bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B52: HIF-ZMYND8-BRD4 axis mediates breast cancer progression and metastasis
Authors: Chen Yan , Zhang Bo , Bao Lei , Jin Lai , Yang Mingming , Peng Yan , Wang Jennifer , Wang Chenliang , Zou Xuan , Wang Yingfei , Luo Weibo 
Published: August 2018

Abstract
Metastatic breast cancer is lethal and incurable. The major obstacle to ending this aggressive disease is the absence of definitive prognostic biomarker and effective therapeutic target. Epigenetic dysregulation plays a crucial role in breast cancer metastasis. However, how epigenetic dysregulation under tumor hypoxia stimulates breast cancer progression and metastasis remains unknown.
We recently identified the epigenetic reader ZMYND8 as a novel HIF target gene by analyzing expression changes of 720 epigenetic genes in three microarray gene expression and mRNA sequencing datasets. Analysis of a human breast cancer tissue microarray revealed that ZMYND8 is highly expressed in invasive breast tumors and high levels of ZMYND8 are significantly correlated with poor clinical outcomes in patients with breast cancer. ZMYND8 depletion significantly suppresses colony formation, invasion, and migration of breast cancer cells in vitro, and inhibits breast tumor growth and metastasis in mice. To figure out the underlying mechanism, we performed co-immunoprecipitation, chromatin immunoprecipitation, and quantitative PCR assays and found that ZMYND8 interacts with HIF complex and acetyl lysine 16 of histone H3 at the hypoxia response elements (HREs) to stimulate the expression of HIF target genes LOX, AGR2, AQP1, and VEGFA. HIF is required for ZMYND8-mediated breast cancer growth and metastasis in mice. We further found that p300 binds and acetylates ZMYND8 in breast cancer cells. Acetylated ZMYND8 interacts with the bromodomains of BRD4 and recruits BRD4 to the HREs to stimulate RNA polymerase II phosphorylation and subsequent transcriptional elongation of HIF target genes. ZMYND8 acetylation is necessary and sufficient for breast tumor growth and metastasis in vitro and in mice. Together, these findings indicate that p300-acetylated ZMYND8 mediates breast cancer progression and metastasis by BRD4-dependent activation of HIF.
In summary, ZMYND8 represents a positive-feedback mechanism that amplifies HIF-mediated breast cancer progression and metastasis, and may be a potential epigenetic target for the prognosis and treatment of breast cancer.
Citation Format: Yan Chen, Bo Zhang, Lei Bao, Lai Jin, Mingming Yang, Yan Peng, Jennifer Wang, Chenliang Wang, Xuan Zou, Yingfei Wang, Weibo Luo. HIF-ZMYND8-BRD4 axis mediates breast cancer progression and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B52.
Abstract B59: Multiparametric imaging to evaluate human and mouse breast carcinoma in situ
Authors: Sinha Vidya C. , Yang Fei , Rinkenbaugh Amanda L. , Zhou Xinhui , Zhang Xiaomei , Wistuba Ignacio I. , Piwnica-Worms Helen 
Published: August 2018

Abstract
Our overall goal is to distinguish aggressive from indolent breast cancers by characterizing determinants of breast cancer progression. The detection of early-stage (in situ) neoplastic lesions in the breast has risen dramatically due to widespread mammography. Early detection represents a significant opportunity to intervene and halt the progression of these early lesions to invasive breast cancer. However, our understanding of the natural history of in situ lesions remains limited. Here, we describe our efforts to characterize the microenvironment of DCIS in patient samples and mouse models using a combination of traditional and novel multiplexed immunostaining methods. In particular, we present our early work on applying multispectral fluorescence imaging as well as highly parametric imaging mass cytometry to describe the immune cells surrounding and infiltrating DCIS, with focus on the interaction of these immune cells with each other and the incipient invasive tumor cells. Future studies will be directed at determining if the immune microenvironment of DCIS can identify patients at risk for progression or recurrence so that these patients can be appropriately managed upfront.
Citation Format: Vidya C. Sinha, Fei Yang, Amanda L. Rinkenbaugh, Xinhui Zhou, Xiaomei Zhang, Ignacio I. Wistuba, Helen Piwnica-Worms. Multiparametric imaging to evaluate human and mouse breast carcinoma in situ [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B59.
Abstract B60: Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib
Authors: Mills Caitlin E. , Hafner Marc , Subramanian Kartik , Chen Chen , Boswell Sarah A. , Everley Robert A. , Juric Dejan , Sorger Peter K. 
Published: August 2018

Abstract
The recent introduction of small-molecule inhibitors of cyclin-dependent kinases (CDK) 4/6 to the clinic has improved the treatment of hormone receptor-positive breast cancer, and shown promise in other malignancies. The three clinically used CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are reported to be broadly similar, although recent data suggest that abemaciclib has distinct single-agent activity in patients and a unique toxicity profile. In vitro profiling of the CDK4/6 inhibitors has shown abemaciclib to be more potent on target, but less selective than either palbociclib or ribociclib. We sought to systematically investigate the functional consequences of abemaciclib’s polypharmacology. We used molecular and phenotypic profiling by mRNA sequencing, mass spectrometry-based proteomics, and GR-based dose-response assays to characterize the mechanisms of action of the three CDK4/6 inhibitors. Inhibition of CDKs other than CDK4/6 by abemaciclib resulted in an arrest in the G2 phase of the cell cycle, a prolonged inhibition of growth, and cytotoxicity, even in retinoblastoma protein (pRb)-deficient cells. Abemaciclib elicited unique molecular responses at clinically achievable concentrations that are likely to be therapeutically advantageous and prevented cross-resistance with ribociclib and palbociclib. More generally, we propose that multi-omic approaches are required to fully elucidate the spectrum of targets relevant to drug mechanisms of action in cells, and we expect such understanding to assist in stratifying patient populations and in ordering sequential therapies when resistance arises.
Citation Format: Caitlin E. Mills, Marc Hafner, Kartik Subramanian, Chen Chen, Sarah A. Boswell, Robert A. Everley, Dejan Juric, Peter K. Sorger. Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B60.
Abstract B69: The effects of patient-physician relationships on perceptions of breast cancer treatment in African American women
Authors: Lauray Alexandria N. , Bigatti Silvia 
Published: August 2018

Abstract
According to Indiana.gov, 4,400 new cases of breast cancer are diagnosed in Indiana annually. “During 2008 to 2012, the mortality rates of African American breast cancer patients were almost 40% higher than Caucasian Americans” (Cancer.org), which sheds light on the health disparities African Americans face in the United States. Disparities among cancer patients have not only led to African American women (AAW) being diagnosed in later stages of this disease than their counterparts and thus raising their mortality rates, but AAW tend to be diagnosed with more aggressive forms of cancer such as triple-negative breast cancer, which occurs in 10% to 20% of patients. AAW face many barriers today: limited access to screening services, lack of quality screening equipment, limited access to treatment services, and an unspoken distrust of health care providers. Research indicates that during their breast cancer treatment trajectory, AAW experience delay in initiating chemotherapy after surgery, less satisfaction with treatment, increased symptoms, and lower participation in clinical trials (Mcarthy). Despite this, there is no study that has followed and assessed AAW during the treatment sessions to examine challenges in their lives and their impact. Studies of AAW who have survived breast cancer suggest the need to look not only at factors within the medical care system, but well beyond it into the everyday lives of these women and the resources available to them through social networks and other means to overcome challenges. This project explores themes in the baseline and exit interviews of 38 participants. In their initial interview, we asked questions related to support system, their views of treatment going into the process, and the quality of care that they feel they have received. At the end of treatments, we ask about patient-physician relationships and how the women perceived their care. Women in the study reported the need to readdress concerns with physicians. Patient-physician relationships among AAW diagnosed with breast cancer have been strained and have had a negative impact on patient satisfaction with care.
Note: This abstract was not presented at the conference.
Citation Format: Alexandria N. Lauray, Silvia Bigatti. The effects of patient-physician relationships on perceptions of breast cancer treatment in African American women [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B69.
Abstract IA26: Clinical development of PI3K/AKT pathway inhibitors in breast cancer
Authors: Derynck Mika 
Published: August 2018

Abstract
Targeting the PI3K/AKT/mTOR pathway has been a focus for drug development since the discovery of PI3K-activating mutations in p110α over 10 years ago. Breast cancer has been a primary indication for development of this class of drugs because of the high prevalence of these mutations, up to 45% in hormone receptor-positive breast cancer, and the synergy observed in combinations with endocrine therapies. An mTOR inhibitor, everolimus, was approved in breast cancer in combination with exemestane in 2012, indicating the synergy between ER and PI3K pathway translates to the clinic. Apitolisib, a dual PI3K pan-isoform and mTOR inhibitor, has discontinued development due to toxicities, despite compelling preclinical activity across multiple tumor types regardless of PI3K and PTEN status. Pictilisib, a pan-isoform PI3K inhibitor, has shown some evidence of activity, but in phase II studies has demonstrated that the activity is limited by dose intensity. Buparlisib, a pan-isoform PI3K inhibitor, has demonstrated efficacy in a large phase III study, but was not deemed sufficiently active relative to the toxicity in HR+ breast cancer to be submitted for regulatory approval. Second-generation PI3K and AKT inhibitors with higher selectivity and mutant specificity are in clinical development and hope to thread a better therapeutic index by dosing higher for more profound inhibition, and/or selectively inhibiting mutated forms of PI3K. Taselisib (GDC-0032) is a beta-sparing and PI3K-mutant selective inhibitor that leads to degradation of only the mutant form of PI3K and is currently in phase III. More recently, taselisib met the primary endpoint of improved response rates in a randomized, neoadjuvant phase II trial, LORELEI. Alpelisib is an alpha-selective PI3K inhibitor that is also in phase III. Recent data with ipatasertib, an AKT inhibitor, has demonstrated better tolerability and efficacy in randomized phase II trials of both prostate cancer and triple-negative breast cancer, where the PI3K/AKT signaling pathway is activated by either loss of PTEN or PI3K mutations, and may offer a better therapeutic index given its unique mechanism of action and place in the PI3K signaling pathway. Overall, the PI3K/AKT pathway is still considered an important pathway to target for certain cancers; however, target selectivity, dosing, and the right combination are critical to find a therapeutic index to provide a good option for patients.
Citation Format: Mika Derynck. Clinical development of PI3K/AKT pathway inhibitors in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA26.
Abstract IA31: What limits the response of breast cancer to immunotherapy?
Authors: Loi Sherene 
Published: August 2018

Abstract
Checkpoint blockade has been evaluated successfully in the classically immunogenic solid tumor types such as melanoma and renal cell carcinoma, as well as in hematologic malignancies. While a large degree of T-cell infiltrate has been observed in primary breast cancers, particularly triple-negative and Her2-positive subtypes, efficacy with checkpoint blockade as monotherapy has been modest so far in studies in advanced disease.
Given that higher levels of T-cell infiltrate have been associated with improved prognoses and response to cytotoxic chemotherapy, my lab has hypothesized that these T cells would have functional characteristics that would be important in immunosurveillance of breast cancer. We have characterized these T cells using methods such as multiplex immunohistochemistry, bulk gene expression, and flow cytometry, as well as single-cell transcriptomic sequencing in order to better characterize these T cells. We have also observed lower levels of immune infiltrate in samples from metastatic breast cancer lesions, suggesting that the primary disease setting may be the most amenable to checkpoint inhibitor approaches. Data currently support that line of therapy in the advanced breast cancer setting; tumor burden and T-cell infiltrate predict for higher response rates to PD-1 blockade as monotherapy.
Finally, given that most patients with advanced breast cancer have a “noninflamed” tumor microenvironment, my lab has been evaluating how therapeutics can modulate the immune microenvironment. Certain agents such as MEK inhibitors as well as combination targeted therapies can potentially increase tumor immunogenicity as well as synergize well with immunotherapies. These combinatorial approaches may serve to increase the response rate of immunotherapy in breast cancer patients as well as prolong duration of response in patients treated with new therapeutic agents.
Citation Format: Sherene Loi. What limits the response of breast cancer to immunotherapy? [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA31.
Abstract 48: Acid ceramidase inhibition: A targeted therapy for acute myeloid leukemia
Authors: Pearson Jennifer M. , Tan Su-Fern , Sharma Arati , Fox Todd E. , Abad Jose Luis , Fabrias Gemma , Claxton David F. , Feith David J. , Kester Mark , Loughran Thomas P. 
Published: August 2018

Abstract
Acute myeloid leukemia (AML) is a disease characterized by uncontrolled proliferation of immature myeloid cells in the blood and bone marrow. Patient 5-year survival rate is only 26%, and there have been no significant treatment advances for decades. Therefore, there is an urgent need to identify novel therapeutic targets. We have previously shown that acid ceramidase (AC) is upregulated in AML and high AC activity correlates with poor patient survival. We continue to validate AC as a potential therapeutic target in AML through inhibitor screening and characterization. We utilize viability assays, enzyme activity assays, Western blotting, qPCR, lipidomics, and flow cytometry to examine the effects of inhibitors on AML cell lines, patient samples, and normal controls. We have found that a newly developed selective AC inhibitor, SACLAC, significantly reduces viability of AML cells with an EC50 of approximately 3 μM, with limited effect on normal cells at an EC50 of approximately 13 μM. Treatment of AML cell lines with SACLAC effectively blocks AC activity, induces a drastic decrease of sphingosine 1-phosphate, and a 2.5-fold increase in total ceramide levels. Ongoing studies continue to explore the mechanistic basis for the loss of viability. These data support the investigation of AC as a therapeutic target in AML and define SACLAC as a potent and selective inhibitor that presents promise for preclinical studies and future clinical development.
Citation Format: Jennifer M. Pearson, Su-Fern Tan, Arati Sharma, Todd E. Fox, Jose Luis Abad, Gemma Fabrias, David F. Claxton, David J. Feith, Mark Kester, Thomas P. Loughran, Jr.. Acid ceramidase inhibition: A targeted therapy for acute myeloid leukemia [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 48.
Abstract IA19: Directing blood cancer therapy with mitochondrial BH3 profiling
Authors: Letai Anthony G. 
Published: August 2018

Abstract
Connecting the right drugs to the right tumor is the fundamental job of cancer precision medicine. While there is a tendency to equate precision medicine with genomics, we are surrounded by examples where very effective modern targets are deployed effectively in disease without genomic guidance. One example is in chronic lymphocytic leukemia (CLL) where there have been several recent FDA approvals for drugs targeting CD20, PI3K, BTK, and BCL-2. Combinations of these highly active agents will likely dramatically alter practice, yet their discovery and assignment to CLL was not guided by genomics, as CLL generally lacks genetic alterations in any of these pathways. Instead, use in CLL was guided by the identification of vulnerabilities that had more to do with lineage than with genetics. In this talk, I will describe how my laboratory is using a probe of apoptotic signaling at the mitochondrion to identify drugs that provoke apoptotic signaling in cancer cells. This approach, called “BH3 profiling,” has so far been effective in guiding clinical trials of the BCL-2 inhibitor venetoclax in CLL and acute myelogenous leukemia. I will describe how we can deploy this tool as a predictive biomarker or as a discovery tool to directly identify drug vulnerabilities of cancer cells.
Citation Format: Anthony G. Letai. Directing blood cancer therapy with mitochondrial BH3 profiling [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA19.
Abstract A09: Rational combinational therapy with PARP and BRD4 inhibitor in ovarian cancer
Authors: Sun Chaoyang , Yin Jun , Fang Yong , Mills Gordon B. 
Published: August 2018

Abstract
Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other pathway members. We thus sought small-molecule inhibitors that induce HRD in HR competent cells to identify approaches to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrate that inhibition of bromodomain containing 4 (BRD4) induces HRD and sensitizes cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF status.
Note: This abstract was not presented at the conference.
Citation Format: Chaoyang Sun, Jun Yin, Yong Fang, Gordon B. Mills. Rational combinational therapy with PARP and BRD4 inhibitor in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A09.
Abstract A67: Effects of the atypical PKC-ι inhibitor ICA-1 on ovarian cancer proliferation and survival
Authors: Smalley Tracess , Acevedo-Duncan Mildred 
Published: August 2018

Abstract
Ovarian cancer is the most lethal gynecologic cancer diagnosis. There is no efficient screening process for ovarian cancers and the average stage of diagnosis is stage III. Atypical PKCs (PKC-ζ and PKC-ι/λ) have been shown to be overexpressed in various malignant cells lines and to be linked to pathways for cellular proliferation and survival. Estrogen is also highly linked to carcinogenesis. In this investigation, ovarian cell lines (HEY, COV644, T80) were treated with the atypical PKC-ι inhibitor ICA-1 in two different systems, with and without estrogen, and assayed to determine the effects on proliferation and cellular survival. These assays included protein quantification, cell proliferation, and wound healing. Our preliminary data suggest that PKC-ι is a novel target in carcinogenesis and inhibition of this protein decreases the rate of proliferation. Our results also suggest that estrogen has a great effect on cell proliferation, even in estrogen receptor-negative cells.
Citation Format: Tracess Smalley, Mildred Acevedo-Duncan. Effects of the atypical PKC-ι inhibitor ICA-1 on ovarian cancer proliferation and survival. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A67.