bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A044: The discovery of potent KAT6 inhibitors that demonstrate anti-tumor activity in preclinical models of ER+ breast cancer
Authors: Palanisamy Gopinath S. , Venkateshappa Chandregowda , Goyal Megha , Barratt Susanna A. , Hearn Brian R. , Daginakatte Girish , B Aravind A , S Samiulla D , Bera Kalisankar , S Sangeetha , Khare Leena , Parisian Alison D. , Heerding Dirk A. , Ng Raymond A. , Harmon Cyrus L. , Samajdar Susanta , Ramachandra Murali , Myles David C. 
Published: December 2023

Abstract
KAT6 paralogs KAT6A (MOZ; MYST3) and KAT6B (MORF; MOZ2; MYST4) are histone acetyltransferase (HAT) enzymes that acetylate histone H3 and thereby epigenetically regulate gene transcription by altering chromatin structure. Dysregulation of KAT6 activity (gene amplification, overexpression, fusion, mutation, etc.) is observed in breast and other cancers. In several subtypes of breast cancer, KAT6A is amplified as part of the 8p11-p12 amplicon and/or is overexpressed in 11 to 15% of overall breast cancer population. Overexpression of KAT6 correlates with worse clinical outcome in ER+/HER2− breast cancers. Here we present the discovery of novel and potent KAT6 inhibitors with robust in vitro and in vivo anti-tumor efficacy and high selectivity against other KAT family members KAT5 and KAT8. Our lead KAT6 inhibitor compounds demonstrate strong anti-proliferative effects in ER positive breast cancer cell lines with KAT6 dysregulation while demonstrating robust target engagement biomarker activity (inhibition of histone H3 acetylation at lysine residue 23). In addition, these compounds exhibit desirable ADME and pharmacokinetic properties including good oral bioavailability in tested species, supporting potential once daily dosing in humans. The lead compounds also demonstrate enhanced in vitro cellular efficacy in breast cancer cell lines when combined with OP-1250, a complete ER antagonist (CERAN), and CDK4/6 inhibitors, illustrating their combination potential. In addition, these lead compounds demonstrate excellent dose-dependent anti-tumor activity resulting in tumor growth inhibition and tumor regression in a KAT6A amplified ER+ breast cancer xenograft model, highlighting their potential as a novel therapy in ER+ breast cancer. Additional nonclinical efficacy testing, and safety profiling of these lead compounds is currently underway to select a clinical candidate.
Citation Format: Gopinath S. Palanisamy, Chandregowda Venkateshappa, Megha Goyal, Susanna A. Barratt, Brian R. Hearn, Girish Daginakatte, Aravind A B, Samiulla D S, Kalisankar Bera, Sangeetha S, Leena Khare, Alison D. Parisian, Dirk A. Heerding, Raymond A. Ng, Cyrus L. Harmon, Susanta Samajdar, Murali Ramachandra, David C. Myles. The discovery of potent KAT6 inhibitors that demonstrate anti-tumor activity in preclinical models of ER+ breast cancer [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 A044.
Abstract A056: Treatment with dual BRG1/BRM (SMARCA4/2) inhibitor FHD-286 ablates tumor-associated androgen response elements (AREs) in prostate cancer
Authors: Sandoval Gabriel J , Centore Richard C , Topal Sal , Lahr Dave , Elliott GiNell , Gandevia Heena , Adam Ammar , Piel Jessica , Nguyen Holly M , Corey Eva , Chen Yu , Bellon Steven , Hentemann Murphy 
Published: December 2023

Abstract
The Androgen Receptor (AR) cistrome is critical in the development of prostate cell identity while its misregulation promotes prostate cancer development. The pioneer transcription factor Forkhead box A1 (FOXA1) has been shown to be essential for the recruitment of AR to androgen response elements (AREs) allowing for reprogramming of the AR cistrome resulting in prostate cell transformation. FHD-286 is a BRM/BRG1 dual ATPase inhibitor currently in clinical trials for AML. Here, we show that treatment of prostate cancer cell lines with FHD-286 results in ablation of FOXA1 mediated AREs at tumor-associated AR binding sites (T-ARBS). Dual ATPase treatment subsequently reduces the expression level of various oncogenic AR target genes, leading to a decrease in tumor cell viability. Both patient derived organoid and In vivo studies provide further validation by showing a decrease in tumor growth. Strikingly, inhibition of BAF complex activity bypasses AR resistance mechanisms commonly seen after castration and Enzalutamide treatment as cell lines containing AR-V7 splice variants and neuroendocrine organoids display sensitivity. Taken together, our data illustrates a novel mechanism of treating AR mediated prostate cancer though the inhibition tumor associated AREs by treatment with FHD-286.
Citation Format: Gabriel J Sandoval, Richard C Centore, Sal Topal, Dave Lahr, GiNell Elliott, Heena Gandevia, Ammar Adam, Jessica Piel, Holly M Nguyen, Eva Corey, Yu Chen, Steven Bellon, Murphy Hentemann. Treatment with dual BRG1/BRM (SMARCA4/2) inhibitor FHD-286 ablates tumor-associated androgen response elements (AREs) in prostate cancer [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 A056.
Abstract A057: Small molecule microarray screening identifies novel androgen receptor ligands
Authors: Kobylarz Marek J , Shum Michelle G , Glore Wayne L , Saffren Ava , Carpenter Shannon , Pingili Mulini , Clay Andrew , Hopkins Tamara D , Gao Hua , Schinzel Anna C , Pop Marius S , Obholzer Nikolaus D , Freeman David B , Dinsmore Christopher J , Trotter Benjamin W , Lin Charles Y , Rahl Peter B 
Published: December 2023

Abstract
The androgen receptor (AR) is a well-established oncogenic driver of prostate cancer, and AR-targeting hormone therapy has proven an efficacious treatment option for patients with metastatic prostate cancer. Due to the importance of AR in prostate cancer disease progression, we leveraged small molecule microarray (SMM) screening technology to identify compounds that bind to transcriptional complexes of a common AR splice-variant, AR-V7, present along with AR in castration-resistant prostate cancer cell lysates. A subset of SMM hits were identified to modulate the AR Transcription Regulatory Network (TRN) in hormone-sensitive, but not castration-resistant prostate cancer models using a functional cell-based transcription signature approach. Several AR SMM hits directly engaged the AR ligand binding domain in a biophysical assay. One of these AR SMM hits altered AR nuclear translocation and antagonized steroid receptor co-activator recruitment to AR but did not antagonize the glucocorticoid receptor. Leveraging structural data for known AR ligands, we propose a computational model for binding of this molecule to the known AR ligand binding domain. Together, the data demonstrates that the AR SMM lysate screen successfully identified structurally novel small molecules that modulate the AR TRN and bind the AR ligand binding domain.
Citation Format: Marek J Kobylarz, Michelle G Shum, Wayne L Glore, Ava Saffren, Shannon Carpenter, Mulini Pingili, Andrew Clay, Tamara D Hopkins, Hua Gao, Anna C Schinzel, Marius S Pop, Nikolaus D Obholzer, David B Freeman, Christopher J Dinsmore, Benjamin W Trotter, Charles Y Lin, Peter B Rahl. Small molecule microarray screening identifies novel androgen receptor ligands [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 A057.
Abstract A060: Discovery of potent and selective EP300 degraders with anti-cancer activity
Authors: Zimmerman Mark , Sappal Darshan , Adam Ammar , Adams Benjamin , Adhikari Ketaki , Austin Wesley , Bullock Breanna , DiBernardo Julie , Dixon Thomas , Elliot GiNell , Ethell Brian , Gervais Anais , Hossain Md Imran , Huang David , Lahr Dave , Lin Mei Yun , Mayhew David , Mizeracka Karolina , Negretti Solymar , Nguyen Tyler , Prifti Olga , Schiller Shawn , Sherbanee Brenna , Terry David , Ucisik Nihan , Wittenborn Elizabeth , LaBonte Laura , Daniels Danette 
Published: December 2023

Abstract
E1A binding protein (EP300) and CREB binding protein (CBP) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcriptional co-activators. Dysregulation of one or both proteins has been implicated in various cancers, and functional genomic screens have demonstrated a bidirectional synthetic lethal relationship between the two genes in tumor cells. Due to the high homology between EP300 and CBP, identifying chemical matter that selectively targets EP300 or CBP has proven challenging. Here, we describe a potent, highly selective heterobifunctional degrader of EP300 with biological activity in CBP-deficient and EP300-dependent tumor cells. This compound achieves robust degradation of EP300 in vivo at doses that sustain EP300 degradation with minimal effects on CBP protein level. Targeted degradation of EP300 protein resulted in a stronger suppression of cell growth and survival than targeting the bromodomain or HAT activity of EP300/CBP with small molecule inhibitors. Strong anti-proliferative effects have been demonstrated in multiple cancer types, including lymphomas and prostate tumors, highlighting the essential role of EP300 in the malignant phenotype of these tumors.
Citation Format: Mark Zimmerman, Darshan Sappal, Ammar Adam, Benjamin Adams, Ketaki Adhikari, Wesley Austin, Breanna Bullock, Julie DiBernardo, Thomas Dixon, GiNell Elliot, Brian Ethell, Anais Gervais, Md Imran Hossain, David Huang, Dave Lahr, Mei Yun Lin, David Mayhew, Karolina Mizeracka, Solymar Negretti, Tyler Nguyen, Olga Prifti, Shawn Schiller, Brenna Sherbanee, David Terry, Nihan Ucisik, Elizabeth Wittenborn, Laura LaBonte, Danette Daniels. Discovery of potent and selective EP300 degraders with anti-cancer activity [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 A060.
Abstract A106: Pharmacological activation of CLIP3 reduces radioresistance by suppressing stemness and glycolysis in glioblastoma
Authors: Kang Hyunkoo , Shin Eunguk , Lee Haksoo , Youn BuHyun 
Published: December 2023

Abstract
Glioblastoma (GBM) is a malignant primary brain tumor in which the standard treatment, ionizing radiation (IR), achieves a median survival of less than 15 months. GBM harbors glioblastoma stem cells (GSCs), which are crucial in therapeutic resistance and recurrence. Here, we report that GSCs that survive standard treatment radiation upregulate Speedy/RINGO cell cycle regulator family member A (Spy1) and downregulate CAP-Gly domain-containing linker protein 3 (CLIP3). We discovered that Spy1 activation and CLIP3 inhibition coordinately shift GBM cell glucose metabolism to favor glycolysis via two cellular processes: transcriptional regulation of CLIP3 and facilitating Glucose transporter 3 (GLUT3) trafficking to cellular membranes in GBM cells. Importantly, in combination with IR, glimepiride, an FDA-approved medication used to treat type 2 diabetes mellitus, disrupts GSCs maintenance and suppresses glycolytic activity by restoring CLIP3 function. In addition, combining radiotherapy and glimepiride significantly reduced GBM growth and improved survival in a GBM orthotopic xenograft mouse model. Collectively, our data suggest that repurposing glimepiride for GBM therapy could be an attractive strategy for overcoming tumor recurrence. [This research was supported by National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2020M2D9A2094156) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00207904).]
Citation Format: Hyunkoo Kang, Eunguk Shin, Haksoo Lee, BuHyun Youn. Pharmacological activation of CLIP3 reduces radioresistance by suppressing stemness and glycolysis in glioblastoma [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 A106.
Abstract A107: Diacylglycerol kinase B mediates radioresistance by regulating mitochondrial lipotoxicity in glioblastoma
Authors: Lee Haksoo , Kang Hyunkoo , Shin Eunguk , Youn BuHyun 
Published: December 2023

Abstract
Glioblastoma (GBM) is a malignant primary brain tumor in which the standard treatment, ionizing radiation (IR), achieves a median survival of about 15 months. GBM cells that survive radiotherapy contribute to tumor progression and recurrence with metabolic rewiring. We established radioresistant GBM cells and identified that diacylglycerol kinase B (DGKB), a regulator of the intracellular concentration of diacylglycerol (DAG), is significantly downregulated in these cells. The downregulation of DGKB increases DAG accumulation and reduces fatty acid oxidation, conferring radioresistance by reducing mitochondrial ROS. Diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the formation of triglycerides from DAG, is also increased in radioresistant GBM cells. Genetic inhibition of DGAT1 using miR-3918 mimic suppresses radioresistance. We discover that cladribine, an FDA-approved drug, activates DGKB and inhibits DGAT1 and sensitizes GBM cells to radiotherapy. Taken together, our study demonstrates that DGKB downregulation and DGAT1 upregulation contribute to radioresistance by reducing mitochondrial ROS and suggests DGKB and DGAT1 as therapeutic targets to overcome GBM radioresistance. [This research was supported by National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2020M2D9A2094156) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00207904).]
Citation Format: Haksoo Lee, Hyunkoo Kang, Eunguk Shin, BuHyun Youn. Diacylglycerol kinase B mediates radioresistance by regulating mitochondrial lipotoxicity in glioblastoma [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 A107.
Abstract A120: Differentilal roles of PI3K catalytic kinases in glioblastoma's chemoresistance
Authors: Sheng Zhi 
Published: December 2023

Abstract
Resistance to chemotherapies such as temozolomide presents a major hurdle to effectively treat glioblastoma. This challenge arises possibly from the activation of phosphatidylinositol 3-kinase (PI3K) signaling, which makes PI3K an appealing therapeutic target. However, non-selectively blocking the four highly homologous PI3K catalytic kinases p110α, β, δ, and γ has yielded undesired clinical outcomes. It is therefore imperative to investigate individual PI3K kinases in glioblastoma’s chemosensitivity. Here we report that PI3K kinases differentially regulate chemosensitivity. We found that the four kinases were unequally expressed in grade II/III glioma and glioblastoma with levels of p110β being the highest. Concomitantly, glioblastoma patients deficient of O6-methylguanine-DNA-mehtyltransferase and expressing high levels of p110β and low levels of other kinases (p110β-high) were more likely resistant to temozolomide, thereby experiencing poor prognosis. Perturbation of p110β, but not other kinases, sensitized p110β-high glioblastoma cells or mouse xenograft tumors to temozolomide. Moreover, p110β-selective inhibitors and temozolomide synergistically mitigated the growth of resilient glioblastoma stem cells. Our results have demonstrated the essential role of p110β in regulating chemosensitivity, suggesting that selectively blocking p110β is an effective chemosensitizer for therapy-resistant glioblastoma.
Citation Format: Zhi Sheng. Differentilal roles of PI3K catalytic kinases in glioblastoma's chemoresistance [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 A120.
Abstract A141: Preclinical pharmacokinetic (PK) and tumor growth inhibition (TGI) modeling for mANK-101, an anchored murine interleukin-12 (IL-12) complex for intratumoral administration for solid cancer
Authors: Mistry Hitesh , Hodson David , Orrell David , Battula Sailaja , Emens Leisha A , Kaufman Howard L , Schmidt Michael M , Chassagnole Christophe 
Published: December 2023

Abstract
Introduction – Murine ANK-101 (mANK-101) is a stable complex composed of a modified murine IL-12 cytokine with aluminum hydroxide at a 1:10 ratio designed for intratumoral delivery to established solid cancers. The objective of this work was to build a preclinical PK/PD/TGI model to gain a better mechanistic understanding of the pharmacology of mANK-101 and potential impact on therapeutic efficacy.
Methods - Data were collected from in vivo studies measuring PK, intratumoral immune cells and tumor growth inhibition (TGI) in a CT26 syngeneic mouse model treated with mANK-101. A PK model was derived from Momin et al. [1], the surrogacy potential of immune cells was assessed via a statistical model and subsequently a mathematical model linking immune cell activation to TGI was developed.
Results – A two-compartment PK model was established to take into account both the intratumoral depot effect of mANK-101 and the release into the peripheral circulation for mIL12 from the mANK-101 complex. CD8+ T-cell infiltration was found to be a surrogate biomarker for anti-tumor activity and was subsequently used to link PD-TGI. The model was able to capture various doses and schedules of mANK-101 at different starting tumor volumes on therapeutic responses.
Conclusions – A PK-PD-TGI model was developed that links the release of mIL12 from mANK-101 to immune cell-activation through to tumor growth inhibition thus providing a causal understanding of the mechanism of action. The model could potentially form the basis of a translational model to assist in designing first-in-man dose and schedule.
References:[1] Momin, N., Palmeri, J.R., Lutz, E.A. et al. Maximizing response to intratumoral immunotherapy in mice by tuning local retention. Nat Commun 13, 109 (2022). https://doi.org/10.1038/s41467-021-27390-6
Citation Format: Hitesh Mistry, David Hodson, David Orrell, Sailaja Battula, Leisha A Emens, Howard L Kaufman, Michael M Schmidt, Christophe Chassagnole. Preclinical pharmacokinetic (PK) and tumor growth inhibition (TGI) modeling for mANK-101, an anchored murine interleukin-12 (IL-12) complex for intratumoral administration for solid cancer [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 A141.
Abstract A144: HM99462, a Novel & potent SOS1 inhibitor, induces tumor regressions in combination with KRAS G12C inhibitor, MEK inhibitor, or EGFR mutant inhibitor
Authors: Choi Jaeyul , Jung Seung Hyun , Park Wongi , Byun Jooyun , Lim Semi , Lee Youngjoo , Jeon Soye , Kim Yu-Yon , Ahn Young Gil , Kim Young Hoon , Suh Kwee Hyun 
Published: December 2023

Abstract
Son of sevenless homolog 1 (SOS1) is one of guanine nucleotide exchange factor (GEF) responsible for a binary molecular switch to activate KRAS as well as a node in the negative feedback loop in the RTK-KRAS-MAPK signaling pathway. Therefore, combination strategies with a SOS1 inhibitor are being explored as a promising therapeutic options to target the MAPK-mediated bypass, which may improve antitumor activity or delay the induction of resistance after treatment. Herein, we presented a novel and potent SOS1 inhibitor, HM99462, which abrogates GTP-binding to KRAS and the profile of drug potency and mechanism of action was examined with in vitro and in vivo models. Biochemical activity on SOS1 was evaluated by a GTP-exchange assay on diverse KRAS G12X mutant types, NRAS Q61H, and HRAS G12V, and HM99462 showed excellent inhibitory activity, while SOS2 action was not affected. Moreover, HM99462 decreased ERK phosphorylation in various cancer cell lines harboring different major KRAS mutation statuses such as KRAS G12C, G12D, G12V, or G13D. Growth inhibition assay was performed using a three-dimensional (3D) conformation culture that mimics the complexity and heterogeneity of tumors and has elevated p-ERK. In this 3D spheroid growth inhibition assay, HM99462 demonstrated significantly effective GI50 against various KRAS mutant cancer cell lines. Additionally, HM99462 was evaluated in cancer cell xenograft mouse models harboring KRAS or EGFR mutation. The combination of HM99462 with KRAS G12C, MEK, or EGFR mutant inhibitor led to significantly synergistic anti-tumor activity in both in vitro and in vivo models with several KRAS or EGFR mutations. Based on our exploratory study, a novel and potent SOS1 inhibitor, HM99462 could be suggested as an appropriate therapeutic agent for diverse inhibitory activity against cancers causing by the hyperactivation of oncogenic KRAS or RTK signaling. And it has the potential to overcome the limitations of KRAS G12C, MEK or EGFR inhibitor through combination. IND enabling GLP-toxicity studies with HM99462 are currently underway, and we planned to initiate clinical study in early 2024.
Citation Format: Jaeyul Choi, Seung Hyun Jung, Wongi Park, Jooyun Byun, Semi Lim, Youngjoo Lee, Soye Jeon, Yu-Yon Kim, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. HM99462, a Novel & potent SOS1 inhibitor, induces tumor regressions in combination with KRAS G12C inhibitor, MEK inhibitor, or EGFR mutant inhibitor [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 A144.