bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2951: Vitamin C is selectively toxic to cancer cells harboring KRAS or BRAF mutations by targeting GAPDH
Authors: Yun Jihye , Kavalier Adam , Mullarky Edouard , Bosch Kaitlyn , Roper Jatin , Rago Carlo , Paik Jihye , Asara John , Gross Steven , Vogelstein Bert , Papadopoulos Nickolas , Cantley Lewis 
Published: May 2015

Abstract
Although more than half of colorectal cancer patients have either KRAS or BRAF mutations, targeted therapies for these subgroups of cancer patients are still lacking. Here, we report that KRAS or BRAF mutant cells exhibit a significant increase in the uptake of oxidized vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased uptake of DHA in the mutant cell lines causes oxidative stress as intracellular DHA is immediately reduced back to vitamin C by reduced glutathione. Elevated reactive oxygen species inactivate GAPDH and thus divert glycolytic flux into the pentose phosphate pathway. Because KRAS or BRAF mutant cells are highly dependent on glycolysis, this altered glucose metabolism induced by vitamin C ultimately leads to an energy deficit in KRAS or BRAF mutant cells and thereby cell death. There are currently a growing number of clinical trials in phases I/II examining the effect of high dose vitamin C as a treatment for cancers, including colorectal cancers. Our results provide a rationale for the pharmacological use of vitamin C as a therapeutic agent to treat colorectal cancer patients with oncogenic KRAS or BRAF mutations.
Citation Format: Jihye Yun, Adam Kavalier, Edouard Mullarky, Kaitlyn Bosch, Jatin Roper, Carlo Rago, Jihye Paik, John Asara, Steven Gross, Bert Vogelstein, Nickolas Papadopoulos, Lewis Cantley. Vitamin C is selectively toxic to cancer cells harboring KRAS or BRAF mutations by targeting GAPDH. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2951. doi:10.1158/1538-7445.AM2014-2951
Abstract 2954: A noncanonical mechanism for BCL-2 inhibition of pro-apoptotic BAX
Authors: Barclay Lauren A. , Lee Susan , Stewart Michelle L. , Braun Craig R. , Bird Gregory H. , Walensky Loren D. 
Published: May 2015

Abstract
In response to cellular stress, pro-apoptotic BCL-2 family members such as BAX initiate apoptosis by forming toxic pores in the mitochondrial outer membrane. It is well established that BAX is inhibited by BCL-2 through a sequestering interaction between a surface groove on BCL-2 and the alpha-helical BH3 death domain of BAX. Indeed, BCL-2 overexpression is a cardinal mechanism exploited by cancer cells to resist apoptosis. Novel BCL-2 inhibitors, such as ABT-199, are showing promise as pharmacologic activators of apoptosis in BCL-2-dependent cancers. Emerging data suggest that a distinct interaction between the BH4 domain of BCL-2 and BAX may also account for BCL-2 inhibition of BAX. To dissect this putative interaction mechanism, we generated stabilized alpha-helices of BCL-2 domains (SAHBs) modeled after the BH4 motif of BCL-2 and assessed their capacity to inhibit BAX. We find that distinct BCL-2 BH4 SAHBs directly engage BAX and block BAX-mediated membrane poration. Mutagenesis studies defined key residues for the inhibitory activity of BCL-2 BH4 SAHBs and confirmed the sequence-dependent specificity of action. We extended our findings to full-length BCL-2, demonstrating that point mutagenesis within the BH4 domain disrupts co-immunoprecipitation of expressed BCL-2 and BAX proteins. Taken together, we find that a noncanonical interaction between BCL-2 and BAX contributes to the functional regulation of these critical apoptotic proteins and may serve as a new and complementary target for therapeutic reactivation of cell death in human cancer.
Citation Format: Lauren A. Barclay, Susan Lee, Michelle L. Stewart, Craig R. Braun, Gregory H. Bird, Loren D. Walensky. A noncanonical mechanism for BCL-2 inhibition of pro-apoptotic BAX. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2954. doi:10.1158/1538-7445.AM2014-2954
Abstract 2956: The role of apoptotic blebbing in tissue homeostasis and cancer
Authors: Julian Linda , Olson Michael F. 
Published: May 2015

Abstract
Efficient apoptotic cell clearance prevents the release of potentially immunogenic intracellular contents into the surrounding environment to maintain tissue homeostasis; however, the importance of membrane blebbing for apoptotic cell recognition and clearance has not been established. To address fundamental questions regarding the influence of ROCK1 cleavage and consequent apoptotic membrane blebbing in cellular corpse clearance and the maintenance of tissue homeostasis, mice were generated with a single amino acid substitution in the caspase cleavage site (D1113A) that converts ROCK1 to a non-cleavable (ROCK1nc) form. We previously showed that during apoptosis, caspase cleavage of ROCK1 removes an auto-inhibitory carboxy-terminal region to yield a constitutively active kinase fragment that leads to phosphorylation of downstream targets which promote contractile force generation leading to shrinkage, blebbing and nuclear disintegration. When apoptosis was induced in mouse embryonic fibroblasts, the biochemical apoptotic programme itself was unaffected, although cells had significantly impaired morphological alterations. Furthermore, by imaging apoptosis of GFP labelled melanoblasts in ex vivo embryonic skin explants, the effect of the ROCK1nc point mutation was to impair typical apoptotic morphological changes. To understand the biological role of membrane blebbing in the maintenance of tissue homeostasis, we used the liver-selective genotoxic compound diethylnitrosamine (DEN) to induce acute tissue damage. Following DEN treatment, we found that TUNEL positive apoptotic cells were inefficiently cleared in ROCK1nc mice, which resulted in increased neutrophil infiltration in response to the accumulating apoptotic debris. Histologically, the ROCK1nc livers appeared more damaged with evidence of steatohepatitis and perivenular damage, which was accompanied by higher serum alanine transferase levels. We then asked whether defects in tissue damage responses in ROCK1nc mice would affect tumor development in a model of DEN-induced hepatocellular carcinoma. Interestingly, ROCK1nc mice had reduced tumor volume and numbers, suggesting that defective blebbing may be beneficial for reducing tumor initiation and growth. Taken together, our results indicate that efficiency of phagocytic clearance may contribute to cancer susceptibility.
Citation Format: Linda Julian, Michael F. Olson. The role of apoptotic blebbing in tissue homeostasis and cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2956. doi:10.1158/1538-7445.AM2014-2956
Abstract 2962: Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression
Authors: Goka Erik T. , Lippman Marc E. 
Published: May 2015

Abstract
The transition from ductal carcinoma in situ (DCIS) to invasive disease is a crucial step in breast cancer progression. The specific alterations that govern this transition have not been elucidated. HER2/neu overexpression is frequently seen (50-60%) at the DCIS stage but is significantly less common in invasive breast cancer (20-30%) suggesting that additional alterations cooperate with HER2/neu to fully transform mammary epithelial cells. We identified novel genes that are capable of cooperating with HER2/neu allowing full malignant transformation, we used a transgenic mouse model that expresses wild-type neu and performed an insertional mutagenesis screen to identify genes whose alterations induce anchorage-independent growth on primary mouse mammary epithelial cells, an in vitro tumor formation assay. We identified the HECT and ankyrin domain containing E3 ligase 1 (HACE1) as a breast cancer tumor suppressor gene whose loss contributes to the transformation process. Loss of HACE1 expression is commonly seen in breast cancer patients and established breast cancer cell lines supporting the role of HACE1 as a breast cancer tumor suppressor gene. HACE1 ubiquitylates the activated GTP-bound form of the Rho family GTPase Rac1, resulting in ubiquitin mediated degradation of Rac1 via the 26S proteasome. The loss of HACE1 results in the accumulation of activated Rac1 leading to enhanced clonogenicity, migration, and invasion of human mammary epithelial cells (HMECs). In addition, the overexpression of HER2 results in activation of Rac1 levels which is further enhanced upon HACE1 loss in HMECs that further enhance colony formation in soft agar, migration, invasion and allows tumor formation in mice. Importantly, knocking down Rac1 using RNA interference or targeting RAC1 using the small molecule inhibitor EHT 1864 can rescue the effects of HACE1 loss mediated transformation. The results establish HACE1 as a breast cancer tumor suppressor gene by attenuating Rac1 signaling. In addition, our work further supports the role of Rac1 as a critical signaling node in breast cancer and that loss of HACE1 leads to enhanced Rac1 signaling that may contribute to breast cancer progression. These results suggest that HACE1 loss may identify precancerous lesions capable of becoming malignant as well as identify cancers susceptible to RAC targeted therapies.
Citation Format: Erik T. Goka, Marc E. Lippman. Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2962. doi:10.1158/1538-7445.AM2014-2962
Abstract 2966: Targeting defective DNA repair as a novel chemoprevention strategy for BRCA1-mutated breast cancer
Authors: Alli Elizabeth , Solow-Cordero David , Casey Stephanie C. , Ford James M. 
Published: May 2015

Abstract
Carriers of germline mutations in the Breast Cancer Susceptibility Gene 1 (BRCA1) have an increased risk for developing breast cancer. Unfortunately, BRCA1-mutated cancers are not amenable to current chemoprevention options, often associate with an aggressive clinical course, and thus, are in need of an effective prevention strategy. We previously found that BRCA1 plays a role in DNA base-excision repair (BER) of oxidative DNA damage, and that BRCA1-mutated breast cancers exhibit a compromised ability for BER of oxidative DNA damage. Given that excessive oxidative DNA damage leads to tumorigenesis, we hypothesized that small molecules may be used to enhance the repair of oxidative DNA damage, and in turn, prevent tumorigenesis of BRCA1-mutated breast cancer cells. First, a high-throughput chemical screen identified small molecules that enhance BER of oxidative DNA damage in the presence of mutant BRCA1. These molecules have been termed DNA repair-activating agents. At least two DNA repair-activating agents significantly enhanced BER in mutant BRCA1 but not wild-type BRCA1 cell lines. These molecules also decreased basal levels of oxidative DNA damage as determined by flow cytometry using a FITC-conjugated 8oxoG-binding protein and decreased H2O2-induced oxidative DNA damage as determined by the alkaline comet assay modified for detection of oxidized lesions. Both DNA repair-activating agents directly activated BER, rather than indirectly as a result of induction of DNA damage, as evidenced by the alkaline comet assay for DNA strand breaks. Both agents also showed no cytotoxicity at concentrations that enhanced BER of oxidative DNA damage, which is ideal for chemoprevention. Finally, at least one of the DNA repair-activating agents decreased BRCA1-associated tumorigenesis in vitro and in vivo. The DNA repair-activating agent decreased anchorage-independent growth of BRCA1-mutant/deficient cells without a significant effect on cell viability, as well as delayed tumor formation and decreased tumor burden in a dose-response manner in a xenograft mouse model. Taken together, these data suggest that enhancing DNA base-excision repair of oxidative DNA damage may be a novel strategy for the targeted chemoprevention of BRCA1-associated breast cancers.
Citation Format: Elizabeth Alli, David Solow-Cordero, Stephanie C. Casey, James M. Ford. Targeting defective DNA repair as a novel chemoprevention strategy for BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2966. doi:10.1158/1538-7445.AM2014-2966
Abstract 2993: Dll4 inhibition plus aflibercept markedly reduces ovarian tumor burden and ascites
Authors: Huang Jie , Hu Wei , Dalton Heather J. , Bottsford-Miller Justin , Coleman Robert L. , Jaffe Robert B. , Sood Anil K. 
Published: May 2015

Abstract
Purpose: To determine the effects of Dll4 blockade with and without aflibercept on ovarian tumor burden and ascites in preclinical models.
Methods: Using Dll4-Fc and anti-Dll4 antibodies, we evaluated the biological effects of Dll4 inhibition combined with aflibercept in vivo (orthotopic mouse models of ovarian cancer). Reverse phase protein array (RPPA) analysis was used to identify potential biomarkers of treatment response.
Results: To address the biological significance of Dll4 expression in tumor cells versus endothelial cells, we used human and mouse anti-Dll4 antibodies in vivo. In the A2780 model, treatment with mouse (REGN1035) or human (REGN421) anti-Dll4 antibodies reduced tumor weight by 61.5% and 82.4%, respectively, compared to the controls (P &lt; 0.05 for both). Aflibercept alone reduced tumor weight by 90% (p &lt; 0.05). The combinations of REGN1035 plus aflibercept, and REGN421 plus aflibercept resulted in the greatest inhibition of tumor growth, reducing respective tumor weight by 95.8% and 93.9%, compared to the controls (P &lt; 0.05). The anti-tumor effects were related to decreased angiogenesis and increased apoptosis. RPPA analysis revealed that caspase3 and GATA3 were significantly increased; cyclin D1, Bcl-2 and pS6-s240_s244 were decreased in response to Dll4 Inhibition plus aflibercept. Among these, GATA3, a transcription factor for E-cadherin, was significantly induced by Dll4 Inhibition plus aflibercept, resulting in the up-regulation of E-cadherin expression in human cancer cells. Furthermore, GATA3 and E-cadherin expression might be useful as potential biomarkers of response.
Conclusions: Dual targeting of Dll4 and VEGF shows promise for inhibiting ovarian tumor growth and may have important clinical implications.
Citation Format: Jie Huang, Wei Hu, Heather J. Dalton, Justin Bottsford-Miller, Robert L. Coleman, Robert B. Jaffe, Anil K. Sood. Dll4 inhibition plus aflibercept markedly reduces ovarian tumor burden and ascites. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2993. doi:10.1158/1538-7445.AM2014-2993
Abstract 2995: Metronomic albumin-bound paclitaxel and topotecan has potent antitumor activity in ovarian cancer
Authors: Davis Ashley N. , Lin-Liu Yvonne G. , Previs Rebecca A. , Dalton Heather J. , Zand Behrouz , Bottsford-Miller Justin , Coleman Robert , Sood Anil K. 
Published: May 2015

Abstract
Objective: There is growing recognition of the important role of metronomic chemotherapy for cancer treatment. Based on their unique anti-angiogenic effects, we tested the efficacy of dual albumin-bound paclitaxel (ABP), which stimulates Thrombospondin-1, and topotecan, which inhibits Hypoxia-inducible factor 1-α, chemotherapy at metronomic dosing in ovarian carcinoma.
Methods: We examined the effects of ABP and topotecan in vitro (MTT) and in vivo using SKOV3ip1, HeyA8 and HeyA8-MDR orthotopic mouse models of ovarian cancer. We also examined effects on proliferation (Ki67), apoptosis (TUNEL), and angiogenesis (MVD) in tumor samples obtained at necropsy.
Results: In vitro cytotoxicity assays revealed similar effects (IC50=20-60 nM) of maximum tolerated dosing (MTD) and metronomic dosing of ABP on HeyA8 tumor cells (p&lt;0.05). In vivo therapy experiments using the SKOV3ip1 and HeyA8 tumor models demonstrated that treatment with metronomic ABP alone and in combination with metronomic topotecan resulted in significant reductions in tumor weight, 62% and 96% respectively as compared to controls (p&lt;0.01). Combination treatment with metronomically dosed ABP and topotecan further reduced tumor growth by 82% compared to topotecan alone (p&lt;0.01). In the chemoresistant tumor model, HeyA8-MDR, metronomically dosed monotherapy with either cytotoxic agent had a modest effect on tumor growth however, combination therapy decreased tumor burden by 74% when compared to controls (p&lt;0.01). Metronomic ABP monotherapy resulted in reduced cell proliferation (p&lt;0.001), reduced tumor angiogenesis (p≤0.01), and increased apoptosis (p&lt;0.01).
Conclusions: Metronomically-dosed albumin-bound paclitaxel and topotecan offer a highly effective and novel therapeutic approach in ovarian carcinoma that merits further clinical development.
Citation Format: Ashley N. Davis, Yvonne G. Lin-Liu, Rebecca A. Previs, Heather J. Dalton, Behrouz Zand, Justin Bottsford-Miller, Robert Coleman, Anil K. Sood. Metronomic albumin-bound paclitaxel and topotecan has potent antitumor activity in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2995. doi:10.1158/1538-7445.AM2014-2995
Abstract 3: Imaging of stromal cells during hepatocellular metastasis formation in the RFP-MUP-uPA mouse
Authors: Suetsugu Atsushi , Ogata Hisanobu , Hiroshima Yukihiko , Momiyama Masashi , Osawa Yosuke , Moriwaki Hisataka , Saji Shigetoyo , Karin Michael , Hoffman Robert M. 
Published: May 2015

Abstract
Major urinary protein-urokinase type plasminogen activator (MUP-uPA) transgenic mice develop liver disease. We have developed the RFP-MUP-uPA mice, by crossing MUP-uPA mice with transgenic mice ubiquitously-expressing RFP. Hepatocyte RFP fluorescence in this model is very strong. In addition, RFP fluorescence of stromal cells is very bright enabling the portal vein and sinusoid structures to be clearly visualized. Huh7 liver cancer cells expressing green fluorescent protein (GFP) were injected in the spleen of MUP-uPA transgenic mice. The vessels of the MUP-uPA liver are filled with Huh7-GFP cells as imaged in live mice 3h after cell injection. Huh7-GFP cells formed tumor colonies in the liver 28 days after cell transplantation to the spleen. The Huh7-GFP cells were visualized in the liver with the Olympus FV1000 confocal microscope. In large metastatic liver tumors in RFP-MUP-uPA mice, stroma cells derived from the host animal appeared around and into the edge of Huh7-GFP tumors. In contrast, in small metastatic liver tumors, there were no stromal cells observed. The stromal cells were observed in the spleen primary tumor, as well as kidney and the lung metastasis in addition to the large liver tumors. This model enables imaging the effects of uPA on liver metastasis and stromal recruitment enabling the metastasis to progress.
Citation Format: Atsushi Suetsugu, Hisanobu Ogata, Yukihiko Hiroshima, Masashi Momiyama, Yosuke Osawa, Hisataka Moriwaki, Shigetoyo Saji, Michael Karin, Robert M. Hoffman. Imaging of stromal cells during hepatocellular metastasis formation in the RFP-MUP-uPA mouse. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3. doi:10.1158/1538-7445.AM2014-3
Abstract 3002: ID3 expression and oxidative DNA damage are associated with growth of benign and malignant vascular lesions
Authors: Felty Quentin H. , Das Jayanta K. 
Published: May 2015

Abstract
Higher levels of Id3 expression have been reported in tumor-infiltrating blood vessels from various tumors, but the exact role of Id3 in vascular lesion formation is poorly understood. This study aims at identifying the status of Id3 expression and distribution in benign vascular lesions and attempts to correlate this information with the progression of vascular lesion. In this study we investigated the expression pattern of Id3 in malignant, benign, and normal human vascular tissue specimens. Expression analysis of Id3 was carried out using immunohistochemical analysis in 48 sporadic samples of a heterogeneous group of benign and malignant vascular tissue. Immunohistochemical analysis confirmed that many of the malignant vascular lesions exhibited strong Id3 expression that correlated positively with increased 8-hydroxydeoxyguanosine (8-OHdG) a marker of oxidative DNA damage. In contrast, in normal human vascular tissue, Id3 expression and 8-OHdG was low. In malignant vascular tissue, Id3 protein displayed a stronger nuclear localization when compared to the cytoplasm. Id3 expression levels in benign vascular lesions while still expressing Id3 were to a lesser extent when compared to malignant vascular tissue. To our knowledge, this is the first study to compare benign and malignant vascular lesions to assess the role of Id3 and 8-OHdG. Our data reveals Id3 expression and oxidative DNA damage to be highly associated in malignant cells and to a lesser extent in their benign counterparts, indicating that the growth of vascular lesions may require oxidative stress signaling converging on Id3. The results also support the involvement of Id3 in tumor angiogenesis a process that critically influences the malignant behavior of cancer cells.
Citation Format: Quentin H. Felty, Jayanta K. Das. ID3 expression and oxidative DNA damage are associated with growth of benign and malignant vascular lesions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3002. doi:10.1158/1538-7445.AM2014-3002