bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4793: A role for fibroblast derived SASP factors in the activation of non-apoptotic cell death in normal mammary epithelial cells
Authors: Hom Lisa M. , Sun Seunghoon , Campbell Jamie , Murphy Ireland , Culbert Shannon 
Published: April 2023

Abstract
In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous, biological outcomes. Fibroblasts are one cell type in constant communication with neighboring epithelial cells, and as a result, can alter various cellular parameters. Additionally, fibroblasts are prone to undergo senescence, exemplified by an irreversible cell cycle arrest, in response to a variety of stimuli. Senescent cells exhibit alterations in gene expression and are characterized by substantial changes in their secretome; termed the senescence associated secretory phenotype (SASP). The role of fibroblast derived SASP factors on normal epithelial cells is an area that remains poorly understood. Our studies have found that treatment of normal mammary epithelial cells with conditioned media from senescent fibroblasts (SASP CM) results in a robust programmed cell death. The capacity of SASP CM to cause cell death is maintained across multiple senescence-inducing stimuli. Interestingly, our data suggest that the cell death caused by SASP CM is dependent on caspase activation, but independent of canonical extrinsic or intrinsic apoptotic pathways. shRNA-mediated reduction of caspase 1 or GSDMD in normal mammary epithelial cells ameliorates the ability of the SASP CM to induce cell death, suggesting that these cells are dying by pyroptosis. Interestingly, breast cancer cells and normal mammary epithelial cells engineered to express oncogenic signals are not susceptible to this SASP CM induced cell death, suggesting that cancer cells have evolved a mechanism to evade SASP CM-mediated pyroptosis.. Taken together, our data reveal a novel relationship between the activation of senescence in stromal cells and the induction of non-apoptotic cell death in normal mammary epithelial cells.
Citation Format: Lisa M. Hom, Seunghoon Sun, Jamie Campbell, Ireland Murphy, Shannon Culbert. A role for fibroblast derived SASP factors in the activation of non-apoptotic cell death in normal mammary epithelial cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4793.
Abstract 4794: Deciphering tumor recurrence post-therapy: Interactions between the tumor microenvironment and therapy-induced senescent glioblastoma
Authors: DeLuca Valerie , Digumarti Priya , Berens Michael E. 
Published: April 2023

Abstract
Glioblastoma (GBM) remains one of the most lethal forms of cancer due, in part, to the capacity of tumor cells to persist during therapy and then recover. Understanding how these residual tumor cells survive is therefore imperative to developing more effective treatment strategies. We have demonstrated that GBM cells, including those from patient-derived xenografts, undergo a state of therapy-induced senescence (TIS) rather than cell death following temozolomide (TMZ) and radiation (IR). Both TMZ and IR treatment at physiologically relevant doses result in elevated senescence-associated-β-galactosidase, altered morphology, p21 induction, and increased expression of the senescence-associated-heterochromatic-foci marker H3K9Me3. Further, despite TIS-induction in a majority of the residual cells post-treatment, GBM viable cell number increases after a prolonged stasis, indicating that populations are capable of reentering a proliferative state. However, our current understanding of how the tumor microenvironment influences this growth arrest and subsequent proliferative recovery is underdeveloped. We aim to bridge that gap by investigating the paracrine communications between astrocytes and GBM cells undergoing IR-induced senescence in order to identify how these interactions foster disease progression. Current studies are focused on evaluating the effect of astrocytes on the induction and durability of TIS in GBM cells. Proteomic studies will be pursued to characterize the secretome of astrocyte-GBM co-cultures and identify factors that drive GBM senescent response to IR. Finally, based on preliminary data demonstrating that normal astrocytes are also damaged by IR, we will undertake mechanistic studies to understand how cell-intrinsic events within the astrocyte population drive extrinsic-influence on GBM cells. We anticipate that these identified signaling events may serve as potential therapeutic targets.
Citation Format: Valerie DeLuca, Priya Digumarti, Michael E. Berens. Deciphering tumor recurrence post-therapy: Interactions between the tumor microenvironment and therapy-induced senescent glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4794.
Abstract 4837: Inhibition of mitochondrial fission activates glycogen storage to support cell survival in colon cancer
Authors: Hasani Sumati , Young Lyndsay E. , Banerjee Moumita , Rivas Dylan , Kim Jinhwan , Sun Ramon , Gentry Matthew , Xiong Xiaopeng , Gao Tianyan 
Published: April 2023

Abstract
Metabolic reprogramming has been increasingly recognized as one of the major mechanisms that fuels tumorigenesis and disease progression. Our previous studies have shown that in response to fatty acid uptake, colon cancer cells activate mitochondrial fission to support fatty acid oxidation and downstream Wnt signaling. Given the potential benefit of inhibiting mitochondrial fission, Dynamin-Related Protein 1 (Drp1), a pro-fission factor, has become an attractive target for developing anticancer agents. Here we investigated the role of Drp1 in promoting metabolic adaptation in colon cancer. We found that knockdown of Drp1 decreased mitochondrial respiration which resulted in increased glucose uptake and lactate production. In addition, downregulation of Drp1 increased AMP-activated protein kinase (AMPK) activity which coincided with glycogen accumulation. Consistently, results from GC/MS analysis of cellular metabolites revealed that the levels of glucose-6-phosphate, a precursor for glycogenesis, were significantly elevated in Drp1 knockdown cells whereas pyruvate and other TCA cycle metabolites remained unchanged. Mechanistically, AMPK transcriptionally activates the expression of glycogen synthase 1 (GYS1) and hexokinase 2 (HK2) genes and silencing GYS1 abolished the glycogen accumulation phenotype in Drp1 knockdown cells. Using APC-derived 3D organoids, we demonstrated that the glycogen levels were elevated in Apcf/f Drp1f/f tumor organoids upon deletion of Drp1. Similarly, increased GYS1 expression and glycogen levels were detected in xenograft tumors derived from Drp1 knockdown colon cancer cells compared to control. Functionally, increased glycogen storage allowed Drp1 knockdown cells to survive glucose starvation conditions suggesting an enhanced survival capacity compared to control cells. Taken together, our findings indicate that Drp1 inhibition by itself is unlikely to be sufficient to eradicate cancer cells as adaptive metabolic mechanisms are activated to promote cell survival. However, combining Drp1 inhibition may enhance the efficacy of chemotherapeutic agents for colon cancer treatment.
Citation Format: Sumati Hasani, Lyndsay E. Young, Moumita Banerjee, Dylan Rivas, Jinhwan Kim, Ramon Sun, Matthew Gentry, Xiaopeng Xiong, Tianyan Gao. Inhibition of mitochondrial fission activates glycogen storage to support cell survival in colon cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4837.
Abstract 4964: SW-682: A novel TEAD inhibitor for the treatment of cancers bearing mutations in the Hippo signaling pathway
Authors: Chen Lei , de Marval Paula Milani , Powell Kendall , Johnson Mark , Falls Greg , Lawhorn Brian , Candi Aurélie , Kilonda Amuri , Vanderhoydonck Bart , Marchand Arnaud , Versele Matthias , Halder Georg , Gwaltney Stephen L. , Kamal Adeela 
Published: April 2023

Abstract
Many cancers harbor mutations in the Hippo pathway that lead to constitutive activation of the transcriptional co-activators YAP/TAZ that then bind the transcription factor TEAD and drive aberrant transcription of target genes involved in cell proliferation and tumor progression. Hyperactivation of YAP/TAZ has also been associated with resistance to targeted therapies, including MAPK pathway inhibitors. To target cancers that bear mutations in the Hippo pathway or are resistant to therapies due to YAP/TAZ activation, we developed SW-682, a pan-TEAD small molecule inhibitor that blocks TEAD-dependent transcription by binding to the palmitoylation pocket of all TEAD isoforms. In vitro, SW-682 inhibited the proliferation of human Hippo-mutant mesothelioma cells with nanomolar potency, with little to no effect on Hippo wild-type tumor cells. SW-682 down-regulated TEAD-dependent reporter gene expression in a dose-dependent manner, while having no effect on reporters monitoring other pathways. In vivo, daily oral administration of SW-682 to adult mice resulted in tumor regression in Hippo-mutant mesothelioma models and caused down-regulation of expression of the TEAD-dependent genes CCN1 and CCN2 and a YAP gene signature, as measured by qPCR or RNA-seq analysis. SW-682 has a favorable PK profile with good oral bioavailability in the mouse and was well tolerated with no signs of body weight loss. To test the hypothesis that TEAD inhibition can overcome YAP-driven resistance mechanisms, we explored SW-682 in combination with MEK inhibitors in several in vitro and ex vivo patient-derived tumor models including BRAF and NRAS mutated melanoma. Moreover, to identify new indications that may benefit from TEAD inhibition, we screened patient-derived 3D organoid tumor cells and matching patient-derived xenograft models that have been molecularly profiled. In summary, SW-682 is a potent and selective investigational TEAD inhibitor which demonstrated anti-tumor effects in models harboring aberrant expression of the Hippo pathway, suggesting therapeutic potential in multiple Hippo-mutant solid tumors.
Citation Format: Lei Chen, Paula Milani de Marval, Kendall Powell, Mark Johnson, Greg Falls, Brian Lawhorn, Aurélie Candi, Amuri Kilonda, Bart Vanderhoydonck, Arnaud Marchand, Matthias Versele, Georg Halder, Stephen L. Gwaltney, Adeela Kamal. SW-682: A novel TEAD inhibitor for the treatment of cancers bearing mutations in the Hippo signaling pathway. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4964.
Abstract 509: DM5167, a novel selective PARP1 inhibitor, efficiently reduces growth of triple-negative breast cancers
Authors: Nam Sujin , Chae Jiyoung , Cho Kyung-Ok , Koo Tae-Sung , Kim Jungho , Jung Myungeun , Kim Jeongmin , Kim Eunhee 
Published: April 2023

Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) has been portrayed as a synthetic lethal target in cancers with homologous recombination deficiency. As all four PARP inhibitors on the market target both PARP1 and PARP2 isotypes, hematological toxicity issue emerged by PARP2 inhibition. To address the unmet need, we screened and optimized compounds exempt from the toxicity issue. Here, we present DM5167 as a new molecular entity with 0.41 nM of IC50 on the catalytic activity of PARP1. In addition, DM5167 exhibits an inhibitory profile against various PARP isotypes that differs from the four commercial PARP inhibitors. Specifically, DM5167 shows selectivity for PARP1 6.88 and 347.83 fold greater than PARP2 in the in vitro enzyme assay and DNA trapping assay, respectively. This contrasts with the corresponding PARP1/PARP2 selectivity values of 0.14 and 0.89 fold for olaparib, respectively. Moreover, DM5167 showed higher selectivity than AZD5305 in the enzymatic assay. The GLP toxicity studies assigned DM5167 as a safe compound based on its high NoAEL value, a general toxicity parameter. In addition, the safety margin of DM5167 was acceptable, indicating that DM5167 is a plausible drug candidate. To find suitable indications, we screened various human cancer cell lines using their inhibitory potentials against proliferation and colony formation. Several hits were seen in triple-negative breast cancer cell lines including MDA-MB-231, MDA-MB-436, MDA-MB-468 and HCC1395. In an orthotopic xenograft experiment in which MDA-MB-231 cells were implanted, oral administration of 50mpk of DM5167 inhibited tumor growth by 45.8%. In contrast, olaparib failed to reduce xenograft tumors derived from MDA-MB-231 cells. Collectively, these studies present DM5167 as an attractive anti-TNBC drug candidate.
Citation Format: Sujin Nam, Jiyoung Chae, Kyung-Ok Cho, Tae-Sung Koo, Jungho Kim, Myungeun Jung, Jeongmin Kim, Eunhee Kim. DM5167, a novel selective PARP1 inhibitor, efficiently reduces growth of triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 509.
Abstract 5093: Chemically inducible splice-neoantigens for cancer immunotherapy
Authors: Matsushima Shingo , Ajiro Masahiko , Iida Kei , Chamoto Kenji , Honjo Tasuku , Hagiwara Masatoshi 
Published: April 2023

Abstract
Although immune checkpoint blockade therapies have dramatically improved the survival rate of patients with cancer compared with other treatment approaches, a substantial number of patients show poor response or resistance to these therapies. Meta-analyses for programmed cell death 1 (PD-1) blockade responses highlight the importance of neoantigens, derived from non-synonymous mutations in cancer cells, for antitumor immune responses. Intriguingly, recent transcriptome and genomics studies predict the presence of putative neoantigens as a result of an irregular pre-mRNA splicing regulation in cancer cells, indicating that alterations in RNA splicing in cancer cells might induce antitumor immune responses. Here, we report that induction of serine/arginine-rich splicing factor (SRSF)-dependent splicing boosts the production of splicing-associated neoantigens (splice-neoantigens) and potentiates the response to PD-1 blockade. Administration of a synthetic SRSF activator RECTAS suppressed tumor growth in a host CD8+ T cell- and tumor major histocompatibility complex class I-dependent manner and promoted the antitumor effect of anti-PD-L1 antibody without detectable autoimmunity. Subsequent transcriptome analysis and validation for immunogenicity identified six splice-neoantigen candidates whose expression was induced by RECTAS treatment. Importantly, vaccination of the identified neoepitopes elicited T cell responses capable of killing cancer cells in vitro, in addition to suppression of tumor growth in vivo upon sensitization with RECTAS. Collectively, these results provide support for the further development of splice variant-inducing treatments for cancer immunotherapy.
Citation Format: Shingo Matsushima, Masahiko Ajiro, Kei Iida, Kenji Chamoto, Tasuku Honjo, Masatoshi Hagiwara. Chemically inducible splice-neoantigens for cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5093.
Abstract 512: Identification of SS008871, a novel Polθ inhibitor that effectively inhibits tumors with homologous recombination deficiency in vitro and in vivo
Authors: Zhou Feng , Liu Lu , Jiang Lei , Tang Feng , Li Zhen , Yang Wenqing , Xue Liting , Chen L , Tang Renhong 
Published: April 2023

Abstract
The repair of DNA double strand break (DSB) is crucial for genome stability and cell survival. There are three main DSB repair pathways: homologous recombination (HR), non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ). HR is a high-fidelity, error-free DSB repair pathway, and the dysfunction of HR confers cell genome instability and leads to tumorigenesis. HR deficiency is especially prevalent in gynecologic tumors, sharing about 10% population of all the gynecologic tumor patients. In situation of HR deficiency, MMEJ, in which DNA polymerase theta (Polθ) plays an essential role, is up-regulated to serve as a backup pathway for DSB repair. Several studies have proved that the inhibition of Polθ causes synthetic lethality with HR deficiency. Hence, Polθ emerges as a potential DNA damage repair target for the treatment of HR deficient tumors. Here we report a novel small molecular Polθ inhibitor, SS008871, which inhibits Polθ activity with an IC50 of 22 nM, and strongly inhibits cellular MMEJ pathway with an IC50 of single-digital nanomolar level. SS008871 strongly inhibits proliferation of HR deficient BRCA2-/- DLD-1 cells, and shows a &gt;125× selectivity folds over DLD-1 parent cells as well as non-malignant cells. Besides, SS008871 elicits synergetic anti-proliferation activities in combination of a PARP inhibitor, olaparib on BRCA2-/- DLD-1 and MDA-MB-436 cells. In the BRCA2-/- DLD-1 xenograft model, SS008871 shows tumor growth inhibition as a single agent, and the combination of SS008871 and olaparib further results in tumor regression. Accordingly, the level of γH2AX, a common DSB marker, correlates well to the anti-tumor efficacy. In a human hematopoietic stem cells based in vitro hematotoxicity assay, SS008871 shows no significant inhibition on lineage-specific (myeloid, erythroid and megakaryocytic) cell differentiation and survival, suggesting the low hematotoxicity risk. In comparison, olaparib significantly attenuated hematopoietic stem cells on both differentiation and survival in the parallel assay, which is consistent with the hematological toxicity observed in human. Furthermore, there is no clinical abnormalities observed after a high dose treatment of SS008871 in mice, demonstrating that SS008871 is well-tolerated. Taken together, SS008871 is proved to be an encouraging Polθ inhibitor with good safety.
Citation Format: Feng Zhou, Lu Liu, Lei Jiang, Feng Tang, Zhen Li, Wenqing Yang, Liting Xue, L Chen, Renhong Tang. Identification of SS008871, a novel Polθ inhibitor that effectively inhibits tumors with homologous recombination deficiency in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 512.
Abstract 5149: Age-associated remodeling of anti-tumor T cell immunity and metabolism
Authors: Han SeongJun , Georgiev Peter , Ringel Alison , Sharpe Arlene , Haigis Marcia 
Published: April 2023

Abstract
Aging results in remodeling of T cell immunity and is associated with poor clinical outcome in age-related diseases such as cancer. Amongst the hallmarks of aging, changes in host and cellular metabolism are critically involved in the development, maintenance, and functional responses of T cells. Although metabolic perturbations impact anti-tumor T cell responses, the link between age-associated metabolic dysfunction and anti-tumor immunity remains unclear. First, we utilized B16, MC38 and E0771 tumor-bearing young (2-4 months) and aged (18-24 months) C57BL/6 mice to examine the effects of aging on tumor growth. Aged mice exhibited accelerated tumor growth in B16, MC38 and E0771 tumor models. Flow cytometric analyses of tumor infiltrating lymphocytes (TILs) revealed distinct changes in CD8+ T cell population, decreased activation status and tumor-specificity in aged mice. Consistent with these findings, CD8+ T cells functionally played a limited role in controlling tumor growth in aged mice. Here, we will explore the mechanisms of age-associated metabolic dysfunction in T cells and its implications in anti-tumor immunity. As the average life expectancy continues to increase, understanding the interplay between age-related metabolic reprogramming and maladaptive T cell immunity will be instrumental in the development of novel therapeutic strategies for older patients.
Citation Format: SeongJun Han, Peter Georgiev, Alison Ringel, Arlene Sharpe, Marcia Haigis. Age-associated remodeling of anti-tumor T cell immunity and metabolism. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5149.
Abstract 515: Discovery of potent and orally available small molecule inhibitors of the SOS1-KRAS interaction
Authors: Yu Ha Na , Ki Dong Hyuk , Nam Joonwoo , Kim Eun-Jung , Kim Sungeun , Choi Hunmi , Kim Jieun , Yu Jihyun , Kim Donggeon , Park Dohyun , Yoon Kyeong Jin , Jo Seongin , Hwang So-Hyeon , Lim Sang Kyun , Shin Young Sook , Han Wooseok 
Published: April 2023

Abstract
Abnormal activating mutation of KRAS is frequently found in many human cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). KRAS activating mutations lead to hyperactivation of the MAPK/ERK signaling pathway, resulting in promotion of cell proliferation and growth. SOS1 is one of the major guanine nucleotide exchange factors (GEFs) that regulates RAS proteins including KRAS. Since SOS1 plays a critical role in converting the GDP-bound inactive KRAS “off” state to the GTP-bound active KRAS “on” state, disruption of SOS1 and KRAS protein-protein interaction would be effective to block KRAS-driven oncogenic signaling regardless of its mutation status. Importantly, SOS1 activity is crucial during the reactivation of the KRAS/MAPK signaling upon the treatment of RAS/MEK/ERK inhibitors, thus a SOS1 inhibitor would be an effective therapeutic option to treat KRAS-driven tumors in combination with RAS pathway inhibitors. We developed potent, selective, and orally available small molecules that effectively disrupt the interaction between SOS1 and KRAS. Current lead compounds originated from a virtual screening displayed excellent ADME and PK profiles. In cellular assays, a robust reduction of phospho-ERK level and cancer cell growth were shown. We also observed excellent in vivo antitumor activity in the mouse xenograft models. Moreover, combination with Sotorasib synergistically inhibited tumor cell growth both in vitro and in vivo. Overall, our SOS1 inhibitors demonstrate great therapeutic potential for cancer patients with KRAS mutations.
Citation Format: Ha Na Yu, Dong Hyuk Ki, Joonwoo Nam, Eun-Jung Kim, Sungeun Kim, Hunmi Choi, Jieun Kim, Jihyun Yu, Donggeon Kim, Dohyun Park, Kyeong Jin Yoon, Seongin Jo, So-Hyeon Hwang, Sang Kyun Lim, Young Sook Shin, Wooseok Han. Discovery of potent and orally available small molecule inhibitors of the SOS1-KRAS interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 515.