bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4758: SETD4 transcription levels correlates with leukemic burden and SMYD2 transcription in acute lymphoblastic leukemia
Authors: Telles Luis Augusto Muniz , Sakamoto Luis Henrique , Assis Alan Jhones , Rabello Doralina de Amaral , Motoyama Andrea Barretto , Pittella-Silva Fabio 
Published: April 2023

Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy worldwide. It has a history of great rates of success in treatment, but adults and infants still share a dismal prognosis. This condition makes the development of new prognostic markers linked to effective therapeutic strategies a matter of pressing concern. While cancer has traditionally been viewed as a genetic disease derived from alterations in oncogenes and tumor suppressors, it is well known nowadays that epigenetic changes also play a fundamental role in tumorigenesis. The SET family of lysine methyltransferases (KMT) has been implicated in a number of cancers, and SETD4 is a member that is still poorly characterized. In the present study we used qPCR to analyze the expression pattern of SETD4 among 83 pediatric ALL patients and non-neoplastic bone marrow (BM) samples and investigated the correlation between SETD4 transcription changes with the leukemic burden in ALL patients during chemotherapy. We found that SETD4 transcription levels are significantly upregulated in BM samples derived from ALL patients compared to non-neoplastic BM (8,5-fold higher, p &lt; 0,001) and its expression correlated with leukemic burden. Importantly, levels of SETD4 decreased in patients that responded to chemotherapy treatment. We further investigated whether SETD4 transcription levels associates with that of SMYD2, another KMT previously identified as a prognostic marker in ALL. Transcription levels of SETD4 and SMYD2 were examined on day 15th and 29th of chemotherapy. Surprisingly, a high level of correlation (Spearman r = 0.925, p &lt; 0.01) between both genes was observed in both treatment time points. Finally, survival outcomes were worst in ALL patients with high levels of SETD4 transcription (log-rank test, p &lt; 0,05), evidencing its dysregulated expression is associated with an unfavorable disease prognosis. Together, these results point to SETD4 as a useful prognostic marker, a possible tool to assess response to therapy and an attractive target for drug development.
Citation Format: Luis Augusto Muniz Telles, Luis Henrique Sakamoto, Alan Jhones Assis, Doralina de Amaral Rabello, Andrea Barretto Motoyama, Fabio Pittella-Silva. SETD4 transcription levels correlates with leukemic burden and SMYD2 transcription in acute lymphoblastic leukemia. [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 4758.
Abstract 4759: Dissecting EP300 and CBP function in prostate cancer models
Authors: Mirpuri Kiran , Tewari Alok K. , Brown Myles A. 
Published: April 2023

Abstract
Prostate adenocarcincoma is dependent on androgen and its cellular receptor the androgen receptor (AR) for most of the natural history of the disease including progression to the advanced and lethal state. Many prostate cancer therapeutics target the androgen signaling pathway, although tumors invariably become resistant to these treatments. EP300 and CBP are protein paralogs that are co-regulators of AR-mediated gene transcription and are mutated at low frequency in prostate cancers. Expression of CBP and EP300 has been found to correlate with AR expression in advanced disease, and their inhibition can impact AR-mediated transcription in model systems. However, both proteins are not equally essential in prostate cancer cell lines. As drugs inhibiting the bromodomains of these proteins are in early clinical trials, a greater understanding of the common and unique functions of EP300 and CBP may inform the clinical application of these therapeutics. Using chemical inhibition or degradation of either each paralog or both, in combination with genetic depletion, we identify converging and diverging epigenomic and transcriptional programs regulated by each paralog both in the presence and absence of androgens. If validated in tumor samples from patients, these results may nominate biomarkers of response to EP300/CBP inhibitors.
Citation Format: Kiran Mirpuri, Alok K. Tewari, Myles A. Brown. Dissecting EP300 and CBP function in prostate cancer 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 4759.
Abstract 4760: KDM4A promotes NEPC progression through regulation of MYC expression
Authors: Mak Celia Sze Ling , Zhu Ming , Liang Xin , Wang Feng , Hoang Anh G. , Song Xinzhi , Shepherd Peter , Liang Derek , Suh Jessica , Park Jiwon , Zhang Miao , Metzger Eric , Schule Roland , Jain Abhinav K. , Karasik Ellen , Foster Barbara A. , Lee Min Gyu , Corn Paul , Logothetis Christopher J. , Aparicio Ana , Navone Nora , Troncoso Patricia , Zhang Jianhua , Lin Sue-Hwa , Wang Guocan 
Published: April 2023

Abstract
Despite advancements in treatment, prostate cancer (PCa) remains the second leading cause of death among men. Neuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of PCa and lacks life-prolonging treatment. Here we identified histone lysine demethylase KDM4A as a driver in NEPC progression and an effective therapeutic target. KDM4A mRNA and protein are overexpressed in human and mouse NEPC compared to adenocarcinoma. Knockdown or knockout of KDM4A in NEPC cell lines suppressed cancer cell growth in vitro and in vivo. Importantly, the inactivation of Kdm4a in a genetically engineered mouse model of prostate cancer reduces tumor burden, reduces the incidence of NEPC, and prolongs overall survival. Mechanistically, KDM4A directly regulates the transcription of MYC, which is hyper-activated in human and mouse NEPC. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduces NEPC cell growth in vitro and in vivo. Taken together, we demonstrate that KDM4A promotes NEPC progression through regulation of MYC expression and targeting KDM4A can be an effective therapeutic strategy for NEPC.
Citation Format: Celia Sze Ling Mak, Ming Zhu, Xin Liang, Feng Wang, Anh G. Hoang, Xinzhi Song, Peter Shepherd, Derek Liang, Jessica Suh, Jiwon Park, Miao Zhang, Eric Metzger, Roland Schule, Abhinav K. Jain, Ellen Karasik, Barbara A. Foster, Min Gyu Lee, Paul Corn, Christopher J. Logothetis, Ana Aparicio, Nora Navone, Patricia Troncoso, Jianhua Zhang, Sue-Hwa Lin, Guocan Wang. KDM4A promotes NEPC progression through regulation of MYC expression. [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 4760.
Abstract 4788: Oxidative stress promotes colorectal cancer aggressiveness through transmembrane chloride intracellular channel 1 (tmCLIC1) antioxidant activity
Authors: Cianci Francesca , Verduci Ivan , Tacconi Carlotta , Cannavale Gaetano , Ranucci Matteo , Bertolini Giulia , Malatesta Paolo , Barbieri Federica , Fantin Alessandro , Roz Luca , Florio Tullio , Mazzanti Michele 
Published: April 2023

Abstract
In developed countries, colorectal cancer is the third leading cause of mortality. Despite significant advances in therapeutic approaches, metastases remain the primary concern in the treatment of colorectal cancer. Ion channels have an important role in the development of aggressive behavior, but the majority of them are involved in regular physiological activities. Chloride Intracellular Channel 1 (CLIC1) is a promising contender among the new possible biomarkers. CLIC1 is expressed as a cytosolic monomer by all cell types during physiological homeostasis. The main characteristic of this protein is that it can exist in both cytosolic and transmembrane forms (tmCLIC1), with the latter being involved in a variety of clinical conditions, including cancer. CLIC1 mRNA overexpression in colorectal cancer cells has been linked to a poor prognosis. The primary goal of this study is to understand the role of tmCLIC1 in the carcinogenesis, invasion, and migratory potential of colorectal cancer. We initially investigated the level of CLIC1 protein expression and the activity of its transmembrane form as an ion channel in numerous colorectal cancer cells at various stages of development. Our results show that tmCLIC1 protein expression and activity are related to cell aggressiveness, and that its role in cellular proliferation, migration, and invasion is critical. The role of tmCLIC1 activity in colorectal cancer was confirmed also in in vivo models. Experiments in zebrafish and mouse models have shown that silencing CLIC1 impairs primary tumor development and significantly reduces the generation of distal metastases. Furthermore, when the CLIC1 protein is missing, many distinct metastatic genes are downregulated, particularly those associated to oxidative stress, typical of cancer cells. As a matter of fact, CLIC1's peculiar activity and its interaction with glutathione make this protein critical for the redox equilibrium of colorectal cancer cells. Overall, the findings could be considered as a beginning point for elucidating a mechanism of action that could constitute a new milestone in anticancer research.
Citation Format: Francesca Cianci, Ivan Verduci, Carlotta Tacconi, Gaetano Cannavale, Matteo Ranucci, Giulia Bertolini, Paolo Malatesta, Federica Barbieri, Alessandro Fantin, Luca Roz, Tullio Florio, Michele Mazzanti. Oxidative stress promotes colorectal cancer aggressiveness through transmembrane chloride intracellular channel 1 (tmCLIC1) antioxidant activity. [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 4788.
Abstract 4789: Spin oscillating magnetic field sOMF of oncomagnetic device selectively kills glioma cancer cells by inducing oxidative stress and DNA damage
Authors: Hambarde Shashank , Pandey Arvind , Baskin David S. , Helekar Santosh A. 
Published: April 2023

Abstract
A new noninvasive therapeutic device developed in our laboratory called the Oncomagnetic device provides a novel approach to glioblastoma (GBM) treatment. It involves repeated stimulation with oscillating magnetic fields (sOMF) produced by spinning permanent magnets. It is technologically and mechanistically distinct from the Optune® device approved by the FDA for the treatment of newly diagnosed and recurrent GBM. Use of this device in end-stage GBM patients reversed the progression of their recurrent tumor causing &gt;30% reduction in its contrast-enhanced volume within 4-6 weeks of treatment. Mice with implanted mouse glioma cells in their brains also showed marked reduction in tumor size, increased survival (p&lt; 0.05, n = 10) and higher DNA damage (γ-H2AX foci) after sOMF treatment with a whole-body stimulation method developed by us. Normal mice exposed to sOMF for 4 months had no adverse effects on the brain and other organs. In-vitro, sOMF markedly increased reactive oxygen species (ROS) levels in cancer cells leading to the selective death of these cells, while sparing normal neurons and astrocytes. Detection of γ-H2AX and 53BP1 foci showed that sOMF caused significant DNA damage in GBM cells and diffuse intrinsic pontine glioma (DIPG) cells but not in normal astroglial SVGp12 cells. Furthermore, sOMF exposure for just 2 h resulted in &gt;40% loss of surviving GBM and DIPG cell colonies detected by clonogenic cell survival assay, similar to that produced by 2 Gy radiation dose. This loss was rescued by the antioxidant Trolox. These results indicate that sOMF stimulation has high anticancer potency comparable to low dose radiation therapy at the cellular level with an underlying mechanism of action that is substantially different from that proposed for Optune® TTF.
Citation Format: Shashank Hambarde, Arvind Pandey, David S. Baskin, Santosh A. Helekar. Spin oscillating magnetic field sOMF of oncomagnetic device selectively kills glioma cancer cells by inducing oxidative stress and DNA damage. [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 4789.
Abstract 4808: Hypoxic HIF-1α stabilization dependent on β3-adrenoceptor localization in Ewing sarcoma
Authors: Pasha Amada , Masi Claudia , Carrozzo Francesco , Rosati Martina , Boaretto Alessia , Pini Alessandro , Favre Claudio , Calvani Maura 
Published: April 2023

Abstract
Hypoxia is a condition of oxygen deficiency which occurs in most growing solid tumors and stimulates a cascade of cell signals through a family of transcription factors named as hypoxia inducible factors (HIFs) that transactivate several regulatory genes involved in tumor proliferation. β3-adrenoceptors (β3-ARs) are involved in several hypoxic scenarios and in pathological conditions where hypoxia leads to important steps for cancer progression. Studies showed that β-AR blockade of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo. In this work we assumed that β3-AR mediates hypoxia sensing and that it was necessary for HIF-1α stabilization thus we investigated a putative correlation between β3-AR/HIF-1α. Data showed a similar outcome of β3-ARs and HIF-1α at short time of hypoxia, and that β3-AR antagonist, SR59230A reduced HIF-1α protein expression under hypoxia. β3-AR silencing under hypoxia revealed an evident reduction of HIF-1α protein expression that confirmed the β3-AR modulation of HIF-1α expression. SR59230A treatment strongly reduced the HIF-1α target genes as GLUT1, HK-2 and HIF-1α expression at long time treatment confirming the β3-AR modulation of HIF-1α transcriptional activity. Conversely, the HIF-1α-transcriptional inhibitor Topotecan did not affect β3-AR expression confirming that is β3-AR that mediates HIF-1α activation. Immunofluorescence analysis showed that β3-AR co-localized with the nucleus under hypoxia more than normoxia. These results were confirmed by nuclear-cytoplasmic fragmentation that showed the presence of both β3-AR and HIF-1α proteins in the nucleus under hypoxia. Co-immunoprecipitation of β3-AR/HIF-1α revealed that under hypoxia, HIF-1α dissociates from β3-AR binding, but this process was abrogated by SR59230A. HIF-1α, released under hypoxia from the link with β3-AR, can play its transcriptional activity in the nucleus, while the binding with β3-AR blocks its transcriptional activity. Moreover, β3-AR regulation on HIF-1α was exerted through PHD2 activity at short time as SR59230A treatment under hypoxia increased the PHD2 protein expression but not at long time treatment, thus showing a different regulation of HIF-1α at different time points. In conclusion, the β3-AR upstream of the signaling β3-AR/HIF-1α axis exerts its role by PHD2 activity.
Citation Format: Amada Pasha, Claudia Masi, Francesco Carrozzo, Martina Rosati, Alessia Boaretto, Alessandro Pini, Claudio Favre, Maura Calvani. Hypoxic HIF-1α stabilization dependent on β3-adrenoceptor localization in Ewing sarcoma. [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 4808.
Abstract 4853: Evaluating the role of melatonin in thyroid cancer cell (MDA-T41) apoptosis and metabolism modulation
Authors: Huang Angela , Sanches Daniel 
Published: April 2023

Abstract
Melatonin, a hormone produced by the pineal gland, is typically known for its modulation of a number of physiological functions, alongside its ability to synchronize the sleep-wake rhythms. In recent years, however, its interactions with cancerous cells and role in prevention and treatment have been increasingly studied. It has been demonstrated that melatonin can improve the efficacy of chemotherapeutic drugs and directly inhibit tumorigenesis in experimental models of neoplasia. In addition, while melatonin typically displays anti-apoptotic effects in normal cells, it holds pro-apoptotic effects in cancer cells. Despite this, the mechanisms by which melatonin affects cell death and metabolism remain unclear due to the seeming difference from cell to cell. We aim to better understand the role of melatonin in regulating thyroid cancer cell apoptosis and metabolism. The MDA-T41 thyroid cancer cell line was cultured with varying quantities of melatonin. Steady volumes of staurosporine (an inductor of apoptotic cell death) were applied to cultures, and cell death levels were subsequently measured using the Realtime-Glo Annexin V Apoptosis and Necrosis assay. Our results showed that melatonin provided anti-apoptotic effects to MDA-T41 cells treated with staurosporine. Both apoptosis and necrosis were reduced by 50% in melatonin-treated cells 24 hours after staurosporine-induced cell death. Our next steps will be to evaluate the mechanisms and further signaling pathways involved in this apoptosis inhibition through Bcl-2 and p53 protein expression.
Citation Format: Angela Huang, Daniel Sanches. Evaluating the role of melatonin in thyroid cancer cell (MDA-T41) apoptosis and metabolism modulation. [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 4853.
Abstract 4911: A novel C-terminal of HSP90 inhibitor NCT-547 eliminates cancer stem-like subpopulation in triple-negative breast cancer
Authors: Jung Eunsun , Jang Seojin , Sung Daeil , Park Soeun , Park Minsu , Ko Dongmi , Kim Seongjae , Seo Juyeon , Nam Kee Dal , Kim Yoon-Jae , Kim Ji Young , Seo Jae Hong , Kang Yong koo , Seock So Ra , Park Jung Min 
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) harbors a higher cancer stem cell (CSC)-like population and exhibits a more aggressive metastatic phenotype. Due to the limitations of currently available targeted therapies, there remains a significant unmet need for the development of new targeted therapies for TNBC. Molecular chaperone heat shock protein 90 (HSP90) is attracting attention as an ideal therapeutic target due to it regulates essential biological functions such as cell proliferation, angiogenesis and metastasis. Although N-terminal HSP90 inhibitors have had little clinical success to date, C-terminal HSP90 inhibitors have received relatively little attention. We sought to investigate the effects of a new rationally designed NCT-547 on apoptosis, breast cancer stem cell (BCSC)-like properties, migration ability and heat shock response (HSR) in vitro and tumor growth and metastasis in CSC-enriched allograft model in vivo. NCT-547 inhibits TNBC cell proliferation by simultaneously inactivating several survival factors including AKT, MEK, and STAT3. In addition, NCT-547 effectively targets BCSC-like properties with impairment of ALDH1 activity, CD44+/CD24- phenotype, and 3D mammosphere-forming ability. The expression of HSF-1 target genes such as Hsp90, Hsp70, Hsp27, Hsp40 and Hsp65 is highly overexpressed in TNBC patients. The mRNA abundances of target genes were significantly decreased after NCT-547 challenge. NCT-547 effectively targets both the proliferating TNBC tumor cells and CSCs, markedly reducing tumor growth, coinciding with decreased Ki-67 proliferation index and enhanced apoptosis. Anti-tumor effect of NCT-457 was independent of heat shock response as evidenced by significant downregulation of HSF1 phosphorylation and expression of downstream targets HSPs members. It is noteworthy that NCT-547 did not affect markers of hepatic and renal acute toxicity and was not cytotoxic in non-malignant cells. NCT-547 may therefore have potential to address current limitations in the treatment of TNBC.
Citation Format: Eunsun Jung, Seojin Jang, Daeil Sung, Soeun Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo, Yong koo Kang, So Ra Seock, Jung Min Park. A novel C-terminal of HSP90 inhibitor NCT-547 eliminates cancer stem-like subpopulation 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 4911.
Abstract 4919: Estrogen regulates the immune microenvironment and immunotherapy response of colorectal liver metastases
Authors: Benslimane Yasmine , Lapin Sarah , Chambon Julien , Perrino Stephanie , Brodt Pnina 
Published: April 2023

Abstract
Liver metastases (LM) remain a major cause of cancer-related death and many cancers preferably metastasize to the liver due to its unique anatomical location, rich blood supply and immune-tolerant microenvironment. Up to 50% of colorectal carcinoma patients develop LM during their disease and this is associated with a poor prognosis. Our laboratory previously identified a sexual dimorphism in the regulation of the immune microenvironment (IME) of LM and showed that estrogen could promote the accumulation of myeloid-derived suppressor cells (MDSCs) and Tregs in the liver in response to invading cancer cells. The objective of this study was to elucidate the role of estrogen in the recruitment and polarization of other immune cells and to determine the therapeutic potential of Selective Estrogen Receptor Degrader (SERD) therapy in CRCLM bearing female mice, and evaluate if SERD would improve anti PD-1 immunotherapy efficacy. In estrogen-competent female mice bearing CRCLM, we found increased gene and protein expression of the immunosuppressive cytokine TGF-β, and inversely a decrease in the pro-inflammatory cytokine TNF-alpha. Furthermore, we identified a significant decrease of immunosuppressive CD68+CD163+ M2 macrophages, and an increase of the pro-inflammatory CD68+TNF-alpha+ M1 macrophages in estrogen-depleted (ovariectomized) mice as compared to estrogen-competent mice. This observation was reversed upon estradiol supplementation. Moreover, treatment of female mice with the SERD Fulvestrant, markedly reduced the number of CRCLM compared to vehicle-treated mice, reduced the cell frequencies and counts of M2 macrophages, significantly increased NK cells recruitment in the liver. The addition of SERD to immunotherapy has a better therapeutic effect than both therapies alone, and increased CD8+ T-cells, NK cells, and M1/M2 macrophages ratio. Taken together, our results identify estrogen as a critical regulator of an immunosuppressive TME in the liver and a potential therapeutic target to enhance immunotherapy efficacy.
Citation Format: Yasmine Benslimane, Sarah Lapin, Julien Chambon, Stephanie Perrino, Pnina Brodt. Estrogen regulates the immune microenvironment and immunotherapy response of colorectal liver metastases. [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 4919.