tbuckley/cabot-search huggingface dataset:
Abstract 2489: Mre11-CDK2 interaction during the DNA double-strand break response
Authors: Mary J. Morgan, Todd A. Festerling, Jeffrey Buis, David O. Ferguson
Journal: Cancer Research (2017)

Abstract The MRN (Mre11/Rad50/NBS1) complex is a group of highly conserved proteins central to the detection and repair of DNA double-strand breaks (DSBs). Inherited deficiencies in DNA DSB signaling result in a spectrum of disorders featuring cancer predisposition, neurodegeneration, and immunodeficiency. MRN directly binds DNA DSB ends and facilitates activation of ataxia-telangiectasia mutated (ATM) kinase, which initiates cellular responses including DNA repair, cell cycle checkpoints, and in some circumstances, apoptosis. Cellular responses to DNA DSBs require rapid communication between DNA repair complexes and the cell cycle machinery, but much about this relationship remains unclear. Our lab recently discovered an interaction between Mre11 and Cyclin-dependent kinase 2 (CDK2), a key component of the cell cycle machinery (Buis et al., NSMB, 2012). CDK2, when bound to its regulatory partner Cyclin A, promotes cell cycle progression through S phase. We demonstrated that the Mre11-CDK2/Cyclin A interaction is important in regulating the capacity for DNA repair by homologous recombination in normally dividing cells. Current work is focused on understanding the role of this interaction during DNA damage responses. We hypothesize that Mre11 interaction with CDK2 is a component of a molecular switch between the normal cell cycle and the DNA damage response. To test our hypothesis, we take advantage of murine alleles of Mre11 previously generated in the lab. We performed immunoprecipitation studies to investigate the protein-protein interaction in the presence of DNA damage. We also utilized kinase inhibitors to investigate the role of apical kinases in regulating the interaction. Finally, we are currently optimizing in vitro kinase assays to further understand a relationship between Mre11 and CDK2 enzymatic activity.Unpublished findings reveal that the Mre11-CDK2/Cyclin A interaction is altered upon DNA damage, a process which appears to be important for cell cycle checkpoint regulation. In conclusion, we demonstrate that the Mre11-CDK2 interaction plays important roles both in normally dividing cells and in the DNA damage response. Taken together, our data suggests that Mre11 may act to bridge the gap between DNA repair complexes and the cell cycle machinery. Citation Format: Mary J. Morgan, Todd A. Festerling, Jeffrey Buis, David O. Ferguson. Mre11-CDK2 interaction during the DNA double-strand break response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2489. doi:10.1158/1538-7445.AM2017-2489
Abstract 3071: Exploring the molecular mechanism underlying SETD2-PI3Kβ synthetic-lethal interaction in renal cell carcinoma (RCC)
Authors: Esteban Terzo, Jeanne Chiang, W. Kimryn Rathmell
Journal: Cancer Research (2017)

Abstract Epigenetic regulators are emerging as major drivers of renal cell carcinoma (RCC). SETD2, a tumor suppressor commonly mutated in RCC, is the sole enzyme responsible for tri-methylating histone H3 on lysine 36 (H3K36me3) of actively transcribed genes. We recently discovered that SETD2 also trimethylates the non-histone target α-tubulin on lysine 40 (α-TubK40Me3) of mitotic microtubules. We have demonstrated that mutations altering SETD2’s ability to trimethylate H3K36 and α-TubK40 are associated with genomic instability in cancer progression. We hypothesized that defective SETD2 methylating activity gives rise to deleterious cell signaling cascades that promote the tumorigenic features of SETD2 loss. Preliminary data show that RCC-derived 786-0 cells that are deleted for SETD2 (SETD2-KO) or harbor pathogenic mutations are more sensitive to treatment with the PI3Kβ-specific inhibitor TGX-221 than their wild type counterparts. Phosphatidylinositol 3kinases (PI3Ks) are a family of lipid kinases that coordinate signals from growth factors, cytokines and other environmental cues, translating them into intracellular signals controlling diverse signaling pathways. Several members of the PI3K/AKT signaling pathway, including the PI3K α and β isoforms, are frequently mutated in a variety of cancers, making this pathway a prime drug target for anti-cancer therapy. These pathways control numerous biological processes, such as cell proliferation, growth, and motility. Examination of structurally variant SETD2 mutants suggests that the loss of SETD2 methylating activity mediates this interaction, and future studies will examine the functional consequences of inhibiting this pathway. In summary, these data suggest a synthetic-lethal type of interaction between SETD2 loss (and specifically loss of methylating activity) and an aberrant PI3K/AKT pathway. Citation Format: Esteban Terzo, Jeanne Chiang, W. Kimryn Rathmell. Exploring the molecular mechanism underlying SETD2-PI3Kβ synthetic-lethal interaction in renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3071. doi:10.1158/1538-7445.AM2017-3071
Abstract LB-229: Mutation spectra of aflatoxin B1 in <i>vivo</i> establish biomarkers of exposure for human hepatocellualr carcinoma
Authors: Supawadee Chawanthayatham, Charles C. Valentine, Bogdan I. Fedeles, Stephen L. Slocum, Gerald N. Wogan, Robert G. Croy, John M. Essigmann
Journal: Cancer Research (2017)

Abstract Responding to a need to identify the mutational processes that are responsible for malignant transformation, highly accurate duplex sequencing (DS) was employed to monitor acquisition of context-dependent high-resolution mutational spectra (MS) during the process of hepatocarcinogenesis. Aflatoxin B1 (AFB1) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB1-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C&amp;gt;T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Four-day old male mice were treated with AFB1 using a regimen that induced hepatocellular carcinoma within 72 weeks. The DS technology revealed a distinctive MS of AFB1 at 10 weeks after dosing, well before evidence of neoplasia. Importantly, 25% of all mutations were G&amp;gt;T in one trinucleotide context (5’-CGC-3’), which is also a hotspot mutation in human liver tumors whose incidence correlates with AFB1 exposure. At 72 weeks, livers were separated into tumor tissue and normal surrounding cellular fractions (primarily hepatocytes). The MS in normal cells surrounding the tumors revealed clear evidence of previous AFB1 exposure with predominantly G:C&amp;gt;T:A mutations and strong representation of the CGC&amp;gt;CTC hotspot. Analysis of tumor tissue revealed a more complex pattern than that observed in surrounding hepatocyte fraction; tumor MS were a composite of the 10-week spectrum and a more heterogeneous set of mutations that emerged during tumor outgrowth. The 10-week AFB1-exposed mouse MS was then used as bait to computationally identify human HCC sequences that have similarity to it. This analysis revealed that the mouse spectrum has striking similarity to human HCCs from hepatitis B infected people who have the R249S mutation in P53. The data also provide insight into the molecular basis for the synergism between hepatitis B exposure and AFB1. The MS provided by DS technology provides a method to identify mutational processes in normal and tumor tissues enabling reconstruction of the molecular etiology of human hepatocarcinogenesis and other genetic diseases. Citation Format: Supawadee Chawanthayatham, Charles C. Valentine III, Bogdan I. Fedeles, Stephen L. Slocum, Gerald N. Wogan, Robert G. Croy, John M. Essigmann. Mutation spectra of aflatoxin B1 in vivo establish biomarkers of exposure for human hepatocellualr carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-229. doi:10.1158/1538-7445.AM2017-LB-229
Abstract 3909: Investigating the role of ANXA2R in metastatic prostate cancer
Authors: Gonzalo Torga, Kenneth J. Pienta
Journal: Cancer Research (2017)

Abstract Skeletal metastasis is the most life-threatening complication in prostate cancer. The molecular mechanisms behind the interactions between prostate cancer and the bone marrow premetastatic niche remain unknown. Understanding and preventing such interactions could lead to new promising therapeutic strategies against lethal prostate cancer. Annexin 2 receptor (ANXA2R) was originally identified as a cell surface receptor for Annexin 2 (ANXA2) that mediates the stimulatory effects of ANXA2 during osteoclastic activation and osteoblast mineralization. Moreover, ANXA2R is able to induce apoptosis independent of its ligand, partially through activating caspases using non-conventional apoptotic pathways. Osteoblasts and marrow endothelial cells express ANXA2 which functions as a regulator of hematopoietic stem cell engraftment. Previous studies demonstrated blocking ANXA2 or its receptor prevents prostate cancer cells from establishing bone metastases in mouse models. It has been recently proven that ANXA2R does not bind to ANXA2 directly but to S100A10 present in the complex annexin A2 heterotetramer (AIIt), composed of 2 ANXA2 bound to a S100A10 dimer. Higher levels of ANXA2 and S100A10 are associated with proliferating and invasive cancers and correlate with poor prognosis. However, the loss of ANXA2 expression appears to be specific for prostate cancer. Previous work on prostate cancer has focused solely on ANXA2 as a ligand. In this study, we demonstrate that S100A10 and ANXA2 are co-localized in prostate cancer, and their expression and ANXA2R levels vary with grade in primary tumors as well as within the different metastatic sites. Given prostate cancer cells as well as bone marrow stroma can simultaneously express the ligand and receptor and levels of AIIt decrease with tumor stage in the primary site, we hypothesize prostate cancer cells require S100A10 and not only ANXA2 to spread to bone and other tissues. ANXA2R could act as a dependence receptor, mediating withdrawal-induced programed cell death in prostate cancer cells in the absence of AIIt. Furthermore, AIIt-ANXA2R interactions between prostate cancer cells and the premetastatic bone marrow niche might play an important role in the development of skeletal metastasis by inducing selective pressures on prostate cancer cells to metastasize to the bone marrow which is abundant of AIIt. Citation Format: Gonzalo Torga, Kenneth J. Pienta. Investigating the role of ANXA2R in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3909. doi:10.1158/1538-7445.AM2017-3909
Abstract LB-209: RON kinase: a target for treatment of cancer-induced bone destruction and osteoporosis
Authors: Kelsi Andrade, Jaime Fornetti, Ling Zhao, Scott C. Miller, Lor R. Randall, Neysi Anderson, Susan E. Waltz, Mark McHale, Alana L. Welm
Journal: Cancer Research (2017)

Abstract Bone destruction occurs in aging and numerous diseases, including osteoporosis and cancer. Many cancer patients have bone osteolysis that is refractory to state-of-the-art treatments, which block osteoclast activity with bisphosphonates or by inhibiting the RANKL pathway. We previously showed that macrophage-stimulating protein (MSP) signaling, which is elevated in approximately 40% of breast cancers, promotes osteolytic bone metastasis, but it was unknown whether this was due to activation of the MSP signaling pathway in the tumor cells or in the bone microenvironment. Here we show that MSP signals through host expression of its receptor, RON tyrosine kinase, to directly activate osteoclasts by a previously undescribed pathway that is complementary to RANKL signaling and converges on SRC. Genetic or pharmacologic inhibition of RON kinase blocked cancer-mediated bone destruction and osteoporosis in several mouse models. Furthermore, the RON kinase inhibitor BMS-777607/ASLAN002 altered markers of bone turnover in a first-in-human clinical cancer study, indicating potential for normalizing bone loss in patients. These findings uncover a new therapeutic target for pathogenic bone loss and provide a rationale for treatment of bone destruction in various diseases with RON inhibitors. Citation Format: Kelsi Andrade, Jaime Fornetti, Ling Zhao, Scott C. Miller, Lor R. Randall, Neysi Anderson, Susan E. Waltz, Mark McHale, Alana L. Welm. RON kinase: a target for treatment of cancer-induced bone destruction and osteoporosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-209. doi:10.1158/1538-7445.AM2017-LB-209
Abstract CT145: A phase I window, dose escalating and safety trial of Metformin in combination with induction chemotherapy (VPLD)in relapsed/refractory acute lymphoblastic leukemia: NCT01324180
Authors: Matteo Trucco, Julio Barredo, John Goldberg, Gregory Hale, Jonathan Gill, Bhuvana Setty, Tiffany Smith, Jae Lee, Damon Reed
Journal: Cancer Research (2017)

Abstract Background: Relapsed Acute Lymphoblastic Leukemia (ALL) remains a major cause of cancer-related deaths in children. We identified the AMP activated protein kinase (AMPK) as a potential target for ALL therapy due to its regulatory effects on the unfolded protein response (UPR), leading to increased vulnerability of ALL cells to endoplasmic reticulum (ER) stress inducers. In vitro, metformin leads to ALL cell death via AMPK-mediated inhibition of the UPR. Methods: Metformin was administered twice daily continuously on a 28 day cycle in addition to the Vincristine, Dexamethasone, PEG-Asparaginase and Doxorubicin (VPLD) systemic regimen and CNS-directed therapy in pediatric patients with relapsed/refractory ALL. Metformin doses were increased in a standard 3+3 phase I design with three dose levels evaluated, 666, 1,000 and 1,333 mg/m2/day. Pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways were ascertained on days 1 and 7, and treatment response was assessed on day 29. Results: Fourteen patients were enrolled, 11 evaluable. DL3 was the maximum administered dose with 2 related DLT’s of diarrhea and acidosis. A single DLT of hypoglycemia and acidosis during an episode of sepsis was observed in DL2. Infectious SAE’s occurred in 7 patients. Two patients had posterior reversible encephalopathy syndrome; both died of disease progression within 30 days of coming off study. A single patient had stable disease, 2 had a partial response, and 3 achieved a complete response. PK studies demonstrated levels within the therapeutic range for patients with diabetes, and PD evaluation showed induction of ER stress and inhibition of the UPR. Conclusions: This trial has been completed. We found induction of ER stress with inhibition of UPR consistent with that observed in vitro leading to metformin-induced apoptosis. The chemotherapeutic backbone was tolerable and the combination with metformin yielded responses in a heavily pretreated population. Toxicities attributable to metformin occurred in all dose levels, but DLT’s were only observed in dose levels above the standard dosing for diabetes. Clinical trial information: NCT01324180 Citation Format: Matteo Trucco, Julio Barredo, John Goldberg, Gregory Hale, Jonathan Gill, Bhuvana Setty, Tiffany Smith, Jae Lee, Damon Reed. A phase I window, dose escalating and safety trial of Metformin in combination with induction chemotherapy (VPLD)in relapsed/refractory acute lymphoblastic leukemia: NCT01324180 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT145. doi:10.1158/1538-7445.AM2017-CT145
Abstract 1786: Predictive value of LRP8, KPNA2 and GDF15 expression to anthracycline/taxane based chemotherapy response in patients with locally advanced breast cancer
Authors: Hector Maldonado-Mtz, Alonso-Luna Oscar, Ali Flores-Perez, Meneses-Garcia Abelardo, Erika B. Ruiz-Garcia, Cesar Lopez-Camarillo, Horacio Astudillo-de la Vega
Journal: Cancer Research (2017)

Abstract Background: Chemotherapy plays a major role in its treatment, though overtreatment is frequent since its choice is based on clinicopathological prognostic data. The identification and validation of new predictive profiles or markers continues to be relevant. New findings may contribute to achieve better results in this area, as well as to provide new targets of the pathways involved in chemoresistance. Karyopherin α2 (KPNA2), low density lipoprotein receptor-related protein 8 (LRP8) and growth and differentiation factor 15 (GDF15), are three candidate predictive biomarkers in breast cancer, previously identified on DNA microarrays reports. Methods: Using tissue microarrays technology and immunohistochemistry, we compared the expression of these three markers between cases of breast cancer with response to chemotherapy (absence of recurrence), and those with failure (with recurrence). All patients received chemotherapy based on anthracyclines and taxanes. Potential confounding factors, as known recurrence and progression risk factors, were controlled for during the comparison. Results: 20 out of 63 patients had tumor recurrence. Potential confounding factors were similar among cases with response and failure to chemotherapy. For KPNA2 no differences were found between cases with response or failure. LRP8 showed higher expression in cases with failure to chemotherapy (mean 7.22 vs 14.01%, p =0.025). In Cox multivariable regression analysis, which included potential confounding factors as covariates, only LRP8 remained as a significant predictive factor (HR 1.28, p=0.016). GDF15 showed no expression in our cases, nor in an external set of cases. Conclusions: We demonstrated increased expression of LRP8 in breast cancer cases recurring after chemotherapy. KPNA2 and GDF 15 showed no predictive value for chemotherapy response in our study. LRP8 is a potential predictive marker worth of further investigation for its role in chemoresistance as well as for its potential validation. Note: This abstract was not presented at the meeting. Citation Format: Hector Maldonado-Mtz, Alonso-Luna Oscar, Ali Flores-Perez, Meneses-Garcia Abelardo, Erika B. Ruiz-Garcia, Cesar Lopez-Camarillo, Horacio Astudillo-de la Vega. Predictive value of LRP8, KPNA2 and GDF15 expression to anthracycline/taxane based chemotherapy response in patients with locally advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1786. doi:10.1158/1538-7445.AM2017-1786
SAT0400 Is whiplash injury a triggering or exacerbating factor for axial spondyloarthritis?
Authors: F Urano, S Ono, R Hara, M Yasumura, T Muramatsu, S Suzuki
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Axial spondyloarthritis (AxSpA) can be triggered by infection and environmental factors, and some cases involve trauma. Whiplash injury in a traffic accident may lead to exacerbation of symptoms of AxSpA. <h3>Objectives</h3> The aims of this study are to survey the prevalence of trauma before or after onset of AxSpA and to examine the prevalences of neck trauma and other trauma in patients with a history of AxSpA. <h3>Methods</h3> The patients completed a questionnaire, and clinical presentation, inflammatory markers (ESR, CRP), radiographs, MRI of sacroiliac joints, Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), and Bath ankylosing spondylitis metrology index (BASMI) were assessed. Onset of symptoms was evaluated using European criteria for spondyloarthritis and patients were asked about mechanical stress (spinal trauma, extremity trauma, and internal organ injury). Patients with rheumatoid arthritis (RA) were included as controls and underwent the same evaluation. Patients with neck trauma were divided into four groups based on a short (&lt;3 years) (group A) or long (≥3 years) (group B) period between disappearance of trauma symptoms and onset of inflammatory back pain (IBP); continuous IBP after trauma (group C); and a gradual change from minor symptoms to severe IBP after trauma (group D). <h3>Results</h3> The subjects were 124 patients with AxSpA and 102 with RA. Trauma occurred at a significantly higher rate in patients with AxSpA than in those with RA (66 (53.2%) vs. 12 (11.8%), p&lt;0.0001). Neck trauma was also significantly more frequent in patients with AxSpA (63 (53.2%) vs. 9 (8.8%), P&lt;0.0001) (Table 1). There were no significant differences in clinical background between patients with AxSpA with and without trauma (Table 2). Regarding the period from neck trauma to onset of IBP in patients with AxSpA, there were 4 (6.3%), 22 (34.9%), 14 (22.2%), and 23 (36.5%) cases in groups A, B, C and D, respectively. <h3>Conclusions</h3> The remarkable finding in this study is that half of patients with AxSpA had a history of whiplash injury. These results suggest that trauma may influence the course of AxSpA through the immunological system or hypothalamic-pituitary-adrenal axis. <h3>Disclosure of Interest</h3> None declared
Abstract 1810: Dysregulation of myristoylated alanine-rich C kinase substrate (MARCKS): A novel therapeutic target in renal cell carcinoma
Authors: Ching-Hsien Chen, Wen-Hsin Chang, Eric Yu, Muhammad S. Arif, Reen Wu, Robert H. Weiss
Journal: Cancer Research (2017)

Abstract Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/VEGF signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably VEGF-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multi-kinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multi-kinase inhibitors. Citation Format: Ching-Hsien Chen, Wen-Hsin Chang, Eric Yu, Muhammad S. Arif, Reen Wu, Robert H. Weiss. Dysregulation of myristoylated alanine-rich C kinase substrate (MARCKS): A novel therapeutic target in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1810. doi:10.1158/1538-7445.AM2017-1810