bluuebunny/crossref_metadata_2025 huggingface dataset:
Obesity blunts amelioration of cardiac hypertrophy and fibrosis by human mesenchymal stem/stromal cell-derived extracellular vesicles
Authors: Hong Siting , Huang Weijun , Zhu Xiangyang , Tang Hui , Krier James D. , Xing Li , Lu Bo , Gandhi Deep , Jordan Kyra L. , Saadiq Ishran M. , Lerman Amir , Eirin Alfonso , Lerman Lilach O.
Published: June 2023

Injection of A-MSC-derived EVs harvested from patients who are lean can resolve myocardial injury in mice with experimental renovascular hypertension more effectively than A-MSC-derived EVs from patients with obesity. These observations underscore and might have important ramifications for the self-healing capacity of patients with obesity and for the use of autologous EVs as a regenerative tool.
mTORC1 inhibition impairs activation of the unfolded protein response and induces cell death during ER stress in cardiomyocytes
Authors: Hofmann Christoph , Löwenthal Zoe , Aghajani Marjan , Kaufman Randal J. , Katus Hugo A. , Frey Norbert , Glembotski Christopher C. , Völkers Mirko , Doroudgar Shirin
Published: June 2023

Cells coordinate translation rates with protein quality control to ensure that protein synthesis is initiated primarily when proper protein folding can be achieved. Long-term activity of the unfolded protein response is therefore associated with an inhibition of mTORC1, a central regulator of protein synthesis. Here, we found that mTORC1 is transiently activated early in response to ER stress before it is inhibited. Importantly, partial mTORC1 activity remained essential for the upregulation of adaptive unfolded protein response genes and cell survival in response to ER stress. Our data reveal a complex regulation of mTORC1 during ER stress and its involvement in the adaptive unfolded protein response.
Evaluation of Risk Factors and Outcomes of Isolated Tricuspid Valve Replacement with a Conventional Surgical Approach: A Retrospective Cohort Study
Authors: Shahmohamadi Elnaz , Hadizadeh Alireza , Ayati Aryan , Tayebi Amirhossein , Ahmadi Tafti Seyed Hossein , Abbasi Kyomars , Movahedi Namvar , Bagheri Jamshid , Davoodi Saeed
Published: June 2023

Introduction. Tricuspid valve (TV) disease is substantially less common than mitral or aortic valve disease, and it is commonly missed due to the tolerability of stenosis or regurgitation. Adults seldom have primary tricuspid valve regurgitation, which is linked to rheumatic heart disease, infectious endocarditis, myxomatous valve disease, congenital heart disease, carcinoid syndrome, and/or infiltrative valvopathy. Materials and Methods. The authors examined the Valve Surgery Data Bank retrospectively to identify all patients who underwent TV replacement without concomitant surgeries between 2004 and 2014. In addition, the exclusion criteria suggested that all instances involving solitary valve repair were eliminated. Through visits or phone interviews, long-term follow-up was collected through the end of June 2022 in order to gather information on postoperative occurrences among the patients. The average follow-up time was 10.7 + 2.1 (5–15) years. Results. The overall survival rate was 90.9%. Survival rate was not significantly different between bioprostheses and mechanical ones (log rank

p
=
0.05

). The incidence of endocarditis and valvar thrombosis in short-term was higher in the mechanical group than in the biological group, but the frequency of valve malfunction and redo surgery was higher in the replacement group. We found a higher incidence of valvular thrombosis, GI bleeding, and myocardial infarction rate in mechanical valve complications compared to the bioprosthetic group regarding late complications.
Predictive Factors of Nonmalignant Pathological Diagnosis and Final Diagnosis of Ultrasound-Guided Cutting Biopsy for Peripheral Pulmonary Diseases
Authors: Li Qing , Zhang Li , Liao Xinhong , Zhong Yanfen , Li Zhixian
Published: June 2023

This study aimed to explore the predictive factors of nonmalignant pathological diagnosis and final diagnosis of ultrasound-guided cutting biopsy for peripheral pulmonary diseases. A total of 470 patients with peripheral lung disease diagnosed as nonmalignant by ultrasound-guided cutting biopsy in the First Affiliated Hospital of Guangxi Medical University from January 2017 to May 2020 were included. Ultrasound biopsy was performed to determine the correctness of pathological diagnosis. Independent risk factors of malignant tumor were predicted by multivariate logistic regression analysis. Pathological biopsy results showed that 162 (34.47%) of the 470 biopsy data were specifically benign, and 308 (65.53%; malignant lesions: 25.3%, benign lesions: 74.7%) were nondiagnostic findings. The final diagnoses were benign in 387 cases and malignant in 83 cases. In the nondiagnostic biopsy malignant risk prediction analysis, lesion size (OR = 1.025,

P
=
0.005

), partial solid lesions (OR = 2.321,

P
=
0.035

), insufficiency (OR = 6.837,

P
<
0.001

), and presence of typical cells (OR = 34.421,

P
=
0.001

) are the final important independent risk factors for malignant tumors. In addition, 30.1% (25/83) of patients with nonmalignant lesions who were finally diagnosed with malignant tumors underwent repeated biopsy, and 92.0% (23/25) were diagnosed during the second repeated biopsy. 59.0% (49/83) received additional invasive examination. Nondiagnostic biopsy predictors of malignant risk include lesion size, partial solid lesions, insufficiency, and presence of atypical cells. When a nonmalignant result is obtained for the first time, the size of the lesion, whether the lesion is subsolid, and the type of pathology obtained should be reviewed.
Exploring the Effects of Solid-State Fermentation on Polyphenols in Acanthopanax senticosus Based on Response Surface Methodology and Nontargeted Metabolomics Techniques
Authors: Su Jianqing , Fu Xiang , Zhang Rui , Li Xiaoli , Li Ying , Chu Xiuling
Published: June 2023

In order to optimize the process of solid-state fermentation and understand the changes of active ingredients during fermentation of A.senticosus, we used response surface methodology to optimize the solid-state fermentation process of A.senticosus and analyzed the effect of fermentation on the active components of A.senticosus by nontargeted metabolomics techniques. The effects of fermentation conditions on polyphenol content were studied in terms of fermentation time, fermentation temperature, water content, and the inoculum level through Plackett–Burman design and response surface experiments. The optimized fermentation conditions were a fermentation time of 60 h, a fermentation temperature of 37°C, a water content of 55%, and an inoculum level of 12.5%, and the polyphenol content reached 10.25 ± 0.05 mg·g−1, which was 40% higher than that before fermentation. Furthermore, the metabolites and metabolic pathways of A. senticosus were analyzed before and after fermentation using nontargeted metabolomics techniques, and differences in metabolites were investigated based on the analysis of the principal components. The results showed that A.senticosus contained 57 phenolics, and a total of 12 polyphenolic metabolites were significantly different before and after fermentation (including phenols and isoflavonoids), among which the content of caffeic acid and its derivatives with antioxidant capacity was significantly increased, which may improve the antioxidant capacity of fermented A.senticosus. Therefore, solid-state fermentation opens new avenues for the clinical development and application of A. senticosus.
An Analysis of Fuel Oil Sloshing in Partially Filled Cargo Tanker Trucks under Cornering Conditions Using Various Baffle Systems
Authors: Siraye Woinshet , Wakjira Alemayehu , Nallamothu Ramesh Babu
Published: June 2023

Ethiopia imports all fuel and crude oils from abroad at high cost, and transportation of these fluids has been carried out by using various capacity of road transportation heavy-duty truck vehicle. Most tanker truck accidents happen during turning because of the fluid splashing in partially loaded tanks and of the uniqueness of the carrying liquids. This is a result of the fact that current baffle configurations are effective at reducing sloshing when braking or accelerating but ineffective at doing so when turning. Consequently, the primary goal of this thesis work is to investigate how different baffle systems affect lateral sloshing reduction. In this work, the optimal baffle configuration and its arrangements for modified oval tanks at 50% and 80% fill levels were tried, and the dynamic analysis of tanker trucks was researched. The tanker truck and baffle system are designed in CATIA V5 for the numerical analysis, and the CFD study is completed in ANSYS Fluent 2021. R2 and the dynamic analysis are carried out in ANSYS LS-DYNA to study the stability of truck. The computational simulation is carried out as a tank with eight types of baffle systems such as existing baffles (TB), TB with BMLB, UMLB, CLB, 2HLB, 2VHLB, 4HLB, and 4VHLB with similar meshing resolution, similar turbulence modeling, similar boundary conditions, and also similar solution strategies. Transverse baffles with bottom-mounted four holes longitudinal baffle with hole-varying position (4VHLB) are discovered to be the best baffle type after evaluating all baffle designs. This suggests that the quantity of sloshing is reduced as the number of holes with small diameters increases. Maximum lateral force and roll moment are reduced by the most, by 47.76% and 58.66%, respectively, at 50% fill level and by 58.08% and 22.52%, at 80% fill level. Consequently, the case tanker truck’s use of this revised design baffle will be crucial for enhancing rollover stability while cornering.
Figure S3 from Identification of 2′,4′,6′-Trihydroxyacetophenone as Promising Cysteine Conjugate Beta-Lyase Inhibitor for Preventing Cisplatin-Induced Nephrotoxicity
Authors: Sukeda Nao , Fujigaki Hidetsugu , Ando Tatsuya , Ando Honomi , Yamamoto Yasuko , Saito Kuniaki
Published: June 2023

Supplementary Figure S3
Figure S2 from Identification of 2′,4′,6′-Trihydroxyacetophenone as Promising Cysteine Conjugate Beta-Lyase Inhibitor for Preventing Cisplatin-Induced Nephrotoxicity
Authors: Sukeda Nao , Fujigaki Hidetsugu , Ando Tatsuya , Ando Honomi , Yamamoto Yasuko , Saito Kuniaki
Published: June 2023

Supplementary Figure S2
Figure S1 from An Oncolytic Poxvirus Encoding hNIS, Shows Antitumor Efficacy and Allows Tumor Imaging in a Liver Cancer Model
Authors: Chaurasiya Shyambabu , Valencia Hannah , Zhang Zhifang , Kim Sang-In , Yang Annie , Lu Jianming , Woo Yanghee , Warner Susanne G. , Ede Nicholas J. , Fong Yuman
Published: June 2023

PET imaging at different time points
Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma
Authors: Rana Manjul , Kansal Rita G. , Bisunke Bijay , Fang Jie , Shibata David , Bajwa Amandeep , Yang Jun , Glazer Evan S.
Published: June 2023

Identifying novel, unique, and personalized molecular targets for patients with pancreatic ductal adenocarcinoma (PDAC) remains the greatest challenge in altering the biology of fatal tumors. Bromo- and extra-terminal domain (BET) proteins are activated in a noncanonical fashion by TGFβ, a ubiquitous cytokine in the PDAC tumor microenvironment (TME). We hypothesized that BET inhibitors (BETi) represent a new class of drugs that attack PDAC tumors via a novel mechanism. Using a combination of patient and syngeneic murine models, we investigated the effects of the BETi drug BMS-986158 on cellular proliferation, organoid growth, cell-cycle progression, and mitochondrial metabolic disruption. These were investigated independently and in combination with standard cytotoxic chemotherapy (gemcitabine + paclitaxel [GemPTX]). BMS-986158 reduced cell viability and proliferation across multiple PDAC cell lines in a dose-dependent manner, even more so in combination with cytotoxic chemotherapy (P < 0.0001). We found that BMS-986158 reduced both human and murine PDAC organoid growth (P < 0.001), with associated perturbations in the cell cycle leading to cell-cycle arrest. BMS-986158 disrupts normal cancer-dependent mitochondrial function, leading to aberrant mitochondrial metabolism and stress via dysfunctional cellular respiration, proton leakage, and ATP production. We demonstrated mechanistic and functional data that BETi induces metabolic mitochondrial dysfunction, abrogating PDAC progression and proliferation, alone and in combination with systemic cytotoxic chemotherapies. This novel approach improves the therapeutic window in patients with PDAC and offers another treatment approach distinct from cytotoxic chemotherapy that targets cancer cell bioenergetics.
Abstract 1111: The status of Government-funded radiotherapy centres in Nigeria
Authors: Aruah Simeon C. , Chidebe Runcie C. , Orjiakor Tochukwu C. , Uba Fatima , Shagaya Uchechukwu , Ugwanyi Charles , Umar Aisha A. , Ige Taofeeq , Asogwa Obinna C. , Ahmadu Oiza T. , Ali-Gombe Musa , Adewumi Alabi , Okwor Vitalis C. , Jimoh Mutiu A. , Bello Basheer , Eriba Lucy O. , Ahmed Yusuf A. , Bisalla Awwal , Itanyi Ukamaka , Balogun Ramatallah A. , Alabi Suleiman , Pistenmaa David , Norman Coleman C. , Manjit Dosanjh
Published: June 2023

PURPOSE: Access to radiotherapy (RT) is now one of the stark examples of global cancer inequities. Over 800,000 new cancer cases require potentially curative or palliative RT services in Africa, arguably less than 15% of these patients currently have access to this important service. For a population of over 200 million, Nigeria requires a minimum of 280 RT machines for the increasing number of cancer cases. Painfully the country has only 8 government-funded radiotherapy machines. This study aimed to evaluate the status of the eight (8) Government-funded RT centres in Nigeria regarding RT equipment, workforce and infrastructure to quantify their ability to deliver effective RT to their patients.

METHODS: A survey addressing ten (10) critical areas was used to assess the eight (8) Government-funded RT centres in Nigeria.

RESULTS: Unfortunately, 6 of the 8 centres (75%) surveyed have not treated patients with RT over the last 2 years because they do not have functioning teletherapy machines. Only 2 RT centres have the capability of treating patients using advanced RT techniques. There is no PET-CT scan in any of the Government-funded RTcentres. The workforce capacity and infrastructure across the 8 centres are limited. All of the centres lack residency training programmes for medical physicists and radiation therapy technologists (RTTs) resulting in very few well-trained staff.

CONCLUSION: As the Nigeria government plans for the new National Cancer Control Plan, there is an urgent need to scale up access to radiotherapy by upgrading the RT equipment, workforce and infrastructure to meet the current needs of Nigerian cancer patients. While the shortfall is apparent from a variety of radiotherapy-capacity data bases, this detailed analysis provides essential information for an implementation plan involving solutions from within Nigeria and with global partners.

Citation Format: Simeon C. Aruah, Runcie C. Chidebe, Tochukwu C. Orjiakor, Fatima Uba, Uchechukwu Shagaya, Charles Ugwanyi, Aisha A. Umar, Taofeeq Ige, Obinna C. Asogwa, Oiza T. Ahmadu, Musa Ali-Gombe, Alabi Adewumi, Vitalis C. Okwor, Mutiu A. Jimoh, Basheer Bello, Lucy O. Eriba, Yusuf A. Ahmed, Awwal Bisalla, Ukamaka Itanyi, Ramatallah A. Balogun, Suleiman Alabi, David Pistenmaa, Coleman C. Norman, Dosanjh Manjit. The status of Government-funded radiotherapy centres in Nigeria [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 1111.
Abstract 1151: CD6 isoforms improve CAR T cell fitness
Authors: Morris Jessica S. , Gad Ahmed Z. , Godret-Miertschin Lea M. , Fleischmann Ryan , Salsman Vita , Joseph Sujith K. , Ahmed Nabil
Published: June 2023

The ability of chimeric antigen receptor (CAR) T cells to initiate and sustain an effective immune response entails a delicate balance between T-cell activation and deactivation and is key for complete tumor elimination. CD6 is a co-receptor that fine-tunes T cell receptor signal strength through a unique dual function intracellular domain. CD6 is alternatively spliced, creating isoforms that lack distinct regions which interact with activating or inhibitory adapter proteins, thereby delivering inhibitory or activating signals, respectively. We hypothesized that CAR T cell fitness, namely their ability to sustain their effector function, can be achieved by using alternatively spliced CD6 isoforms which lack exons responsible for inhibitory signaling. First, we discovered that overexpression of the canonical full-length CD6 molecule, isoform CD6A, resulted in marginal improvement of CAR T cell function, while its deletion using CRISPR/Cas9 depressed the antitumor CAR T cell functionality. This supported a net stimulatory role for CD6 in CAR T cell function. To study their effect on cellular fitness, we then synthesized and overexpressed known alternatively spliced cytoplasmic isoforms CD6B, CD6C, CD6D, CD6E, and CD6F on CAR T cells and, noted a significant tendency towards preserving the CAR T cell naïve and central memory compartments, upon tumor encounter. Overexpression of isoform CD6F, which lacks exon 9, and to a lesser extent isoforms CD6C and CD6E enhanced the short- and long-term cytotoxicity of HER2 and CD19 targeting CAR T cells when compared to CAR T cells alone or CAR T cells overexpressing, CD6A. Despite exhibiting a lower proliferation index, and lower CAR CD3ζ phosphorylation at rest, CD6F CAR T cells secreted significantly higher concentrations of the Th1 cytokine, IFN-γ, and mediated more sustained in vitro cytotoxicity long-term, with more complete elimination of large tumor cell loads. Lastly, in an orthotopic model of human glioblastoma, the adoptive transfer of CD6F HER2 CAR T cells induced a more significant but also more sustained anti-glioma effect that translated into a significant survival advantage for experimental animals. Our data support that the overexpression of the alternatively spliced CD6 isoforms improves CAR T cell fitness resulting in superior antitumor activity both in vitro and in vivo.

Citation Format: Jessica S. Morris, Ahmed Z. Gad, Lea M. Godret-Miertschin, Ryan Fleischmann, Vita Salsman, Sujith K. Joseph, Nabil Ahmed. CD6 isoforms improve CAR T cell fitness [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 1151.
Abstract 1176: Quantitative integration of PIK3CA hotspots and paralogy identifies occult oncogenic mutants in PIK3CD
Authors: Elzein Arijh , Gorelick Alexander N. , de Bruijn Ino , Taylor Barry S. , Hanrahan Aphrothiti J. , Solit David B.
Published: June 2023

The majority of somatic variants identified by tumor genomic profiling are low frequency alterations of unknown biologic and clinical significance. To facilitate the systematic identification of likely oncogenic versus benign somatic mutations, there has been a growing interest in harnessing additional computationally amenable metrics such as sequence paralogy. Here, we developed a novel paralogy-directed computational methodology called Enriched Paralogy to identify Occult Cancer Hotspots (EPOCH), which calculates the significance of mutational recurrence at aligned positions in evolutionarily related genes to prioritize likely oncogenic mutations for in depth functional characterization. We validated the utility of EPOCH using sequencing data from a cohort of 52,676 tumor/normal pairs, with a focus on identifying likely oncogenic mutations in the well characterized PIK3CA (p110α) class 1a PI3K isoform and the lesser characterized PIK3CD (p110δ) isoform. p110δ mutants nominated as likely oncogenic by EPOCH induced AKT pathway activation, enhanced anchorage-independent colony formation, and demonstrated allele-specific dependencies on p85 regulatory protein binding. The potency of PI3K inhibitors against p110δ mutants was at best equal to or less than wildtype p110δ. In sum, we present the novel algorithm EPOCH that integrates paralogy to extend the utility of current recurrence-based precision oncology predictions and to automate the functional interpretation of less common mutations. Our work identifies novel oncogenic and targetable p110δ mutants and supports the inclusion of PIK3CD in targeted sequencing panels despite the relative rarity of mutations in this gene. The therapeutic studies herein also provide the rationale for the development and clinical testing of isoform- or mutant-specific p110δ inhibitors for patients with rare, yet druggable, oncogenic p110δ mutations.

Citation Format: Arijh Elzein, Alexander N. Gorelick, Ino de Bruijn, Barry S. Taylor, Aphrothiti J. Hanrahan, David B. Solit. Quantitative integration of PIK3CA hotspots and paralogy identifies occult oncogenic mutants in PIK3CD [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 1176.
Abstract 1240: mSin1 regulates epithelial-mesenchymal transition
Authors: Huang Shile , Luo Yan , Liu Lei , Cheng Bing
Published: June 2023

The mammalian target of rapamycin (mTOR) functions as two complexes, mTORC1 and mTORC2. Extensive studies have focused on mTORC1 in the regulation of cell growth, autophagy, and metabolism. However, the role of mTORC2 is poorly understood. mTORC2 has been found to control cell migration, but the underlying mechanism remains to be determined. Here we show that mammalian stress-activated protein kinase interacting protein 1 (mSin1), a unique component of mTORC2, plays an important role in cell migration. Knockout of mSin1 reduced the migration of mouse embryo fibroblasts (MEFs). Similarly, knockdown of mSin1 also inhibited the migration of tumor cells (Rh30 and HeLa). Furthermore, we observed that mSin1 is crucial for the epithelial-mesenchymal transition (EMT). Knockout or knockdown of mSin1 promoted the mesenchymal-epithelial transition (MET), a transition from multipolar or spindle shape to apico-basal polar shape. In addition, depletion of mSin1 increased the cellular protein level of E-cadherin (an MET marker) and decreased the cellular protein levels of N-cadherin and Twist (EMT markers). The results suggest that mSin1 positively regulates cell migration at least partly by promoting induction of EMT. Our findings support that mSin1 is crucial for mTORC2-mediated cell migration. (Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA)

Citation Format: Shile Huang, Yan Luo, Lei Liu, Bing Cheng. mSin1 regulates epithelial-mesenchymal transition [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 1240.
Abstract 1326: Perineural invasion and bone metastases in prostate cancer - is there a link
Authors: Sigorski Dawid , Galli Susana , Hong Sung Hyeok , Iżycka-Świeszewska Ewa , Kitlinska Joanna B.
Published: June 2023

Bone metastases are the most common secondary lesions in prostate cancer (PCa) patients. Typically, initial bone metastases develop in the lower part of the spine and pelvis. While this metastatic pattern is not consistent with the random nature of the arterial osseous dissemination, previous reports suggested the role of the retrograde venous spread in this phenomenon. However, clinical data also indicate a positive association between the degree of perineural invasion (PNI) and bone metastases in PCa patients. Yet, the mechanism linking these two means of dissemination remains unknown. To identify the processes involved in the initial PCa dissemination we used the PC3-ML cell line, which was previously shown to trigger bone metastases, in the orthotopic xenograft model. To this end, the cells were injected into the prostates of male SCID/Bg mice and tumor development and progression was followed by magnetic resonance imaging (MRI) and histopathology. MRI indicated local invasion of the primary tumor, which later resulted in the formation of multiple secondary lesions along the lower spine. However, histopathological analysis revealed that these lesions were initiated in the soft tissues surrounding the vertebral column, while the subsequent invasion of the vertebra was the secondary event. The staining for neuronal markers, neurofilament (NF), tyrosine hydroxylase (TH) and neuropeptide Y (NPY), revealed that PCa cells created multicellular clusters spreading longitudinally along the small nerve fibers, particularly in the paraspinal muscle compartment. The staining for the endothelial cell marker, CD31, detected small vessels present within PCa clusters. However, no evident encapsulation of the PCa cells within blood vessels consistent with the retrograde venous spread was observed. Altogether, these results suggest PNI as the main route of the initial local dissemination of the PCa cells toward the bone, which then triggers bone invasion and subsequent hematogenous spread to distant bones. Further mechanistic studies are required to confirm this hypothesis.

Citation Format: Dawid Sigorski, Susana Galli, Sung Hyeok Hong, Ewa Iżycka-Świeszewska, Joanna B. Kitlinska. Perineural invasion and bone metastases in prostate cancer - is there a link [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 1326.
Abstract 1339: Targeting specific extracellular matrix proteins to reactivate T cell trafficking in triple-negative breast cancer
Authors: Gauthier Valentine , Tyler Elly , Liu Ying , Sharp Tyson V. , Pearce Oliver MT
Published: June 2023

It is now widely recognised that the tumour microenvironment (TME) is playing a crucial role in promoting tumour immune evasion by modulating the local immune infiltration. A growing body of evidence highlights the crucial role of the tumour extracellular matrix (ECM) in limiting trafficking of newly activated T cells in solid cancers, thus restricting their access to tumour and preventing the success of cancer immunotherapies. Accordingly, we are investigating whether targeting specific tumour ECM components may enhance T cell infiltration in triple-negative breast cancer (TNBC). Matrisome profiling of patient-derived fibroblasts and patient tumour tissues allowed us to identify two matrix proteins overexpressed in tumours and associated with T cell signatures, the matrix proteoglycan, versican (VCAN) and the glycoprotein, fibronectin (FN1). As there are currently no specific inhibitors of matrix proteins, we have modelled their loss-of-function using the clustered, regularly interspaced, short palindromic repeats-associated nuclease Cas9 (CRISPR-Cas9) technology with the goal of engineering cell-editable matrisomes which are enriched, reduced, or absent for specific matrix proteins. First, we constituted a panel of human and murine mammary fibroblast and TNBC cancer cell lines, which we have introduced with an inducible Cas9 protein expression. We measured VCAN and FN1 expression in the panel which showed distinct VCAN levels. Therefore, depending on VCAN basal levels, we have generated cell lines with VCAN overexpression, transient knockdown or stable knockout. Proteomic matrisome profiling of transient VCAN knockdown cells revealed that reducing VCAN may impact ECM abundance by decreasing VCAN direct binding partners. Finally, we used the edited cells to build 2D and 3D in vitro TME models to evaluate the impact of modulating VCAN expression on chimeric antigen receptor (CAR) T cell cytotoxicity and location. In parallel, we built in vivo mouse models of TNBC with controlled ECM deposition. Specifically, we have targeted mVcan and mFn1 in tumours and investigated the impact of their removal on tumour growth and immune cell infiltration. Overall, this work aims to identify immunomodulating features of the ECM which could be targeted to boost response to immunotherapies in solid cancers.

Citation Format: Valentine Gauthier, Elly Tyler, Ying Liu, Tyson V. Sharp, Oliver MT Pearce. Targeting specific extracellular matrix proteins to reactivate T cell trafficking in triple-negative breast 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 1339.
Abstract 1381: Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells
Authors: He Jianping , Abikoye Abigail M. , McLaughlin Brett P. , Middleton Ryan S. , Sheldon Ryan , Jones Russell G. , Schafer Zachary T.
Published: June 2023

Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Ferroptosis is an iron dependent non-apoptotic cell death due to catastrophic accumulation of lipid peroxidation. While the mechanism that determines ferroptosis sensitivity has been extensively investigated in attached cells, how cells respond to ferroptosis under ECM detachment is largely unknown. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis. While alterations in membrane lipid content are observed during ECM-detachment, it is instead fundamental changes in iron metabolism that underlie resistance of ECM-detached cells to ferroptosis. More specifically, our data demonstrate that levels of free iron are low during ECM-detachment due to changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of iron storage proteins sensitizes ECM-detached cells to death by ferroptosis. Taken together, our data suggest that therapeutics designed to kill cancer cells by ferroptosis may be hindered by lack of efficacy towards ECM-detached cells.

Citation Format: Jianping He, Abigail M. Abikoye, Brett P. McLaughlin, Ryan S. Middleton, Ryan Sheldon, Russell G. Jones, Zachary T. Schafer. Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached 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 1381.
Abstract 1476: FOXM1 inhibition: A novel therapeutic approach for small cell lung cancer
Authors: Khan Md Arafat , Khan Parvez , Fatima Mahek , Rehman Asad Ur , Maurya Shailendra Kumar , Mohiuddin Sameer , Venkata Ramakanth Chirravuri , Cox Jesse L. , Kim Sung Hoon , Katzenellenbogen Benita S. , Katzenellenbogen John A. , Ganti Apar K. , Batra Surinder K. , Nasser Mohd Wasim
Published: June 2023

Outcomes from small cell lung cancer (SCLC) are dismal. Most SCLC patients have distant metastasis at diagnosis and the 5-year survival of these patients is around 2.8%. Despite initial response to chemotherapy and immunotherapy, relapses are very common. No targeted therapy is available for SCLC. Thus, there is an urgent need to understand the acquisition of chemoresistance, and to identify novel targets and therapeutic strategies for this deadly disease. Recently, FOXM1 was identified as an essential component in SCLC tumor growth. Our aim is to develop FOXM1-targeted therapy to thwart SCLC progression and the development of chemoresistance. We have targeted FOXM1 using highly specific small molecule inhibitor FDI-6 and found that FOXM1 inhibition drastically reduces colony formation and cell migratory capabilities in multiple SCLC cell lines (SBC3, SBC5). Additionally, we observed that FOXM1 downregulation via FDI-6 reduced SCLC growth both as monotherapy and in combination with cisplatin. Based on these studies, we conclude that FOXM1 inhibition alone or in combination with cisplatin could be a unique therapeutic approach for SCLC.

Citation Format: Md Arafat Khan, Parvez Khan, Mahek Fatima, Asad Ur Rehman, Shailendra Kumar Maurya, Sameer Mohiuddin, Ramakanth Chirravuri Venkata, Jesse L. Cox, Sung Hoon Kim, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Apar K. Ganti, Surinder K. Batra, Mohd Wasim Nasser. FOXM1 inhibition: A novel therapeutic approach for small cell lung 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 1476.
Abstract 1486: The regulatory mechanism of LncRNA CCAT1 via three-dimensional genome structure in colorectal cancer cells
Authors: Yokoyama Yuhki , Yamamoto Hirofumi
Published: June 2023

Kruppel-like factor 5 (KLF5) belongs to zinc finger transcription factors and its expression is up-regulated in specific cancer types, such as gastrointestinal cancer and squamous carcinoma. It is reported that KLF5 is associated with the maintenance of stemness and essential for the integrity of intestinal epithelium and oncogenesis. Colon Cancer Associated Transcript 1 (CCAT1) is a long noncoding RNA that was initially found to be up-regulated in colorectal cancer (CRC), and studies have reported that high CCAT1 expression is associated with poor prognosis in CRC patients. In this study, we performed in vitro enChIP (engineered DNA-binding molecule-mediated chromatin immunoprecipitation)-sequencing to identify the KLF5 enhancer region which interacts with KLF5 promoter region. We successfully identified the KLF5 enhancer region in colorectal cancer cells and further found that KLF5 promoter region interacted with the transcription start site (TSS) region of CCAT1 gene, which is located at the different chromosome. Our results indicated that KLF5 protein participated in the core regulatory circuitry together with co-factors (BRD4, MED1, and RAD21), which contributes to construction of the three-dimensional genome structures consisting of KLF5 promoter, enhancer and CCAT1 TSS region. We also found that CCAT1 expression was highly correlated with KLF5 expression in CRC clinical samples and that KLF5 regulated CCAT1 expression. In conclusion, our data propose the mechanistic insight that KLF5 protein constructs the core regulatory circuitry with co-factors in the three-dimensional genome structure and coordinately regulates KLF5 and CCAT1 expression in CRC.

Citation Format: Yuhki Yokoyama, Hirofumi Yamamoto. The regulatory mechanism of LncRNA CCAT1 via three-dimensional genome structure in colorectal cancer 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 1486.
Abstract 1532: Next generation IgM antibody based multimeric platform: ePENDY (engineered pentamer body)
Authors: Kang Sungmuk , Kang Hyeonju , Koo Jihye , Kim Yoojin , Park Suho , Lee Inyoung , Yi Jiye , Lee Hong Jai , Cho Yonghyun , Hwang Hyunju , Hyun Kyunggi , Lee Chungmin , Ha Gyongsik
Published: June 2023

Among many candidates from the recent diverging research to develop a multivalent platform, IgM has shown potential as a pharmaceutical because of its avidity coming from natural multimeric target binding ability. IgM has a great advantage of naturally forming multimers, however, there are some unfulfilled needs to become a good pharmaceutical platform, such as limited biological activity, short half-life, safety concerns, and difficult purification steps compared to IgG. Here, we developed an antibody platform, ePENDY, by engineering IgM to improve efficacy, safety, and convenience of manufacturing process. ePENDY has a self-assembling decavalent pentameric structure and it is an improved IgM with maximized biological activity as therapeutics by using flexible linkers. In addition, ePENDY was engineered one of the effector functions of antibodies, ADCC, was greatly increased compared to IgG as well as IgM which does not have this function. More importantly, the presence or absence of effector functions can be controlled depending on the MoA (Mode of action) of the target. Serum half-life of ePENDY was significantly increased compared to natural IgM, and ePENDY showed similar PK profiles as the IgG Fc-based molecules through FcRn recycling. Unlike natural IgM, ePENDY does not bind to any IgM receptors, such as pIgR, FcμR, and Fcα/μR, thereby eliminating possible side effects. In addition, it has been confirmed that ePENDY showed a comparable expression level to that of IgG, and since the purification process can also be set up in a process like IgG, thus production of ePENDY can be facilitated. Based on these results, we are researching ePENDY which are applying various therapeutic molecules, such as antibodies, protein ligand-based active molecules and therapeutic cancer vaccines. We expect that our versatile applicable platform, safe and long acting ePENDY, can be a superior tool for the various therapeutic targets.

Citation Format: Sungmuk Kang, Hyeonju Kang, Jihye Koo, Yoojin Kim, Suho Park, Inyoung Lee, Jiye Yi, Hong Jai Lee, Yonghyun Cho, Hyunju Hwang, Kyunggi Hyun, Chungmin Lee, Gyongsik Ha. Next generation IgM antibody based multimeric platform: ePENDY (engineered pentamer body) [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 1532.
Abstract 1590: Identification and characterization of a first-generation inhibitor of claudin-1 to inhibit colon cancer progression and metastasis
Authors: Fatima Iram , Uppada Jaya Prakash , Chhonker Yashpal S. , Gowrikumar Saiprasad , Barman Susmita , Roy Sourav , Tolentino Kirsten T. , Palermo Nicholas , Natarajan Amar , Beauchamp Daniel R. , Vecchio Alex , Murry Daryl J. , Singh Amar B. , Hopkins Corey R. , Dhawan Punita
Published: June 2023

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is urgent. Several studies, including ours, have reported a causal role for an upregulated claudin-1 expression in promoting CRC metastasis through the activation of the Src and β-catenin-signaling. In murine models of colon tumorigenesis, claudin-1 overexpression promotes oncogenic properties such as transformation and invasiveness. Conversely, the downregulation of claudin-1 inhibits colon tumorigenesis. Despite being a desirable target for cancer treatment, there are currently no known claudin-1 inhibitors with antitumor efficacy. Using a rigorous analytical design and implementing in-vitro and in-vivo testing and a brief medicinal chemistry campaign, we identified a claudin-1-specific inhibitor and named it I-6. Despite its high potency, I-6 was rapidly cleared in human liver microsomes. We, therefore, synthesized I-6 analogs and discovered a novel small molecule, PDS-0330. We determined that PDS0330 inhibits claudin-1-dependent CRC progression without exhibiting toxicity in in-vitro and in-vivo models of CRC and that it binds directly and specifically to claudin-1 with micromolar affinity. Further analyses revealed that PDS-0330 exhibits antitumor and chemosensitizer activities with favorable pharmacokinetic properties by inhibiting the association with metastatic oncogene Src. Overall, our data propose that PDS-0330 interferes with claudin-1/Src association to inhibit CRC progression and metastasis. Our findings are of direct clinical relevance and may open new therapeutic opportunities in colon cancer treatment and/or management by targeting claudin-1.

Citation Format: Iram Fatima, Jaya Prakash Uppada, Yashpal S. Chhonker, Saiprasad Gowrikumar, Susmita Barman, Sourav Roy, Kirsten T. Tolentino, Nicholas Palermo, Amar Natarajan, Daniel R. Beauchamp, Alex Vecchio, Daryl J. Murry, Amar B. Singh, Corey R. Hopkins, Punita Dhawan. Identification and characterization of a first-generation inhibitor of claudin-1 to inhibit colon cancer progression and metastasis [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 1590.
Abstract 1659: Development of HJC0152, its analogs and protein degraders to modulate STAT3 for triple-negative breast cancer therapy
Authors: Vontz Gabrielle , Li Jun , Ma Ruixia , Xu Jimin , Zhou Mingxiang , Chen Haiying , Zhou Jia , Shen Qiang
Published: June 2023

Breast cancer represents the most commonly diagnosed female malignancy worldwide. Although breast cancer screening and treatments have improved significantly over the last half-century, aggressive subtypes like triple-negative breast cancer (TNBC) as well as growing chemoresistance cases continue to evade frontline therapies. STAT3, a transcription factor involved in cell proliferation, survival, and malignant transformation, plays a key role in mammary carcinogenesis, resistance, and recurrence. Both STAT3 overexpression and aberrant activation are frequently observed in primary breast tumors and their metastatic lesions. Although STAT3 is recognized as an attractive preventive and therapeutic target, there are no FDA-approved STAT3 inhibitors in clinical use. Via structure- and fragment-based drug design strategies as well as in silico molecular modeling and docking, our team previously developed a putative STAT3 inhibitor, HJC0152. This study aims to further characterize the anticancer mechanism of HJC0152 as well as optimize its potency. Our results show that HJC0152 interacts with STAT3 with a similar specificity to an experimental STAT3 inhibitor, Stattic. To further improve its potency and efficacy, we developed several HJC0152 derivatives including HJC0152-based proteolysis targeting chimera (PROTAC) degraders. Several molecules showed comparable or improved potency to HJC0152 against several breast cancer cell lines including TNBC cells. While the total STAT3 protein level reduces moderately with HJC0152 treatment, several new compounds decrease STAT3 protein level more profoundly. In particular, the newly developed HJC0152-PROTACs showed a significant late inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues as well as a reduction in total STAT3 protein. Our data indicate that HJC0152-based analogs and protein degraders can suppress breast cancer cell proliferation, likely through targeting STAT3 signaling pathway. Future experiments will determine the molecular prolife of promising molecules as well as assess their in vivo anticancer efficacy using xenograft models. This project is supported by NIH/NCI Awards R01CA226001 and R01CA231150 to Q.S. and J.Z.

Citation Format: Gabrielle Vontz, Jun Li, Ruixia Ma, Jimin Xu, Mingxiang Zhou, Haiying Chen, Jia Zhou, Qiang Shen. Development of HJC0152, its analogs and protein degraders to modulate STAT3 for triple-negative breast cancer therapy [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 1659.
Abstract 1667: Elimusertib shows stronger antitumor activity than standard of care chemotherapy in pediatric solid tumor models
Authors: Pusch Fabian Fadi , García Heathcliff Dorado , Xu Robin , Guergen Dennis , Bei Yi , Brueckner Lotte , Roeefzaad Claudia , von Stebut Jennifer , Bardinet Victor , Gonzalez María del Rocío Chamorro , Eggert Angelika , Schulte Johannes H. , Hundsdoerfer Patrick , Seifert Georg , Haase Kerstin , Schaefer Beat , Wachtel Marco , Kühl Anja A. , Ortiz Michael , Wengner Antje M. , Scheer Monika , Henssen Anton G.
Published: June 2023

Elimusertib is a small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR) currently being tested in clinical trials. Despite the known anti-tumor activity in various cancer entities, its effect on many pediatric malignancies remains unknown. We assessed the preclinical activity of elimusertib in a cohort of over 40 cell lines and 30 patient-derived xenograft (PDX) models derived from pediatric solid tumors. Elimusertib reduced tumor growth in all PDX models, with 50% of them achieving stable disease, partial or total response, even in those derived from relapsed tumors. Moreover, elimusertib outperformed the effect of standard of care chemotherapy, particularly in alveolar rhabdomysarcoma. Molecular characterization of the models provide information on response biomarkers with diagnostic potential. In summary, elimusertib shows strong preclinical anti-tumor activity in pediatric solid tumor models, that may translate to clinically meaningful responses in patients.

Citation Format: Fabian Fadi Pusch, Heathcliff Dorado García, Robin Xu, Dennis Guergen, Yi Bei, Lotte Brueckner, Claudia Roeefzaad, Jennifer von Stebut, Victor Bardinet, María del Rocío Chamorro Gonzalez, Angelika Eggert, Johannes H. Schulte, Patrick Hundsdoerfer, Georg Seifert, Kerstin Haase, Beat Schaefer, Marco Wachtel, Anja A. Kühl, Michael Ortiz, Antje M. Wengner, Monika Scheer, Anton G. Henssen. Elimusertib shows stronger antitumor activity than standard of care chemotherapy in pediatric solid tumor 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 1667.
Abstract 1669: In vitro and in vivo synthetic lethality: Potent tumor suppression by a novel FLT3/cKIT/CSF1R/CDK19 inhibitor
Authors: Chen Hui , Paradise Marc , Shepard Ryan , Varner Judith
Published: June 2023

Tumor cells are characterized by aberrant signal transduction and cell cycle control pathways that lead to unchecked cell proliferation. Unchecked tumor cell proliferation, as well as macrophage proliferation, contributes to tumor growth and spread. Inhibitors of PI3K or MEK signaling pathways can initially inhibit tumor growth until resistance due to upregulation of the alternative pathway develops. We identified a novel allosteric cKIT/FLT3/CSF1R inhibitor that induces synthetic lethality in AML, lung carcinoma, pancreatic carcinoma and other tumor cells and in proliferating macrophages in vitro and in tumors in vivo by simultaneously inhibiting the MEK-ERK and PI3K-AKT pathways and activating stress activated kinase-mediated cell cycle arrest. A series of related cKIT/FLT3/CSF1R/PDGFR allosteric inhibitors suppressed receptor tyrosine phosphorylation as well as downstream MEK-ERK and PI3K-AKT signaling and mTorc1 and cMyc gene expression pathways that control cell growth. Select cKIT/FLT3/CSF1R/PDGFR inhibitors with a unique positioning of a single side chain also inhibited CDK8/19 and stimulated phosphorylation and activation of JNK and p38. JNK activation promoted sustained ATF-2 and cJun-mediated p53 and Chk1/Chk2 activation, thereby promoting cell cycle arrest in G2/M and ultimately, apoptosis. These inhibitors potently suppressed tumor growth in vivo by halting tumor cell and macrophage proliferation in G2/M. They synergized with anti-PD-1 and anti-CTLA-4 and led to tumor eradication and immunological memory formation. These studies identify novel allosteric inhibitors with potent synthetically lethal anti-tumor activity.

Citation Format: Hui Chen, Marc Paradise, Ryan Shepard, Judith Varner. In vitro and in vivo synthetic lethality: Potent tumor suppression by a novel FLT3/cKIT/CSF1R/CDK19 inhibitor [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 1669.