bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5295: Targeting Rb phosphatase activity to circumvent CDK4/6 inhibitor resistance
Authors: DiSalvo Kathleen H. , Velez Brian C. , Kravtsov Rebecca L. , Krucher Nancy A. 
Published: August 2019

Abstract
The Retinoblastoma (Rb) tumor suppressor protein plays a role in the control of proliferation, apoptosis, differentiation, invasion and the maintenance of genome stability. Its activity is regulated by phosphorylation on several serine/threonine sites, which is thought to inactivate its tumor suppressive function. Cyclin dependent kinases (CDKs) are responsible for most of the Rb phosphorylation that occurs in cells. It is well established that alterations in the Rb pathway (consisting of CDK4/6, D-type cyclins, the CDK inhibitor p16INK4a, and Rb itself) that lead to excessive phosphorylation of Rb have been observed in almost all cancer types. Alterations that lead to increased CDK activity toward Rb are more common than mutations to the Rb gene itself, a finding that prompted investigations into the development of clinical treatments that inhibit the phosphorylation of Rb by CDKs. The CDK4/6 inhibitors palbociclib and abemaciclib were recently clinically approved for use in breast cancer. However, acquired resistance to CDK4/6 inhibition has been shown to limit clinical efficiency. Targeting Rb phosphorylation by CDK4/6 inhibition has been shown to activate alternate pro-survival pathways such as the AKT pathway. In our studies we developed a method of siRNA-mediated activation of Rb phosphatase that targets Rb phosphorylation in attempt to circumvent the development of resistance. Phosphatase Nuclear Targeting Subunit (PNUTS) associates with and regulates PP1 activity toward Rb. In several cancer cell types, such as HCT116 colon cancer, MIA PaCa-2 pancreatic cancer and MCF7 breast cancer, PNUTS depletion causes dephosphorylation of Rb without AKT activation. Furthermore, in Panc1 pancreatic cancer cells, activation of AKT is observed after 1-hour palbociclib (500nM) treatment, whereas PNUTS depletion does not induce AKT. In MD-MBA-231 breast cancer cells, 1-hour treatment of palbociclib or abemaciclib (20nM) induces the AKT pathway as well as the STAT pathways, however PNUTS depletion in these cells does not induce AKT activation. It has been shown that CDK4/6 inhibitors activate AKT by causing loss of Rb interaction with SIN1, a component the mTORC2 complex. Our studies reveal that PNUTS depletion causes dephosphorylation of Rb, without disrupting Rb-mediated inhibition of mTORC2. Thus, the stimulation of Rb phosphatase activity may target Rb phosphorylation without the development of resistance.
Citation Format: Kathleen H. DiSalvo, Brian C. Velez, Rebecca L. Kravtsov, Nancy A. Krucher. Targeting Rb phosphatase activity to circumvent CDK4/6 inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5295.
Abstract 5296: DNAJA1 promotes cancer progression by stabilizing mutant p53
Authors: Iwakuma Tomoo 
Published: August 2019

Abstract
The tumor suppressor p53 is mutated in approximately 50% of human cancers. Majority of them are missense mutations, which results in accumulation of dysfunctional p53 proteins in tumors. Increasing evidence suggests that accumulation of mutant p53 is crucial for its oncogenic gain-of-function activities, such as proliferation, metastasis, and chemotherapy resistance. Previous work from our lab has revealed that DNAJA1, a HSP40 family member, specifically binds to and stabilizes conformational/misfolded mutant p53. DNAJA1 downregulation induces ubiquitination and proteasomal degradation of conformational p53 mutants, but does not affect the levels of wild-type p53 or DNA contact mutants. Based on these observations, we hypothesize that DNAJA1 promotes cancer progression in a manner dependent on conformational/misfolded mutant p53. To test this hypothesis, we examined the effects of DNAJA1 deletion/knockdown on malignant properties of head and neck squamous cell carcinoma (HNSCC) cells. Genetic deletion/knockdown of DNAJA1 resulted in reduced proliferation, colony formation, migration, and orthotopic tumor growth of HNSCC cells expressing conformational mutant p53, but not DNA contact mutant p53. These cellular phenotypes induced by DNAJA1 knockdown/knockout were substantially rescued by overexpression of DNAJA1 or mutant p53. We also conducted RNA sequencing analyses using HN31 cells (control, DNAJA1 knockdown or mutant p53 knockdown). Notably, 77.2% of downregulated genes by p53 knockdown were overlapped with genes downregulated by DNAJA1 knockdown. Moreover, genes involved in cancer-related pathways, including adhesion and actin cytoskeleton organization, were commonly downregulated. These results strongly suggest that DNAJA1 promotes HNSCC progression mostly dependent on conformational mutant p53. Our results may also suggest that DNAJA1 could be a novel therapeutic target for cancers carrying conformational/misfolded mutant p53.
Citation Format: Tomoo Iwakuma. DNAJA1 promotes cancer progression by stabilizing mutant p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5296.
Abstract 5301: The role of ID4 in regulating SAT1 gene expression in prostate cancer phenotype
Authors: Al-Zahrani Majid 
Published: August 2019

Abstract
Introduction: Inhibitor of DNA binding 4 (ID4), a bHLH protein and a transcriptional regulator, is a tumor suppressor gene in prostate cancer. ID4 is expressed in prostate cancer cells (LNCaP), which are androgen sensitive, but epigenetically silenced in a more aggressive DU145 cells. The epigenetic silencing of ID4 is associated with increasing tumor grade and castration resistant prostate cancer (CRPC). ID4 regulates the expression of some other genes such as SAT1, which is a rate limiting enzyme found in the X chromosome involved in the catabolic pathway of polyamine metabolism by catalyzing the N(1)-acetylation of spermidine and spermine. Recently, SAT1 was also shown to mediate histone H3 acetylation suggesting its role in regulating gene expression. Next generation sequencing (NGS) data showed a significant low expression of SAT1 when ID4 is up regulated and vise-versa, which led to a hypothesis that ID4 might regulate the expression of SAT1 gene in prostate cancer cells.
Experimental procedures: The NGS (exon sequencing) was performed on prostate cancer cells either over-expressing ID4 (DU145(+)ID4) or cells in which ID4 was genetically silenced (LNCaP(-)ID4). Moreover, immunohistochemistry (IHC) analysis was performed on mice prostates tissues (WT and ID4-/- mice) and DU145(+)ID4 tumor xenografts tissues to analyze SAT1 protein expression in the presence and the absence of ID4.
Results: The NGS and IHC data analysis suggested that Spermidine/spermine N(1)-acetyltransferase (SAT1) is up-regulated in cells lacking ID4 such as (LNCaP(-)ID4) but down-regulated in cells which express ID4 (DU145(+)ID4). These results prompted us to investigate the effect of silencing SAT1 on ID4 expression and on cancer phenotype.
Conclusion: The expression of ID4 gene in prostate cancer cell lines LNCaP, and DU145(+)ID4 cells showed low expression of SAT1 gene compared with cells lacking ID4 gene as in LNCaP(-)ID4 and DU145 cells.
Acknowledgment: These studies were supported by the NIH/NIMHD/P20 Grant
#P20MD002285.
Citation Format: Majid Al-Zahrani. The role of ID4 in regulating SAT1 gene expression in prostate cancer phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5301.
Abstract 5308: BRMS1L, a metastatic suppressor gene, is transcriptionally regulated by p53
Authors: Tokino Takashi , Koyama Ryota , Idogawa Masashi , Sasaki Yasushi 
Published: August 2019

Abstract
The tumor suppressor p53 plays a pivotal role in the cell fate determination in response to diverse upstream signals. p53 regulates a number of genes that are involved in cell cycle arrest, apoptosis, senescence, and maintenance of genomic stability. Recent studies revealed that p53 is also important for the regulation of cell invasion and migration. Our group has previously revealed that the p53 transactivates anti-invasion genes such as CLCA2, ICAM2, and LIMA1. However, the role of the p53 downstream pathway in cancer invasion, migration, and metastasis remains unclear. In this study, microarray analysis showed that breast cancer metastasis-suppressor 1- like (BRMS1L) is upregulated by p53. We identified two responsive elements of p53 family proteins in the first intron and upstream of BRMS1L. These response elements are well conserved among mammals. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration; knockdown of BRMS1L by siRNA induced the opposite effect. Importantly, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. Together, these results strongly demonstrate that BRMS1L is one of the mediators downstream of the p53 pathway, and that BRMS1L inhibits cancer cell invasion and migration, which are essential steps in cancer metastasis. Collectively, our results suggest that BRMS1L is involved in cancer cell invasion and migration, and could be a therapeutic target for cancer.
Citation Format: Takashi Tokino, Ryota Koyama, Masashi Idogawa, Yasushi Sasaki. BRMS1L, a metastatic suppressor gene, is transcriptionally regulated by p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5308.
Abstract 548: Evaluation of novel SIRP antibodies as potential cancer therapeutics
Authors: Hiebsch Ronald R. , Bouchlaka Myriam N. , Capoccia Benjamin J. , Donio Michael J. , Chakraborty Prabir , Wilson W. Casey , Puro Robyn J. , Pereira Daniel S. 
Published: August 2019

Abstract
Targeting immune checkpoints of adaptive immunity has shown great therapeutic efficacy in oncology, but in a limited fraction of patients. Innate immune cells represent the most abundant immune cell types in many solid tumors and are often linked to a poor prognosis.
SIRPα is expressed by innate immune cells and its interaction with CD47, expressed by most tumor cells, is an important immune checkpoint of the innate response, involved in the regulation of phagocytosis by macrophages, dendritic cells and neutrophils.
Recently, first generation agents targeting CD47 (CD47 antibodies and SIRPα-Fc fusion proteins) have shown promise in clinical trials, but they have also experienced hematological toxicities such as anemia or thrombocytopenia. Consequently, we have previously reported on the development of AO-176, a next generation anti-CD47 antibody that not only blocks the CD47/SIRPα interaction and induces phagocytosis, but also preferentially binds tumor versus normal cells (including RBCs where it binds negligibly) and directly kills tumor cells via a programmed cell death type III and an immunogenic cell death process.
Here we report the discovery of novel anti-SIRP antibodies that recognize either SIRPα selectively or SIRPα/γ. These antibodies are being evaluated for their ability to induce phagocytosis of tumor cells - we have identified antibodies that induce phagocytosis of tumor cells alone and in combination with Rituxan. The ability of our anti-SIRP antibodies to induce immunomodulatory activities in a variety of ex vivo cultured immune cells expressing either SIRPα or SIRPα/γ is also under investigation and will be presented.
Citation Format: Ronald R. Hiebsch, Myriam N. Bouchlaka, Benjamin J. Capoccia, Michael J. Donio, Prabir Chakraborty, W. Casey Wilson, Robyn J. Puro, Daniel S. Pereira. Evaluation of novel SIRP antibodies as potential cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 548.
Abstract 555: A novel human TNFR2 antibody (MM-401) modulates T cell responses in anti-cancer immunity
Authors: Sampson James F. , Kurella Vinodh B. , Paragas Violette , Kumar Sandeep , Lulo James E. , Qiu James A. , Razlog Maja , Fulton Ross B. , Camblin Adam J. , Richards Jennifer M. , Wong Christina S. , Koshkaryev Alexander , Suchy James J. , Grabow Stephanie , Muda Marco , Raue Andreas , Drummond Daryl C. , Tam Eric M. 
Published: August 2019

Abstract
TNFR2 is an emerging therapeutic target in immuno-oncology. We have previously shown that an agonistic mouse TNFR2 antibody was able to activate CD8+ T cells in vitro and has anti-tumor activity in multiple syngeneic mouse tumor models. This activity required CD8+ T cell and NK cell response and involves Fc γ receptor engagement. Based on this compelling evidence, we have developed MM-401, a human antibody targeting the TNFR2 receptor. MM-401 was humanized from a mouse hybridoma antibody by CDR grafting and includes additional mutations for improved affinity and biophysical properties. Consequently, MM-401 binds with low nanomolar affinity to a region in human TNFR2 that corresponds to the mouse TNFR2 epitope of our mouse surrogate antibody. Although the antibody competes with TNF α in binding the receptor, MM-401 has agonistic activity and induces TNFR2 signaling as observed using a NFκB reporter cell assay. Upon incubation of MM-401 with CD4+ and CD8+ T cells from healthy human blood, we observed upregulation of activation markers and cytokine production comparable to utomilumab (anti-4-1BB), MEDI6469 (anti-OX40), and TRX518 (anti-GITR). We also observed that MM-401 promotes antibody-dependent cellular cytotoxicity (ADCC) in an NK cell-mediated in vitro assay and a reduction in the number regulatory T (Treg) cells in ovarian cancer ascites samples. These data suggest that MM-401 could also promote anti-tumor immunity by mediating ADCC, as well as by direct co-stimulation of T cell responses. Currently, we are evaluating MM-401 in patient derived xenograft (PDX) models in humanized mice generated using NSG-SGM3 mice with cord blood CD34+ hematopoietic stem cells. These results justify the continued development of MM-401 as a modulator of anti-tumor immunity for the treatment of cancer.
Citation Format: James F. Sampson, Vinodh B. Kurella, Violette Paragas, Sandeep Kumar, James E. Lulo, James A. Qiu, Maja Razlog, Ross B. Fulton, Adam J. Camblin, Jennifer M. Richards, Christina S. Wong, Alexander Koshkaryev, James J. Suchy, Stephanie Grabow, Marco Muda, Andreas Raue, Daryl C. Drummond, Eric M. Tam. A novel human TNFR2 antibody (MM-401) modulates T cell responses in anti-cancer immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 555.
Abstract 609: Vitamin D binding protein and risk of renal cell carcinoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Kratzer Tyler B. , Mondul Alison M. , Weinstein Stephanie J. , Albanes Demetrius 
Published: August 2019

Abstract
Introduction/Study purpose: Vitamin D binding protein (DBP) is the major carrier of vitamin D in circulation. In addition to its role in vitamin D transport, DBP has several other biologic mechanisms that may be relevant to cancer risk including macrophage activation, apoptosis, and angiogenesis. Although previous studies have demonstrated no association between vitamin D and RCC, our group has conducted two previous studies which found strong inverse associations between DBP and RCC. We undertook the current analysis to replicate our findings in a different study population.
Methods: We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Cases (n=323) were matched 1:1 to controls on age (+/- 1 year), race, date of blood collection (+/- 30 days) and sex. We performed conditional logistic regression to estimate the odds ratios and 95% confidence intervals for the association between quartiles of circulating DBP and risk of RCC. In addition to conditioning on the matching factors, multivariable models were further adjusted for history of diabetes or hypertension, family history of renal cancer, body mass index (BMI), and smoking status. Additionally, we performed stratified analyses by sex, family history of renal cancer, BMI, smoking status, and tumor stage at diagnosis.
Results: We observed a statistically significant positive association between DBP and RCC that persisted after multivariable adjustment (mv-adj Q4 vs. Q1 OR=3.1, 95% CI=1.8-5.6; p-trend &lt;0.0001). Sensitivity analyses were performed removing matched pairs where the case was diagnosed within 2 years of blood collection or experienced a large weight loss (&gt;40 lbs), with little effect on the overall trend (Q4 vs. Q1 OR=2.5 CI=1.4-4.6 p-trend=&lt;0.0001).
Conclusions: In the present study, those with higher serum concentrations of DBP were at increased risk of RCC, which differs from previously-published findings. Further research is necessary to determine the true
association between DBP and risk of RCC, and whether different DBP phenotypes via GC variation may have different associations with risk of RCC.
Note: This abstract was not presented at the meeting.
Citation Format: Tyler B. Kratzer, Alison M. Mondul, Stephanie J. Weinstein, Demetrius Albanes. Vitamin D binding protein and risk of renal cell carcinoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 609.
Abstract 615: Roles of XRCC1 genetic polymorphism in head and neck cancer patients receiving radiation therapy in Taiwan
Authors: Huang Shiang-Fu , Chien Huei-Tzu , Liao Chun-Ta , Wang Hung-Ming , Wang Yuan-Hung 
Published: August 2019

Abstract
In Taiwan, oral cancer (including sub-sites in the oral cavity, oropharynx and hypopharynx) is the fourth most common cancer in men. The incidence of oral cancer still increased in the past decade. Oxidative stress generated from cigarette smoking, AQ chewing and alcohol drinking was shown to contribute to oral cancer development. The oxidative stress associated DNA lesions are repaired via the DNA base excision repair (BER) pathway. In constrast, radiation therapy was an important treatment modality either as primary or adjuvant in these patients. Ionizing radiation induced DNA damage was also repaired by BER related mechanisms. To investigate the role of BER genes XRCC1 in patients receiving radiation therapy in Taiwan, a comprehensive study on evaluation of polymorphisms of XRCC1 genes was carried out in 753 oral cancer male cases received radiation therapy as primary or adjuvant treatment. Patients with XRCC1 194Arg, XRCC1 280Arg, and XRCC1399Gln homozygous genotypes had worse disease-free survival (p = 0.015, p = 0.587 and p = 0.013, respectively). A linkage disequilibrium exists between XRCC1 194Arg and XRCC1 399Gln genotyping. We further investigated the influence of XRCC1 194Arg and XRCC1 399Gln haplotype in the radiation effects in oral cancer patients. XRCC1 194 Arg/Arg homozygous and its combination with XRCC1 399 Arg/Gln genotyping were selected. We found that the XRCC1 194Arg/Arg and XRCC1 399Gln/Gln haplotype had the worse survival (p = 0.022, ). Multivariate Cox regression adjusting tumor stage, lymph node metastasis and tumor differentiation confirmed that XRCC1 194Arg and XRCC1 399Gln haplotype was an independent prognostic factor for oral cancer receiving radiation therapy. These indicated that XRCC1 194Arg and XRCC1 399Gln genotypes had adverse influence in oral cancer patients receiving radiation therapy. XRCC1 194Arg and XRCC1 399Gln haplotype predicts poor prognosis in these patients.
Citation Format: Shiang-Fu Huang, Huei-Tzu Chien, Chun-Ta Liao, Hung-Ming Wang, Yuan-Hung Wang. Roles of XRCC1 genetic polymorphism in head and neck cancer patients receiving radiation therapy in Taiwan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 615.
Abstract 62: HIC1 inhibits cells metastasis via epithelial-mesenchymal transition in esophageal squamous cell carcinoma
Authors: Sha Beibei , Chen Ping , Liu Xingge , Hu Xuanyu , Li Miaomiao , Li Pei 
Published: August 2019

Abstract
Invasion and metastasis are the main causes of death in patients with esophageal squamous cell carcinoma (ESCC). Epithelial-mesenchymal transition (EMT) has been reported to be closely related with tumor metastasis. Although HIC1 (hypermethylated in cancer 1) gene has been observed to be epigenetically modified in many cancers, its intrinsic role and mechanism in ESCC metastasis, especially in EMT, remains unclear. Our previous study showed that hypermethylation of the HIC1 promoter markedly elevated in metastatic ESCC tissues compared with primary and adjacent normal tissues and it was associated with poor patients’ survival. In the present study, we used immunohistochemistry (IHC) to detect the expression of HIC1 in ESCC tissues and adjacent normal tissues, and the results showed that HIC1 was down-expressed in ESCC tissues and overexpressed in adjacent normal tissues. Results from trans-well-migration and wound healing experiments showed that overexpression of HIC1 in ESCC cells (KYSE 30) can reduce cell migration and metastasis behavior. Moreover, Western blot showed that overexpression of HIC1 could down-regulate EphA2 expression, simultaneously induced the markers of EMT target changed, in which E-cadherin was observed up-regulated, Snail and Vimentin were down-regulated. In summary, our results suggests that HIC1 may regulate EphA2-SirT1-P53 signaling pathway to mitigate ESCC aggressiveness.
Note: This abstract was not presented at the meeting.
Citation Format: Beibei Sha, Ping Chen, Xingge Liu, Xuanyu Hu, Miaomiao Li, Pei Li. HIC1 inhibits cells metastasis via epithelial-mesenchymal transition in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 62.