bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2643: BL-M07D1, a novel HER2-targeting ADC, demonstrates potent anti-tumor efficacy in preclinical pharmacodynamic models
Authors: Wan Weili , Zhao Shuwen , Zhuo Shi , Zhang Yong , Chen Lan , Li Gangrui , Khalili Jahan Salar , Xiao Sa , Yan Yongqi , Shen Xuejiao , Zhu Yi 
Published: April 2023

Abstract
HER2 is a member of the epidermal growth factor receptor family. Activation of the HER2 signaling pathway has been shown to strongly promote carcinogenesis. It is therapeutically targeted in cancer owing to its overexpression and pathway dependence in a variety of human carcinomas, especially human breast cancers. We created a promising therapeutic anti-tumor agent, BL-M07D1, an anti-HER2-Ed-04 ADC. It is comprised of a humanized anti-HER2 antibody Trastuzumab, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04), which is a derivative of the alkaloid camptothecin, driving cell cycle arrest at the S phase and subsequent apoptosis. The BL-M07D1 drug-to-antibody-ratio is 8:1 (DAR=8), similar to Trastuzumab Deruxotecan (DS-8201), while possessing a more stable linker.
To evaluate the pharmacological potential of BL-M07D1, xenograft tumor inhibition assays were used to compare BL-M07D1 with the commercialized HER2-targeting ADCs, T-DM1 and DS-8201, which have been approved worldwide for patients with HER2-expressing tumors. Results from the in vivo murine studies show that BL-M07D1 has strong tumor inhibition effects in multiple cell line-derived xenograft (CDX) tumor models. 1) BL-M07D1 exhibited better anti-tumor efficacy than DS-8201 in CDX with low HER2 expression, human epidermal cancer A431 and human non-small cell lung cancer NCI-H1975. Both models are considered be T-DM1-insensitive. 2) BL-M07D1 exhibited better anti-tumor efficacy in comparison to either T-DM1 or DS-8201 in a CDX with JIMT-1, a HER2-positive human breast cancer cell line. 3) BL-M07D1 exhibits potent bystander effects in a heterogeneous xenograft model of HER2-positive and HER2-negative tumor cells composed of NCI-N87 and MDA-MB-468 cells. In this model, BL-M07D1 exhibited stronger tumor inhibition than T-DM1, consistent with bystander effects that are also exhibited by DS-8201.
In conclusion, in vivo studies suggest that BL-M07D1, a novel HER2-targeting ADC, is potentially more efficacious in a broader patient population than T-DM1, and mediate superior anti-tumor efficacy than DS-8201. The clinical phase I is under way and the available data exhibit excellent efficacy in breast cancer therapy with acceptable tolerability.
Citation Format: Weili Wan, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Gangrui Li, Jahan Salar Khalili, Sa Xiao, Yongqi Yan, Xuejiao Shen, Yi Zhu. BL-M07D1, a novel HER2-targeting ADC, demonstrates potent anti-tumor efficacy in preclinical pharmacodynamic models [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 2643.
Abstract 2648: In vivo efficacy and preclinical safety profile of NN3201, an anti-cKIT antibody-drug conjugate, for treating SCLC and AML
Authors: Ko Han-Jik , Kim Sung Tae , Cho Jin Gu , Kim Jin-Ock , Lee Jung Tae , Park Sang Gyu 
Published: April 2023

Abstract
Overexpression and activating mutations of cKIT are associated with tumor aggressiveness and poor prognosis in various cancer patients such as small cell lung cancer (SCLC), gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), and mastocytoma. Since small molecule inhibitors including imatinib frequently have a limited therapeutic application due to eventual drug resistance and severe adverse events, we developed the cKIT-directed antibody-drug conjugate (ADC), NN3201, for the treatment of wild-type and mutant cKIT-positive cancers. NN3201 is an ADC conjugate of the antimitotic payload MMAE to the fully human 2G4 antibody, directed against cKIT, via the cysteine re-bridging technology ThioBridge® at a drug-to-antibody ratio (DAR) of 4. NN3201 displayed preferable biophysical properties and broadly potent in vitro antitumor activities across various cKIT-positive tumor cell lines. NN3201 exhibited potent in vivo antitumor activities in cKIT-positive tumor cell line xenograft and patient-derived tumor xenograft models of SCLC and AML, representing robust and durable antitumor responses. Furthermore, in a single-dose toxicity study with cynomolgus monkey, no significant or severe clinical toxicity signs were observed in animals dosed at 1, 2, and 3 mg/kg. Even though a decrease in reticulocyte, red cell mass (hemoglobin and red blood cell), neutrophil, and monocyte counts, along with bone marrow recovery and reticulocyte compensatory mechanism, red blood cell and white blood cell recovery were observed from day 14 in the low and medium dose groups and day 21 in the high dose group, dose-dependently. These preclinical results suggest that NN3201 is a potential therapeutic agent for the treatment of cKIT-positive cancers and support the further clinical evaluation in SCLC and AML.
Citation Format: Han-Jik Ko, Sung Tae Kim, Jin Gu Cho, Jin-Ock Kim, Jung Tae Lee, Sang Gyu Park. In vivo efficacy and preclinical safety profile of NN3201, an anti-cKIT antibody-drug conjugate, for treating SCLC and AML [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 2648.
Abstract 2675: Vactosertib combined treatment with T1-44, a PRMT5 activity inhibitor, improves the survival and inhibits tumor invasion of murine pancreatic cancer model
Authors: Hong Eunji , Park Sujin , Park Seok Hee , La Thangue Nick B. , Kim Seong-Jin 
Published: April 2023

Abstract
Pancreatic cancer is the most lethal type of cancer and the third leading cause of cancer death with the lowest 5-year survival rate. Heterogeneity, difficulty in diagnosis, and rapid metastatic progression are the causes of high mortality in pancreatic cancer. Recent studies have shown that Protein arginine methyltransferase 5 (PRMT5) is overexpressed in pancreatic cancers, and these patients have a worse prognosis. Therefore, PRMT5 as an anti-cancer target has gained considerable interest. In this study, we investigated whether inhibition of PRMT5 activity was synergistic with blockade of TGF-β1 signaling, which plays an important role in the construction of the desmoplastic matrix and invasiveness in pancreatic cancer and induces therapeutic vulnerability. Compared with T1-44, a selective inhibitor of PRMT5 activity, the combination of T1-44 with the TGF-β1 signaling inhibitor vactosertib significantly reduced tumor size and surrounding tissue invasion and significantly improved long-term survival. RNA sequencing analysis of mouse tumors revealed that the combination of T1-44 and vactosertib significantly altered the expression of genes involved in cancer progression, such as cell migration, extracellular matrix, and apoptotic processes. These data demonstrate that the combination therapy of T1-44 with vactosertib is synergistic for pancreatic cancer, suggesting that this novel combination therapy has value in the treatment strategy of patients with pancreatic cancer.
Citation Format: Eunji Hong, Sujin Park, Seok Hee Park, Nick B. La Thangue, Seong-Jin Kim. Vactosertib combined treatment with T1-44, a PRMT5 activity inhibitor, improves the survival and inhibits tumor invasion of murine pancreatic cancer model [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 2675.
Abstract 2682: Targeting phosphoglycerate dehydrogenase (PHGDH) in combination with tamoxifen reduces hormone receptor positive breast cancer growth in vivo
Authors: Clem Brian F. , Imbert-Fernandez Yoannis , Petri Belinda , Klinge Carolyn 
Published: April 2023

Abstract
Breast cancer afflicts thousands of individuals every year and is clinically diagnosed in various subtypes, including hormone receptor positive (HR+ BC). Significant strides have been made in treating HR+ BC through the development of endocrine therapies, such as tamoxifen, fulvestrant, and aromatase inhibitors. While these have improved the survival outcomes of these patients, many eventually relapse and, ultimately succumb to metastatic endocrine resistant disease. Subsequent work has identified various cellular pathways contributing to endocrine resistance, including alterations in cellular metabolism. We previously demonstrated that de novo serine synthesis (SSP) is increased in endocrine resistant cell types and genetic disruption of SSP enzymes impacts tamoxifen sensitivity. Further, elevated transcript expression is inversely correlated with survival outcomes in HR+ BC patients treated with tamoxifen. From this, we aimed to assess whether pharmacological targeting of SSP activity in combination with tamoxifen affects the growth of HR+ BC in vivo. We confirmed the presence of ER-alpha in three distinct patient derived xenograft (PDX) models and found varying levels of both phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1), which are the first and second enzymatic steps in the SSP pathway, respectively. In our efficacy studies, we initially found differential sensitivity to tamoxifen administration across the PDX models. While treatment with a PHGDH inhibitor (PHGDHi) had no anti-tumor activity against an endocrine-sensitive PDX, it moderately reduced the growth of endocrine resistant PDX tumors. Notably, combinatorial treatment resulted in a substantial decrease in tumor growth in all three models compared to single agents alone. Together, these data suggest that targeting of SSP activity in combination with endocrine therapies may be a promising therapeutic strategy in HR+ BC.
Citation Format: Brian F. Clem, Yoannis Imbert-Fernandez, Belinda Petri, Carolyn Klinge. Targeting phosphoglycerate dehydrogenase (PHGDH) in combination with tamoxifen reduces hormone receptor positive breast cancer growth 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 2682.
Abstract 2692: The combination of ulixertinib (ERK1/2 Inhibitor) and KRASG12C inhibition demonstrates significant efficacy in preclinical models
Authors: Knoerzer Deborah , Reddy Anupama , Box Jessica A. , Groover Anna , Kreider Brent , Teresk Martin , Emery Caroline M. 
Published: April 2023

Abstract
Ulixertinib (BVD-523) is a first-in-class and best-in-class small molecule inhibitor of ERK1/2 currently being investigated in several oncology clinical trials, both as a single agent and in combination with other therapeutics. Ulixertinib has demonstrated efficacy in patients with tumors harboring alterations within the RAS-MAPK pathway. KRAS is the most frequently mutated oncogene in cancer and is a key mediator of the RAS-MAPK signaling pathway resulting in proliferation and cellular growth. The specific KRASG12C mutation occurs in approximately 10% of non-small cell lung cancer (NSCLC), 3% of colorectal cancer, and 1-2% across all other tumor types. KRASG12C mutant-inhibitors, including AMG-510 (sotorasib), MRTX849 (adagrasib), and JDQ443 have demonstrated efficacy in KRASG12C-mutant cancers, including NSCLC. Clinically described mechanisms of acquired resistance to KRASG12C inhibitors converge on reactivation of the RAS-MAPK pathway. We hypothesized combining ulixertinib with a KRASG12C inhibitor would circumvent resistance to single agent KRASG12C inhibition, generating increased magnitude and duration of response compared to either single agent alone.
The efficacy of ERK1/2 inhibitor, ulixertinib, in combination with KRASG12C inhibitor, adagrasib, was assessed in cell line derived xenograft models harboring KRASG12C mutations. Models were selected based on response to single agent adagrasib, ranging from sensitive to partially responsive. Combination treatment resulted in superior tumor growth inhibition compared to dosing of either single agent. RNA sequencing was performed on tumor samples that were collected 2 hours after the last dose of treatment. Expression of the mutant KRAS alleles were readily confirmed from RNA sequencing data in all models. Gene expression analysis showed differential expression of MAPK pathway genes in monotherapy versus combination therapy treated groups.
In summary, ulixertinib combined with adagrasib exhibited robust pre-clinical activity in a variety of xenograft models with KRASG12C and should be further evaluated.
Citation Format: Deborah Knoerzer, Anupama Reddy, Jessica A. Box, Anna Groover, Brent Kreider, Martin Teresk, Caroline M. Emery. The combination of ulixertinib (ERK1/2 Inhibitor) and KRASG12C inhibition demonstrates significant efficacy in preclinical models [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 2692.
Abstract 2707: Therapeutic effects of WT1 silencing by respiratory administration of liposomal siRNA in a melanoma murine model
Authors: Ramos-Gonzalez Martin , Vázquez-Garza Eduardo , García-Rivas Gerardo , Rodríguez-Aguayo Cristian , Chávez-Reyes Arturo 
Published: April 2023

Abstract
Introduction: Cancer is considered among the main causes of death worldwide and the number of cases keeps rising every year, as there is not an effective treatment to offer for most of them. The lungs represent a frequent target of primary and metastatic tumors due to his high oxygenation and large air spaces to grow. Melanoma is the most aggressive type of skin cancer showing a high affinity to metastasize into the lungs, being the overexpression of the WT1 protein associated with the development of this cancer, as well as several other types.
Methods: In this study, we evaluated the effects of siRNA silencing the WT1 protein in both, in vitro in the B16F10 melanoma cell line, and in vivo in a murine model of pulmonary metastatic melanoma implementing a novel delivery strategy of neutral DOPC liposomal-siRNA system administrated via inhalation.
Results: In vitro studies showed an effective silencing of WT1 protein (86%) in the siRNAsWT1 treated cells when compared with controls, resulting in a loss of viability (40%) and proliferation (49%) of the cells, induced G1 cell-cycle arrest (11%), a restriction of migration (87%) and invasion (100%) capacities, as well as an activation of apoptosis (12%). In vivo, we tested our delivery system obtaining an efficient biodistribution in lungs, kidney, liver and spleen. The respiratory administration of LWT1siRNA after two weeks of treatment resulted in silencing of WT1 protein (59%), achieving an important antitumor activity with a 44% reduction in tumor weight. In the survival study 80% of the L-WT1siRNA treated mice were alive after all the controls mice had died, delaying the death almost a week at the end of the study.
Conclusions: This work demonstrates the efficacy of the neutral DOPC liposomal-siRNA delivery system by respiratory administration as a novel therapy to reduce the malignancy of pulmonary tumors and to increase survivability by silencing specific cancer biomarkers as WT1.
Citation Format: Martin Ramos-Gonzalez, Eduardo Vázquez-Garza, Gerardo García-Rivas, Cristian Rodríguez-Aguayo, Arturo Chávez-Reyes. Therapeutic effects of WT1 silencing by respiratory administration of liposomal siRNA in a melanoma murine model [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 2707.
Abstract 2813: Pyruvate kinase M2 confers radioresistance in head and neck cancer through reprograming the tumor-immune microenvironment via ECM1
Authors: Chen Fanghui , Fan Yang , Tang Chris , Richard Qin , Wei Zheng , Teng Yong 
Published: April 2023

Abstract
Radiotherapy plays an essential role in cancer treatment, yet radioresistance remains a major barrier to therapeutic efficacy. A better understanding of the predominant pathways determining radiotherapy response could help develop mechanism-informed therapies to improve cancer management. PKM2, an enzyme that regulates the final rate-limiting step of glycolysis, has different functions in the occurrence, progression and metastasis of cancer. However, whether PKM2 plays a vital role in radioresistance is unclear, especially in head and neck squamous cell carcinoma (HNSCC). Here we report the upregulation of PKM2 in primary post-radiotherapy tumor tissues collected from radioresistant HNSCC patients. Using multidisciplinary approaches, we found elevated PKM2 in response to radiation, which confers radioresistance in HNSCC cells via extracellular matrix protein 1 (ECM1). Mechanistically, PKM2 activates STAT5 signaling pathway in HNSCC cells upon radiation, which enhances ECM1 expression. Moreover, ECM1 upregulation mediated by PKM2 prevents effector T cells from migrating to radioresistant head and neck tumors. While depletion of ECM1 overcomes PKM2-mediated radioresistance in orthotopic xenograft mice through altering the profile of chemo-attractants, which in turn remodels the tumor microenvironment to promote more cytotoxic T cells home to tumors. These novel and significant findings not only demonstrate a novel mechanism underpinning the interaction between tumor-derived PKM2 and immune cells in radioresistance but also provide a possible therapeutic strategy to overcome the failure of radiotherapy in HNSCC patients.
Citation Format: Fanghui Chen, Yang Fan, Chris Tang, Qin Richard, Zheng Wei, Yong Teng. Pyruvate kinase M2 confers radioresistance in head and neck cancer through reprograming the tumor-immune microenvironment via ECM1 [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 2813.
Abstract 2844: BMP inhibition overcomes chemoresistance of prostate cancer
Authors: Hao Jijun , Xie Chen , Wang Zhijun , Bar Yong , Aguilar Jose , Kyan Austin , Zhing Li 
Published: April 2023

Abstract
Chemoresistance is a major therapeutic challenge to prostate cancer and its underlying molecular mechanism is poorly understood. Previously, it has been suggested that bone morphogenetic protein (BMP) signaling is down-regulated during the prostate cancer progression from the early androgen-sensitive stage to the metastatic castration-resistant stage. However, no literature reports are available for BMP signaling in the more advanced-chemoresistant prostate cancer. In this study, we found the expression levels of the BMP type I receptor members, Activin-like kinase-2 (ALK2) and Activin-like kinase-3 (ALK3), were significantly higher in the chemoresistant prostate cancer cells than those in the chemosensitive prostate cancer cells. In addition, the phospho-Smad1/5/9 proteins, the pivotal intracellular effectors of the BMP signaling, were notably elevated in the chemoresistant prostate cancer cells over the chemosensitive prostate cancer cells, indicating that BMP signaling is highly activated in the chemoresistant prostate cancer cells. We also found that BMP signaling inhibition with either DMH1 or the knockdown of ALK2/ALK3 sensitized chemoresistant prostate cancer cells to the chemotherapy drug docetaxel in a dose dependent manner. Our further study indicates that DMH1 suppressed the migration and invasion of chemoresistant prostate cancer cells in vitro, and attenuated chemoresistant prostate tumor growth in the mouse xenograft model in vivo. In addition, we showed that DMH1 disrupted the sphere formation in DU145-TxR and PC3-TxR cells, suppressed the expression of marker genes of the cancer stem cells (CSCs), and inhibited the efflux activity of multidrug resistance P-glycoprotein (P-gp1). In conclusion, our study demonstrates that BMP signaling is associated with prostate cancer chemoresistance and BMP signaling inhibition effectively overcomes the cancer chemoresistance potentially through the disruption of CSCs’ stemness and P-gp1 efflux activity.
Citation Format: Jijun Hao, Chen Xie, Zhijun Wang, Yong Bar, Jose Aguilar, Austin Kyan, Li Zhing. BMP inhibition overcomes chemoresistance of prostate 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 2844.
Abstract 3064: Exosome-based therapeutic strategy for neuroendocrine prostate cancer
Authors: Sreekumar Amritha , Saini Sharanjot 
Published: April 2023

Abstract
Background: Therapy-induced neuroendocrine prostate cancer (NEPC) is an aggressive variant of castration-resistant prostate cancer (CRPC) that is increasing in incidence with the widespread use of second generation of androgen receptor (AR)-pathway inhibitors (APIs) such as Enzalutamide (ENZ). NEPC arises from CRPC-Adenocarcinomas (CRPC-Adeno) via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED) wherein prostate cancer cells (PCa) undergo a lineage switch. As a result of this lineage switching, PCa cells exhibit neuroendocrine (NE) features, characterized by expression of neuronal markers such as enolase 2 (ENO2), chromogranin A (CHGA) and synaptophysin (SYP). Due to lack of AR signaling, these PCa variants are impervious to anti-androgen therapy and constitute an aggressive variant of advanced CRPC with survival times &lt; 1 year. Clinically, NEPC manifests as the presence of visceral metastatic disease including metastasis to liver, lung, central nervous system or bone despite low serum PSA levels. Current therapeutic options for NEPC are limited to highly toxic platinum drugs. The primary objective of our study is to evaluate novel, exosome-based therapies for NEPC.
Methods: Exosomes were isolated from HEK-293T cells by ultracentrifugation. Isolated exosomes were characterized by Nanoparticle Tracking Analyses and electron microscopy. These exosomes were engineered to express biotinylated CEACAM-5 antibody on their cell surface. Exosomes were packaged with a combination of drugs (EZH2 inhibitor and AR inhibitor) by sonication. Engineered exosomes were tested in vitro using NEPC cell line NCI-H660 and in vivo using LuCaP 145.1 patient-derived xenograft model.
Results: Engineered exosomes reduced the viability of NEPC cells. CEACAM5-labelled exosomes trafficked to tumor cells as CECAM5 is a surface protein expressed by NEPC cells.
Conclusions: Engineered-exosome based therapy may provide a new avenue as a targeted therapy for NEPC.
Citation Format: Amritha Sreekumar, Sharanjot Saini. Exosome-based therapeutic strategy for neuroendocrine prostate 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 3064.