hentemann Murphy 
Published: December 2023

Abstract
The BAF (BRG/BRM-associated factors) complex plays a critical role in shaping the chromatin landscape. The two mutually exclusive ATPases BRM/BRG1 (SMARCA2/4, respectively) drive chromatin remodeling activity in the BAF complex. Genetic alterations in the SMARCA4 gene, encoding BRG1, are found in approximately 10% of non-small cell lung cancer (NSCLC) patients, leaving this subset of BRG1-deficient tumors highly susceptible to inhibition of BRM (Hoffman, 2014; Oike, 2013). However, BRG1 can also have oncogenic activity in NSCLC (Li, 2019) and can serve as a predictive biomarker for chemotherapy outcome in patients (Bell, et al 2015), rationalizing the use of a dual BRG1/BRM ATPase inhibitor (FHD286) in NSCLC patients in combination with chemotherapy. Here, we demonstrate that a panel of in vitro and in vivo NSCLC models respond to BAF ATPase inhibition as a single agent treatment, irrespective of SMARCA4 mutation status. Analysis of gene expression and dependency data suggests that FHD286 sensitivity correlates with activity of genes related to DNA damage response and repair. We furthermore demonstrate an enhancing effect on tumor growth inhibition in vitro and in vivo driven by apoptosis and cell cycle arrest when combining dual FHD286 with current first and second line standards of care. Collectively, these results indicate a path forward for the development of FHD-286, a clinical stage BRM/BRG1 ATPase inhibitor, for the treatment of NSCLC patients both as a single agent treatment and in combination with current standards of care.
Citation Format: Oliver Mikse, Ammar Adam, GiNell Elliott, Dave Lahr, Victoria Amaral, Priyadharshini Viswanathan, Liv Johannessen, Hafiz Ahmad, Jessica Wan, Steven Bellon, Murphy Hentemann. FHD286 is a BRG1/BRM ATPase inhibitor showing efficacy in NSCLC models and is applicable to NSCLC patients both as a single agent treatment and in combination with current standards of care [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A079.
Abstract A089: NST-628 is a potent, fully brain-penetrant, RAS/MAPK pathway molecular glue inhibitor with efficacy in CNS tumor models
Authors: Ryan Meagan B , Li Chun , Han Yongxin , Hoeflich Klaus P , Hale Michael R , Hagel Margit 
Published: December 2023

Abstract
Alterations in the RAS/RAF/MEK/ERK signaling cascade are common across multiple solid tumor types and aberrant signaling of the pathway is a driver for RAS- and RAF-driven cancers. Apart from approved mutation selective inhibitors for BRAF Class I and KRAS G12C mutations, other mutations of RAS and RAF are not directly addressable by currently approved inhibitors and there is a need for inhibitors with superior efficacy, durability and tolerability for the MAPK pathway in RAS- and RAF-driven cancers. Currently approved inhibitors of the RAS-MAPK pathway also have limited central nervous system (CNS) exposure and an area of significant unmet patient need exists for patients with primary and metastatic tumors harboring RAS-MAPK pathway alterations. NST-628 has CNS permeability, with a Kpu,u &gt;1, that is far higher than trametinib or VS-6766 (Kpu,u of 0.11 and 0.18 respectively). The predicted effective human half-life of NST-628 (~9h) is amenable to daily dosing in the clinic. In vivo, NST-628 leads to a dose-dependent inhibition of the MAPK pathway in murine brain tissue[KS1] as measured by phospho-ERK. In an intracranial luciferase-tagged SK-MEL-2 xenograft model (NRAS Q61R), NST-628 leads to tumor regressions with a daily dosing regimen (3 mg/kg QD). Tumor regressions as measured by bioluminescent imaging (BLI) were only seen with NST-628 (50%) in the SK-MEL-2 model, whereas trametinib and VS-6766 showed minimal efficacy due to low exposure in the CNS. In the NF-1 mutant MeWo (NF1 Q1336*) melanoma intracranial xenograft model (luciferase tagged), NST-628 led to tumor regressions at two dosing regimens (1, 3 mg/kg QD) and tumor stasis at lower doses (0.3 mg/kg) as measured by BLI. In contrast, the brain penetrant type II RAF inhibitor DAY101 (formerly TAK580) showed no efficacy in the MeWo model and resulted in paradoxical pathway hyper-activation, as determined by enhanced PD response and tumor growth. Only NST-628 effectively inhibited MAPK signaling as measured by DUSP6 transcript in a time- and dose-dependent manner. Overall, survival of mice harboring MeWo intracranial tumors was also significantly increased versus vehicle control and DAY101 treatment groups. These data collectively support best-in-class potential of NST-628 and initiation of clinical trials in patients with solid tumors harboring RAS- and RAF-mutations, including those presenting clinically with brain metastases and primary intracranial tumors.
Citation Format: Meagan B Ryan, Chun Li, Yongxin Han, Klaus P Hoeflich, Michael R Hale, Margit Hagel. NST-628 is a potent, fully brain-penetrant, RAS/MAPK pathway molecular glue inhibitor with efficacy in CNS tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A089.
Abstract A098: HBI-2376, HUYABIO clinical stage SHP2 inhibitor, displays efficacy signal in patients with KRAS mutations in early clinical studies
Authors: Shojaei Farbod , Ricono Jill M , Fang Che , Xing Yan , Ning John , Lee Gloria , Gillings Mireille 
Published: December 2023

Abstract
SHP2 is an attractive target in oncology drug development due to its dual roles in tumor progression: i) direct growth and proliferation of cancer cells; ii) acting as an immune checkpoint molecule to suppress tumor immunity. HBI-2376 is an orally bioavailable selective SHP2 inhibitor developed for the treatment of solid tumors harboring KRAS or EGFR mutations, such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic cancer (PAC). Additionally, HBI-2376 has the potential to suppress tumor growth via induction of the activity of immune infiltrating cells in the TME (tumor microenvironment). Preclinical studies showed greater potency of HBI-2376 to inhibit cell proliferation in a variety of cancer cell lines compared to other SHP2 inhibitors such as TNO-155 (Novartis AG) and RMC-4550 (Revolution Medicines). Additionally, HBI-2376 was found to be more efficacious in tumor growth inhibition than TNO-155 and RMC-4550 in NCI-H1975L858R_T790M_C797S osimertinib-resistant cell line and other tumor models. Furthermore, Western blotting showed inhibition of p-ERK and DUSP6 in HBI-2376 treated cells indicative of a biomarker of response to the therapy. In addition to xenograft models, we tested efficacy of HBI-2376 as single agent or in combination with anti-PD-1 mAb in MC38 CRC syngeneic model. HBI-2376 showed greater efficacy in tumor growth inhibition vs. TNO-155 and RMC-4550 both as single agent and in combination therapy. IHC data showed reduction in infiltration of M2 macrophages (F4/80+Arg1+) in the HBI-2376 treated tumors suggesting a mechanism of action for its greater efficacy in MC38 model. HBI-2376 is currently being tested in Phase 1 clinical trials. Consistent with preclinical studies, we have observed efficacy signals in early cohorts in two patients with partial responses (PR). Both patients were harboring KRAS mutations beyond KRAS G12C. Additionally, HBI-2376 was well tolerated with no SAEs or DLTs in the first four cohorts indicative of a good tolerability in cancer patients. Analysis of pERK in PBMCs isolated from the treated patients showed dose dependent inhibition in pERK further supporting a mechanism driven response to HBI-2376. Therefore, the preclinical and clinical data may represent HBI-2376 as the best-in-class SHP2 inhibitor.
Citation Format: Farbod Shojaei, Jill M Ricono, Che Fang, Yan Xing, John Ning, Gloria Lee, Mireille Gillings. HBI-2376, HUYABIO clinical stage SHP2 inhibitor, displays efficacy signal in patients with KRAS mutations in early clinical studies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A098.
Abstract A099: Best in class, potent, SOS1 inhibitors demonstrate single agent activity in preclinical models of KRAS driven tumors
Authors: Lakhavath Balakrishna , Pothuganti Manoj , Kummari Githavani , Pathange Hemasankar , Sekar Rajan , Viswanadha Srikant 
Published: December 2023

Abstract
KRAS is an oncogene implicated in a wide variety of tumors (~21% of solid tumors harbor KRAS mutations). Interaction of KRAS with its predominant Guanine Exchange Factor (GEF), SOS1, is crucial for activation of KRAS and further KRAS mediated oncogenic signaling. Thus, pharmacological inhibition of SOS1 is expected to be effective in treating RAS driven cancers. Biochemical potency of compounds was confirmed in a SOS1 mediated FRET based guanine exchange factor (GEF) assay. Multiple potent SOS1 inhibitors were identified with potencies in the low double digit nanomolar range. Selectivity was determined against SOS2 and a host of other kinases in the RAS/RAF/MEK or RAS/PI3K/AKT pathways. Anti-proliferative activity across a panel of WT and mutant KRAS cell lines revealed IC50 between 50-200 nM with synergism observed when combined with MAPK pathway inhibitors as well as the KRAS G12C inhibitor, Sotorasib, in a 3D anchorage independent assay format. Correspondingly, significant reduction in PD biomarkers (&gt;50% at 100 nM), pERK and pAKT, was demonstrated in KRAS mutant as well as EGFR/PI3K mutant cell lines. PK-PD correlation was also established in a tumor bearing mice model, with dose-dependent reduction of both pERK and pAKT. Compounds demonstrated excellent ADME properties with significant tissue distribution upon oral dosing. One of the lead molecules demonstrated significant single agent efficacy with growth inhibition of approximately 70% in a KRAS G12C bearing NSCLC xenograft model. No adverse signs including reduction in food intake or body weight loss were reported during the study period. IND-enabling studies are currently ongoing for the lead compounds.
Citation Format: Balakrishna Lakhavath, Manoj Pothuganti, Githavani Kummari, Hemasankar Pathange, Rajan Sekar, Srikant Viswanadha. Best in class, potent, SOS1 inhibitors demonstrate single agent activity in preclinical models of KRAS driven tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A099.
Abstract A131: Cumulative burden of fatty liver and kidney cancer in young-aged men: A national population-based study
Authors: Lee Hee Yeon , Han Kyung-Do , Kwon Hyuk-Sang 
Published: December 2023

Abstract
Introduction Kidney cancer is considered as a metabolic disease due to its association with metabolic problems including obesity and metabolic syndrome. The association of kidney cancer with metabolic syndrome components and higher association in young-aged male population has been reported. Recent trends show an increasing incidence of kidney cancer, coupled with rising costs due to the development of new drugs. In light of these factors, identifying modifiable factors becomes a meaningful endeavor from a public healthcare perspective. The aim of this study was to determine the association of kidney cancer with cumulative burden of fatty liver in young-aged men using fatty liver index (FLI). Methods Korean National Health Insurance Service database were used. A total of 1,007,906 men aged ≥ 20 years and &lt; 40 years who received four consecutive check-ups from January 2009 to December 2012, excluding those with missing data, history of malignancy, and those who died or diagnosed with cancer within one year after their last check-up were analyzed. They were followed up to the diagnosis of kidney cancer or death until December 2020. Non-alcoholic fatty liver disease (NAFLD) was defined as FLI ≥ 60. Results With increasing cumulative frequency of FLI &gt;60, there was a noticeable rise in the proportion of subjects who were current smokers and heavy drinkers. Furthermore, BMI, WC, glucose and lipid profiles (excluding HDL) demonstrated an upward trend. HR in subjects with mean 30 ≤ FLI &lt; 60 was 1.447 (95% CI 1.26-1.853) and 2.391 (95% CI 1.986-2.879) in those with mean FLI ≥ 60. As the cumulative frequency increased, HR for kidney cancer increased. A group that initially had FLI ≥ 60, and FLI decreased below 60 at the last check-up showed lower HR compared to a group that had FLI ≥ 60 on both measurements (HR 1.374 vs. 2.430). Furthermore, this HR was lower than the group that had FLI &lt; 60 initially but increased to ≥ 60 (1.374 vs. 1.653). Conclusion This study showed the association between cumulative burden of fatty liver using FLI and kidney cancer in young-aged men. As the cumulative burden of NAFLD increased, the incidence of kidney cancer increased. In the cases with initial high FLI (≥ 60) and final low FLI (&lt; 60) showed lower HR compared to the cases with high FLI at initial and final measurements.
Citation Format: Hee Yeon Lee, Kyung-Do Han, Hyuk-Sang Kwon. Cumulative burden of fatty liver and kidney cancer in young-aged men: A national population-based study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A131.