bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5470: ONC206 inhibits tumour growth and is a potential novel therapeutic strategy for refractory medulloblastoma
Authors: Tzaridis Theophilos , Liu Jingbo , Prabhu Varun , Wechsler-Reya Robert , MacDonald Tobey
Published: March 2024

Medulloblastoma is the most common malignant pediatric brain tumor with a for certain molecular subgroups very low overall survival and therefore an urgent need for novel treatment approaches. Dordaviprone (ONC201) and its chemical derivative with nanomolar potency ONC206 are inhibitors of the dopamine receptor 2 (DRD2) and more importantly induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). ONC201 has shown objective responses in patients with diffuse midline gliomas and is currently being evaluated in the Phase 3 ACTION study. ONC206 is currently in Phase I clinical trials for pediatric and adult patients with primary brain tumors. In this study, we evaluated the preclinical therapeutic effects of ONC206 in medulloblastoma in vitro and in vivo and investigated the molecular mode of action for this imipridone. We found evidence for high expression of ClpP at both the RNA and protein level in medulloblastoma tumours, compared to very low expression in normal brain and normal cerebellum. In addition, we saw a pronounced reduction in cell viability of human Group 3 and Group 4 and murine medulloblastoma cells treated with ONC206 with extremely low IC-50s (range: 14nM - 2μM).After treatment with ONC206, we observed a significant downregulation of mitochondrial electron transport chain complexes I and III and mitochondrial hyperpolarization, as well as an induction of the ATF4 pathway, thereby implying that ONC206 induces an integrated stress response and mitochondrial damage. In order to test the efficacy of ONC206 in vivo, we used murine models of SHH-driven and Group 3 medulloblastoma as well as Group 3 patient-derived xenografts (PDXs). ONC206 led to a significant prolongation of survival in both murine models, with the SHH mice demonstrating a remarkable survival benefit. Mice from both Group 3 PDXs also responded to ONC206, with 25% of ONC206 treated animals exhibiting long-term tumor-free survival. Our results highlight ONC206 as a novel attractive therapeutic option for patients with relapsed medulloblastoma and importantly pave the way for a clinical trial testing the efficacy of ONC206 in the treatment of these patients.

Citation Format: Theophilos Tzaridis, Jingbo Liu, Varun Prabhu, Robert Wechsler-Reya, Tobey MacDonald. ONC206 inhibits tumour growth and is a potential novel therapeutic strategy for refractory medulloblastoma [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 5470.
Abstract 5533: The difference of immune microenvironment betweende novometastatic and non-metastatic microsatellite instability-high colorectal cancer
Authors: Chen Kuo-Hsing , Hs Chia-Lang u , Su Yu-Li , Yuan Chang-Tsu , Tsai Jia-Huei , Liang Yi-Hsin , Cheng Ann-Lii , Yeh Kun-Huei
Published: March 2024

Introduction: Microsatellite instability-high (MSI-H) colorectal cancer (CRC) consists of 15% of all CRC but only 2-4% of metastatic CRC. The favorable prognosis of non-metastatic (early-stage) MSI-H CRC may be related to vigorous immune reaction in tumor microenvironment. However, the mechanisms of immune evasion in metastatic (late stage) MSI-H CRC are largely unknown.

Materials and Methods: We retrospectively collected patients with MSI-H CRC from National Taiwan University Hospital and Kaohsiung Chang Gung Memorial Hospital. The archival tumor specimens were used for immune cells analysis by Nanostring PanCancer Immune Panel, and spatial immune characterization by multiplex immunofluorescence stains. Only surgical resected primary tumors and metastatic tumors were included. Gene expression and immune cells composition were compared between non-metastatic and de novo metastatic tumors.

Results: We enrolled 59 and 27 patients with early-stage and late-stage MSI-H CRC, respectively. Twelve metastatic site tumors were also collected. The clinicopathologic characteristics between patients who have early- and late-stage MSI-H CRC were not significantly different. There are heterogeneous immune cell compositions in these 98 MSI-H tumors. Compared to early-stage MSI-H tumors, there are significantly fewer cytotoxic (difference -0.497, p = 0.001) and dendritic cells (difference -0.528, p = 0.021) in late-stage MSI-H tumors. Gene set enrichment analysis disclosed significantly decrease in the expression of JAK-STAT-IFN-γ- and antigen processing-related pathways in late-stage MSI-H tumors. The top 5 genes with significantly differential expression between late-stage and early-stage tumors are C7, TNFRSF12A, MFGE8(up-regulated) and CXCL5, IFNL1, GZMH, HMGB1 and CXCR1 (down-regulated).

Conclusions: There are significantly fewer cytotoxic and dendritic cells in late-stage MSI-H CRC, compared to early-stage MSI-H CRC, which is associated with decrease expression in JAK-STAT-IFN-γ- and antigen processing-related pathways.

Citation Format: Kuo-Hsing Chen, Chia-Lang u Hs, Yu-Li Su, Chang-Tsu Yuan, Jia-Huei Tsai, Yi-Hsin Liang, Ann-Lii Cheng, Kun-Huei Yeh. The difference of immune microenvironment betweende novometastatic and non-metastatic microsatellite instability-high colorectal 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 5533.
Abstract 5546: CRISPR-based kinome screen identifies Ikbkb as a regulator of phagocytic evasion in hepatocellular carcinoma
Authors: Chan Sze Man , Lee Terence Kin Wah
Published: March 2024

Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent malignancies worldwide and is associated with poor prognosis. Recently, immune checkpoint inhibitors (ICIs) have revolutionized the oncology landscape by targeting genes critical for immune checkpoint pathways, leading to the immune evasion of cancer cells. Phagocytosis checkpoints have emerged as essential checkpoints for cancer immunotherapy by functioning as “don’t eat me” signal to suppress immune response. Given the druggable properties of protein kinases, together with recent reports showing the antitumor immunity of kinase inhibitors, we aimed to identify protein kinases critical for phagocytic evasion in HCC by transducing a lentiviral sgRNA expression plasmid containing 2,852 unique single-guide RNAs (sgRNAs) targeting the 713 mouse kinase gene in mouse HCC cells, RIL-175, and subsequently co-incubated with RAW 264.7 macrophages. Based on the deep sequencing analysis comparing the sgRNA distribution in RIL-175 with or without co-incubation, we identified the Ikbkb gene as top-sensitizing hit on this screen, with at least two-fold sgRNA reduction upon incubation with macrophages.

To verify the phagocytic evasive role of Ikbkb in HCC, we have employed CRISPR/Cas9 knockout approach to delete Ikbkb in mouse HCC cell line, RIL-175 cells. The results showed that upon co-incubation with RAW 264.7 cells, the Ikbkb knockout cells exhibited increased phagocytosis, as confirmed by both flow cytometry analysis and microscopy observation. The analysis of the TCGA-LIHC cohort revealed that the expression level of Ikbkb was elevated and associated with unfavorable clinical outcomes. Notably, Ikbkb expression was found to be significantly correlated with established anti-phagocytic markers, including CD24, CD47, and CD274, further supporting their roles in the anti-phagocytic activities of HCC cells.

In summary, we have uncovered IKBKB as a cancer-intrinsic regulator of phagocytosis, which has the potential to target IKBKB as a novel therapeutic strategy to enhance the efficacy of current ICI treatments for HCC patients.

Citation Format: Sze Man Chan, Terence Kin Wah Lee. CRISPR-based kinome screen identifies Ikbkb as a regulator of phagocytic evasion 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 5546.
Abstract 5551: Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment
Authors: Khoury Rami , Kleiner Ron , Yeini Eilam , Ajamil Daniel Rodriguez , Dangoor Sahar Israeli , Sanalla Tamer , Barshack Iris , Satchi-Fainaro Roni
Published: March 2024

Several mutations have been identified that are associated with an increased risk of triple-negative breast cancer (TNBC), including those that are deleterious in the BRCA gene. TNBC is associated with the worst prognosis and the highest incidence of brain metastasis (30%) among all subtypes of BC. Despite objective responses to poly (ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-mutated TNBC, benefits are transitory. Furthermore, our understanding of the effect of PARP inhibitors (PARPi) in treating breast cancer brain metastasis (BCBM) and modulating its tumor microenvironment (TME) is still lacking. To this end, we analyzed the brain TME of BRCA-mutated BCBM in the absence or presence of treatment with PARPi. Interestingly, we found that the immune TME of the brain hinder the antitumor activity of PARPi by upregulating multiple immunosuppressive molecules, including PD-L1. Furthermore, we found that BCBM overexpress P-selectin through its interaction with the tumor-associated microglia, bone marrow-derived macrophages and endothelial cells in the TME. Thus, we designed a novel nanoparticle (NP) targeting P-selectin to serve as a brain-penetrant delivery system for the treatment of BCBM. In order to target BRCA-mutated BCBM, we harnessed our novel P-selectin-targeted NPs to entrap PARPi and other immune modulators that we found to exert synergistic activity when combined. To evaluate the antitumor activity of our P-selectin-targeted NPs, we established 3-dimensional (3D) ex vivo and in vivo BRCA-mutated BCBM models. Importantly, we saw favorable effects of the P-selectin-targeted NPs in comparison to the combination of the free drugs, suggesting that out targeted-NPs overcome the TME-mediated resistance to PARPi through the modulation of the immunosuppressive microenvironment of the brain.

Citation Format: Rami Khoury, Ron Kleiner, Eilam Yeini, Daniel Rodriguez Ajamil, Sahar Israeli Dangoor, Tamer Sanalla, Iris Barshack, Roni Satchi-Fainaro. Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment [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 5551.
Abstract 5554: Breast cancer with different chemosensitivity has distinct influence on the immune microenvironment
Authors: Skourti Eleni , Seip Kotryna , Egeland Eivind V. , Jabeen Shakila , Mensali Nadia , Øynebråten Inger , Juell Siri , Inderberg Else M. , Engebråten Olav , Corthay Alexandre B. , Mælandsmo Gunhild M. , Prasmickaite Lina
Published: March 2024

Triple Negative Breast Cancer (TNBC) is a BC subgroup with the least favorable outcome and limited therapeutic options. Chemotherapy has long been the standard treatment, but resistance often develops. In recent years, various immunotherapy approaches have diversified, including combinations of chemo and immunotherapies. Increased understanding on how the difference in chemosensitivity affects the immune cells is of importance for further development of chemo-immunotherapies for TNBC. In this project we investigate how TNBC with distinct chemosensitivity modulate the immune microenvironment. Specifically, we explore the influence of the secretome, derived from the chemoresistant versus the sensitive BC cells, on macrophages (MØs) and T-cells. We have disclosed the chemosensitivity-dependent differences in the secretome, which were associated with diverse effects on MØ recruitment, polarization, and activation. Currently we investigate the secretome influence on interferon (IFN)-activated MØ. IFN stimuli is known to trigger tumoricidal activities in MØ, and we are setting up a co-culture assay, where such MØ functions could be explored in vitro. To study the secretome influence on T-cells, we employ T cell receptor (TCR)-engineered T cells that become activated in the presence of target cells. The preliminary results indicate that activation of the TCR T-cells was reduced in the presence of the “chemoresistant” secretome, suggesting its immunosuppressive influence. Work is in progress to validate this observation using other TCR T cells and functional markers of active T cells.

Citation Format: Eleni Skourti, Kotryna Seip, Eivind V. Egeland, Shakila Jabeen, Nadia Mensali, Inger Øynebråten, Siri Juell, Else M. Inderberg, Olav Engebråten, Alexandre B. Corthay, Gunhild M. Mælandsmo, Lina Prasmickaite. Breast cancer with different chemosensitivity has distinct influence on the immune microenvironment [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 5554.
Abstract 56: Preclinical in vivo characterization underpinning LGR5-targeting CAR-T cells as a cancer immunotherapy
Authors: Foeng Jade , Tyllis Timona , Abbott Caitlin , McPeake Dylan , Thompson Emma , Bandara Veronika , Gundsambuu Batjargal , Napoli Silvana , Bonder Claudine , Comerford Iain , Sadlon Tim , Barry Simon , McColl Shaun
Published: March 2024

Incidences of early-onset colorectal cancer (CRC) have been accelerating worldwide. To begin to address the lack of therapeutic options for CRC, we have developed a CAR-T cell therapy specific for leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). LGR5 is known to potentiate Wnt/Β-catenin signaling and mark cells-of-origin in intestinal cancers. Extensive screening has demonstrated elevated expression of LGR5 in CRC, which is correlated with reduced patient survival. In CRC, LGR5 has been intimately linked with metastasis, cell survival and perturbation of chemotherapeutic interventions. We have developed a 9-day preclinical manufacturing method to generate LGR5-targeting CAR-T cells with a minimally differentiated T cell phenotype, which was concomitant with significant cytotoxic and activation marker expression. In human CRC xenograft mouse models, LGR5-targeting CAR-T cells eradicated tumors at doses as low as 800,000 CAR+ cells, and were capable of significantly inhibiting advanced tumor growth following delayed administration. Robust CAR-T cell-mediated immunological protection was observed in rechallenge experiments, in which secondary tumor growth was undetectable in mice which had tumors rejected following previous CAR-T cell administration. LGR5 protein and mRNA expression was also detected in a diverse range of cancer families, including ovarian, brain, liver and stomach, expanding upon the clinical indications with which LGR5-targeting CAR-T cells may be harnessed. These results contribute to a preclinical body of work that culminated in a Phase I/IIa clinical trial in metastatic colorectal cancer patients, which was approved for initiation by the FDA and commenced in 2023 (NCT05759728).

Citation Format: Jade Foeng, Timona Tyllis, Caitlin Abbott, Dylan McPeake, Emma Thompson, Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Claudine Bonder, Iain Comerford, Tim Sadlon, Simon Barry, Shaun McColl. Preclinical in vivo characterization underpinning LGR5-targeting CAR-T cells as a cancer immunotherapy [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 56.
Abstract 5604: Modulating DNA repair through endo-exonuclease inhibition: a new therapeutic paradigm in oncology
Authors: Chow Terry , Duan Jianmin , Colin Patrick , Bier Colin
Published: March 2024

DNA damage repair (DDR) mechanisms are crucial for the maintenance of genomic stability and are emerging as potential therapeutic targets for cancer. Endo-exonuclease (EE)1 plays a key role in this process and increase EE expression has been observed in the cancer cells examined. In this context, we identified a dicationic diarylfuran, pentamidine, which is an antiparasitic drug that has been used clinically to treat opportunistic infections such as Pneumocystis carinii. Pentamidine is an inhibitor of the endo-exonuclease as determined by enzyme kinetic assay and is known to be active on cancer cells. In a proof of concept study2, tumor with increased EE expression (determined by IHC) showed the best response to this drug.

We have now identified novel mono- and di-amidine analogs of pentamidine that are more effective than the parent drug in both in vitro and in vivo studies. Furthermore, pre-clinical animal studies of our lead candidate, MTDX203, showed an increased anti-cancer activity with a higher safety index than pentamidine. Based on a predictive PK/PD model, a human iv infusion dose administered twice weekly at ~0.4 mpk (i.e. 28 mg/day, ~10% of pentamidine effective iv dose) is expected to be clinically effective. Our work establishes the EE as a therapeutic target for cancer and identifies a new First in Class of novel anti-cancer agents.

1Chow et al. (2004) MCT 3:911-9182 NCT01378143: Pentamidine (OCZ103-OS) in Patients With Unresectable and Locally Recurrent or Metastatic Colorectal Cancer Undergoing Standard Chemotherap

Citation Format: Terry Chow, Jianmin Duan, Patrick Colin, Colin Bier. Modulating DNA repair through endo-exonuclease inhibition: a new therapeutic paradigm in oncology [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 5604.
Abstract 5639: TIP60-independent mechanism of BRD8 is involved in colorectal tumorigenesis
Authors: Yamaguchi Kiyoshi , Nakagawa Saya , Yamaguchi Rui , Sheridan Paul , Takane Kiyoko , Ikenoue Tsuneo , Nagatoishi Satoru , Kozuka-Hata Hiroko , Oyama Masaaki , Aikou Susumu , Ahiko Yuka , Shida Dai , Tsumoto Kouhei , Miyano Satoru , Imoto Seiya , Furukawa Yoichi
Published: March 2024

Modifications of histone tails control chromatin structure, and the acetylation is generally associated with euchromatin and transcriptional activation. Acetylated lysine residues are recognized by bromodomains, which serve as acetyl-lysine binding modules and participate in transcriptional regulation. Bromodomain-containing protein 8 (BRD8) is a subunit of the NuA4/TIP60-histone acetyltransferase complex. Although BRD8 has been considered to act as a co-activator of the complex, its biological role remains to be unclear. In this study, we revealed that BRD8 accumulates in colorectal cancer cells through the inhibition of ubiquitin-dependent protein degradation by the interaction with MRG domain binding protein (MRGBP). RNA-seq analysis coupled with genome-wide mapping of BRD8-binding sites disclosed that BRD8 transactivates a set of genes independently of TIP60, a catalytic subunit of NuA4 complex, and that BRD8 regulates the expression of multiple subunits of the pre-replicative complex (pre-RC) in concert with the activator protein-1 (AP-1) transcription factor. Depletion of BRD8 induced cell-cycle arrest at the G1 phase and suppressed proliferation of colorectal cancer cells. We have also shown that the bromodomain of BRD8 is indispensable for not only the interaction with histone H4 or transcriptional regulation but also its own protein stability. These findings provide a new insight into the roles played by BRD8 in human colorectal carcinogenesis and will contribute to the development of new chemotherapeutic agents targeting the bromodomain of BRD8.

Citation Format: Kiyoshi Yamaguchi, Saya Nakagawa, Rui Yamaguchi, Paul Sheridan, Kiyoko Takane, Tsuneo Ikenoue, Satoru Nagatoishi, Hiroko Kozuka-Hata, Masaaki Oyama, Susumu Aikou, Yuka Ahiko, Dai Shida, Kouhei Tsumoto, Satoru Miyano, Seiya Imoto, Yoichi Furukawa. TIP60-independent mechanism of BRD8 is involved in colorectal tumorigenesis [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 5639.
Abstract 5689: miR-21: A therapeutic target that delays severe liver disease and hepatocellular carcinoma under high-fat-diet conditions
Authors: Jagtap Urmila , Quan Anan , Ono Yuho , Lee Jonathan , Shen Kylie A. , Manakov Sergei , Szabo Gyongyi , Nasser Imad , Slack Frank J.
Published: March 2024

Liver disease is a major global health concern, claiming approximately 2 million lives worldwide annually, yet curative treatments remain elusive. In our study, we aimed to investigate the role of microRNA-21-5p (miR-21) in metabolic dysfunction-associated steatotic liver disease (previously NAFLD), metabolic-associated steatohepatitis (previously NASH), and hepatocellular carcinoma (HCC) within the context of a Western high-fat diet (HFD) and offering potential therapeutic insights. We found that reduced miR-21 levels correlated with liver disease progression in WT mice fed on HFD, while miR-21 knockout mice showed exacerbated metabolic dysfunction, including obesity, hepatomegaly, hyperglycemia, insulin resistance, steatosis, fibrosis, and HCC. Our study reveals that miR-21 plays a protective role in metabolic syndrome and in the progression of liver disease to cancer. miR-21 directly targets Transforming growth factor beta-induced (Tgfbi), a gene also known to be significantly upregulated and a potential oncogene in HCC. Further, our study showed that intervention with the administration of a miR-21 mimic in WT livers in HFD conditions effectively improves insulin sensitivity, steatosis, fibrosis, tumor burden, as well as Tgfbi expression. These findings indicate that miR-21 could serve as an effective strategy to delay or prevent liver disease in high-fat-diet environments.

Citation Format: Urmila Jagtap, Anan Quan, Yuho Ono, Jonathan Lee, Kylie A. Shen, Sergei Manakov, Gyongyi Szabo, Imad Nasser, Frank J. Slack. miR-21: A therapeutic target that delays severe liver disease and hepatocellular carcinoma under high-fat-diet conditions [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 5689.
Abstract 5695: miR-5787 suppresses cancer cell growth as a Fe3O4-nanoparticles induced pivotal miRNA
Authors: Watanabe Masatoshi , Nakano Hitoshi , Matsuda Chise , Usugi Eri , Imai Hiroshi , Hirokawa Yoshifumi , Iijima Kazutoshi
Published: March 2024

Nanotechnology offers great potential for cancer diagnosis and treatments. Especially, nanoparticles (NPs) have been examined and utilized as drug delivery systems, hyperthermia and combination therapy. We have examined and reported the combined effects of Fe3O4-nanoparticles (Fe3O4-NPs) with chemotherapeutic agents on prostate cancer cell in vitro. miRNAs are an important factor in cancer progression, and elucidating the miRNA-mediated intracellular network of cancer cells could suggest new cancer treatment strategies. In this study, to identify microRNAs (miRNAs) associated with anticancer effects of Fe3O4-NPs, the comprehensive expression of miRNAs by Microarray (Agilent G4780A SuperPrint G3 Human v16 miRNA 8x60K Microarray kit) in A549 (lung cancer cell line), LNCaP (androgen-dependent prostate cancer cell line) and DU145 (androgen-independent prostate cancer cell line) under Fe3O4-NPs exposure was performed. miR-5787 was one of the increased miRNAs in three cancer cell lines under Fe3O4-NPs, and its increase in miR-5787 was due to the reactive oxygen species (ROS) production by Fe3O4-NPs. The additional analysis suggested that miR-5787 might suppressed the cancer cell growth by targeting the eIF5. In this study, we identified miR5787 as a Fe3O4-NPs induced pivotal miRNA in cancer cells, and can be used as a therapeutic target.

Citation Format: Masatoshi Watanabe, Hitoshi Nakano, Chise Matsuda, Eri Usugi, Hiroshi Imai, Yoshifumi Hirokawa, Kazutoshi Iijima. miR-5787 suppresses cancer cell growth as a Fe3O4-nanoparticles induced pivotal miRNA [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 5695.
Abstract 572: Identifying potential therapeutic targets through gene expression analysis of peritoneal cavity cells in gastric cancer with peritoneal dissemination
Authors: Hiroshima Yukihiko , Kawase Wataru , Hashimoto Itaru , Onuma Shizune , Watanabe Hayato , Furuta Mitsuhiro , Oshima Takashi , Miyagi Yohei
Published: March 2024

Background: Peritoneal dissemination (PD) is the primary mode of metastasis in gastric cancer (GC) and is strongly associated with a poor prognosis. However, the mechanisms underlying PD formation in GC remain largely unknown.Methods and Results: In this study, we collected peritoneal washings from three cytology-positive (CY1) and five cytology-negative (CY0) gastric cancer patients undergoing laparotomy. We performed RNA sequencing on cell components in the peritoneal washings and identified 13 genes that were differentially expressed and upregulated in the CY1 group. Among these genes, we focused on thrombospondin 1 (THBS1) and 2 (THBS2). We evaluated their expression levels in 317 patients with gastric or gastroesophageal junction cancer who underwent primary curative resection at the Kanagawa Cancer Center between January 2002 and December 2012. Patients were stratified into two groups based on the median expression values of these genes, and Kaplan-Meier analysis was conducted. THBS2 expression was found to be inversely associated with disease-free survival (DFS) (p = 0.041), peritoneal dissemination-specific DFS (p = 0.041), and overall survival (OS) (p = 0.041) in the study cohort. In contrast, THBS1 expression did not exhibit a significant association with any of the aforementioned outcomes.Conclusion: Our results suggest that THBS2 expression in gastric cancer tissues may serve as a useful independent prognostic factor for patients, potentially playing a crucial role in the formation of PD.

Citation Format: Yukihiko Hiroshima, Wataru Kawase, Itaru Hashimoto, Shizune Onuma, Hayato Watanabe, Mitsuhiro Furuta, Takashi Oshima, Yohei Miyagi. Identifying potential therapeutic targets through gene expression analysis of peritoneal cavity cells in gastric cancer with peritoneal dissemination [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 572.
Abstract 5723: Selectivity profiling of small molecule kinesin inhibitors using microplate-based ATPase activity assay
Authors: Lee Brenna P. , Oh Sung Won , Horiuchi Kurumi Y. , AbdulSalam Safnas F.
Published: March 2024

Kinesin superfamily proteins (KIFs) are a large family of molecular motor proteins, that share a highly conserved motor domain. KIFs play an important role in cell division and transport of vesicles and organelles within cells. Mitotic kinesins hydrolyze ATP through its ATPase activity to move along the spindle microtubules and carry out several functions during mitosis to facilitate precise chromosome segregation. Altered expressions of several kinesins are shown in various cancers, fueling the aggressive nature of cancers leading to genomic instability. KIF11/Eg5 overexpression is shown in various cancers including hepatic carcinoma, lung, prostate, colorectal, gastric, and pancreatic cancers. Small molecule inhibitors of KIF11/Eg5 and CENP-E are shown to result in mitotic arrest leading to apoptosis in tumor cell lines. Despite the poor clinical outcome of several Eg5 and CENP-E inhibitors entered in clinical trials, targeting kinesins remains an attractive anti-cancer therapeutic approach. Recently, an inhibitor of KIF18A has entered clinical trial for treatment of solid tumors with high chromosomal instability. Here we show development of a microplate based biochemical screening assays for a panel of kinesin motor domain proteins. We summarize kinetic characterization of kinesin proteins and study the selectivity of various previously reported KIF18A, Eg5, CENP-E inhibitors across a kinesin selectivity panel.

Citation Format: Brenna P. Lee, Sung Won Oh, Kurumi Y. Horiuchi, Safnas F. AbdulSalam. Selectivity profiling of small molecule kinesin inhibitors using microplate-based ATPase activity assay [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 5723.
Abstract 573: SLC22A17 as a promising target for triple-negative breast cancer
Authors: Kunnumakkara Ajaikumar B. , Thakur Krishan Kumar
Published: March 2024

Introduction: Triple-negative breast cancer (TNBC) represents a highly aggressive subtype of breast cancer, accounting for approximately 15% of all cases of invasive breast cancer globally. The absence of a well-defined cell membrane receptor has significantly limited the therapeutic options available for treating this malignancy. Consequently, there is a compelling need to explore novel receptors that could potentially revolutionize the treatment strategies employed for TNBC. Recent scientific research has unveiled SLC22A17, a cell surface receptor known for its involvement in iron transport, as a substantial contributor to the development of various cancer types. Thus, the primary objective of this study is to comprehensively evaluate the significance of SLC22A17 and its potential as a therapeutic target in TNBC.

Experimental Procedures: In this study, we meticulously examined the expression patterns of SLC22A17 across distinct subtypes of breast cancer utilizing immunohistochemistry. Computational tools were employed to delve into the role of SLC22A17 within TNBC datasets. To assess the impact of SLC22A17 on TNBC, we employed various methods, including siRNA-mediated silencing, to investigate its role in cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), and migration. Additionally, we conducted western blot analyses to assess the expression levels of SLC22A17 and cellular signaling molecules, such as Akt/mTOR and JAK/STAT, within the context of TNBC cells.

Results: Our analysis revealed a significant upregulation of SLC22A17 in both TNBC tissues and cell lines, establishing a direct correlation with patient survival outcomes. Silencing the expression of SLC22A17 resulted in reduced cell proliferation, migration, EMT, increased apoptosis, and enhanced autophagy. These effects were accompanied by the inhibition of Akt/mTOR and STAT3 signaling pathways. Moreover, we observed the involvement of the inflammatory cytokine TNF-α, which induced the expression of SLC22A17 in TNBC cell lines and governed various hallmark features of TNBC. Notably, the suppression of SLC22A17 mitigated these processes.

Conclusion: In conclusion, this investigation suggests the pivotal role played by SLC22A17 in TNBC and posits its potential as a novel and promising therapeutic target for the management of this formidable disease.

Citation Format: Ajaikumar B. Kunnumakkara, Krishan Kumar Thakur. SLC22A17 as a promising target for triple-negative breast 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 573.
Abstract 5783: Receptor tyrosine kinase Tyro3 interaction with ligands and inhibitors
Authors: Hardeman Keisha Nicole , Starbird Chrystal
Published: March 2024

TAM receptors (Tyro3, Axl, Mer) are a sub-family of receptor tyrosine kinases that regulate cell survival and homeostasis primarily through their role in clearance of apoptotic cells. While several receptor tyrosine kinases (RTKs) are targeted in various types of cancer therapies, interest in Tyro3 as a potential target in breast cancers has only recently grown. Determining the structure of Tyro3 with and without tyrosine kinase inhibitors (TKIs) bound will provide important missing information to aid in the design of treatments that can be combined with existing cancer treatments, as dual treatment is often necessary. I have designed constructs that will be used for crystallization of the Tyro3 kinase domains. I mapped the full portion of the kinase (called "Small"), an extended kinase ("Big"), and a smaller catalytic domain ("Cat"). The kinases were made through a molecular cloning method (Gibson Assembly), sequence verified, and expressed in insect cells for large scale purification. Ni-NTA and gel filtration will be used, followed by crystallization and soaking with inhibitors.

Citation Format: Keisha Nicole Hardeman, Chrystal Starbird. Receptor tyrosine kinase Tyro3 interaction with ligands and inhibitors [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 5783.
Abstract 5806: Discovery of a long half-life AURKA inhibitor to treat MYC-amplified solid tumors as a monotherapy and in combination with everolimus
Authors: Chi Ya-Hui , Chang Chun-Ping , Yeh Teng-Kuang , Chen Chiung-Tong , Wang Wan-Ping , Chen Yen-Ting , Tsai Chia-Hua , Chen Yan-Fu , Ke Yi-Yu , Wang Jing-Ya , Chen Ching-Ping , Hsieh Tsung-Chih , Wu Mine-Hsine , Huang Chen-Lung , Chen Ya-Ping , Zhuang Hong
Published: March 2024

Aurora kinase inhibitors such as alisertib can destabilize MYC-family oncoproteins and have demonstrated compelling anti-tumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A (AURKA) inhibitor that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer (BC) cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC. We also report DBPR728, an acyl-based prodrug of 6K465 bearing fewer hydrogen-bond donors that exhibited 10-fold improved oral bioavailability. DBPR728 induced durable tumor regression of c-MYC- and/or N-MYC- overexpressing xenografts including SCLC, triple-negative breast cancer (TNBC), hepatocellular carcinoma and medulloblastoma using a 5-on-2-off or once-a-week dosing regimen on a 21-day cycle. A single oral dose of DBPR728 at 300 mg/kg induced c-MYC reduction and cell apoptosis in the tumor xenografts for more than 7 days. The inhibitory effect of DBPR728 at a reduced dosing frequency was attributed to its uniquely high tumor/plasma ratio (3.6-fold within 7 days) and the long tumor half-life of active moiety 6K465. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC- driven SCLC. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC- and/or N-MYC.

Citation Format: Ya-Hui Chi, Chun-Ping Chang, Teng-Kuang Yeh, Chiung-Tong Chen, Wan-Ping Wang, Yen-Ting Chen, Chia-Hua Tsai, Yan-Fu Chen, Yi-Yu Ke, Jing-Ya Wang, Ching-Ping Chen, Tsung-Chih Hsieh, Mine-Hsine Wu, Chen-Lung Huang, Ya-Ping Chen, Hong Zhuang. Discovery of a long half-life AURKA inhibitor to treat MYC-amplified solid tumors as a monotherapy and in combination with everolimus [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 5806.
Abstract 5831: The TLE1 transcriptional and epigenetic machinery contributes to EGFR targeted therapy resistance in human lung adenocarcinoma
Authors: Biliran Hector Ramos , Yao Xin , Roberts Nasir , Iheukwumere Prince , Chen Renwei , Dela Cruz Ma. Carmela
Published: March 2024

In human lung adenocarcinoma that carry Epidermal Growth Factor Receptor (EGFR) sensitizing mutations, targeting the EGFR pathway with the use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has emerged as a promising therapeutic strategy providing initial clinical benefit to many patients. Unfortunately, resistance to EGFR-TKIs eventually develops leading to disease progression. In addition to genetic mutations, transcriptional and epigenetic mediated changes in gene expression remain an important mechanism contributing to EGFR-TKI resistance. Here, we report a novel function of the transcriptional corepressor Transducin-Like Enhancer of Split-1 (TLE1) in mediating EGFR-TKI resistance in EGFR mutant LUAD cells through its survival promoting gene transcriptional program. In EGFR mutant, EGFR TKI sensitive LUAD cells, sole activation of the TLE1 nuclear function attenuates EGFR TKI sensitivity with concomittant reduction of EGFR-TKI-mediated apoptosis. Conversely, downregulation of endogenous TLE1 expression via siRNAs/shRNAs and deletion of TLE1 gene via CRISPR-Cas9 in EGFR-mutant, EGFR-TKI resistant cells partially restore EGFR-TKI sensitivity via induction of EGFR-TKI apoptosis. Mechanistically, the anti-apoptosis promoting gene transcriptional program of TLE1 is dependent on its functional interaction with the transcriptional repressor HES-1, a downstream Notch target which has been associated with relapse in LUAD patients following EGFR-TKI treatment. Collectively, these studies indicate the TLE1 corepressor as a determinant of resistance to EGFR targeted therapy and raise the possibility that inhibiting TLE1 nuclear function may serve as an adjuct therapy to circumvent EGFR-TKI resistance.

Citation Format: Hector Ramos Biliran, Xin Yao, Nasir Roberts, Prince Iheukwumere, Renwei Chen, Ma. Carmela Dela Cruz. The TLE1 transcriptional and epigenetic machinery contributes to EGFR targeted therapy resistance in human lung adenocarcinoma [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 5831.
Abstract 5904: Targeting NaV1.7 channels in pancreatic cancer: Implications for EF2K and P-Src/P-Fak/integrin β1 signaling pathways
Authors: Erdogan Mumin Alper , Caner Ayse
Published: March 2024

Pancreatic cancer (PaCa) ranks as the fourth leading cause of cancer-related deaths in the United States and is among the top five worldwide. Its hallmark characteristics include early invasion, metastasis, resistance to chemotherapy and radiotherapy, and aggressive tumor progression. Evaluating new generation treatments with significant potential in this ongoing battle against cancer is crucial. Voltage-gated sodium channels (VGSC), long detected in various metastatic cell lines and tissue samples beyond breast, lung, and prostate cancer, are of particular interest. This study aimed to explore the therapeutic effects of inhibiting NaV1.7 and its neonatal variant, nNaV1.7, in pancreatic cancer cells. The study utilized human normal keratinocyte cell line HaCaT and pancreatic cancer cell lines PANC-1 and MiaPaCa-2. It investigated the roles and effects of adult and neonatal isoforms of the NaV1.7 channel in pancreatic cancer proliferation, invasion, and metastasis. The findings revealed significantly higher adult and neonatal NaV1.7 mRNA expressions in PANC-1 and MiaPaCa-2 cell lines compared to HaCaT cells. Specific siRNAs effectively downregulated channel mRNA and protein expressions. Notably, NaV1.7 siRNA treatments significantly inhibited cell proliferation and colony-forming capacity in PANC-1 and MiaPaCa-2 cells, without cytotoxic effects on HaCaT cells. Combining gemcitabine with specific NaV1.7 siRNAs enhanced drug efficacy in the PANC-1 cell line. Furthermore, NaV1.7 siRNAs significantly reduced cell invasion, migration, and wound healing in both cell lines. These siRNAs also induced apoptosis and G1 arrest in the cell cycle. They inhibited protein expressions involved in key signaling pathways, including P-Src/P-Fak/Integrin β1, EF2K, P-Akt, P-mTOR, PARP, Caspase-3/9, Cyclin D1/E1. This study is pioneering, as literature lacks research on the expression and function of NaV1.7 and nNaV1.7 in pancreatic cancer cells or tissue samples. In conclusion, NaV1.7 channel isoforms play a significant role in the development, progression, and metastasis of pancreatic cancer and present as a potential therapeutic target in PaCa.

Citation Format: Mumin Alper Erdogan, Ayse Caner. Targeting NaV1.7 channels in pancreatic cancer: Implications for EF2K and P-Src/P-Fak/integrin β1 signaling pathways [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 5904.
Abstract 5968: CDC7 is a targetable regulator of advanced prostate cancer
Authors: Hartono Alifiani Bonita , Paparaju Sidharth , Lee Chung , Liu Shiqin , Alabi Busola R. , Hsu En-Chi , Brooks James D. , Corey Eva , Stoyanova Tanya
Published: March 2024

Prostate cancer is estimated to contribute to over 34,000 deaths in men residing in the United States, with the majority fatality due to metastatic disease. CDC7 is a kinase that regulates DNA replication and is an emerging cancer biomarker for poor prognosis in carcinomas such as Wilms tumor and hepatocellular carcinomas. In this study, we demonstrated that high level of CDC7 is associated with metastatic prostate cancer when compared to benign prostate tissues or localized prostate cancer. Furthermore, we found that CDC7 expression is highest in prostate cancer patient-derived xenografts (PDX) models of adenocarcinomas with neuroendocrine features. In vitro, we showed that inhibition of CDC7 with TAK-931, a CDC7 specific inhibitor, reduced the ability of aggressive prostate cancer cells to proliferate, migrate, and invade. Similarly, knock-down of CDC7 in prostate cancer cell lines inhibited cell growth in a colony formation assay. TAK-931 treated prostate cancer cell lines also showed an abnormal cell cycle profile, indicating that inhibiting CDC7 in aggressive prostate cancer could contribute to replication stress and promote apoptosis. Overall, this study demonstrates that CDC7 is a targetable protein that regulates advanced and aggressive prostate cancer growth.

Citation Format: Alifiani Bonita Hartono, Sidharth Paparaju, Chung Lee, Shiqin Liu, Busola R. Alabi, En-Chi Hsu, James D. Brooks, Eva Corey, Tanya Stoyanova. CDC7 is a targetable regulator of advanced 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 5968.
Abstract 6147: Genome-wide association study identifies new genetic susceptibility loci for multiple primary cancers
Authors: He Shisi , Perry James , Li Shengchao , Mitchell Braxton D. , Zhang Yuji , Chen Shuo , Beane-Freeman Laura , Barry Kathryn Hughes , Berndt Sonja I.
Published: March 2024

Objectives: Genetic susceptibility is thought to contribute to the development of multiple primary cancers (MPC), often called secondary cancers. Although rare variants contribute to risk, these only account for a small fraction of MPC cases. The contribution of common variants to risk is unknown.

Methods: To identify common genetic variants associated with the risk of MPC, we conducted a trans-ancestry meta-analysis of genome-wide association studies (GWAS), including 7,360 MPC cases and 138,684 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and UK Biobank (UKBB). Association analyses were performed separately by genetic ancestry, genotype platform, and study, adjusting for age, sex, and principal components, and the results were meta-analyzed together using a fixed effects model. Genome-wide SNP heritability was estimated using GCTA. Pathway and functional enrichment analyses were conducted to gain insights into potential biological mechanisms underlying discovered loci.

Results: We identified one novel locus at chromosome 3q26.2 (LRRC34, rs7621631) that was associated with MPC risk (P=1.16x10-8). Variants in this region have been previously associated with telomere length, suggesting a possible underlying mechanism. In sex-stratified analyses, we identified an additional locus at chromosome 12q24.33 (intergenic, rs10466868) associated with MPC in men (P= 7.76x10-8), but not women. Although the risk associated with these two discovered loci was small, the genome-wide SNP heritability was estimated to be 12%, suggesting that there are likely more common variants to be discovered for MPC risk.

Conclusions: Our study demonstrates that common genetic variation contributes to the risk of multiple primary cancers and suggests additional loci are likely to be identified with larger studies.

Citation Format: Shisi He, James Perry, Shengchao Li, Braxton D. Mitchell, Yuji Zhang, Shuo Chen, Laura Beane-Freeman, Kathryn Hughes Barry, Sonja I. Berndt. Genome-wide association study identifies new genetic susceptibility loci for multiple primary cancers [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 6147.
Abstract 6303: Innovative strategies for managing chemotherapy-induced alopecia: Scalp cooling
Authors: Gaumond Simonetta I. , Abdin Rama , McPhillips Rory O. , Ferrari Lina M. , Mufarrej Sammya , Jimenez Joaquin J.
Published: March 2024

Chemotherapy-Induced Alopecia (CIA) is a visibly distressing consequence of chemotherapy. Although it does not pose a life-threatening risk, CIA can significantly affect patient’s self-esteem. Regarding the mechanism of action, stress induced by chemotherapy treatment can lead to the shedding of hair follicles, generating varying degrees of hair loss. In recent years, scalp cooling has emerged as a beneficial preventative agent for CIA due to its ability to induce vasoconstriction in the scalp and reduce follicular metabolic rate. To assess the efficacy of scalp cooling in preventing CIA, we conducted a review of randomized control trials published on PubMed in the last 10 years. Five studies met our inclusion criteria, in which three examined hair preservation and two evaluated treatment duration efficacy. All studies investigating hair preservation with scalp cooling reported highly significant results from the cooling device when compared to a placebo (56.3% vs. 0%, 39.3% vs. 0%, and 50.5% vs. 0%, respectively). Additionally, one of these studies also assessed hair regrowth, revealing higher rates in the scalp cooling group compared to the control at 6 weeks (89% vs. 12%) and at 12 weeks (100% vs. 59%). Both studies evaluating the effectiveness of scalp cooling based on treatment duration concluded that 20 minutes of cooling was as effective as 45 and 90 minutes in preventing CIA. Collectively, these findings add to the mounting evidence endorsing scalp cooling as a powerful management strategy in averting CIA.

Citation Format: Simonetta I. Gaumond, Rama Abdin, Rory O. McPhillips, Lina M. Ferrari, Sammya Mufarrej, Joaquin J. Jimenez. Innovative strategies for managing chemotherapy-induced alopecia: Scalp cooling [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 6303.