bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7145: Identification of Debio 0432 as a potent and selective USP1 inhibitor for cancer therapy
Authors: Luong Noemie , Kunze Annett , Quesnot Nicolas , Aho Erin R. , Berry Loren , Boiko Scott , Buckmelter Alex J. , Lofek Sebastien , Vigano Selena , Chardonnens Christophe 
Published: March 2024

Abstract
Introduction: Debio 0432 is a Ubiquitin Specific Protease 1 (USP1) inhibitor at preclinical stage. This study presents the first data on this small molecule and its activity as an anti-cancer therapy in multiple preclinical models. USP1 is a deubiquitinase, member of the deubiquitinating enzyme (DUB) family that plays an important role at the replication fork during DNA replication. Its prominent role in DNA repair, targeting Proliferating Cell Nuclear Antigen (PCNA) that regulates polymerase recruitment in the translesion synthesis (TLS), makes it an emergent target in the DNA damage repair (DDR) field.
Methods: In silico docking has been used to identify a likely binding site of Debio 0432. Biochemical and cellular assays have been performed to show its activity on the target and in cell lines of different cancer types. In vivo models in cell line derived xenograft (CDX) and patient derived xenograft (PDX) were then used to confirm the activity of the compound and to study PK/PD relationship.
Results: Debio 0432 likely binds USP1 in an allosteric pocket and is very selective across the 58 members of the USP family. Furthermore, it does not affect any kinase. Its biochemical activity on USP1 is in the low nanomolar range and cellular activity ranges between from single digit nM to above 1uM. In vivo, Debio 0432 shows antitumor activity in the BRCA mutant breast cancer model MDA-MB-436. The downstream target Ub-PCNA, selected as pharmacodynamic marker, is modulated in a dose and plasma exposure-dependent manner. Further in vivo experiments in PDX models showed dose-dependent activity in different cancer types, in both BRCA wild type and mutant models. Treatments in all in vivo studies were well tolerated.
Conclusion: Overall, we show that Debio 0432 is a selective and potent small molecule targeting USP1, an emerging target in the DDR field. It shows good activity in different preclinical models and is well tolerated at active doses. Debio 0432 is currently undergoing IND-enabling studies and in preparation for entry into clinical development.
Citation Format: Noemie Luong, Annett Kunze, Nicolas Quesnot, Erin R. Aho, Loren Berry, Scott Boiko, Alex J. Buckmelter, Sebastien Lofek, Selena Vigano, Christophe Chardonnens. Identification of Debio 0432 as a potent and selective USP1 inhibitor for 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 7145.
Abstract 7146: HSK39775: A USP1 inhibitor for the treatment of cancers with homologous recombination deficiencies
Authors: Xu Jun , Li Yangguang , Wang Ju , Tang Pingming , Wang Jianmin , Zhang Chen , Yan Pangke 
Published: March 2024

Abstract
Tumors with BRCA1/2 mutations or homologous repair deficiency (HRD) are vulnerable to agents that target DNA repair pathways, including platinum-containing chemotherapeutics and poly (ADP-ribose) polymerase-1 (PARP1) inhibitors. Despite the significant therapeutic benefits in patients with BRCAm or HRD, innate and acquired resistance to PARPi is still a challenge in the clinic. To address this clinical challenge, we developed HSK39775, a potent, highly selective inhibitor of ubiquitin carboxyl-terminal hydrolase 1 (USP1), which acts as an oncogenic and PARP inhibitor resistance driver involved in DNA damage repair pathway through the deubiquitylation of proteins in Translesion Synthesis pathway and Fanconi Anemia pathway, paired with BRCA as a synthetic lethality target. HSK39775 was active in enzymatic level to inhibit USP1/UAF1 complex. Enzymatic panel screening containing 50 deubiquitinase demonstrated high selectivity of HSK39775. Ubiquitinated PCNA was accumulated treated by HSK39775, indicating target engagement. HSK39775 also demonstrated potent anti-proliferation activity against cancer cell lines with BRCA mutation and excellent selectivity between BRCA WT vs. BRCAm. Combining HSK39775 with PARP inhibitors indicated synergy in cell lines with partial or insensitivity to each agent alone. Triple-negative BRCA mutant breast cancer xenograft model demonstrated strong dose-dependent tumor growth inhibition of HSK39775 as a single agent with Tumor Growth Inhibition (TGI) of 63.2% at 30 mg/kg QD, and ubiquitinated PCNA was also accumulated in HSK39775 treated tumor tissue. Meanwhile, combination with PARP inhibitors significantly enhanced the therapeutic efficacy of HSK39775 in xenograft model and led to tumor regressions and durable tumor control even at low dose (TGI:89% (HSK39775, 5 mg/kg + Olaparib, 50 mg/kg)). Interestingly, HSK39775 inhibited the tumor growth of a HRP and BRCA wild-type lung cancer xenograft as a single agent with TGI of 94% at 30 mg/kg QD, suggesting the therapeutic effect of USP1 inhibitors beyond canonical BRCA mutant or HRD tumors. In summary, these results indicate HSK39775 as a potent and selective USP1 inhibitor and support further development.
Citation Format: Jun Xu, Yangguang Li, Ju Wang, Pingming Tang, Jianmin Wang, Chen Zhang, Pangke Yan. HSK39775: A USP1 inhibitor for the treatment of cancers with homologous recombination deficiencies [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 7146.
Abstract 7170: Pharmacokinetic profiling of Re-Phenformin in vivo: A novel approach in pancreatic cancer therapy
Authors: Gholizadeh Amir Mohammad , Dai Lu , Dagher Fatima , Xiong Chiyi , Li Chun , Chow Diana S-L 
Published: March 2024

Abstract
Phenformin, a biguanide medication, has long been utilized in the treatment of diabetes. Recent research indicates that phenformin may also serve as an effective anticancer agent. This study introduces the synthesis and evaluation of Re tricarbonyl phenformin complex (Re-(CO)3-Phenformin, Re-Phen), as a derivative of Phenformin and novel anticancer agent for pancreatic cancer treatment. Re-Phen was synthesized, purified, and characterized through preparative HPLC, NMR, mass spectrometry, and FT-IR. Subsequent in vitro studies, utilizing the MTS assay, assessed its cytotoxicity against pancreatic cancer cell lines, including Kras* murine PDAC and MiaPaca-2 human PDAC. Notably, Re-Phen exhibited significantly higher cytotoxic effects in MiaPaca-2 cells (IC50= 0.755 mM) and Kras* cells (IC50= 0.410 mM) compared to Phenformin treatment (IC50= 4.02 mM and 2.36 mM, respectively). These results highlight Re-Phen's enhanced anticancer activity, outperforming Phenformin in potency. Further investigation into the pharmacokinetics of Re-Phen involved an in vivo study with rats intravenously administered 2 mg/kg of Re-Phenformin. Blood samples were collected at intervals (10 min to 24 h post-dose) and were analyzed by validated LC-MS/MS. The pharmacokinetic profile of Re-Phen was best described by a 2-compartment model, using Phoenix® WinNonlin (version 8.0), with a particular focus on comparing the profiles of Phenformin and Re-Phen. The study revealed that Re-Phen has a significantly extended half-life compared to Phenformin (9.13 hr vs 2.11 hr), indicating prolonged systemic retention. Additionally, Re-Phen demonstrated an increased area under the curve (AUC), suggesting greater systemic exposure at equivalent dosing (90.55 hr*ng/ml vs 7.13 hr*ng/ml). This could imply enhanced bioavailability or altered metabolic clearance of Re-Phen compared to its parent compound. The two-Compartment of Re-Phe, provide a deeper understanding of its pharmacokinetic characteristics. In conclusion, Re-Phen not only demonstrates superior anticancer efficacy in vitro but also exhibits a more favorable pharmacokinetic profile in vivo. The extended half-life and increased AUC of Re-Phen suggest the potential of offering improved therapeutic efficacy in pancreatic cancer treatment. These promising findings warrant further investigation and could position Re-Phen as a promising therapeutic agent for the pharmacological management of pancreatic cancer.
Citation Format: Amir Mohammad Gholizadeh, Lu Dai, Fatima Dagher, Chiyi Xiong, Chun Li, Diana S-L Chow. Pharmacokinetic profiling of Re-Phenformin in vivo: A novel approach in pancreatic 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 7170.
Abstract 7222: Antiandrogen equipped with HDAC inhibitors activates autophagy-mediated growth inhibition in castrate-resistant prostate cancer
Authors: Chandrasekaran Balaji , Yalla Kiran Kumar , Tyagi Ashish , Shukla Vaibhav , Tyagi Neha , Tyagi Bhawna , Vashishta Mohit , Oyelere Adegboyega K , Damodaran Chendil 
Published: March 2024

Abstract
Targeting androgen receptor (AR) by pharmacologic intervention is one of the practical approaches for the treatment of castration-resistant prostate cancer (CRPC). Hence, this study aimed to develop novel molecules that employ multiple mechanisms to inhibit AR expression and curtail the growth of CRPC. The target antiandrogen-equipped histone deacetylase inhibitors were synthesized, adapting the convergent chemistry we used to synthesize the first-generation compounds. The final compounds were characterized using 1H-NMR, 13C-NMR, and high-resolution mass spectrometry. We synthesized and analyzed several compounds, in which KK62 emerged as the lead compound. KK62 significantly inhibits a panel of CRPC cell lines in nanomolar concentrations without causing toxicity to healthy prostate epithelial cells. The molecular analysis suggested that inhibition of AR and AR-splice variants was evident, followed by downregulation of PSA expression in AR-positive CRPC cell lines. Further analysis confirmed that KK62 overcomes dihydrotestosterone (DHT) induced AR signaling and enzalutamide-resistant CRPC cells by downregulating AR and AR-splice variants in CRPC cells. Subsequent analysis confirmed that KK62 induces autophagy signaling by upregulating autophagosome (LC3B) and lysosome (LAMP1) markers expression and facilitating the autophagosome and lysosome fusion, which resulted in the induction of apoptosis in all AR-positive CRPC cell lines. The pro-apoptotic markers, such as BAX and cleaved caspase, were upregulated, whereas the downregulation of pro-survival markers was evident in KK62-treated CRPC cells. Our ongoing castrated and non-castrated xenotransplanted CRPC tumors and Patient-derived xenograft in vivo studies would validate our in vitro findings and confirm that KK62 is a potent compound that may improve therapeutic advances in treating CRPC.
Citation Format: Balaji Chandrasekaran, Kiran Kumar Yalla, Ashish Tyagi, Vaibhav Shukla, Neha Tyagi, Bhawna Tyagi, Mohit Vashishta, Adegboyega K Oyelere, Chendil Damodaran. Antiandrogen equipped with HDAC inhibitors activates autophagy-mediated growth inhibition in castrate-resistant prostate 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 7222.
Abstract 7257: Examining the promise of precision medicine in immuno-oncology: Vectors for targeted therapeutic delivery
Authors: Richardson Crystal , Rao Prassanna , Koole Cassandra , Karney Michael J. , Kumar Sumit 
Published: March 2024

Abstract
At the forefront of therapeutic delivery is an array of vectors and targeting methods that hold immense promise for precision medicine. Vehicles such as viral vectors (AAV and lentivirus), lipid nanoparticles (LNPs) or liposomes, and peptide micelles each possess distinct and inherent properties, empowering researchers with tools to navigate the intricate challenges of specificity and efficiency in drug transport. Herein, we discuss and demonstrate design principles underpinning these vectors, elucidating their unique mechanisms for targeted delivery including:- A high-throughput viral packaging process to enable rapid downstream CRISPR or shRNA screening- Proprietary AAV plasmid synthesis and preparation techniques to maintain ITR integrity and improve gene delivery- Rapid synthesis, in vitro transcription, and novel sequencing of mRNA constructs for complete characterization of critical components such as the polyA tailBy synthesizing advancements in vector technologies, this poster serves as a roadmap for researchers and practitioners navigating the evolving landscape of targeted drug delivery in immuno-oncology.
Citation Format: Crystal Richardson, Prassanna Rao, Cassandra Koole, Michael J. Karney, Sumit Kumar. Examining the promise of precision medicine in immuno-oncology: Vectors for targeted therapeutic 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 7257.
Abstract 7268: The SOS1 inhibitor MRTX0902 demonstrates activity across cancer models with mutations in proximal components of the RAS-MAPK pathway
Authors: Sudhakar Niranjan , Yan Larry , Qiryaqos Fadia , Laguer Jade , Briere David , Hebbert Allan , Calinisan Andrew , Coma Silvia , Pachter Jonathan , Christensen James G. , Olson Peter , Khare Shilpi 
Published: March 2024

Abstract
Genetic alterations in the RAS-MAPK pathway are one of the most frequent causes of human cancers. While targeted therapies are approved for patients harboring mutations in KRAS G12C in advanced or metastatic non-small cell lung cancer, there remains a need for an effective therapy for cancers characterized by additional RAS-MAPK pathway mutations across cancer types. Previous studies have shown that genetic or pharmacological inhibition of Son of Sevenless homolog 1 (SOS1) demonstrates antiproliferative activity in cancer cells addicted to KRAS signaling, including cell lines with oncogenic mutations in KRAS, SOS1, PTPN11, or EGFR or a loss-of-function mutation in NF1. These genetic alterations each function to increase SOS1-mediated GTP-loading of KRAS and increase signaling flux through the MAPK pathway. Inhibition of SOS1 by MRTX0902 is anticipated to shift the tumor cell equilibrium of KRAS towards the inactive GDP-bound KRAS, leading to MAPK pathway inhibition. MRTX0902 is a selective inhibitor of SOS1 under evaluation in clinical trials for the treatment of advanced, unresectable, or metastatic cancers with mutations in the KRAS-MAPK pathway. In the present studies, we have shown that MRTX0902 demonstrates single-agent anti-proliferative activity and modulates ERK1/2 phosphorylation (pERK) across a panel of human tumor cell lines harboring oncogenic mutations in SOS1, PTPN11, BRAF (class III) and NF1. Furthermore, oral administration of MRTX0902 as a monotherapy in preclinical human tumor cell-derived xenograft models harboring these oncogenic mutations results in significant tumor growth inhibition. Additionally, combination with the RAF/MEK clamp avutometinib demonstrated greater antitumor activity versus either monotherapy treatment. These data support the clinical utility of MRTX0902 as a single agent or combination partner of avutometinib for the treatment of human cancers harboring oncogenic mutations implicated in dysregulation of RAS-dependent signaling including SOS1, PTPN11, NF1, and BRAF (class III).
Citation Format: Niranjan Sudhakar, Larry Yan, Fadia Qiryaqos, Jade Laguer, David Briere, Allan Hebbert, Andrew Calinisan, Silvia Coma, Jonathan Pachter, James G. Christensen, Peter Olson, Shilpi Khare. The SOS1 inhibitor MRTX0902 demonstrates activity across cancer models with mutations in proximal components of the RAS-MAPK pathway [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 7268.
Abstract 7295: A novel XNA technology-based assay to detect JAK2 V617F mutation by real-time PCR
Authors: Shen Shuo , Brown Robert , Kim Daniel , Pastor Larry , Fu Andrew Y. , Kaur Pushpinder , Babu Alisha , Liu Wei , Zhang Aiguo , Tanaka Hiromi , Sha Michael Y. 
Published: March 2024

Abstract
The Janus kinase 2 (JAK2) gene is located on chromosome 9p24.1 and encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signaling. The JAK2 protein is especially important for controlling the production of blood cells from hematopoietic stem cells. In fact, the JAK2 mutation at amino acid 617 (Valine 617 to Phenylalanine, V617F) is the most frequently detected mutation in myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). This dominant gain-of-function V617F mutation results in constitutive tyrosine phosphorylation activity, leading to uncontrolled blood cell production, including increased numbers of erythrocytes, neutrophils, and platelets. To detect the JAK2 V617F mutation in DNA from patient blood samples, we developed a unique real-time PCR assay using our proprietary XNA technology that enables the assay to selectively amplify the mutant sequence by using a synthetic DNA analog XNA (Xenonucleic Acid). The JAK2 V617F mutation detection assay is designed to detect a valine-to-phenylalanine mutation at amino acid 617 (V617F). PCR primers, TaqMan probes, and XNA were designed for the JAK2 V617F mutation, along with primers and probes for an internal control gene in the duplex setting. The analytical performance of the assay was verified and validated using a variety of control samples. The results revealed that the XNA completely suppressed the amplification of wildtype sequence while only the V617F mutant sequence was amplified. The JAK2 V617F mutation detection assay is highly reproducible with intra- and inter-assay coefficients of variation of less than 10%. Results for the assay’s analytical sensitivity indicated that V617F could be detected with about 0.25% mutant allele frequency in 10 ng DNA input. In addition, no significant cross-amplification between V617F and V617I was observed. Thus, the JAK2 V617F mutation detection assay is specific for the V617F mutation. The JAK2 V617F mutation detection assay, using XNA-based technology, provides high sensitivity and specificity to detect the JAK2 V617F mutation. Thus, this assay would be a useful tool for clinical decision-making in determining the presence of the JAK2 V617F mutation in DNA from patient blood samples.
Citation Format: Shuo Shen, Robert Brown, Daniel Kim, Larry Pastor, Andrew Y. Fu, Pushpinder Kaur, Alisha Babu, Wei Liu, Aiguo Zhang, Hiromi Tanaka, Michael Y. Sha. A novel XNA technology-based assay to detect JAK2 V617F mutation by real-time PCR [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 7295.
Abstract 730: Leveraging microdissection for proteogenomic analysis of histological sections to advance drug development
Authors: Shin Ik Jae , Tangrea Michael , Emmert-Buck Michael R. , Johann Donald J. 
Published: March 2024

Abstract
Background: Combining proteogenomics with laser capture microdissection (LCM) in cancer research offers a targeted way to explore the intricate interactions between tumor cells and the tumor microenvironment. This is especially important for immuno-oncology (IO) research where improvements in the predictability of patient response to IO-based drugs is sorely needed. An improved understanding of the spatial relationships involving tumor cells proper, stromal cells, blood supply and immune cell interactions may help to inform drug development and improve the indicators of success for IO-based drug regimens.
Methods: LCM is used to isolate and obtain distinct histological cell types from fresh frozen tissue. Once cells have been captured, nucleic acids and proteins are extracted for in-depth multi-modality molecular profiling assays involving multiple genomic modalities and a customized solution-based mass spectrometry proteomics approach for samples or specimens with a limited amount of tissue.
Results: Optimizing analysis of minute tissue quantities from LCM captured cells is challenging. Following the isolation of nucleic acids, RNA-seq may be performed for gene expression and DNA sequencing performed for the discovery and analysis of actionable mutations, copy number variation, and methylation profiles. Regarding genomic-based studies, commercial kits are often utilized for these steps due to their general availability, rapid innovation, and the robust performance of these products. However, this kit-based adaptive approach is not true for proteomics. There remains a need for highly sensitive proteomic methods targeting small-sized samples. A significant part of our proteogenomics approach is focused around an enhanced liquid chromatography mass spectrometry (LC-MS) analysis of micro-scale and/or nano-scale tissue sections. This is achieved with a silver-stained one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) approach developed for LC-MS analysis of fresh-frozen tissue specimens obtained via LCM. This includes an in-gel digestion method adjusted and specifically designed to maximize the proteome coverage from amount-limited LCM samples to better facilitate in-depth molecular profiling.
Conclusions: Reported here is a proteogenomic approach that is leveraging from microdissected fresh frozen tissue. The methodology may also be applicable to other types of specimens having limited nucleic acids, protein quantity, and/or sample volume.
Citation Format: Ik Jae Shin, Michael Tangrea, Michael R. Emmert-Buck, Donald J. Johann. Leveraging microdissection for proteogenomic analysis of histological sections to advance drug development [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 730.