bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B19: The oncogenic TBX2 activates the ATM-CHK2-p53 axis to confer cisplatin resistance in breast cancer and melanoma
Authors: Kimani Serah , Wansbelen Sabina , Davis Emily , Peres Jade , Prince Sharon 
Published: November 2016

Abstract
A prominent mechanism through which tumors develop resistance to DNA damaging chemotherapeutic agents is by cancer cells preferentially arresting in S-phase, thereby acquiring the ability to repair drug-induced DNA damage and consequently evading apoptosis. Combining DNA damaging therapies with targeted approaches that disrupt the DNA damage repair process may therefore prove to be more effective against such tumors. The developmentally important transcription factor TBX2 has been suggested as a novel anti-cancer drug target, as it is overexpressed in several cancers and possesses strong anti-senescence and pro-proliferative functions. Indeed, when TBX2 is silenced, we are able to reverse several features of transformation in both breast cancer and melanoma cells. We and others have previously showed that ectopic expression of TBX2 confers resistance to DNA damaging chemotherapeutic drugs, cisplatin and doxorubicin. However, whether endogenous TBX2 confers resistance to these DNA damaging agents in TBX2-driven cancers and the mechanism(s) by which this may occur have not been reported. To address this, we have silenced TBX2 in cisplatin-resistant breast cancer and melanoma cells and we show that knocking down TBX2 sensitizes the cells to cisplatin by disrupting the ATM-CHK2-p53 signalling cascade. Cell cycle analyses demonstrate that when TBX2 is knocked down there is an abrogation of an S-phase arrest but a robust G2/M arrest that correlates with a reduction in p-CHK2 and p53 levels. This prevents DNA repair resulting in TBX2 deficient cells entering mitosis with damaged DNA and consequently undergoing mitotic catastrophe. These results provide compelling evidence that targeting TBX2 in combination with chemotherapeutic drugs such as cisplatin could improve their efficacy and that it may be a viable treatment of TBX2-driven cancers.
Citation Format: Serah Kimani, Sabina Wansbelen, Emily Davis, Jade Peres, Sharon Prince. The oncogenic TBX2 activates the ATM-CHK2-p53 axis to confer cisplatin resistance in breast cancer and melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B19.
Abstract B22: IT-141, a stabilized polymer micelle formulation, prolongs the pharmacodynamic effect of SN-38
Authors: Sethuraman Jyothi , Costich Tara Lee , Carie Adam , Buley Taylor , Ellis Tyler , Semple J. Edward , Vojkovsky Tomas , Sill Kevin , Bakewell Suzanne 
Published: November 2016

Abstract
IT-141 is a formulation of SN-38 encapsulated in an iron-stabilized polymer micelle. SN-38 is the active metabolite of irinotecan (CPT-11) which in combination with 5-FU and leucovorin is first-line FDA approved therapy for metastatic colorectal cancer. Although SN-38 is 1,000 times more potent than irinotecan alone, there is about 100-fold lower concentration of SN-38 in plasma from irinotecan. In the clinic only 2% to 10% of the administered dose of irinotecan is converted by carboxylesterases to SN-38 and there is great interpatient variability with toxicity. In vitro, IT-141 demonstrated nanomolar IC50s against a panel of human cancer cell lines in comparison to irinotecan's micromolar IC50 concentrations. SN-38 binds to the topoisomerase I-DNA complex resulting in double stranded breaks and cell death. We compared the mechanism of action of IT-141 compared to irinotecan treatment in HT-29 xenografts tumors. We demonstrated the incidence of double stranded breaks by immunohistochemistry (IHC) of γ- H2AX expression in tumors treated with IT-141 compared to irinotecan treatment at different time points (24, 48, 72 and 144 hours). In irinotecan treated tumors, γ- H2AX expression peaked at 72 hours followed by a sharp decrease in expression at 144 hours. In IT-141 treated tumors, γ- H2AX positive staining increased steadily from 24 through 144 hours. This shift in the kinetics of the mechanism corroborates the biodistribution studies where IT-141 delivered 34-fold more SN-38 to the tumor compared to irinotecan. The AUC and Cmax in IT-141 treated tumors was 30.9 μg*h/g and 12.2 μg/g respectively compared to an AUC of 1.1 μg*h/g and a Cmax of 0.2 μg/g in the irinotecan treated tumors. In an HT-29 xenograft model IT-141 inhibited tumor growth by 157% compared to a 57% with irinotecan. IT-141 demonstrates successful encapsulation of SN-38 leading to a safer, more effective formulation. Our DNA damage assay demonstrated that IT-141 extended the pharmacodynamic effect over irinotecan in treated tumors. Further studies are required to determine the duration of IT-141's pharmacodynamics effect. This data validates the increased tumor accumulation of SN-38 and increased efficacy of IT-141 over irinotecan.
Citation Format: Jyothi Sethuraman, Tara Lee Costich, Adam Carie, Taylor Buley, Tyler Ellis, J. Edward Semple, Tomas Vojkovsky, Kevin Sill, Suzanne Bakewell. IT-141, a stabilized polymer micelle formulation, prolongs the pharmacodynamic effect of SN-38. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B22.
Abstract B23: The deubiquitinating enzyme USP37 stabilizes Chk1 to promote the cellular response to replication stress
Authors: Singh Mayank , Pal Debjani , Burrows Amy C. , Messina Abbey , Dickson Andrew , Summers Matthew K. 
Published: November 2016

Abstract
Ubiquitin-mediated proteolysis is a key regulatory process in cell cycle progression. Recently, we identified mutual antagonism between the deubiquitinase USP37 as and the tumor suppressor APCCdh1 to regulate S-phase entry. Here we report that elevated USP37 expression correlates with cellular transformation. Depletion of USP37 leads to diminished cellular proliferation and loss of viability in tumor cells. USP37-depleted cells exhibit altered replication kinetics and increased levels of the DNA damage markers γH2AX and 53BP1 as well as increased sensitivity to agents that induce replication stress. Underlying the increased sensitivity, we find that USP37 interacts with the checkpoint kinase Chk1 and its binding partner Claspin and promotes the response to replication stress by stabilizing the active form of Chk1. In turn, activation of Chk1 promotes the down-regulation of APCCdh1 activity, which requires checkpoint mediated weakening of the USP37-APCCdh1 interaction. Our data suggest a model whereby the temporally regulated interplay of USP37, APCCdh1, and the replication checkpoint machinery promotes the ability of tumor cells to survive their intrinsic replication stress by enhancing replication checkpoint activity and driving the G1/S transition. These data provide an improved understanding of the replication checkpoint, control of APCCdh1, and maintenance of genome stability.
Citation Format: Mayank Singh, Debjani Pal, Amy C. Burrows, Abbey Messina, Andrew Dickson, Matthew K. Summers. The deubiquitinating enzyme USP37 stabilizes Chk1 to promote the cellular response to replication stress. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B23.
Abstract B28: FKBP6 gene is involved in progression of cervical cancer
Authors: Ili Carmen Gloria , Viscarra Tamara , Araya Juan Carlos , Lopez Jaime , Mora Barbara , Retamal Javier , Aedo Susana , Bellolio Enrique , Roa Juan Carlos , Brebi Priscilla 
Published: November 2016

Abstract
Introduction: Cervical Cancer (CC) is an important heath problem in developing countries. The silencing of tumor suppressor genes (TSG) could be implied in cervical carcinogenesis. Methylation microarray showed an aberrant hypermethylation of FKBP6, a potential TSG gen in CC. The aim of this study was to characterizer FKBP6 role in cervical carcinogenesis.
Materials and methods: ECT1 E6/E7 (immortalized normal squamous epithelia cell line) and three CC cell lines: SiHa, C-4I and C-33A were cultivated for experiments. FKBP6 expression was determined by qRT-PCR and western blot. Treatment with 10 μM 5-aza-2′deoxycytidine (5-aza) was performed to evaluate a possible epigenetic regulation. Transfection with pCMV6-FKBP6-GFP (FKBP6) and pCMV6-GFP (Empty) was carried out in SiHa cell line through lipofection followed by G418 selection to obtain stable transfection. Viability and clonogenic assay was performed to evaluate transfected cell behaviour. In other hand, 497 biopsy samples of the cervix were analyzed by FKBP6 immunohistochemistry (48 normal; 192 low-squamous intraepithelial lesions; 200 high- squamous intraepithelial lesions and 57 squamous cervical cancers).
Results: FKBP6 mRNA and protein expression was significantly downregulated in all cervical cancer cell lines respect to ECT1 E6/E7. In western blot, also could be observed a variant of FKBP6 mainly in C-4I cell line. After treatment with 5-aza, mRNA (p&lt;0.001) and protein expression of FKBP6 of all CC cell lines were restored. FKBP6 transfected SiHa showed a significant colony formation (p&lt;0.05) decrease. However, cell viability was found incremented (p&lt;0.001) compared with SiHa transfected with the empty vector. Immunohistochemistry showed an increased expression of FKBP6 in cervical cancer compared with normal (p&lt;0.001).
Conclusions: There is a FKBP6 dysregulation in CC cell lines, and the inactivation mechanism seems to be methylation. Restored expression of FKBP6 in SiHa cell line modifies the tumor phenotype, decreasing colony formation, but increasing cell viability. These results suggest that FKBP6 could be implied in cervical progression, but more studies are necessary to evaluate FKBP6 functions in cervical cancer.
Acknowledgments: FONDECYT N°3130630, Project Corfo N° 09CN14-5960, Project Corfo N°12IDL2-18157. Project FONDECYT N° 11150802, Project FONDECYT N°1115062
Citation Format: Carmen Gloria Ili, Tamara Viscarra, Juan Carlos Araya, Jaime Lopez, Barbara Mora, Javier Retamal, Susana Aedo, Enrique Bellolio, Juan Carlos Roa, Priscilla Brebi. FKBP6 gene is involved in progression of cervical cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B28.
Abstract B29: ZNF516 a potential tumor suppressor gene candidate is implied in tumor progression in cervical cancer
Authors: Ili Carmen Gloria , Viscarra Tamara , Araya Juan Carlos , Lopez Jaime , Mora Barbara , Retamal Javier , Bellolio Enrique , Aedo Susana , Roa Juan Carlos , Brebi Priscilla 
Published: November 2016

Abstract
Background: In Cervical Cancer (CC) the role of HPV is fundamental; however, not all HPV infected women will develop this disease. Therefore, other mechanisms, such as silencing of tumor suppressor genes (TSG), could be implied in cervical carcinogenesis. In a previous study, we constructed methylation microarrays, where we found promoter aberrant hypermethylation of ZNF516 gen in CC, postulating it as TSG candidate. The aim of this study was to characterizer ZNF516 role in cervical carcinogenesis and cell cycle.
Materials and methods: ECT1 E6/E7 (immortalized normal squamous epithelia cell line) and three CC cell lines: SiHa, C-4I and C-33A were cultivated for experiments. ZNF516 expression was determined by qRT-PCR and western blot. Treatment with 10 μM 5-aza-2′deoxycytidine (5- aza) was performed to evaluate a possible epigenetic regulation. Transfection with pCMV6-ZNF516-GFP (ZNF516) and pCMV6-GFP (Empty) was carried out in C-33A cell line through lipofection followed by G418 selection to obtain stable transfection. Viability and clonogenic assay was performed to evaluate transfected cell behaviour. Also, immnunohistochemical analysis was performed in 509 cervical biopsy tissues (55 normal; 188 low-squamous intraepithelial lesions; 205 high- squamous intraepithelial lesions and 57 squamous cervical cancers).
Results: ZNF516 mRNA expression was significantly downregulated in SiHa (p&lt;0.01) and C-33A (p&lt;0.001) respect to ECT1 E6/E7. Western blot showed a deregulated protein expression of ZNF516 in all CC cell lines. After treatment with 5-aza, mRNA (p&lt;0.05) and protein expression of ZNF516 of all CC cell lines were restored. ZNF516 transfected C-33A showed a significant colony formation (p&lt;0.01) and viability (p&lt;0.01) decrease compared with C-33A transfected with the empty vector. Nuclear expression of ZNF516 in cervical biopsies showed a diminished expression in SCC respect to normal epithelia (p&lt;0.001)
Conclusions: There is a clear ZNF516 dysregulation in CC cell lines, and the inactivation mechanism seem to be methylation. Restored expression of ZNF516 in C-33A cell line modifies the tumor phenotype, decreasing cellular viability and colony formation. These results suggest that ZNF516 could be a TSG, and its inactivation promotes CC developing.
Citation Format: Carmen Gloria Ili, Tamara Viscarra, Juan Carlos Araya, Jaime Lopez, Barbara Mora, Javier Retamal, Enrique Bellolio, Susana Aedo, Juan Carlos Roa, Priscilla Brebi. ZNF516 a potential tumor suppressor gene candidate is implied in tumor progression in cervical cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B29.
Abstract IA04: The Targeting of CDK4/6: Have we gone full circle?
Authors: Schwartz Gary K. 
Published: November 2016

Abstract
Cyclin Dependent kinase 4 (CDK4) is a critical kinase that regulates the G1/S phase transition within the cell cycle. There has been a major effort to develop drugs that inhibit this kinase. The first CDK4 inhibitor to be approved is Palbociclib. It is approved in combination with letrozole for the treatment of postmenopausal women with metastatic estrogen receptor (ER)-positive breast cancer as initial endocrine-based therapy. In this study Palbociclib (Palbo) improved median progression free survival (mPFS) from 10.2 months with letrozole alone to 20.2 months with Palbo in the combination therapy [Hazard Ratio (HR) 0.488 (95% CI 0.319, 0.748)]. Response rates were 55.4% with the combination and 39.4% with letrozole alone. Palbo has been tested in other disease including dedifferentiated and well-differentiated liposarcoma where CDK4 is amplified. In this disease Palbo has been reported to increase the PFS at 12 weeks to 66% surpassing the primary end of 40% in patients who had progressed on at least one primary regimen. The major toxicity is neutropenia. Other CDK4 inhibitors are in clinical trial, including LEE001 (Novartis) and LY2835219 (Eli Lilly). These agents exhibit a somewhat different toxicity profile with neutropenia and QTc prolongation with LEE001 and gastrointestinal toxicity with LY2835219. Recently, CDK4 inhibition has been shown to induce either a reversible cell cycle arrest or an irreversible senescent state. The proteolytic turnover of MDM2 appears to be critical for cellular senescence induced by CDK4 inhibition in liposarcoma, breast, lung and glioma cell lines. MDM2 turnover depends on its E3 ligase activity and expression of ATRX. In a small series of liposarcoma patients treated with Palbo the suppression of MDM2 expression correlated with improved clinical outcome suggesting that loss of MDM2 by inhibition of CDK4 could be a predictive biomarker for improved clinical outcome with this class of drugs.
Citation Format: Gary K. Schwartz. The Targeting of CDK4/6: Have we gone full circle? [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA04.
Abstract IA10: The senescence response - yin and yang
Authors: Campisi Judith 
Published: November 2016

Abstract
Cellular senescence is a stress response that irreversibly arrests cell proliferation and engages a complex senescence-associated secretory phenotype (SASP). The senescence growth arrest prevents the development of cancer by halting cells at risk for malignant transformation. The SASP, which comprises numerous cytokines, chemokines, growth factors, proteases and small metabolites, serves to optimize tissue repair and regeneration in the face of damage. Despite these beneficial effects, the SASP can be deleterious, especially when senescent cells are chronically present such as when they accumulate during aging and at sites of age-related pathology. In addition, persistent senescent cells can stimulate hyperplastic pathologies, including, ironically, cancer metastases. Recent findings using complex cell culture models and genetically modified mice have provided new insights into the dual nature of the senescence response. Together, these new results hold both enormous promise as well as formidable challenges to developing approaches for maintaining the beneficial effects, while minimizing the deleterious effects, of this complex stress response – with the ultimate goal of delaying or preventing a host of age-related diseases.
Citation Format: Judith Campisi. The senescence response - yin and yang. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA10.
Abstract IA12: Targeting the cell cycle in pediatric solid tumors
Authors: Dyer Michael 
Published: November 2016

Abstract
My lab is interested in understanding how proliferation and differentiation are coordinated during development and how those processes become uncoupled in pediatric solid tumors. We are also interested in identifying tumor vulnerabilities that can be exploited therapeutically. We have developed a unique resource for studying the developmental origins of childhood solid tumors and this resource is shared freely with no obligation to collaborate through the Childhood Solid Tumor Network (www.stjude.org/cstn). We have also developed a rigorous and comprehensive preclinical phase I/II/III testing program (Langenau et al. Cancer Research, 2015) that recapitulate many of the features of human clinical trials. In my presentation, I will compare and contrast cell cycle and checkpoint vulnerabilities across 4 pediatric solid tumor types including ongoing efforts to exploit those vulnerabilities in preclinical studies and clinical trials. These examples will provide a foundation for targeting the cell cycle across diverse cancer types.
Citation Format: Michael Dyer. Targeting the cell cycle in pediatric solid tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA12.
Abstract PR06: Sox2 functions as a critical oncogene in Rb loss initiated tumors
Authors: Kareta Michael S. , O'Brien Megan , Wernig Marius , Sage Julien 
Published: November 2016

Abstract
Tumor suppressors, while important proteins to in the context of tumor formation, are difficult to target for therapeutic purposes. The Rb tumor suppressor, which is lost or functionally inactivated in nearly every human tumor type, is not unique in that regard because restoration of the loss of Rb function has been challenging. Using cellular reprogramming to iPS cells as a model for tumor formation, we identified Sox2 as a direct target of Rb repression. Sox2 is a core pluripotency member with strong reprogramming abilities, and as such, is a potent oncogene in some cellular contexts. Using mouse genetics and genomic analysis we have confirmed that Sox2 does indeed promote tumor formation upon Rb loss. We have also investigated the consequence of Sox2 suppression in tumors initiated by Rb loss, including small cell lung cancer. This raises the possibility of using Sox2 inhibition as a more clinically feasible form of treatment than restoration of Rb loss.
This abstract is also being presented as Poster B05.
Citation Format: Michael S. Kareta, Jr., Megan O'Brien, Marius Wernig, Julien Sage. Sox2 functions as a critical oncogene in Rb loss initiated tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR06.
Persistent Microvascular Obstruction After Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse Remodeling
Authors: Kali Avinash , Cokic Ivan , Tang Richard , Dohnalkova Alice , Kovarik Libor , Yang Hsin-Jung , Kumar Andreas , Prato Frank S. , Wood John C. , Underhill David , Marbán Eduardo , Dharmakumar Rohan 
Published: November 2016

Background—
Emerging evidence indicates that persistent microvascular obstruction (PMO) is more predictive of major adverse cardiovascular events than myocardial infarct (MI) size. But it remains unclear how PMO, a phenomenon limited to the acute/subacute period of MI, drives adverse remodeling in chronic MI setting. We hypothesized that PMO resolves into chronic iron crystals within MI territories, which in turn are proinflammatory and favor adverse remodeling post-MI.

Methods and Results—

Canines (n=40) were studied with cardiac magnetic resonance imaging to characterize the spatiotemporal relationships among PMO, iron deposition, infarct resorption, and left ventricular remodeling between day 7 (acute) and week 8 (chronic) post-MI. Histology was used to assess iron deposition and to examine relationships between iron content with macrophage infiltration, proinflammatory cytokine synthesis, and matrix metalloproteinase activation. Atomic resolution transmission electron microscopy was used to determine iron crystallinity, and energy-dispersive X-ray spectroscopy was used to identify the chemical composition of the iron composite. PMO with or without reperfusion hemorrhage led to chronic iron deposition, and the extent of this deposition was strongly related to PMO volume (
r
>0.8). Iron deposits were found within macrophages as aggregates of nanocrystals (≈2.5 nm diameter) in the ferric state. Extent of iron deposits was strongly correlated with proinflammatory burden, collagen-degrading enzyme activity, infarct resorption, and adverse structural remodeling (
r
>0.5).

Conclusions—
Crystallized iron deposition from PMO is directly related to proinflammatory burden, infarct resorption, and adverse left ventricular remodeling in the chronic phase of MI in canines. Therapeutic strategies to combat adverse remodeling could potentially benefit from taking into account the chronic iron-driven inflammatory process.