tbuckley/cabot-search huggingface dataset:
Abstract 3789: Therapeutic targeting of the YAP/TAZ pathway in glioblastoma with verteporfin
Authors: Nathaniel H. Boyd, Krish Vigneswaran, Shoeb Lallani, Se-Yeong Oh, Andrew Boucher, Jeffrey Olson, Renee Read
Journal: Cancer Research (2020)

Abstract Glioblastoma (GBM) is a particularly lethal brain neoplasm accounting for half of malignant primary brain tumors diagnosed in adults and maintains a devastating diagnosis, with a median survival of 14 months despite standard clinical interventions of surgical, chemotherapeutic, and radiation treatments. GBM tumorigenicity is often driven by aberrations in receptor tyrosine kinases (RTKs) such as EGFR, and the Pi-3 kinase (PI3K) signaling pathway. Using a Drosophila glioma model and human patient-derived glioma cells, we identified YAP/TAZ, effectors of the Hippo pathway that promote expression of stemness factors and oncogenes via activation of the TEAD transcription factors, as drivers of glioma tumorigenicity. This led to the discovery that YAP/TAZ are highly expressed in human patient-derived glioma stem cells and that knockdown of these inhibits cell growth. We hypothesized that Verteporfin, a benzoporphyrin derivative approved by the FDA for the treatment of macular degeneration, may have therapeutic benefit for glioblastoma due to its published ability to inhibit interaction between YAP and TEAD transcription factors. Using in vitro culture-based assays and in vivo in GBM xenograft models, we observed Verteporfin specifically induces apoptosis in GBM cells, slows tumor growth, and durably suppressesexpression of known and novel TEAD transcriptional targets in tumor tissue. We validated several direct targets using chromatin immunoprecipitation, and are seeking to further identify the full transcriptional program controlled by YAP/TAZ-TEAD in GBM. Our efforts have led to a phase 0 clinical trial where we were able to observe Verteporfin uptake in GBM tumors in human patients. These data indicate that Verteporfin is a promising therapeutic target for GBM. Citation Format: Nathaniel H. Boyd, Krish Vigneswaran, Shoeb Lallani, Se-Yeong Oh, Andrew Boucher, Jeffrey Olson, Renee Read. Therapeutic targeting of the YAP/TAZ pathway in glioblastoma with verteporfin [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3789.
Abstract 5627: BALB/c-hCD3E transgenic mice to evaluate humanCD3-bispecific antibodies
Authors: Cunxiang Ju, Mingkun Zhang, Dongjing Jia, Rui Mao, Jing Tang, Shuai Li, Jing Zhao, Xiang Gao
Journal: Cancer Research (2020)

Abstract T cell-mediated immunotherapy is an attractive strategy for treatment of various tumors. T-cell bispecific antibody (TCB) can binds tumor associated antigen (TAA) and CD3 molecule (especially epsilon chain, CD3ϵ), and directs target specific killing of cells carrying the TAA. However, there is a challenge to evaluate the therapeutic efficacy of TCB due to the lack of immune competent animal that have both human immune system and TAA. Considering that CD3ϵ plays a critical role in formation and function of the TCR-CD3 complex while human CD3ϵ (hCD3ϵ) shares only 47% homology with mouse CD3ϵ (mCD3ϵ) in the extracellular domain, we established a CD3ϵ BAC transgenic model (BALB/c-hCD3E) carrying hCD3E gene and its entire regulatory sequence to meet this need. These transgenic mice co-express human and mouse CD3ϵ in over 90% of T-cells. Besides, the expression pattern of hCD3ϵ in spleen and thymus of BALB/c-hCD3E mice are similar with mCD3ϵ in wild type mice. With a normal immune system, splenic T cells from this strain could be activated by either anti-hCD3ϵ or anti-mCD3ϵ antibodies to produce IFNγ, IL2 and TNFα in vitro. We also tested the T cell-dependment cellular cytotoxicity on BALB/c-hCD3E mice use blinatumomab (bscCD19xCD3), the results shown significant anti-tumor effect. It's worth noting that further knockout of mCd3e in BALB/c-hCD3E mice cause remarkable reduce of splenic T cells, strong tumor inhibition of anti-mCTLA4 was observed in BALB/c-hCD3E but not BALB/c-hCD3E/mCd3e-KO mice, demonstrate that mCD3ϵ is indispensable for T-cell development and function in BALB/c-hCD3E transgenic mice. Taken together, these findings indicate that BALB/c-hCD3E mice with intact mCd3e is a novel and valuable model to assessing the therapeutic efficacy of TCBs. Citation Format: Cunxiang Ju, Mingkun Zhang, Dongjing Jia, Rui Mao, Jing Tang, Shuai Li, Jing Zhao, Xiang Gao. BALB/c-hCD3E transgenic mice to evaluate humanCD3-bispecific antibodies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5627.
Abstract 5708: Deciphering Warburg effect: hypoxia inhibits tumor cell differentiation through reducing acetyl-CoA generation and chromatin accessibility
Authors: Jiangbin Ye, Yang Li, Joshua J. Gruber, Ulrike M. Litzenburger, Yiren Zhou, Yu R. Miao, Edward L. LaGory, Albert M. Li, Zhen Hu, Lori S. Hart, John M. Maris, Howard Y. Chang, Amato J. Giaccia
Journal: Cancer Research (2020)

Abstract The Warburg effect is a metabolic hallmark of all cancer cells, characterized by increased glucose uptake and glycolysis for lactate generation. The generation and excretion of lactate would appear be a waste of carbon backbone and energy that is needed for proliferation. It was proposed by Warburg that the cause and consequence of the Warburg effect were the injury of respiration and cell dedifferentiation, respectively. One common factor that damages mitochondrial respiration is hypoxia, which is a metabolic stress that blocks cell differentiation and promotes cancer progression. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma (NB) differentiation model, we have discovered that hypoxia represses the differentiation induced by retinoic acid (RA) as demonstrated by loss of neuron differentiation markers and changes in cell morphology, associated with reduction of global histone acetylation, that are caused by the induction of pyruvate dehydrogenase kinases (PDKs). PDKs phosphorylate pyruvate dehydrogenase (PDH), thereby blocking pyruvate entry into the TCA cycle, reducing acetyl-CoA generation, and promoting the Warburg effect. Genetic and pharmaceutical inhibition of PDK restores histone acetylation and NB cell differentiation morphology. Acetate supplementation restores histone acetylation, along with differentiation markers expression and neuron differentiation. In addition, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduces chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. These findings suggest that (1) combining RA and acetate supplementation represents a potentially effective therapeutic strategy for neuroblastoma treatment; (2) diverting pyruvate away from acetyl-CoA generation is a key mechanism by which the Warburg effect blocks cell differentiation. Citation Format: Jiangbin Ye, Yang Li, Joshua J. Gruber, Ulrike M. Litzenburger, Yiren Zhou, Yu R. Miao, Edward L. LaGory, Albert M. Li, Zhen Hu, Lori S. Hart, John M. Maris, Howard Y. Chang, Amato J. Giaccia. Deciphering Warburg effect: hypoxia inhibits tumor cell differentiation through reducing acetyl-CoA generation and chromatin accessibility [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5708.
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Authors: Dana E. Orange, Nathalie E. Blachere, Mayu O. Frank, Salina Parveen, Edward F. DiCarlo, Serene Mirza, Tania Pannellini, Mark P. Figgie, Vivian P. Bykerk, Caroline S. Jiang, Ellen M. Gravallese, Ana‐Maria Orbai, Sarah L. Mackie, Susan M. Goodman
Journal: Arthritis & Rheumatology (2020)
Health Assessment Questionnaire at One Year Predicts All‐Cause Mortality in Patients With Early Rheumatoid Arthritis
Authors: Safoora Fatima, O. Schieir, M. F. Valois, S. J. Bartlett, L. Bessette, G. Boire, G. Hazlewood, C. Hitchon, E. C. Keystone, D. Tin, C. Thorne, V. P. Bykerk, J. E. Pope
Journal: Arthritis & Rheumatology (2020)

Higher self-reported disability (high Health Assessment Questionnaire [HAQ] score) has been associated with hospitalizations and mortality in established rheumatoid arthritis (RA), but associations in early RA are unknown.Patients with early RA (symptom duration <1 year) enrolled in the Canadian Early Arthritis Cohort who initiated disease-modifying antirheumatic drugs and had completed HAQ data at baseline and 1 year were included in the study. Discrete-time proportional hazards models were used to estimate crude and multi-adjusted associations of baseline HAQ and HAQ at 1 year with all-cause mortality in each year of follow-up.A total of 1,724 patients with early RA were included. The mean age was 55 years, and 72% were women. Over 10 years, 62 deaths (3.6%) were recorded. Deceased patients had higher HAQ scores at baseline (mean ± SD 1.2 ± 0.7) and at 1 year (0.9 ± 0.7) than living patients (1.0 ± 0.7 and 0.5 ± 0.6, respectively; P < 0.001). Disease Activity Score in 28 joints (DAS28) was higher in deceased versus living patients at baseline (mean ± SD 5.4 ± 1.3 versus 4.9 ± 1.4) and at 1 year (mean ± SD 3.6 ± 1.4 versus 2.8 ± 1.4) (P < 0.001). Older age, male sex, lower education level, smoking, more comorbidities, higher baseline DAS28, and glucocorticoid use were associated with mortality. Contrary to HAQ score at baseline, the association between all-cause mortality and HAQ score at 1 year remained significant even after adjustment for confounders. For baseline HAQ score, the unadjusted hazard ratio (HR) was 1.46 (95% confidence interval [95% CI] 1.02-2.09), and the adjusted HR was 1.25 (95% CI 0.81-1.94). For HAQ score at 1 year, the unadjusted HR was 2.58 (95% CI 1.78-3.72), and the adjusted HR was 1.75 (95% CI 1.10-2.77).Our findings indicate that higher HAQ score and DAS28 at 1 year are significantly associated with all-cause mortality in a large early RA cohort.
Abstract 290: Development and characterization of antibodies specific for the SS18-SSX fusion protein in synovial sarcoma
Authors: Curtis Desilets, Fang Chen, Christopher Comeau, Katrina Costa, Katherine Crosby, Michelle Ferrante, Christopher Grange, Maggie Patrikas, Matthew McBride, Esther Baranov, Jason Hornick, Cigall Kadoch
Journal: Cancer Research (2020)

Abstract Synovial sarcoma (SS) is a soft tissue cancer characterized by the fusion of the SS18 gene, which encodes for a subunit of the BAF ATP-dependent chromatin remodeling complex, with either SSX1, SSX2, or SSX4 genes. The resulting SS18-SSX fusion protein is incorporated into the BAF complex, where it evicts wild-type SMARCB1 (BAF47) and retargets the complex to polycomb-repressed chromatin domains, thus activating oncogenic gene expression to drive tumor progression. Traditional means of diagnosis of SS include immunohistochemical staining, including that for the biomarker TLE1, but TLE1 is not overexpressed in all tumors and cases ultimately need to be confirmed by either FISH or PCR assays to detect the SS18-SSX fusion. We have developed the first highly specific, recombinant monoclonal antibodies for the detection of SS18-SSX fusion proteins by immunohistochemistry and for the capture of SS18-SSX-containing BAF complexes in cells, with downstream utility in biochemistry and genomics-centered approaches such as ChIP-seq. The E9 × 9V clone directly targets the highly conserved fusion breakpoint, while the E5A2C clone detects the C-terminus of the SSX protein family and is capable of recognizing alternative breakpoints. Taken together, our data show that these antibodies can accurately and reproducibly detect the SS18-SSX fusion protein in SS cells and tissues. Citation Format: Curtis Desilets, Fang Chen, Christopher Comeau, Katrina Costa, Katherine Crosby, Michelle Ferrante, Christopher Grange, Maggie Patrikas, Matthew McBride, Esther Baranov, Jason Hornick, Cigall Kadoch. Development and characterization of antibodies specific for the SS18-SSX fusion protein in synovial sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 290.
Abstract 5052: CD44 inhibits the transition of ductal carcinoma in situ to invasive breast carcinoma
Authors: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh
Journal: Cancer Research (2020)

Abstract Ductal carcinoma in situ (DCIS) transition to invasive tumor is a big problem for breast cancer. The human MCF10DCIS.com cell line (abbreviated as MCF10DCIS) is derived from the human MCF10A breast epithelial cell line. The MCF10DCIS xenografts are similar to human high grade comedo DCIS. In the xenograft assay, MCF10DCIS cells form DCIS-like lesion, remain as DCIS-like lesion in the first several weeks, and then progress into invasive carcinoma. Thus, it is an excellent model to study human breast cancer transition from DCIS to invasive carcinoma. We investigated the role of CD44 in breast cancer transition from DCIS to invasive carcinoma by knockdown the expression of CD44 in the MCF10DCIS xenograft model. Our results show that knockdown of CD44 expression in the MCF10DCIS cells promotes DCIS transition to invasive carcinoma. Our finding is supported by a previous study that showed CD44 expression is higher in DCIS than in invasive breast carcinomas for human patients. Furthermore, we will present our ongoing studies for the underlying mechanisms. Our findings have important implications for breast cancer. Citation Format: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh. CD44 inhibits the transition of ductal carcinoma in situ to invasive breast carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5052.
Abstract 287: A nuclear cAMP microdomain suppresses tumor growth by Hippo Pathway inactivation
Authors: Marek M. Drozdz, Ashley Doane, Garrett Desman, Jenny Wang, Michael Reilly, Kelsey Aguirre, Elsbeth Kane, Jedd Wolchok, Taha Merghoub, Olivier Elemento, Elena Piskounova, Jonathan Zippin
Journal: Cancer Research (2020)

Abstract Cyclic AMP can both promote and suppress tumor growth; however, how this single second messenger can simultaneously have such disparate effects on cancer remains largely undefined. It is well appreciated that cAMP does not diffuse within a cell but is made in microdomains, which consist of a unique adenylyl cyclase, one or more phosphodiesterases, and cAMP effector proteins, but the role of specific cAMP microdomains in cancer is unclear. Examination of human tissue biopsies revealed that the nuclear cAMP microdomain, defined by the soluble adenylyl cyclase (sAC), is upregulated early in tumorigenesis, but is lost with melanoma invasion and metastasis. Further, we showed that loss of sAC led to the transformation of melanocytes and reintroduction of sAC, only into the nucleus, was sufficient to block tumorigenesis in vitro and in mice. Neither mitochondrial, nor cytoplasmic cAMP microdomains affected tumor cell growth. Activation of nuclear sAC led to significant changes in chromatin accessibility suggesting that this cAMP microdomain regulates numerous transcription factors. Specifically, activation of nuclear sAC led to reduced chromatin accessibility for the TEAD and SMAD family of transcription factors, the key effectors of the Hippo Pathway. Consistent with those data, nuclear sAC suppressed TEAD-dependent pro-cancer gene expression profiles (e.g., MYC) by inhibiting YAP, one of the main oncoproteins in this signaling cascade. Moreover, we showed that nuclear cAMP evokes the same YAP-dependent inhibition of the Hippo Pathway in a variety of cancers, suggesting tumor suppression by nuclear sAC is not limited to melanoma. These studies reveal that a cAMP microdomain wholly contained within the nucleus is a pivotal a tumor suppressor that acts via Hippo Pathway inactivation. Citation Format: Marek M. Drozdz, Ashley Doane, Garrett Desman, Jenny Wang, Michael Reilly, Kelsey Aguirre, Elsbeth Kane, Jedd Wolchok, Taha Merghoub, Olivier Elemento, Elena Piskounova, Jonathan Zippin. A nuclear cAMP microdomain suppresses tumor growth by Hippo Pathway inactivation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 287.
Abstract 2154: Immune pressure selects ANKRD52 mutations for cancer cells to escape T cell-mediated killing
Authors: Tianyu Y. Song, Haixin Zhao, Hongjie Fan, Min Long, Chenlu Geng, Xiaoxiao Xie, Yang Liu, Wenrong Zhou, Ziyu Chen, Dawei Huang, Bo Peng, Zhengang Peng, Yong Cang
Journal: Cancer Research (2020)

Abstract Cancer arises after somatic mutations override cellular and immunological control of cell proliferation. Mutations in oncogenes and tumor suppressor genes endow cancer cells intrinsic growth advantage over neighboring cells. Mutations can also enable cancer cells to survive immune clearance during cancer progression, but systematic analysis of such mutations is lacking. We hypothesized that some genetic alterations carried in cancer cell lines might specifically affect the cell fitness to T cell-mediated killing. By deep sequencing of syngeneic xenograft tumors receiving different levels of immune pressure, we enriched 53 mutations in clonal populations against T cell immunity. To differentiate the driver from passenger mutations, we performed in vivo and T cell co-culture CRISPR screens with a guide RNA library targeting these candidate genes. We identified ANKRD52, a promoter of miRNA-mediated silencing, as required for PD-1-independent T cell cytotoxicity by activating the JAK-STAT signaling and antigen presentation in cancer cells. ANKRD52 mutations found in prevalent cancer patients failed to activate the interferon-γ pathway and these patients exhibit poor overall survival. We hereby provide an approach for interrogating cancer genetic heterogeneity to uncover evolutionarily conserved evasion mechanism from host immunity. Citation Format: Tianyu Y. Song, Haixin Zhao, Hongjie Fan, Min Long, Chenlu Geng, Xiaoxiao Xie, Yang Liu, Wenrong Zhou, Ziyu Chen, Dawei Huang, Bo Peng, Zhengang Peng, Yong Cang. Immune pressure selects ANKRD52 mutations for cancer cells to escape T cell-mediated killing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2154.
Abstract 5212: The benefits of Didox in triple negative breast cancer treatment targeting mutant p53
Authors: Nahid Sultana, Elizabeth A. Wilson, Khyati N. Shah, Howard L. Elford, Jesika S. Faridi
Journal: Cancer Research (2020)

Abstract Triple-negative breast cancer (TNBC) is an aggressive histological subtype of malignancy with limited treatment options. Frequently, doxorubicin (DOXO)- based chemotherapy is utilized in this patient population due to the lack of molecular targets available. While DOXO is an effective chemotherapeutic agent, its efficacy is limited due to acquired drug resistance and cardiotoxicity. Therefore the identification of other treatment options for TNBC is needed. TNBC is a heterogeneous malignancy, with 70% of cases classified as a basal subtype, which further complicates the search for an effective molecular target. However, it has been identified that 80% of TNBC samples carry TP53 (tumor protein p53) mutations, which leads to a mutant p53 protein no longer able to act as a tumor suppressor and thus failing to halt cell growth. Mutant p53, when present in malignant cells, is far less susceptible to degradation than its wild-type counterpart, and thus accumulates within the cell. As such, the TP53 is an attractive therapeutic target for TNBC. We have previously identified that ribonucleotide reductase M2 (RRM2) is upregulated in TNBC cells and is a key contributor to acquired drug resistance. The ribonucleotide reductase inhibitor Didox has been shown to be a powerful free radical scavenger and iron chelator. Through these mechanisms, Didox alleviates the non-selective cytotoxic effects of DOXO on non-cancerous tissue, including cardiotoxicity and potentiates DOXO's efficacy against malignant cells. We have previously reported that Didox in combination with DOXO effectively treats TNBC by enhancing tumor inhibition and minimizing DOXO-induced heart damage. Our current study shows that Didox alone or in combination with DOXO downregulates mutant p53 protein levels in the mutant p53 TNBC cell lines MDA-MB 468, MDA-MB 231 and BT-20. This effect is notably absent in breast cancer cell lines with wild-type p53, including MCF7, A3B5 and ZR751, where p53 successfully acts as a tumor suppressor allowing for cell cycle arrest or apoptosis after DNA damage. We hypothesize that mutant p53 is a valid therapeutic target in TNBC. As shown here, the addition of Didox downregulates mutant p53 levels and thus enhances tumor inhibition while alleviating DOXO-associated cardiotoxicity. Citation Format: Nahid Sultana, Elizabeth A. Wilson, Khyati N. Shah, Howard L. Elford, Jesika S. Faridi. The benefits of Didox in triple negative breast cancer treatment targeting mutant p53 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5212.