bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB_B08: The SRG OncoRat supports tumors derived from several RAS mutant cell lines for pre-clinical testing of RAS-inhibitors
Authors: Walton Grace , Begemann Diane , Dunn Cynthia , Steffey Valeriya , Brenzel Christopher , Noto Fallon 
Published: December 2023

Abstract
RAS family proteins have emerged as important molecular targets in multiple cancer therapeutics due to their role in hypertrophic and pro-mitotic signaling. KRAS is a small GTPase that is activated in response to growth factors including HGF, TGFα, and EGF. KRAS then activates the MAP kinase (MAPK; RAF/MEK/ERK) signaling pathway, driving ERK translocation to the nucleus, and resulting in transcription of pro-mitotic and hypertrophic genes. Furthermore, KRAS contributes to PI3K/AKT/mTOR signaling, leading to transcriptional activation as well as protein synthesis via mTOR. We validated several RAS mutant cell-derived tumor xenograft models in the SRG OncoRat. Cells were inoculated subcutaneously in the flank of SRG rats. To date, we have validated tumor growth using the HT-1080 fibrosarcoma NRAS mutant (Gln61Lys (c.181C&gt;A)) cell line. We have also validated a suite of KRAS mutant lines in the SRG OncoRat, including: A-549 lung adenocarcinoma (Gly12Ser (c.34G&gt;A)); NCI-H2122 NSCLC adenocarcinoma (Gly12Cys (c.34G&gt;T)); MIA PaCa-2 pancreatic ductal adenocarcinoma and H-358 NSCLC adenocarcinoma (Gly12Cys (c.34G&gt;T)); Capan-2 pancreatic ductal adenocarcinoma (Gly12Val (c.35G&gt;T)); NCI-H441 NSCLC papillary adenocarcinoma (Gly12Val (c.35G&gt;T)); NCI-H1734 NSCLC adenocarcinoma (Gly13Cys (c.37G&gt;T)); and MDA-MB-231 breast adenocarcinoma (Gly13Asp (c.38G&gt;A)). All cell lines showed robust and consistent tumor growth when injected subcutaneously into the SRG OncoRat. These models provide valuable tools for pre-clinical testing of RAS inhibition.
Citation Format: Grace Walton, Diane Begemann, Cynthia Dunn, Valeriya Steffey, Christopher Brenzel, Fallon Noto. The SRG OncoRat supports tumors derived from several RAS mutant cell lines for pre-clinical testing of RAS-inhibitors [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 LB_B08.
Abstract LB_B10: Non-V600 BRAF mutants and their precise targeting
Authors: Hu Jiancheng 
Published: December 2023

Abstract
Hyperactive RAS/RAF/MEK/ERK signalling is responsible for a large portion of cancers and targeting this signalling pathway has achieved a promising outcome in clinic cancer treatment. However, significant challenges such as drug resistance are still existing. To resolve these problems, we need a deeper understanding of the regulatory mechanism and hence develop better targeting approaches against this signalling pathway. In this study, we investigated the molecular mechanism that controls that activity of BRAF, a key component of this signalling pathway, and found that BRAF cycled between inactive monomeric status and active dimeric status, which is coordinatively regulated by Cdc37/Hsp90 chaperone and 14-3-3 scaffold. Further, we found that most non-V600 mutations of BRAF in cancer genomes undermined this regulatory mechanism through disturbing the association of BRAF with Cdc37/Hsp90 chaperone or 14-3-3 scaffold and hence trapped BRAF in active dimeric status. Given the high dimer affinity of these non-V600 BRAF mutants, we next examined whether their activity could be inhibited effectively RAF dimer breaker PLX8394 in vitro and in vivo. Indeed, we found that in contrast to clinic RAF inhibitor Vemurafenib (PLX4720), PLX8394 strongly inhibited the activity of non-V600 BRAF mutants and induced a rapid regression of fibroblastomas driven by non-V600 BRAF mutants. Together, our data clearly illustrates how oncogenic non-V600 mutations break down the regulation of BRAF by Cdc37/Hsp90 chaperone and 14-3-3 scaffold, and how these BRAF mutations could be precisely targeted by RAF dimer breaker, which has important implications for anti-BRAF cancer therapy.
Citation Format: Jiancheng Hu. Non-V600 BRAF mutants and their precise targeting [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 LB_B10.
Abstract LB_B22: DrugMap: A quantitative pan-cancer analysis of cysteine ligandability
Authors: Bar-Peled Liron 
Published: December 2023

Abstract
Cysteine-focused chemical proteomic platforms have expanded the repertoire of protein targets for covalent inhibitors. However, it remains unknown how cysteine targeting varies across multiple cancer contexts. To address this question, we compiled an atlas of cysteine ligandability across 417 cancer cell lines. We unexpectedly find that cysteine ligandability fluctuates across cancers, which we attribute to differences in cellular redox state, protein complex formation and mutation. Focusing on lineage-restricted liganding, we identify highly actionable cysteines in SOX10, leveraging this information to develop covalent inhibitors. We find the SOX10 ligand functions as a covalent molecular glue and disrupts transcriptional activity in a dominant negative manner. Our findings reveal pervasive heterogeneity in cysteine ligandability across cancer, pinpoint cell-intrinsic features driving cysteine targeting, and exemplify the use of covalent probes to disrupt [BPL2] oncogenic transcription factor activity.
Citation Format: Liron Bar-Peled. DrugMap: A quantitative pan-cancer analysis of cysteine ligandability [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 LB_B22.
Abstract LB_C11: Small-molecule bifunctional inhibitors of PARP1/2 and HDAC enzymes
Authors: Truong Sarah , Ramos Louise , Zhai Beibei , Joshi Jay , Ghaidi Fariba , Marzban Mona , Adomat Hans , Chen Charles , Langlands John , Brown Dennis , Bacha Jeffrey , Collins Colin , Sorensen Poul , Shen Wang , Daugaard Mads 
Published: December 2023

Abstract
Background: Poly(ADP-ribose) polymerase (PARP) plays a major role in DNA repair and PARP inhibitors (PARPi) have shown promise for the treatment of cancers with DNA damage repair defects, such as BRCA mutations. PARPi are currently approved for treatment of BRCA-mutated cancers and as a maintenance therapy for patients who have responded to platinum-based chemotherapy. To improve efficacy, overcome resistance, and expand the usage of PARPi to non-BRCA mutated disease, combination therapies with PARPi have emerged as an area of interest. Histone deacetylases (HDACs) play a major role in DNA repair and inhibition of HDACs has been shown to reduce tumor growth. PARPi combined with HDACi has shown enhanced efficacy in pre-clinical studies in various cancers, and a clinical trial of olaparib and vorinostat against metastatic breast cancer is ongoing. However, combination therapies can be limited clinically due to overlapping toxicities and differing pharmacokinetics. Here, we report the efficacy of a novel class of bifunctional small-molecule compounds (kt-3000) with both PARP1 and PARP2 inhibitory and HDAC inhibitory activities.
Methods: PARP1 and PARP2 activity was measured using Trevigen Universal Colorimetric PARP Assay kit and BPS Bioscience PARP2 Colorimetric Assay kit respectively. HDAC activity was measured using HeLa nuclear extracts and a fluorogenic peptide-based biochemical assay. In vitro metabolism was determined by HPLC after incubation with human liver microsomes for up to 45 mins. Pharmacokinetic profiling was examined in mice up to 6 h after oral/intraperitoneal (IP) dosing.
Results: kt-3000 compounds showed potent inhibition of PARP1 and PARP2 activity with IC50 values comparable to olaparib (low nM) and inhibition of HDACs with IC50 values in the low µM range. Metabolic and pharmacokinetic profiling suggest drug-like qualities in the class.
Conclusion: kt-3000 molecules demonstrate potent inhibition of PARP1/2 and HDAC activities, with suitable pharmacokinetic properties for oral delivery. Further refinement and development of these bifunctional single-molecule inhibitors may offer a novel therapeutic opportunity for treatment of cancers with and without DNA damage repair defects.
Citation Format: Sarah Truong, Louise Ramos, Beibei Zhai, Jay Joshi, Fariba Ghaidi, Mona Marzban, Hans Adomat, Charles Chen, John Langlands, Dennis Brown, Jeffrey Bacha, Colin Collins, Poul Sorensen, Wang Shen, Mads Daugaard. Small-molecule bifunctional inhibitors of PARP1/2 and HDAC enzymes [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 LB_C11.
Abstract LB_C19: Suppression of the antitumoral activity of natural killer cells by cancer-associated fibroblasts in a pancreatic TIME-on-Chip model
Authors: Kim Hyun-Ah , Kim Hyunsoo , Nam Min-Kyung , Park Jong Kook , Lee Moo-Yeal , Chung Seok , Lee Kyung-Mi , Kuh Hyo-Jeong 
Published: December 2023

Abstract
Background: Recently, natural killer (NK) cells emerged as a treatment option for various solid tumors. However, the immunosuppressive tumor immune microenvironment (TIME) can reduce the cytotoxic ability of NK cells in pancreatic ductal adenocarcinoma. Cancer-associated fibroblasts within the tumor stroma can suppress immune surveillance by dysregulating factors involved in the cellular activity of NK cells. Herein, the effect of activated pancreatic stellate cells (aPSCs) on NK cell-mediated anticancer efficacy under three-dimensional (3D) coculture conditions was investigated.
Methods: 3D cocultures of PANC-1 tumor spheroids (TSs) with aPSCs and NK-92 cells in a collagen matrix were optimized to identify the occurring cellular interactions and differential cytokine profiles in conditioned media using microchannel chips. PANC-1 TSs and aPSCs were indirectly cocultured, whereas NK-92 cells were allowed to infiltrate the TS channel using convective medium flow.
Results: Coculture with aPSCs promoted PANC-1 TSs growth and suppressed the antitumor cytotoxic effects of NK-92 cells. Mutual inhibition of cellular activity without compromising migration ability was observed between aPSCs and NK-92 cells. Moreover, the reduced killing activity of NK-92 cells was found to be related with reduced granzyme B expression in NK cells.
Conclusions: Herein, a novel TIME-on-chip model based on the coculture of PANC-1 TSs, aPSCs, and NK-92 cells was described. This model may be useful for studying the detailed mechanisms underlying NK cells dysregulation and for exploring future therapeutic interventions to restore NK cell activity in the tumor microenvironment.
Citation Format: Hyun-Ah Kim, Hyunsoo Kim, Min-Kyung Nam, Jong Kook Park, Moo-Yeal Lee, Seok Chung, Kyung-Mi Lee, Hyo-Jeong Kuh. Suppression of the antitumoral activity of natural killer cells by cancer-associated fibroblasts in a pancreatic TIME-on-Chip model [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 LB_C19.
Abstract LB_C22: Dynamic interactions of disordered N-terminal domain of p53 in cancer
Authors: Wang Chunyu , Christopher Baines , Chen Jianhan , Loh Stewart 
Published: December 2023

Abstract
TP53 is mutated in over half of all human cancers, making it the most important tumor suppressor. p53 sequence includes an N-terminal domain (NTD), a DNA binding domain (DBD), and others. NTD is intrinsically disordered and interacts with many proteins, acting as a hub for cellular signaling. Using a combination of computational and experimental approaches, we show NTD have dynamic interactions with cyclophilin D (CypD), a mitochondria proline isomerase with key roles in cellular necrosis and mitochondrial energy metabolism. We show that a subset of p53 truncation mutations can promote cancer cell proliferation and mitochondrial metabolism in a CypD-dependent manner. Although dynamic interfaces are often considered “undruggable”, we have demonstrated that EGCG, the active ingredient of green tea, can bind to NTD and disrupt NTD-CypD interaction, inhibiting the effects of p53 truncation mutants. Our studies point to a novel mechanism for p53 gain-of-function (GOF) mutations through NTD interaction with mitochondrial CypD. Our data also provide novel insights into dynamic interactions of intrinscially disordered proteins and small molecule engagement of such challenging drug targets, with important implications for cancer treatment.
Citation Format: Chunyu Wang, Baines Christopher, Jianhan Chen, Stewart Loh. Dynamic interactions of disordered N-terminal domain of p53 in 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 LB_C22.
Abstract PR009: Discovery of covalent NRAS inhibitors targeting the Palmitoylation site through imaging-based high-throughput screening
Authors: Wang Zhao , Moore Keith , Ng Simon , Wang Chao , Tomlinson Ronald , Loke Huay-Keng , Rice Jamie , Cornella Ivan 
Published: December 2023

Abstract
NRAS mutations play a crucial role as oncogenic drivers of tumor cell growth and chemo-resistance in melanoma and acute myeloid leukemia (AML). In melanoma, NRAS mutations occur in approximately 25% of cases, and are generally mutually exclusive with BRAF-mutations. NRAS mutant tumors often exhibit an aggressive phenotype, such as thicker lesions, increased mitotic activity, and higher rates of lymph node metastasis. Surgical resection of NRAS mutant melanoma has a poor prognosis with a lower median overall survival (OS) compared to non-NRAS-mutant melanoma (8.2 vs. 15.1 months for stage IV disease). Current treatment strategies for stage III/IV non-resectable metastatic NRAS mutant melanoma include immunotherapy and indirect targeting of NRAS associated signaling pathways, highlighting the urgent need to develop small molecule NRAS inhibitors. NRAS palmitoylation is essential for its oncogenic function by regulating its trafficking and anchoring to the plasma membrane. Unlike other RAS isoforms, NRAS relies on a single palmitoylation site (C181) for its plasma membrane localization and this unique dependency makes NRAS more sensitive to palmitoylation inhibitors. To identify selective NRAS inhibitors that covalently modify C181 and prevent its palmitoylation, we employed an imaging-based NRAS translocation high-throughput screen using a library of 23,000 covalent molecules. We identified a set of covalent inhibitors that selectively target NRAS translocation but do not affect HRAS localization. We further confirmed the direct binding of these compound hits to NRAS at its palmitoylation site (C181) using intact mass spectrometry and chemo-proteomic peptide mapping techniques. Moreover, we validated the functional impact of these compound hits by demonstrating their selective inhibition of cell growth in mutant NRAS-driven melanoma cell lines. In conclusion, our study presents the first direct inhibitor for NRAS, discovered through a high-throughput covalent screening approach. This finding holds promising implications for the development of novel targeted therapies for NRAS mutant tumors.
Citation Format: Zhao Wang, Keith Moore, Simon Ng, Chao Wang, Ronald Tomlinson, Huay-Keng Loke, Jamie Rice, Ivan Cornella. Discovery of covalent NRAS inhibitors targeting the Palmitoylation site through imaging-based high-throughput screening [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 PR009.
Abstract A030: Identifying LGBTQ+-related barriers and gaps in patient and workplace environments: An LGBTQ+ environmental needs assessment at Perlmutter Cancer Center
Authors: Trifonov Alexandr , Monahan Rachel , Haseltine Megan C. , Moore Kevin , Quinn Gwendolyn P. , Nelson Rachel , Chachoua Abraham , Domogauer Jason 
Published: December 2023

Abstract
Background: The LGBTQ+ community faces disproportionately higher cancer-related health disparities compared to the general population. Lack of access, knowledge, and cultural attitudes are known factors attributing to lower rates of receiving cancer-preventative services, as well as higher rates of later-stage cancer diagnoses. Many factors contribute to these disparities, including finding a trusted provider, poor visual representation at clinics, missing sexual orientation and gender identity (SOGI) data, and negative patient experiences. To address these issues and to promote equitable care it is important to identify gaps and barriers that present in patient and healthcare staff environments. The LGBTQ+ Staff Task Force (STF) at NYU Langone Health Perlmutter Cancer Center (PCC) will utilize the Exploration, Planning, Implementation, Sustainment (EPIS) framework to address these inequities. Methods: As part of the “Exploratory” phase, the STF will deploy an environmental needs assessment survey, to evaluate patient and employee areas. The assessment includes the following LGBTQ+ domains to evaluate the environments: Policy; Visualization and Safety; Knowledge and awareness education; Complaint and Feedback Reporting; Workplace Inclusions and Non-discrimination; Resources. The survey will be administered to all clinical and non-clinical departments of PCC and will be completed by STF members from their respective departments and by managers or supervisors from each department location. Surveys will be submitted electronically via REDCap Data will be analyzed by the research team and discussed in small focus groups. Discussion: The LGBTQ+ Needs Assessment will be carried out across all PCC departments and locations within an 8-week period between May and July 2023. The findings from utilizing the EPIS framework will enable the identification of gaps and barriers to inclusive patient care and evaluate the efficacy of current processes and resources in place for LGBTQ+ patients and employees. Findings will inform strategies and planning to decrease identified factors impacting access to equitable healthcare.
Citation Format: Alexandr Trifonov, Rachel Monahan, Megan C. Haseltine, Kevin Moore, Gwendolyn P. Quinn, Rachel Nelson, Abraham Chachoua, Jason Domogauer. Identifying LGBTQ+-related barriers and gaps in patient and workplace environments: An LGBTQ+ environmental needs assessment at Perlmutter Cancer Center [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A030.
Abstract A036: The role of multisectoral partnerships in the dissemination of HPV vaccination campaigns in Puerto Rico
Authors: Valencia-Torres Ileska M. , Sánchez-Cabrera Yara , Fernández María E. , Colón-López Vivian 
Published: December 2023

Abstract
INTRODUCTION: The Human Papillomavirus (HPV) is the most common sexually transmitted infection worldwide. Despite the availability of an effective vaccine, HPV vaccination uptake is suboptimal in Puerto Rico (PR). Knowledge and understanding of the benefits of HPV vaccination can influence the intention to vaccinate. The Puerto Rico Community Cancer Control Outreach Program (PRCCCOP) and our network of multisectoral partners disseminated an HPV vaccination educational campaign tailored to promote HPV vaccination among kids and adolescents aged 9-26. OBJECTIVE: To effectively disseminate Human Papillomavirus (HPV) prevention educational campaigns through a network of multisectoral collaborators to increase HPV vaccination uptake in PR. METHODS: The PRCCCOP trained collaborators on basic HPV, HPV-caused cancers, and HPV vaccine knowledge and the use of educational materials. Collaborators distributed educational materials to their clientele who visited in person, participated in sponsored events, and accessed their virtual platforms or via email. In addition to printable educational materials, PRCCOP public service announcement videos about HPV vaccination were transmitted at our participating Federally Qualified Health Centers (FQHC). The PRCCOP provided all collaborators with continued training, assistance, and educational materials. RESULTS: Our program impacted 65 municipalities (83.3% of the island). Electronic and printed versions of our educational materials were disseminated in 40 clinics and vaccination centers across the island, including all 22 FQHCs in Puerto Rico (PR). Over 2,000 people were reached via in-person events and health fairs. Additionally, 18 workshops were imparted in clinical and academic settings. CONCLUSION: Community outreach can be an expensive and labor-intensive task. By establishing partnerships and sharing resources, the PRCCCOP has lowered costs while widely disseminating its educational campaigns and expanding its network outside the traditional academic/health services arena. Collaborating with multisectoral organizations allowed us to increase our presence throughout the island, diversify the types of dissemination mediums, and reach vulnerable and hard-to-reach populations.
Citation Format: Ileska M. Valencia-Torres, Yara Sánchez-Cabrera, María E. Fernández, Vivian Colón-López. The role of multisectoral partnerships in the dissemination of HPV vaccination campaigns in Puerto Rico [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A036.