bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B12: HPV-positive tumor cell lines exhibit major alterations in Toll-like receptor pathways and depend on HMGB1 expression
Authors: Morale Mirian Galliote , Abjaude Walason da Silva , Silva Aline Montenegro da , Villa Luisa Lina , Boccardo Enrique
Published: May 2019

Cervical cancer is one of the leading causes of cancer death in women worldwide. Persistent infection with high-risk human papillomavirus (HPV) types is the main risk factor for the development of cervical cancer precursor lesions and is usually characterized by innate immune system evasion. The innate immune system is the first line of defense against pathogens and homeostatic changes. Toll-like receptors (TLR) are a family of membrane proteins that actively participate in this process by recognizing molecular patterns derived from pathogens and from cellular danger signals. Alterations in TLR expression and activation may be important for the control of HPV infections and could play a role in the progression of HPV-associated lesions and cancers. In the present study, we analyzed the expression of 84 genes involved in TLR signaling pathways in cervical cancer cell lines and primary human keratinocytes. We observed that 80% of the differentially expressed genes were downregulated in cervical cancer cell lines relative to normal keratinocytes. Major alterations were detected in genes coding for several TLR signaling proteins, including adaptor molecules MyD88 and SARM1, NFκB activation complex components such as Ube2N and TRAF6, and effector proteins such as HMGB1. Specifically, HMGB1, a protein related to stimulation of inflammation after TLR activation, showed increased expression levels in the HPV-positive cell lines HeLa and SiHa relative to normal keratinocytes. HMGB1 silencing also reduced cell viability, proliferation, and colony formation capacity of cervical cancer cell lines. In addition, silenced cervical cancer cell lines exhibited increased activated caspase-3 levels and hypodiploid cell population suggestive of apoptosis triggering. HPV infection may interfere with TLR pathways at different levels, resulting in the impairment of their activation and function and potentially leading to innate immune system evasion. Our results suggest that TLR pathway proteins such as TLR4, SARM1, and HMGB1 may play other roles related to tumor development. In conclusion, HMGB1 is a key factor in the survival of HPV-positive tumor cells, which warrants further studies to evaluate its potential as a therapeutic target or tumor biomarker.

Citation Format: Mirian Galliote Morale, Walason da Silva Abjaude, Aline Montenegro da Silva, Luisa Lina Villa, Enrique Boccardo. HPV-positive tumor cell lines exhibit major alterations in Toll-like receptor pathways and depend on HMGB1 expression [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B12.
Abstract B34: Pyrimidobenzimidazoles as a potential new drug to treat human melanoma
Authors: Azevedo Jéssica Gonçalves , Schultz Iago Carvalho , Santos Jacqueline Fraga de Souza , Maria-Engler Silvya Stuchi , Lenz Guido , Wink Marcia Rosângela
Published: May 2019

Melanoma is the most aggressive skin tumor due to its high capacity to metastasize and resistance to therapy, leading to poor prognosis and high mortality rates. Thus, the aim of this study was to investigate a possible antitumoral action of pyrimidobenzimidazole compounds in human melanoma lineages, SK-Mel-103, SK-Mel-28, and SK-Mel-28 resistant to vemurafenib. Using acute treatment (72 hours) it was possible to select two, among the seven compounds tested, by their effectiveness in decrease the cell viability, by MTT assay, in low concentrations. Further, using chronic assay (120 hours) it was possible to find the IC50 of the best compounds, PBZs 1 and 4. For cell line SK-Mel-103 the IC50 value was 3.2 µM and 4.0 µM, for the two more potent compounds respectively, and for cell line SK-Mel-28 IC50 of 9.7 µM and 9.6 µM was obtained for PBZ01 and PBZ04, respectively. These compounds, alone or in combination with DTIC, were used to analyze the cumulative population doubling, in an attempt to simulate the treatment cycle used for patients. The results show that PBZs 1 and 4, especially when in combination with dacarbazine, were able to cause a significant decrease in the population growth rate and in the number of colonies in clonogenic assay, of the SK-Mel-28, better than dacarbazine alone and in lower concentration. Also, it is important to highlight that the effect of PBZs was selective to melanoma, considering that it did not cause relevant effect in melanocyte and in the proliferative nontumoral cell line, MRC5. The cell cycle analysis showed that the treatment alters the cell complexity, increasing the size (FSC) and granularity (SSC). Furthermore, when vemurafenib-resistant cells were treated with PBZ (cotreatment with vemurafenib), there were a population decrease in the population doubling assay more than vemurafenib alone. These results are important and encourage the study of the mechanism by which these compounds affect the melanomas' viability as well as the development of a preclinical model to confirm their effectiveness in vivo.

Citation Format: Jéssica Gonçalves Azevedo, Iago Carvalho Schultz, Jacqueline Fraga de Souza Santos, Silvya Stuchi Maria-Engler, Guido Lenz, Marcia Rosângela Wink. Pyrimidobenzimidazoles as a potential new drug to treat human melanoma [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B34.
Abstract B41: Transcriptome and proteome analyses of MCF7 cells with different expression profile of SPARC (secreted protein acidic in rich in cysteine) in the presence and absence of docetaxel
Authors: Pavanelli Ana Carolina , Barboza Luciana Pizzatti , Abdelhay Eliana Saul Furquim Werneck , Nagai Maria Aparecida
Published: May 2019

The SPARC (secreted protein, acidic, cysteine-rich) gene encodes a 32kDa protein that belongs to a family of matricellular proteins, which interact with cell-surface receptors, growth factors, and the ECM (extracellular matrix) components. SPARC plays a role in tissue remodeling, cell migration, angiogenesis, embryonic development, tumorigenesis, and chemosensitivity. Docetaxel is an effective chemotherapeutic drug for the treatment of advanced breast cancer. However, a considerable proportion of breast cancer patients do not respond positively to docetaxel. In a previous study, we identified SPARC as differentially expressed in mammary epithelial cells expressing different levels of HER-2. In the present study, we evaluate the effects of SPARC overexpression on the sensitivity of breast cancer cells to docetaxel. MCF7 cells were transfected with the expression vector pCMV6-SPARC or pCMV6-Neo. Real-time PCR, Western blot, and immunofluorescence were used to characterize the clones overexpressing SPARC. Using cDNA microarray and label-free approach for quantitative proteomic analysis, we evaluated the transcriptome and proteome changes in the comparison of the MCF7 cell control and overexpressing SPARC before and after docetaxel treatment. Several differentially expressed genes were identified as potentially involved in SPARC-mediated chemosensitivity to docetaxel. Among the molecular interaction networks from the differentially expressed proteins, extracellular matrix and cytoskeleton remodeling were the top pathway map observed in the comparison between MCF7 cells overexpressing SPARC and the control cells before docetaxel treatment. GTP metabolism pathway was the top pathway map observed in the comparison between MCF7 cells overexpressing SPARC and the control cells after docetaxel treatment. Transcriptome and proteome integrated data resulted in forty commonly up- and downregulated genes, with the WNT pathway represented among them. Our findings suggest that SPARC expression can influence docetaxel sensitivity in MCF7 cells by modulating genes involved in diverse biologic process that might be related to drug sensitivity. (Supported by Fapesp and CNPq.)

Citation Format: Ana Carolina Pavanelli, Luciana Pizzatti Barboza, Eliana Saul Furquim Werneck Abdelhay, Maria Aparecida Nagai. Transcriptome and proteome analyses of MCF7 cells with different expression profile of SPARC (secreted protein acidic in rich in cysteine) in the presence and absence of docetaxel [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B41.
Abstract B59: Role of Dicer on human melanoma progression and resistance
Authors: Victo Nathalia Cruz de , Adjemian Sandy , Nunes Romulo dos Santos Sobreira , Volpini Rildo Aparecido , Giavina-Bianchi Mara Huffenbaecher , Neto Cyro Festa , Câmara Niels Olsen Saraiva , Amarante-Mendes Gustavo Pessini , Jacysyn Jacqueline de Fátima
Published: May 2019

Melanoma is a serious public health problem that affects the population of Latin America and is increasing rapidly compared to other types of tumors. The growth or change in this type of tumor is progressive and is in the horizontal and/or vertical direction. Breslow thickness (vertical staging) is the tumor thickness in the dermis where patients with lesion thickness less than 0.75 mm have good prognosis, unlike lesion thickness larger than 3 mm. This stage is classified into T (primary tumor): T0 (with no evidence of primary tumor); Tis (in situ melanoma); T1 (1 mm); T2 (1.01 to 2 mm); T3 (2.01 to 4 mm); and T4 (above 4 mm). Knowing some molecular markers of melanoma is essential for the identification of genetically predisposed individuals, as well as early detection of the disease. Recent works has demonstrated that microRNAs may be involved in modulation of melanoma. Dicer is an essential member of the RNase III family which controls maturation of miRNAs in the cytoplasm from microRNA precursors (pre-miRNAs). The upregulation of Dicer is associated with aggressive features and proliferation of melanoma and no other skin tumors such as carcinomas and sarcoma. In our present study, we found that the knockdown expression of Dicer using the CRISPR/CAS9 in melanoma cell line induced more chemosensitivity to cisplatin and these changes correlated with the downregulation of Dicer. We examined the consequence of Dicer knockdown on melanoma cell proliferation, clonogenic assays, and overall survival. We also compared Dicer in tissue from patients diagnosed with melanoma in different stages with the prognosis of these patients, suggesting that the reduction in Dicer expression is associated with melanoma progression. Considering the fundamental and multiple biologic roles of Dicer in various cellular processes, our results suggest that modulation of Dicer in melanoma should become a promising therapeutic candidate for further clinical application.

Note: This abstract was not presented at the conference.

Citation Format: Nathalia Cruz de Victo, Sandy Adjemian, Romulo dos Santos Sobreira Nunes, Rildo Aparecido Volpini, Mara Huffenbaecher Giavina-Bianchi, Cyro Festa Neto, Niels Olsen Saraiva Câmara, Gustavo Pessini Amarante-Mendes, Jacqueline de Fátima Jacysyn. Role of Dicer on human melanoma progression and resistance [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B59.
Abstract B66: P53 expression and survivin subcellular localization contribute to the diagnosis and prognosis of patients with astrocytomas
Authors: Faccion Roberta Soares , Bernardo Paula Sabbo , Lopes Giselle Pinto de Faria , Bastos Leonardo Soares , Teixeira Cristina Lordello , Oliveira José Antonio de , Fernades Priscila Valverde , Dubois Luiz Gustavo , Chimelli Leila Maria , Maia Raquel Ciuvalschi
Published: May 2019

Astrocytomas are the most frequent subtype of primary central nervous system (CNS) tumors. Diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma (GB–grade IV) are diffuse infiltrating astrocytomas derived from glial cells or precursors. Despite continuous efforts from the scientific community, these tumors still have a poor prognosis. Histologic grading is still challenging, and prognostic factors are still limited to age and tumor grade. Biomarkers that could improve histologic grading, especially that could help differentiate grade III from the other subtypes, and/or serve as prognostic factors are much needed. Furthermore, the relationship between survivin and p53 in astrocytoma progression and survival is still controversial. The present study aims to investigate the role of these proteins in the accuracy of histologic grading of diffuse astrocytic tumors and treatment response. One hundred thirty-five formalin-fixed, paraffin-embedded astrocytoma samples were obtained from patients. Tumor samples were reviewed and stained for survivin and p53 by immunohistochemistry, and the staining levels and survivin subcellular localization were correlated with histologic grading and patient outcomes. Age and histologic grade were the only clinical features that had a prognostic impact. High nuclear survivin and p53 correlated with grade III astrocytomas. High cytoplasmic survivin correlated with GB. Furthermore, patients whose tumors expressed high cytoplasmic survivin, high nuclear surviving, or high p53 and did not receive radiotherapy had worse short-term and long-term survival. Our results suggest that survivin subcellular localization and p53 expression improve the accuracy of histologic grading. Patients whose tumors overexpress these proteins benefit from radiotherapy regardless of age and histologic grade. Furthermore, patients whose tumors overexpress survivin may benefit from novel targeted antisurvivin treatment.

Citation Format: Roberta Soares Faccion*, Paula Sabbo Bernardo*, Giselle Pinto de Faria Lopes*, Leonardo Soares Bastos, Cristina Lordello Teixeira, José Antonio de Oliveira, Priscila Valverde Fernades, Luiz Gustavo Dubois, Leila Maria Chimelli, Raquel Ciuvalschi Maia. P53 expression and survivin subcellular localization contribute to the diagnosis and prognosis of patients with astrocytomas [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B66.
Abstract B81: SUMO and ubiquitin post-transcriptional modifications regulate the stability of the IRF2BP2 transcriptional cofactor
Authors: Ramalho-Oliveira Renata , Rajão Matheus , Souza Vilenia , Viola João P. B.
Published: May 2019

IRF2BP2 (Interferon Regulatory Factor 2 Binding Protein 2) protein is a gene expression regulator, acting as transcriptional cofactor. IRF2BP2 acts in different cellular process including DNA damage repair, apoptosis, and immune response. Even though a few targets are known, there are several putative IRF2BP2-regulated genes. Novel evidence suggests that IRF2BP2 plays central functions in gene expression regulation. Recently, our group characterized the IRF2BP2 as an NFAT1 transcriptional repressor. To further understand the IRF2BP2 role in cellular functions, this work aims to clarify mechanisms involved in IRF2BP2 regulation. Initially, we performed a yeast two-hybrid screening to identify IRF2BP2-interacting proteins using IRF2BP2 as a bait. Among others, the UBE2I SUMO-conjugating enzyme and SUMO1 were identified as possible IRF2BP2 partners. Confocal microscopy demonstrated that these proteins colocalized in the nucleus. Furthermore, analysis by His-pull down and FRET confirmed the interaction between IRF2BP2 and UBE2I. Moreover, yeast two-hybrid assays showed that the interaction occurs independently of N-terminus C4-zinc finger of IRF2BP2. Subsequently, we observed that IRF2BP2 protein is SUMO1-modified in vivo. Our results indicated that three SUMO-1 molecules are added at three lysine residues. Finally, we demonstrated that the SUMO-modification favors disperse nuclear IRF2BP2 distribution and does not affect its repressor activity on NFAT1 transcription factor. Nevertheless, different assays showed that IRF2BP2 has a long half-life and that SUMO-1 conjugation increases IRF2BP2 protein stability. On the other hand, we showed that IRF2BP2 protein is also poliubiquitinated. Interestingly, the modifications observed were mainly Lys6- and Lys11-linked ubiquitin chains. Moreover, our data suggest that IRF2BP2 is not degraded by the proteasome and that Lys11-linked chain may constitute a signal for lysosome degradation. In conclusion, SUMO-modification upregulates IRF2BP2 protein stability. However, the consequences of Lys6 and Lys11 atypical ubiquitin chains linkage remain to be elucidated.

Citation Format: Renata Ramalho-Oliveira, Matheus Rajão, Vilenia Souza, João P. B. Viola. SUMO and ubiquitin post-transcriptional modifications regulate the stability of the IRF2BP2 transcriptional cofactor [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B81.
Abstract IA04: Opportunities for translational and discovery research: Next-Gen genomics
Authors: Hahn William C.
Published: May 2019

Recent advances in genomics now make it possible to consider enumerating all of the genetic lesions in specific cancers. These approaches will yield critical information regarding the identification, number, and types of alterations found in human tumors and are increasingly being applied prospectively to patient samples in the clinic. We have deployed an enterprise level cancer genotyping test, PROFILE, for all cancer patients at the Brigham and Women's Hospital and the Dana-Farber Cancer Institute. This initial approach has already provided insight into how to integrate such efforts into clinical care. New technologies now also allow the interrogation of tumors from circulating nucleic acids. At the same time, complementary efforts to identify new targets and therapeutics are being used to increase the repertoire of agents to operationalize precision cancer medicine.

Citation Format: William C. Hahn. Opportunities for translational and discovery research: Next-Gen genomics [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA04.
Abstract IA07: ER stress responses as new immune checkpoints in cancer
Authors: Cubillos-Ruiz Juan R.
Published: May 2019

Harnessing the intrinsic ability of our immune system to eliminate malignant cells represents the most promising anticancer strategy since the development of chemotherapy. However, cancer cells employ diverse strategies that enable them to thrive under adverse conditions while simultaneously inhibiting antitumor immune responses. Diverse microenvironmental conditions within tumor masses, such as hypoxia and nutrient deprivation, disturb the protein-folding capacity of the endoplasmic reticulum (ER) and provoke a cellular state of “ER stress.” Sustained activation of ER stress sensors endows malignant cells with greater tumorigenic, metastatic, and drug-resistant capacity. Interestingly, recent studies demonstrate that tumor-infiltrating immune cells also experience ER stress, and that this process causes severe immune cell dysfunction and immunosuppression in cancer hosts. Aggressive ovarian cancers, for instance, cripple protective immunity by inducing excessive activation of the IRE1-XBP1 arm of the ER stress in tumor-associated dendritic cells. These recent findings uncover a new immunoregulatory role for ER stress in the tumor microenvironment and suggest that targeting aberrant ER stress responses may represent a new strategy to control tumor-induced immunosuppression and enhance the effectiveness of emerging immunotherapies.

Citation Format: Juan R. Cubillos-Ruiz. ER stress responses as new immune checkpoints in cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA07.
Abstract IA09: The dynamics of cancer cell heterogeneity
Authors: Lenz Guido , Onzi Giovana R. , Pereira Luiza C. , Breitenbach Karen , Lenz Luana s. , Leonardo Brunnet G. , Dalsin Eloisa
Published: May 2019

Cancer cells behave heterogeneously regarding proliferation and survival to therapy. This heterogeneity is not static, fluctuating over time with different frequencies and amplitudes. Here we set out to measure the dynamics of the proliferative and tolerant phenotype of untreated and glioma cell lines treated with temozolomide (TMZ) and/or cisplatin. For this, we followed single clones of glioma cells and measured the number of cells in each clone for three consecutive time points. The larger the clone, the more similar is their proliferation rate among clones of the same size, indicating that division shuffled the proliferation phenotypes of the cells. The response to TMZ or cisplatin is highly variable in small clones, but this response becomes more homogeneous with the increase in colony size, due to small heritability of the phenotype that controls the response to these drugs. The reduction in variance in relation to colony size is twice as high for the response to TMZ or cisplatin when compared to untreated colonies. Inhibition of HDAC prior to treatment freezes the variability of the response to TMZ, but not cisplatin, so that small and large colonies respond with the same variance. This indicates that the response to TMZ is phenocopied over generations of cells in the presence of HDAC inhibition, but rapidly fluctuates in its absence. With the aid of a computational model of the mother-daughter and sister-sister differences in proliferation and survival in the presence of the chemotherapeutic drugs, we described the dynamics of these phenotypes in response to TMZ, cisplatin, and their combination. We conclude that the proliferative and response to chemotherapeutic phenotypes fluctuate with time and can be stabilized with inhibition of HDACs, with important insights into drug combination to improve therapeutic potential.

Citation Format: Guido Lenz, Giovana R. Onzi, Luiza C. Pereira, Karen Breitenbach, Luana s. Lenz, Brunnet G. Leonardo, Eloisa Dalsin. The dynamics of cancer cell heterogeneity [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA09.
Abstract IA20: Targeting DNA repair in cancer therapy
Authors: D'Andrea Alan D.
Published: May 2019

Human cancer cells have genomic instability resulting from germline or acquired defects in DNA repair. One DNA repair pathway—the Fanconi anemia/BRCA pathway (D'Andrea A. N Engl J Med 2010;362:1909)—is defective in many human cancers, including breast, ovarian, and pancreatic neoplasms. Disruption of the FA/BRCA pathway results in the characteristic chromosome instability and radiation/crosslinker hypersensitivity of these tumors. In general, loss of one DNA repair pathway often leads to hyperdependence on another pathway for tumor cell survival. This hyperdependence offers a unique opportunity for the development of anticancer therapeutics. For instance, FA/BRCA pathway-deficient tumors are hyperdependent on base excision repair (BER) and, accordingly, these tumors are hypersensitive to single-agent treatment with PARP1 inhibitors, which block BER, or with ATM inhibitors. Our research program is focused on profiling the FA/BRCA pathway and the other five major DNA repair pathways in tumor cells (Kennedy RD, D'Andrea A. J Clin Oncol 2006;24:3799, 2006). Each DNA repair pathway has a characteristic biomarker and repairs a specific type of DNA lesion. By profiling these pathways in primary tumor samples with activation-specific antibodies to DNA repair proteins, we have been able (1) to predict the sensitivity of tumors to conventional chemotherapy and radiation; (2) to subset tumors for their sensitivity to novel classes of DNA repair inhibitors, (i.e., PARP1, Chk1, ATM, and proteasome inhibitors); and (3) to screen for new small-molecule inhibitors of other DNA repair pathways. This combination of novel DNA repair inhibitors, conventional DNA-damaging agents, and DNA repair biomarkers offers new opportunities for developing more effective anticancer therapy. In my presentation, I will also discuss novel approaches to sensitizing triple negative breast cancers (TNBCs) and ovarian tumors (OCs) to PARP1 inhibitors. We have previously shown that exposure of these tumors to either a CDK inhibitor or a proteasome inhibitor can block homologous recombination (HR) repair and thereby sensitize the tumor cells to PARP1 inhibitor. The CDK inhibitor/PARP1 inhibitor combination has been examined in orthotopic primary TNBC and OC xenograft models. Finally, we have identified an additional PARP1-dependent DNA repair mechanism in TNBCs and OCs. This pathway is driven by a novel alternative end-joining polymerase, POLθ. These tumors are hypersensitive to inhibitors of this new pathway, suggesting a new target for DNA repair therapies.

Citation Format: Alan D. D'Andrea. Targeting DNA repair in cancer therapy [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA20.
Abstract IA24: Targeting DNA repair dysfunction in advanced prostate cancer
Authors: Knudsen Karen E.
Published: May 2019

Prostatic adenocarcinoma (PCa) is the 2nd leading cause of cancer death in US men. Organ-confined PCa can be effectively managed, but there is no durable treatment for advanced disease. Advanced PCa is treated through androgen deprivation therapy, often coupled with direct AR antagonists, as PCa is exquisitely dependent on androgen receptor (AR) activity for survival. Furthermore, recent studies identified AR as a major effector of DNA repair, manifest through the ability of the receptor to regulate DNAPK expression and activity. While AR-directed therapeutics effectively suppress the proproliferative, prosurvival, and pro-DNA repair functions of AR and result in tumor remission, relapse is common. Recurrent disease arises largely due to resurgent AR activity with 2-3 years, and there is no cure for this castration-resistant phase (CRPC, castration-resistant PCa). Thus, there is a significant need to develop new means for targeting recurrent AR activity or develop adjuvant therapies in advanced PCa.

Emerging data from our laboratory and others strongly support the concept that alterations in DNA damage repair (DDR) pathways are more common than previously thought in sporadic PCa, and that alterations in these pathways may accord new, more effective means of therapeutic intervention. New studies to be discussed will address underlying mechanisms of action with regard to the pathway, and identify clinically actionable ramifications of DNA repair dysfunction. Major concepts to be considered include new discoveries regarding PARP1 function and activity in lethal disease, and that a newly identified gene signature of PARP1-regulated networks is associated with poor outcome. Further, mechanistic investigation revealed new insight into the means by which PARP1 inhibitors likely function as single agents in advanced prostate cancer, manifest through both DNA repair and transcriptional regulatory functions. Other major concepts to be considered include the differential roles of DNAPK in controlling PCa progression. Findings to be discussed strongly support a model wherein selected DDR pathways can be developed as therapeutic targets to tailor treatment for prostate cancer and improve outcome for advanced disease.

Citation Format: Karen E. Knudsen. Targeting DNA repair dysfunction in advanced prostate cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA24.
Abstract IA27: Tumor suppressor and tumor maintenance genes
Authors: Lowe Scott W.
Published: May 2019

Cancer arises through an evolutionary process whereby normal cells acquire mutations that erode growth controls, leading to the expansion of aberrantly proliferating cells. Such mutations activate oncogenes or inactivate tumor suppressors, each bestowing new capabilities to emerging tumors. Still, cancer is not an inevitable consequence of mutation but is instead kept in check by intrinsic tumor-suppressor programs activated in damaged cells. Accordingly, our laboratory studies such mechanisms in order to reveal key regulatory nodes controlling basic cellular processes and to identify the strategies nature uses to combat cancer. More recently, our interests have expanded to explore the action of tumor maintenance genes---those genes needed to sustain the proliferation and survival of malignant cancer cells---with the goal of identifying cancer vulnerabilities and therapeutic targets. Our approach combines powerful mouse models, genetics, and genomics in a coordinated manner that allows us to study tumor suppressor and tumor maintenance networks in a comprehensive way. Recent efforts to combine these tools towards the production of flexible and accurate mouse models and their subsequent use to identify and characterize tumor suppressor and tumor maintenance genes will be discussed.

Citation Format: Scott W. Lowe. Tumor suppressor and tumor maintenance genes [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA27.
Abstract A03: Tumorigenesis involving expansion of CD24 high CD61 cells is abrogated by tamoxifen in mouse models of luminal breast cancer
Authors: Zhdankin Olga , Bomier Melanie , Parke Donna , Holy Jon , Rose-Hellekant Teresa
Published: May 2019

The cells within the mammary gland that are altered by tamoxifen chemoprevention and correlate with abrogation of tumorigenesis are unknown. We have documented that a 60 day tamoxifen chemopreventive regimen reduces tumor incidence in NRL-TGFalpha and MMTV-c-neu mouse models of luminal breast cancer. For this study our goal was to identify the aberrant and/or altered mammary cell subpopulations typically found in the mammary gland of TGFalpha and c-neu mice and determine the effect of tamoxifen on their relative quantity. Mammary cell subpopulations were evaluated using flow cytometric analysis by labeling lineage negative cells with CD24, CD61 and CD49f fluorescently tagged antibodies. TGFalpha mice developed an expanded CD24high CD61positive fraction of cells coinciding with hyperplasia and tumor presence. Prior to tumor development c-neu mice had an expanded CD24medium CD49f high cell fraction and by the time tumors developed, both nontumorous glands and tumors also displayed an expanded CD24high CD61positive cell fraction. Mammary glands from mice that received a 60 day tamoxifen chemopreventive regimen did not display expanded cell fractions compared to placebo treated mice in both models. Our data indicate that tamoxifen chemoprevention abrogates tumorigenesis that involves expansion of CD24high CD61positive cells. Further investigations into tamoxifen effects on mammary cell subpopulations is critical for a clearer understanding of the utility of tamoxifen and other estrogen receptor modulators as chemopreventives.

Citation Format: Olga Zhdankin, Melanie Bomier, Donna Parke, Jon Holy, Teresa Rose-Hellekant. Tumorigenesis involving expansion of CD24 high CD61 cells is abrogated by tamoxifen in mouse models of luminal breast cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A03.
Abstract A22: Development and characterization of an oral cancer cell line resist to the cytotoxic effects of the green tea catechin, (-)-Epigallocatechin-3-gallate
Authors: Tao Ling , Chen Jennifer W. , Park Jong-Yung , Sae-tan Sudathip , Lambert Joshua D.
Published: May 2019

(-)-Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea (Camellia sinensis). Although many studies have demonstrated its cancer chemopreventive and chemotherapeutic effects, the potential for development of EGCG resistance in cancer cells has not been well-studied. The purpose of this study was to develop and characterize an EGCG-resistant oral squamous carcinoma cell line to understand potential mechanisms of resistance to the cytotoxic effects of EGCG. Exposure of oral squamous carcinoma (SCC-25) cells to gradually increasing concentrations of EGCG (10 – 75 μM) resulted in emergence of an EGCG-resistant phenotype (SCC-25E75R). SCC-25E75R cells were significantly resistant to EGCG-induced growth inhibition compared to SCC-25 cells (IC50=157 μM vs 70 μM). Treatment of SCC-25E75R cells with 75 μM EGCG caused a 34% increase in apoptosis compared to a 200% increase in SCC-25 parental cells treated with the same concentration. Microarray analysis showed that under untreated conditions, 73 genes were differentially expressed (≥4 fold change, p<0.05) between SCC-25 and SCC-25E75R cells. The resistant cells have lower expression levels of tumor suppressor genes including absent in melanoma 2 (AIM) and inhibitor of DNA binding 4 (ID4) suggesting the resistance to tumor inhibition. EGCG treatment (75 μM) induced significant changes (≥1.75 fold change, p<0.05) in 52 genes in SCC-25 and 164 genes in SCC-25E75R cells. Among these, 42 genes were found to be differentially regulated by EGCG between the two cell lines. For example, EGCG induced the DNA-damage-inducible transcript 3 (DDIT3) and heat shock 70kDa protein 5 (HSPA5) in resistant cells more significantly than in sensitive cells. This may result in a greater anti-apoptotic protein in SCC-25E75R cells and thereby confirm resistance to the effects of EGCG. In conclusion, this work represents a preliminary investigation into potential mechanisms of resistance to EGCG, and may be useful in understanding responsiveness of oral cancer, as well as other cancer types, to the treatment effects of EGCG.

Citation Format: Ling Tao, Jennifer W. Chen, Jong-Yung Park, Sudathip Sae-tan, Joshua D. Lambert. Development and characterization of an oral cancer cell line resist to the cytotoxic effects of the green tea catechin, (-)-Epigallocatechin-3-gallate. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A22.
Abstract B12: The co-location of academia with the community in addressing cancer health disparities: A new model of partnerships for environmental public health
Authors: Wallington Sherrie Flynt , Dash Chiranjeev , Hamilton Rhonda , Dodson Everett , Adams-Campbell Lucile L.
Published: May 2019

Environmental factors play an important and explanatory role in health disparities. Research suggests that a community should be an integral part of the process of solving community problems. Consequently, there has been a shift from traditional academic research to more community participatory approaches. To our knowledge none of these approaches have examined the role of academic co-locations (multiple site locations) as part of a community-level cancer prevention and disparities approach. Our co-location strategy involves exporting faculty and staff, clinical trials, interventions, outreach, education, and research from Georgetown University's main campus to a newly established office site located in Southeast, DC, a medically underserved area. Using the environmental focus group study as a case example of the impact of our co-location strategy, we seek to put forward an academic co-location definition and framework for implementation. Our findings show that co-location is a viable strategy that should be considered as part of a multifaceted approach in building and sustaining collaborative partnerships and research capacity, particularly within minority underserved communities. Focus group themes emerged around six topical areas: (1) the concept of environment, (2) perception of pollution, (3) perceptions of water quality, 4) perceptions of air quality, 5) health issues related environmental pollutants, (6) personal and community environment, and 7) environmental information received. Our co-location strategy was also associated with the following outcomes: beneficial in establishing trust, respect, accessibility, and success in study accrual and retention. Co-location benefits, challenges, and lessons learned are also discussed.

Citation Format: Sherrie Flynt Wallington, Chiranjeev Dash, Rhonda Hamilton, Everett Dodson, Lucile L. Adams-Campbell. The co-location of academia with the community in addressing cancer health disparities: A new model of partnerships for environmental public health. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B12.
Abstract B17: The evaluation of breast cancer chemoprevention uptake in a high-risk cohort
Authors: Nimmons Scott , Bambhroliya Arvind , Teresa Bevers , Ying Jun , Brown Powel , Cook Elise , Newman Lonzetta , Brewster Abenaa
Published: May 2019

Background: Population-based estimates in the United States indicate that uptake of breast cancer chemoprevention has remained low despite more than a decade of scientific evidence demonstrating clinical benefit. The objective of our study was to evaluate the uptake of breast cancer chemoprevention in a high-risk clinical setting. Methods: We evaluated the uptake of chemoprevention (tamoxifen, raloxifene or exemestane) 2007 to 2011 among 1,151 healthy women at high risk of breast cancer who were seen at the MD Anderson Cancer Center and enrolled in a high-risk breast cancer cohort. We used stepwise multivariable logistic regression to determine patient-related factors associated with use of chemoprevention. Results: Mean age of the cohort was 60 years; 85% of the women were white, 6% black and 9% of other ethnicities. Chemoprevention use was reported among 29% of women (n=340) (22% tamoxifen, 7% raloxifene). Among women with a history of lobular carcinoma in situ (LCIS), a proliferative breast lesion or Gail 5-year risk ≥1.66%, the uptake of chemoprevention was 52%, 42% and 14%, respectively. In multivariable analysis, history of osteoporosis (p=0.0034), prior use of hormone replacement therapy (p=0.0002) and elevated Gail model 5 year risk >3.0% (p=0.003) were positively associated with uptake of chemoprevention. Conclusion: Women seen in a high-risk clinical setting may be more motivated to use chemoprevention and uptake was highest among women with a history of LCIS or a proliferative breast lesion. Individualized strategies are needed to improve breast cancer chemoprevention uptake among different subsets of high-risk patients.

Citation Format: Scott Nimmons, Arvind Bambhroliya, Bevers Teresa, Jun Ying, Powel Brown, Elise Cook, Lonzetta Newman, Abenaa Brewster. The evaluation of breast cancer chemoprevention uptake in a high-risk cohort. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B17.
Abstract B19: Improving initiation of adjuvant hormonal therapy in black women under 50 may contribute towards narrowing racial gaps in breast cancer
Authors: Sheppard Vanessa B. , Isaacs Claudine , Tadesse Mahlet G. , Butler Melissa , Harper Felicity , Hirpa Fikru
Published: May 2019

Background: The advent of adjuvant hormonal therapy has greatly improved breast cancer survival in women with hormonal receptor (HR) positive breast cancer. Unfortunately, racial disparities have been noted in both the uptake of adjuvant hormonal therapy and in women with HR positive breast cancer.

Purpose: In a prospective study, we examined the influence of race, socio-cultural factors, and process of care factors on initiation of adjuvant hormonal therapy.

Methods: Eligible women were newly diagnosed with invasive, non-metastatic hormonal receptor positive (HR) breast cancer. Socio-cultural and healthcare factors were collected via telephone surveys; clinical data were abstracted from charts. Stepwise logistic regression models examined associations between hormonal initiation and study factors.

Results: The sample was 56% Black (n=150) and 44% White (n=120). Overall 70% initiated therapy with Black women <50 having the lowest rate of initiation (51%) among all Black and White age groups. A significant interaction (p= .002) was found between race and age so a stratified race – age composite variable was created. In multivariate models, Black women < 50 years were less likely to initiate therapy compared to Whites ≥50 (OR: .28; 95% CI: .10 to .82), whites <50 (OR: 0.19; 95% CI: 0.05 to 0.68), or compared to blacks ≥50 (OR: .34; 95% CI: 0.12 to 0.96). Women reporting having higher ratings of financial access were more likely to initiate therapy as were those with higher ratings of communication with their providers.

Conclusion: Attention to financial aspects of cancer care and patient-provider communication may be useful points of intervention to improve initiation in patients, particularly Black patients <50 years of age.

Citation Format: Vanessa B. Sheppard, Claudine Isaacs, Mahlet G. Tadesse, Melissa Butler, Felicity Harper, Fikru Hirpa. Improving initiation of adjuvant hormonal therapy in black women under 50 may contribute towards narrowing racial gaps in breast cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B19.
Abstract B22: The synergistic effect of a sulforaphane and maitake mushroom extract combination on the expression of the detoxifying enzymes NQO1 and UGT1A1
Authors: Cornblatt Grace A. , Ownby Stacy , Cornblatt Brian S.
Published: May 2019

Excess estrogen exposure, whether from endogenous estrogen, harmful estrogen metabolites, or exogenous xenoestrogens (e.g. BPA, parabenes, etc.) can be detrimental to overall breast health. Here we describe a novel blend of natural ingredients including sulforaphane and maitake-derived glucans and their effect on detoxifying enzymes capable of diminishing excess estrogens. Sulforaphane, an isothiocyanate found in broccoli seeds and sprouts, results from the hydrolization of a glucosinolate called glucoraphanin by the enzyme myrosinase. In vitro and in vivo studies reveal the ability of sulforaphane to induce Phase 2 detoxifying enzymes (e.g. NAD(P)H:Quinone Oxidoreductase (NQO1) which functions to rid the body of harmful quinone estrogen metabolites and UDP-Glucuronosyltransferase 1-1 (UGT1A1) which has been shown to play a role in the metabolism of Bisphenol-A, an estrogen mimic, via glucoronidation). Previous research involving maitake extracts has largely focused on their immune-boosting properties. We examined the effect of the combination of sulforaphane and maitake-derived glucans on NQO1 and UGT1A1. RAW 246.7 mouse monocyte/macrophages were treated with sulforaphane and maitake mushroom extract alone or in combination. mRNA levels of NQO1 and UGT1A1 were assessed via quantitative RT-PCR revealing a synergistic effect on the induction of both NQO1 and UGT1A1 gene expression. Further, we carried out an in vivo study in rats during which the animals were dosed with sulforaphane, maitake mushroom extract, or the combination for 14 days. The upregulation of UGT1A1 gene expression was greater in the mammary glands of the rats given the combination of sulforaphane and maitake extract compared to those receiving either agent alone. This study demonstrates the synergistic effect of the combination of sulforaphane and a maitake extract on the gene expression of Phase 2 detoxifying enzymes NQO1 and UGT1A1 suggesting the agents together may be effective at detoxifying the body of excess estrogens and promoting breast health.

Citation Format: Grace A. Cornblatt, Stacy Ownby, Brian S. Cornblatt. The synergistic effect of a sulforaphane and maitake mushroom extract combination on the expression of the detoxifying enzymes NQO1 and UGT1A1. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B22.