bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4533: Identification of DAT-2000A, a novel potent PARG inhibitor that selectively inhibits PARPi-resistant and homologous-recombination-deficient tumors
Authors: Yan Dan , Zhang Yan , Yu Zhangqi , Zhang Yao , Zhang Jingxi , Wang Bin , Chen Huixian , Shi Jingxue , Bao Zhiwei , Lin Xiaoling , Zhuo Jincong , Zhou Kevin 
Published: March 2024

Abstract
A significant portion of patients with homologous recombination repair deficiencies(HRD) do not respond to PARP inhibitors, and even among those who initially respond, resistance often develops after PARP inhibitor treatment. This underscores the unmet clinical need to address the challenges in the treatment of HRD patients. Poly (ADP-ribose) glycohydrolase (PARG) plays a key role in hydrolyzing PAR chains from PARylated protein substrates, such as PARP1, serving as a critical checkpoint in DNA damage repair and the control of DNA replication stress. Therefore, PARG has emerged as a promising target for cancer therapy. Cancer cells experiencing replication stress, such as HRD breast cancer cells and those resistant to PARPi, exhibit sensitivity to PARG inhibition. DAT-2000A is a potent, selective, orally bioavailable small-molecule inhibitor of PARG, which directly binds to the catalytic domain of PARG, inducing the accumulation of poly-PAR chains at DNA lesions, and exhibits notable anti-proliferative activity across a wide range of HRD tumors both in vitro and in vivo. Biochemical assays confirm DAT-2000A's high potency and selectivity as an inhibitor of PAR-chain hydrolysis. In cellular assays, DAT-2000A demonstrates selective sensitivity in HRD cells, distinguishing itself from PARPi across various indications. Preclinical studies involving CDX and PDX xenograft models reveal that DAT-2000A exerts robust anti-tumor effects in both PARPi-sensitive and -resistant settings. Furthermore, it induces a dose and time-dependent accumulation of PAR chains, which may serve as a reliable pharmacodynamic biomarker indicative of PARG target engagement. In conclusion, DAT-2000A represents an innovative targeted therapy that warrants further investigation in clinical trials for the treatment of HRD cancers and beyond.
Citation Format: Dan Yan, Yan Zhang, Zhangqi Yu, Yao Zhang, Jingxi Zhang, Bin Wang, Huixian Chen, Jingxue Shi, Zhiwei Bao, Xiaoling Lin, Jincong Zhuo, Kevin Zhou. Identification of DAT-2000A, a novel potent PARG inhibitor that selectively inhibits PARPi-resistant and homologous-recombination-deficient 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 4533.
Abstract 4546: Pegargiminase and melphalan as a novel drug combination strategy for uveal melanoma
Authors: Pavlyk Iuliia , Carpentier Josephine , Szlosarek Emilia Appolonia , Chan Pui Ying , Bomalaski John S. , Szlosarek Peter Wojciech 
Published: March 2024

Abstract
Uveal melanoma (UM) is a hard-to-treat arginine auxotrophic cancer with approximately 50% of patients succumbing to metastases predominantly to the liver with a median overall survival of 19-22 months and a 5 year survival of around 10%. Novel drug strategies are urgently needed beyond the currently available immunotherapies that provide durable disease control in a small subset of patients. Arginine deprivation with pegylated arginine deiminase (ADI-PEG20; pegargiminase) is a novel anti-metabolite therapy which demonstrated activity in early phase trials in patients with UM, and more recently, increased survival in patients with the aggressive arginine-dependent cancer, non-epithelioid mesothelioma in the global phase 3 trial, ATOMIC-Meso. Here, we investigated the preclinical rationale for combining pegargiminase with melphalan, a drug which is delivered directly to the liver using an FDA-approved device from Delcath for patients with hepatic-centric UM disease. Two of four uveal melanoma cell lines were negative for expression of the rate-limiting enzyme for arginine production, argininosuccinate synthetase 1 (ASS1) and were submitted for drug evaluation accordingly. ADI-PEG20 treatment of ASS1-deficient cell lines 91.2 and MP41 demonstrated sensitivity to ADI-PEG20 (500ng/ml) compared to MP38 and MP46 ASS1-proficient cell lines. Moreover, the combination of ADI-PEG20 and melphalan (0.77µM) had at least an additive effect on ASS1 negative cell lines in 2D assay (92.1 p-value 0.0061; MP41 p-value is 0.0053). UM cell line proliferation was decreased by 50% in the combination group compared to ADI-PEG20 alone by 6 days of culture. Experiments to assess cytotoxicity and cell death analysis are ongoing. This drug combination therapy has the potential to improve outcomes in patients with uveal melanoma. Based on the good tolerability and safety of both drugs in patients, a clinical trial of pegargiminase with melphalan is planned for 2024 (ATOMIC-UM).
Citation Format: Iuliia Pavlyk, Josephine Carpentier, Emilia Appolonia Szlosarek, Pui Ying Chan, John S. Bomalaski, Peter Wojciech Szlosarek. Pegargiminase and melphalan as a novel drug combination strategy for uveal melanoma [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 4546.
Abstract 4554: Novel combination therapy for treating proteasome inhibitor-resistant multiple myeloma
Authors: Kim Byung-Gyu , Choi Sung Hee , Nguyen Huong , Liang Fu-Sen , Kim Seong-Jin , Letterio John , Huang Alex 
Published: March 2024

Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by osteolytic bone disease and immunosuppression. Proteasome inhibitors (PIs) have remarkably improved the survival of MM patients, but dose-limiting toxicities and the development of drug resistance limit their long-term utility. Elevated TGF-β levels in MM patient sera correlate with drug resistance, disease progression, metastasis and poor prognosis. Therefore, we evaluated the anti-MM therapeutic potential of a TGF-β type I receptor kinase inhibitor, Vactosertib. In vitro treatment of Vactosertib synergistically inhibited the growth of bortezomib (BTZ)-resistant MM cells in combination with either BTZ or ixazomib (IXZ) by suppressing TGF-β activation of Smad2/3 and expression of PSMB5, which encodes the proteasome 5 catalytic subunit targeted by PIs. Oral administration of Vactosertib as a single agent decreased MM progression and mortality of the mice bearing BTZ-resistant MM. Vactosertib alone also attenuated PSMB5 expression and proteasome activity, reduced the expansion of CD11b+Gr-1+ myeloid derived suppressor cells (MDSCs) in bone marrow (BM) tumor microenvironment (TME), and diminished the population of Foxp3+ regulatory T cells (Treg) in the spleen. Combination therapy of Vactosertib plus PI (BTZ or IXZ) exhibited a synergistic anti-myeloma effect when compared to either Vactosertib or PI alone by greatly prolonged survival and significant a reduction in both MDSCs and Tregs. Furthermore, therapy of BCMA+ CAR T cells in combination with Vactosertib exhibited a synergistic anti-tumor effect, compared to either CAR T cells or Vactosertib. Taken together, our data provide the rationale for clinical evaluation of Vactosertib in MM and demonstrate proof-of-concept that combination of Vactosertib and either PI or cell therapy may overcome drug resistance and enhance durable patient responses.
Citation Format: Byung-Gyu Kim, Sung Hee Choi, Huong Nguyen, Fu-Sen Liang, Seong-Jin Kim, John Letterio, Alex Huang. Novel combination therapy for treating proteasome inhibitor-resistant multiple myeloma [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 4554.
Abstract 4588: Combination of MTA-cooperative PRMT5 inhibitor and direct mutant-selective KRAS inhibitors as a novel therapeutic approach for MTAP-deficient pancreatic cancer
Authors: Drizyte-Miller Kristina , Chang Wen-Hsuan , Waters Andrew M. , Stalnecker Clint A. , Wang Junning , Aguirre Andrew J. , Cox Adrienne D. , Der Channing J. 
Published: March 2024

Abstract
KRAS is mutationally activated in 95% of pancreatic ductal adenocarcinoma (PDAC) patients. Direct KRAS inhibitors are under intense preclinical and clinical development, with two KRASG12C mutant-selective inhibitors (G12Ci) now approved. However, treatment-associated resistance to KRAS inhibitors has been reported in the clinic highlighting an urgent need to identify both additional therapeutic targets and novel combination treatment strategies with KRAS inhibitors. To that end, we performed a CRISPR/Cas9 loss-of-function screen using a library targeting ~2,500 druggable genes in KRASG12C/D-mutant PDAC cell lines. We identified multiple genes that were essential for PDAC cell growth and selected PRMT5, a protein arginine methyltransferase, to assess as a novel therapeutic target for pancreatic cancer. We found that suppression of PRMT5 activity using two distinct first-generation clinical candidate small molecule inhibitors (JNJ-64619178 and GSK3326595) demonstrated single agent activity and reduced PDAC cell growth. We further assessed a mechanistically distinct MTA-cooperative clinical candidate PRMT5 inhibitor, MRTX1719, that is selective for MTAP-deleted tumors, which occur in ~25% of PDAC patients. We determined that MRTX1719 exhibited low nanomolar GI50 activities in MTAP-deficient but not MTAP wild-type KRAS-mutant cell lines. Unexpectedly, PDAC cells treated with MRTX1719 exhibited a paradoxical activation of ERK, suggesting that combined inhibition of PRMT5 and KRAS might be therapeutically advantageous. In support of our hypothesis, we demonstrated that combination treatment with MRTX1719 and mutant selective KRAS inhibitors (G12Ci/MRTX849 and G12Di/MRTX1133) further sensitized KRASG12C/D-mutant PDAC cells to KRAS inhibition in short- and long-term growth assays as well as in vivo xenograft studies. Our ongoing studies are evaluating the consequences of co-targeting PRMT5 and KRAS on gene expression changes using RNA-Seq and cancer cell signaling pathways using RPPA analyses. In summary, our data support concurrent inhibition of PRMT5 and KRAS as a promising therapeutic strategy for MTAP-deficient KRAS-mutant pancreatic cancer.
Citation Format: Kristina Drizyte-Miller, Wen-Hsuan Chang, Andrew M. Waters, Clint A. Stalnecker, Junning Wang, Andrew J. Aguirre, Adrienne D. Cox, Channing J. Der. Combination of MTA-cooperative PRMT5 inhibitor and direct mutant-selective KRAS inhibitors as a novel therapeutic approach for MTAP-deficient pancreatic 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 4588.
Abstract 4611: The co-targeting of PLK1 and FoxM1 contributes to synergistic antitumor effects in PTC
Authors: Poyil Pratheeshkumar , Siraj Abdul K. , Padmaja Divya , Parvathareddy Sandeep Kumar , Thangavel Saravanan , Al-Sobhi Saif S. , Al-Dayel Fouad , Al-Kuraya Khawla S. 
Published: March 2024

Abstract
Polo-like Kinase 1 (PLK1) plays a key role in cell proliferation with vital regulatory functions in mitosis and cell survival. We investigated the expression of PLK1 protein in a large cohort of PTC patient’s samples and explored its functional role in PTC cell lines in vitro and in vivo. PLK1 overexpression was observed in 54% of all PTC and was significantly associated with aggressive clinico-pathological parameter and it was found to be independent prognostic marker for recurrence-free survival. PLK1 inhibition indeed inhibited cell proliferation and induced cell cycle arrest and apoptosis in PTC cell lines. Importantly, silencing of PLK1 decreases the self-renewal ability of spheroids generated from PTC cells. Immunoprecipitation analysis shows that PLK1 binds to FoxM1 and vice versa in vitro. Mechanistically, PLK1 knockdown suppresses FoxM1 expression, whereas inhibition of FoxM1 does not affect PLK1 expression, which suggests that PLK1 acts through the FoxM1 pathway. The combined inhibition of PLK1 with volasertib and FoxM1 with thiostrepton synergistically attenuated PTC cell growth in vitro and in vivo. Our findings suggest that co-targeting of PLK1 and FoxM1 could be a viable therapeutic strategy for treating patients with an aggressive subtype of PTC.
Citation Format: Pratheeshkumar Poyil, Abdul K. Siraj, Divya Padmaja, Sandeep Kumar Parvathareddy, Saravanan Thangavel, Saif S. Al-Sobhi, Fouad Al-Dayel, Khawla S. Al-Kuraya. The co-targeting of PLK1 and FoxM1 contributes to synergistic antitumor effects in PTC [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 4611.
Abstract 4650: RalBP1, a novel approach for ovarian cancer therapy
Authors: Singhal Sharad S. , Ramisetty Sravani , Mohanty Atish , Kulkarni Prakash , Horne David , Awasthi Sanjay , Salgia Ravi 
Published: March 2024

Abstract
Ovarian cancer (OC) is the most devastating gynecologic cancer. The ever-climbing incidence rate of OC makes it the most lethal female reproductive disorder. Triggering apoptosis is one of the potential strategies to overcome chemoresistance. Recent evidence suggests that the failure of drug-induced apoptosis may be an underlying cause of drug-resistance. Molecular mechanisms of failed apoptosis in chemoresistant OC cells include p53 mutations, abnormal expression of the Bcl2 family proteins, and upregulation of other inhibitors of apoptosis that block caspases and stabilize the mitochondrial permeability pore. RalBP1 (Ral-binding protein) is a required stress-defense protein for OC, and its specific depletion or inhibition will cause apoptosis in cancer cells expressing RalBP1. RalBP1 is a multifunctional 76 kDa protein encoded as a splice variant in the human RALBP1 gene (18p11.22). RalBP1 is an ATP dependent efflux transporter for glutathione (GSH) conjugates (GS-E) of products of oxidative stress, like 4HNE and GSH-conjugates of chemotherapy drugs. Our recent studies indicate that upon depletion/inhibition of RalBP1, malignant cells are significantly more sensitive to apoptosis than non-malignant cells, suggesting that the stress-protective, anti-apoptotic activity of RalBP1 is necessary for malignant cells. This differential sensitivity to RalBP1 translates into tumor regression, a lack of toxicity, and the prolonged survival of mice bearing subcutaneous OC cells in which RalBP1 is inhibited by anti-RalBP1 IgG or depleted using RalBP1 antisense oligonucleotides. These studies demonstrate that inhibition or depletion of RalBP1 exerts anti-neoplastic effects in OC and indicate that this GS-E and xenobiotic transporter occupies an important position in the hierarchy of stress defense mechanisms necessary for cancer cell survival. Overall, the present research focuses on hypothesis-driven studies to define novel relationships between RalBP1 and signaling pathways, and to determine the suitability of RalBP1 as an anticancer target for OC.
Citation Format: Sharad S. Singhal, Sravani Ramisetty, Atish Mohanty, Prakash Kulkarni, David Horne, Sanjay Awasthi, Ravi Salgia. RalBP1, a novel approach for ovarian cancer therapy [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 4650.
Abstract 4660: Characterization of a nicotinamide-based kinase inhibitor HSN748 for inhibition of RET-driven tumors
Authors: Khatri Ujjwol , Dayal Neetu , Shen Tao , Hu Xueqing , Sintim Herman , Wu Jie 
Published: March 2024

Abstract
Rearranged during transfection (RET) is a protein tyrosine kinase that is aberrantly activated by gene fusions or mutations in many types of human cancer including thyroid cancer and non-small cell lung cancer (NSCLC). Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are FDA approved RET-selective tyrosine kinase inhibitors (TKIs) being used to treat RET-altered cancer. However, these tumors develop selpercatinib/pralsetinib-resistance via acquisition of RET(G810C/R/S) mutations located at the solvent front of the ATP binding pocket. The overall goal of our research is to discover next-generation of RET kinase inhibitors to inhibit selpercatinib/pralsetinib-resistant RET solvent-front mutants. In this study, we characterized one of the nicotinamide-based RET kinase inhibitor, HSN748, in vitro and in vivo. HSN748 was able to inhibit selpercatinib/pralsetinib-resistant RET(G810C/R) solvent-front mutations. In BaF3/KIF5B-RET(G810C) tumor xenograft experiment, HSN748 treatment resulted in tumor regression. In immune competent transgenic mice, KIF5B-RET-induced lung tumors regressed after HSN748 treatment by oral gavage for one month (10-15 mg/kg, QD) without affecting body weight. These results identify HSN748 as an orally available RET inhibitor capable of inhibiting KIF5B-RET and its solvent-front mutant-driven tumors.
Citation Format: Ujjwol Khatri, Neetu Dayal, Tao Shen, Xueqing Hu, Herman Sintim, Jie Wu. Characterization of a nicotinamide-based kinase inhibitor HSN748 for inhibition of RET-driven 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 4660.
Abstract 4662: High-throughput screening identifies potential combinatorial therapies to overcome lenvatinib resistance in liver cancer
Authors: Chau Kevin , McDermott Martina S. , Gong KeWei , Slamon Dennis J. 
Published: March 2024

Abstract
Liver cancer has seen an increase in mortality rate over recent decades due to limited targeted therapies and growth in specific etiologies. Lenvatinib, a multi-TKI inhibitor, is used as a first-line therapy for liver cancer patients who cannot receive immunotherapy, which is a component of the current standard of care. Unfortunately, lenvatinib efficacy is short. Understanding why liver cancers become resistant and identifying interventions to restore sensitivity can help prolong the clinical efficacy of lenvatinib. A panel of 20 liver cancer lines was screened to identify four lenvatinib-sensitive lines. These lines were subsequently conditioned to grow under increasing lenvatinib concentrations to generate lenvatinib-resistant (LR) models. One such model, Hep3B LR, exhibited a stable resistance to lenvatinib for up to 12 weeks in culture. Hep3B LR showed cross-resistance to selective inhibitors of FGFR4 and FGFR1 but not of MAPK14 and PDGFR, suggesting that the resistance phenotype may result from FGFR dysfunction. Unlike parental Hep3B, Hep3B LR exhibited a 3.4X increase in migration. Western blot detected an increase in pAKT, a survival marker. Additionally, proteins associated with cancer drug resistance were higher in Hep3B LR cells: Notch receptors and ligands, pStat3, and Axl. To identify means of overcoming lenvatinib resistance in Hep3B LR, a Cell-Titer Glo high-throughput assay was developed to measure the growth inhibition of candidate drugs in the presence and absence of lenvatinib. Preliminary results from the first 24 drugs screened reproduced known drug sensitivities associated with lenvatinib resistance (i.e., MEK/ERK, EGFR, GPX4 inhibition) but also identified novel sensitivities to inhibition of PKMYT1 or γ-secretase, the latter a cleavage enzyme involved in Notch signaling activation. Validation of these candidate hits using a grid-based titration of both drugs showed additive growth inhibition of lenvatinib in combination with ERK, EGFR, or GPX4 inhibitors but not with PKMYT1 or γ-secretase inhibitors in resistant cells. Interestingly, EGFRi and lenvatinib were substantially synergistic in parental cells, suggesting that an upfront combination of these inhibitors could potentially be used before the emergence of lenvatinib resistance in liver cancer. We have established a lenvatinib-resistant liver cancer cell model and validated a drug screening assay to identify potential combinatorial therapies to overcome lenvatinib resistance in liver cancer.
Citation Format: Kevin Chau, Martina S. McDermott, KeWei Gong, Dennis J. Slamon. High-throughput screening identifies potential combinatorial therapies to overcome lenvatinib resistance in liver 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 4662.
Abstract 4667: HDAC9 as a potential regulator of lenvatinib resistance in hepatocellular carcinoma
Authors: Xie Yunong , Zhang Minghe , Liu Yan , Liu Linglin , Cheng Alfred Sze-Lok , Ma Stephanie , Tong Man 
Published: March 2024

Abstract
Lenvatinib is used as the first-line therapy for advanced hepatocellular carcinoma (HCC) patients. However, poor response and compromised therapeutic effect with prolonged treatment are frequently observed in HCC patients. To elucidate the underlying mechanisms, lenvatinib responsive and non-responsive stages were modeled in liver tumor-bearing immunocompetent mice which were divided into lenvatinib and vehicle control treatment groups. Tumor tissues after short and prolonged lenvatinib treatment were harvested for single-cell RNA sequencing. Results from single-cell RNA sequencing revealed heterogenous tumor cell sub-populations associated with tumor differentiation and identified an upregulated expression of class IIa histone acetylase HDAC9 in lenvatinib-treated tumor at the non-responsive stage. Upregulation of HDAC9 was similarly observed in lenvatinib-resistant human patient-derived xenograft (PDX). Functional studies suggested that suppressing HDAC9 could re-sensitize lenvatinib response in both in vitro and in vivo models. In sum, we identified a potential regulator of lenvatinib treatment response in HCC.
Citation Format: Yunong Xie, Minghe Zhang, Yan Liu, Linglin Liu, Alfred Sze-Lok Cheng, Stephanie Ma, Man Tong. HDAC9 as a potential regulator of lenvatinib resistance in hepatocellular carcinoma [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 4667.