bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2643: Small molecule identification for the restoration of p53 pathway through p73 and by degradation of mutant p53
Authors: Hernandez Borrero Liz J. , Zhao Shengliang , Dicker David T. , El-Deiry Wafik 
Published: August 2015

Abstract
One of the most explored cancer targets has been the tumor suppressor p53. p53 is mutated in more than half of all human tumors and therefore provides an attractive way to selectively target cancer cells that harbor the mutant protein. Mutant p53 protein can acquire a gain-of-function activity, losing its normal tumor suppressor properties and gaining oncogenic characteristics. Various approaches have been taken to restore the p53 pathway in mutant p53 expressing cells including the modulation of mutant p53 conformation to wild-type, and through the upregulation of p53 family members i.e. p73. Unlike p53, p73 is not commonly mutated in cancer cells and thus confers restoration of the p53 pathway through pharmacological stimulation. We characterized a small molecule that restores the p53 pathway through p73. A high-throughput cell-based screen identified small molecule CB002 as a potential candidate for the restoration of the p53 pathway in mutant p53 containing human colorectal cancer cells. Two colorectal cancer cell lines: SW480, DLD-1, and the RXF393 renal cancer cell line, were treated with different concentrations of CB002 for various time points. SW480 cells treated with CB002 for 8 hrs showed a decrease in p53 followed by an increase in DR5 expression at 16 hrs. DLD-1 cells treated with CB002 showed a decrease in p53 expression at 8 hrs. Although no change was observed in proteins involved in cell cycle arrest or cell death that were tested, colony formation was suppressed as compared to control. RXF393 cells treated with CB002 for 48 hrs showed decreased expression of p53 levels and increased levels of p21. These data suggest that CB002 is able to decrease mutant p53 protein expression, increase p53 target genes and promote expression of proteins involved in apoptosis, such as p21 and DR5, respectively. It appears that the CB002 mechanism is different depending on the cell line tested. We hypothesize that CB002 is capable of degrading mutant p53 and restoring the p53 pathway through p73 in colorectal cancer cells. Current undergoing experiments are focused on unraveling the p73 dependence through p73 knockdown and the mechanism of action involved in each cell line. The following project will aid in the understanding of the role of p73 in pharmacological restoration of the p53 pathway in cancer therapy.
Citation Format: Liz J. Hernandez Borrero, Shengliang Zhao, David T. Dicker, Wafik El-Deiry. Small molecule identification for the restoration of p53 pathway through p73 and by degradation of mutant p53. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2643. doi:10.1158/1538-7445.AM2015-2643
Abstract 2644: Inhibition of PAK4 attenuates renal cell carcinoma (RCC) growth
Authors: Abu Aboud Omran , Senapedis William , Landesman Yosef , Baloglu Erkan , Weiss Robert H. 
Published: August 2015

Abstract
Renal cell carcinoma (RCC) is an increasingly prevalent cancer type that is frequently asymptomatic on presentation and is associated with poor responses and resistance even to the current targeted therapies. Thus, novel therapeutic approaches to treat this disease are urgently needed. P21-activated kinase 4 (PAK4) is a mediator of filopodia formation and stabilizes β-catenin transcriptional activity. PAK4 lies in a pathway integral to both nephrogenesis and cancer. We hypothesized that inhibitors of the PAK4 signaling pathway would result in salutary effects on RCC. To test this, we evaluated the in vitro response of RCC cells to the specific PAK4 Allosteric Modulators (PAMs; KPT-8752 and KPT-9274). Similar to cells of other cancer types, 786-O (VHL-mutant RCC) showed decreases of both Phospho-PAK4 and Phospho-β-catenin after 24 h of incubation with 10 μM KPT-8752. In addition, both 786-O and ACHN (VHL-wildtype RCC cells) showed a marked time-dependent decrease in cell viability from 24 to 72 h of incubation from 2 to 10 μM of KPT-8752. KPT-9274 was orally administered at 25 and 100 mg/kg twice a day for 5 days/week to Caki-1 (VHL-wildtype RCC) and 786-O subcutaneous nude mouse xenograft models. In these studies the tumor growth rate was attenuated at both doses in the 786-O cells and at the higher dose for Caki-1 cells. There was no obvious change in the health of any of the animals suggesting manageable tolerability. We are currently evaluating combination therapy in our laboratory. In summary, PAK4 inhibitors show considerable promise as novel treatments of RCC as a single agent and warrant further investigation.
Citation Format: Omran Abu Aboud, William Senapedis, Yosef Landesman, Erkan Baloglu, Robert H. Weiss. Inhibition of PAK4 attenuates renal cell carcinoma (RCC) growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2644. doi:10.1158/1538-7445.AM2015-2644
Abstract 2645: Preclinical validation of Myc inhibition by a new generation of Omomyc-based inhibitors
Authors: Beaulieu Marie-Eve , Jauset Toni , Massó-Vallés Daniel , Whitfield Jonathan , Serrano Erika , Montagne Martin , Lavigne Pierre , Villaverde Antonio , Pesarrodona Mireia , Vazquez Esther , Soucek Laura 
Published: August 2015

Abstract
Deregulated Myc is associated with most human cancers suggesting that its inhibition would be a useful therapeutic strategy. Indeed, we have shown that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer (i.e. skin, lung, pancreatic cancer and glioma) and causes only mild, well-tolerated and reversible side effects in normal tissues. Furthermore, we demonstrated that Myc has a non-degenerate function in cancer that cannot be replaced by other pathways, even in the most aggressive p53-null tumors. Therefore, Myc could be targeted safely and successfully without eliciting resistance to therapy.
For these studies we employed a dominant negative inhibitor of Myc, called Omomyc, which is an effective inhibitor of Myc transactivation function both in vitro and in vivo. Omomyc has so far been utilized exclusively as a transgene and served as a successful proof of principle. Here we discuss our current research with Omomyc and our efforts to develop a clinically viable approach to Myc inhibition. One is based on the direct use of Omomyc itself as a peptide since we have discovered that it natively possesses cell-penetrating activity and it rapidly biodistributes to the lung and brain after intranasal administration. We are finding that the Omomyc peptide - like its transgenic counterpart before - has a therapeutic impact and we are continuing with the preclinical validation of this innovative therapeutic approach to pharmacological Myc inhibition. The second approach takes advantage of state-of-the-art nanocarrier technology to deliver Omomyc systemically, that can be combined with tumour-targeting ligands. These two novel Myc inhibition strategies have the potential to be translated rapidly to the clinic.
Citation Format: Marie-Eve Beaulieu, Toni Jauset, Daniel Massó-Vallés, Jonathan Whitfield, Erika Serrano, Martin Montagne, Pierre Lavigne, Antonio Villaverde, Mireia Pesarrodona, Esther Vazquez, Laura Soucek. Preclinical validation of Myc inhibition by a new generation of Omomyc-based inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2645. doi:10.1158/1538-7445.AM2015-2645
Abstract 2646: Targeting cancer stem cell pathways with cell-permeable peptide inhibitors
Authors: Arndt Verena , Friebe Annette , Meuser Elena , Ross Katharina , Agerer Franziska , Schulten-Schulz Carmen , Waak Jens , Friedrich Daniel , Hennemann Hanjo , Vollmer Jörg 
Published: August 2015

Abstract
Direct targeting of several important cancer pathways has so far proved challenging, owing to the lack of pathway-specific targets that can be accessed by conventional small molecule drugs or therapeutic antibodies. Nexigen develops and advances peptide-based cancer therapeutics, a new class of drugs that functionally modulate currently undruggable pathways by targeting intracellular protein-protein-interactions.
One of these undruggable pathways, the Wnt signaling cascade, has been identified as a key pathway in cancer stem cells maintenance. Targeting oncongenic Wnt signaling therefore holds great promise for tackling not only tumor growth but also disease relapse, metastasis and drug resistance. Using our proprietary next generation peptide screening system, we could identify cell-permeable peptides that efficiently inhibit the Wnt pathway through a specific interaction with a key component of intracellular signaling. Our most advanced preclinical candidate has nanomolar target affinity and significantly reduces the expression of Wnt target genes in triple-negative MDA-MB-231 breast cancer cells. The further functional analysis of the peptide in various cancer cell lines revealed a dose-dependent inhibition of cell migration, invasion, proliferation, and the cancer stem cell phenotype. The siRNA-mediated knock-down of the target protein or the inhibition of the Wnt pathway recapitulated the inhibitory peptide effect in these assays. Most importantly, we observed a significant suppression of primary tumor growth, tumor cell self-renewal and a reduction of metastatic potential after treatment in different xenograft models.
In summary, our data suggest that our Wnt pathway peptide inhibitor could be a promising new drug candidate for the treatment of cancer stem cells in a broad diversity of cancers.
Citation Format: Verena Arndt, Annette Friebe, Elena Meuser, Katharina Ross, Franziska Agerer, Carmen Schulten-Schulz, Jens Waak, Daniel Friedrich, Hanjo Hennemann, Jörg Vollmer. Targeting cancer stem cell pathways with cell-permeable peptide inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2646. doi:10.1158/1538-7445.AM2015-2646
Abstract 265: Robust anti-tumor effects of combined anti-CD4 depleting antibody and anti-PD-1/PD-L1 immune checkpoint antibody treatment in mice
Authors: Ito Satoru , Matsushima Kouji , Ueha Satoshi , Yokochi Shoji , Ishiwata Yoshiro , Hachiga Kosuke , Ogiwara Haru , Chand Krishant , Nakajima Takumi 
Published: August 2015

Abstract
Depletion of CD4+ cells in tumor-bearing mice has strong anti-tumor effects. However, the mechanisms underlying these effects and the therapeutic benefits of CD4+ cell depletion relative to other immunotherapies have not been fully evaluated. Here, we investigated the anti-tumor effects of an anti-CD4 depleting monoclonal antibody (mAb) as a monotherapy or in combination with immune checkpoint mAbs. In B16F10, Colon 26 or LLC subcutaneous tumor models, administration of the anti-CD4 mAb alone had strong anti-tumor effects that were superior to those elicited by CD25+ Treg depletion or other immune checkpoint mAbs, and which were completely reversed by CD8+ cell depletion. CD4+ cell depletion led to the proliferation of tumor-specific CD8+ T cells in the draining lymph node and increased infiltration of PD-1+CD8+ T cells into the tumor, with a shift towards type I immunity within the tumor. Combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti-PD-1 or anti-PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival. To our knowledge, this work represents the first report of robust synergy between anti-CD4 and anti-PD-1 or anti-PD-L1 mAb therapies.
Citation Format: Satoru Ito, Kouji Matsushima, Satoshi Ueha, Shoji Yokochi, Yoshiro Ishiwata, Kosuke Hachiga, Haru Ogiwara, Krishant Chand, Takumi Nakajima. Robust anti-tumor effects of combined anti-CD4 depleting antibody and anti-PD-1/PD-L1 immune checkpoint antibody treatment in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 265. doi:10.1158/1538-7445.AM2015-265
Abstract 2650: PI 3-Kinase inhibitors enhance the synthetic lethality of Parp inhibitors
Authors: Juvekar Ashish P. , Yadegarynia Sina , Hu Hai , Lyssiotis Costas A. , Liu Hui , Asara John M. , Scully Ralph , Cantley Lewis C. , Wulf Gerburg M. 
Published: August 2015

Abstract
Introduction: Clinical trials have shown promising responses of BRCA-linked breast and ovarian cancers to PARP inhibitor therapy, but remissions are often short-lived and incomplete. Frequent loss of INPP4B and PTEN leads to activation in the PI3K pathway in TNBC, making the PI3K pathway an attractive treatment target. Here we present mechanistic data that explain how PI3K- and PARP-inhibition enhance each other.
Methods: We examined the effects of PI3K-inhibitors BKM120 or BYL719 and PARP-inhibitor Olaparib on the metabolism of HCC1937 cells (BRCA1 5382C mutation and homozygous deletion of PTEN and p53) measuring lactic acid production, via seahorse analysis, carbon metabolism using targeted Mass Spectrometry (LC-MS/MS) and DNA synthesis. PI3K- but not Akt- or SGK-inhibition induced a DNA damage response in this BRCA1 mutant cell line as well as in a mouse model of BRCA1-related breast cancer (K14-Cre BRCA1f/f p53f/f) mouse model.
Summary: Metabolic profiling showed that PI3K-inhibition decreased flux through glycolysis and specifically through the non-oxidative pentose-phosphate pathway, the main source of ribose-5-phosphate required for the de novo synthesis of nucleotides in BRCA1-mutant breast cancer cells. Nucleotide shortage led to replication stress with the appearance of γH2AX, increased poly-ADP-ribosylation and an acute drop in DNA synthesis in cell cultures as well as in vivo. PI3K inhibition led to a reduced and error-prone S-phase due to a decrease in nucleotide biosynthesis which could be rescued upon exogenous supply of nucleosides. In a mouse model (K14-Cre BRCA1f/fp53f/f induced breast cancers) we could confirm that both BKM120 and BYL719 enhanced the efficacy of Parp-inhibitor Olaparib (median PFS for Olaparib 50 days, for BKM120 4 days, for BYL719 6 days and for both combinations, BKM120+Olaparib and BYL719+Olaparib &gt; 120 days).
Conclusion: Preceding cell cycle arrest, PI3K-inhibition leads to a decrease in DNA synthesis due to decreased Ribose-5-phosphate production required for nucleotide synthesis. PI3K-inhibitors lower nucleotide pools, lead to impaired DNA damage repair and S-phase progression and further augment the synthetic lethality of Parp-inhibitors in BRCA1-related breast cancer.
Citation Format: Ashish P. Juvekar, Sina Yadegarynia, Hai Hu, Costas A. Lyssiotis, Hui Liu, John M. Asara, Ralph Scully, Lewis C. Cantley, Gerburg M. Wulf. PI 3-Kinase inhibitors enhance the synthetic lethality of Parp inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2650. doi:10.1158/1538-7445.AM2015-2650
Abstract 2666: PI3K inhibition induces homologous repair defects in endometrioid endometrial cancer patient derived xenografts leading to synergistic anti-tumor activity with PARP inhibitors
Authors: Rueda Bo , Digloria Celeste , Hall Tracilyn , Foster Rosemary , Borger Darrell , Growdon Whitfield 
Published: August 2015

Abstract
Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to induce defective homologous repair in breast carcinoma leading to heightened sensitivity to poly-ADP ribose polymerase (PARP) inhibitors. Our objective was to assess the effects on DNA repair pathways following single agent and combined PI3K and PARP inhibition utilizing endometrial cancer (EnCa) patient derived xenografts (PDX) with and without identified PIK3CA mutations. Under an institutional protocol, tumors from consenting patients with endometrioid carcinoma were collected at the time of primary surgery and genotyped for common oncogenic mutations utilizing the SNaPshot® platform. NOD/SCID mice bearing xenografts derived from two primary human endometrioid endometrial tumors with and without PIK3CA gene mutations (ENCA1 & ENCA2 respectively) were divided into four arm cohorts with equivalent tumor volumes. Vehicle or NVP BKM-120 (30 mg/kg) was administered alone and in combination with veliparib (25 mg/kg) and endometrial xenograft tumor volumes were assessed. Immunoblotting was used to assess downstream PI3K pathway and DNA repair pathway alterations in post treatment samples at specific time points. While NVP BKM120 as a single agent failed to induce significant anti-tumor activity compared to vehicle in either model, decreased pAKT, RAD51 and increased γ-H2AX levels were observed in response to NVP BKM120 alone. PIK3CA mutation status did not affect these molecular alterations. Dual NVP BKM-120 and veliparib therapy significantly impeded tumor growth (p &lt; 0.01) in the ENCA1 model, while in ENCA2, significant tumor regression was observed (p &lt; 0.001). No changes in mouse weight or premature death were observed in the various treatment arms. Combination therapy was associated with reconstitution of baseline RAD51 and increased γ-H2AX levels. In conclusion, these results suggest that PI3K inhibition induces defects in homologous repair mediated by RAD51 and increases reliance on PARP mediated DNA repair mechanisms. Our in vivo data suggest that PI3K inhibition sensitizes endometrial tumors with and without PIK3CA mutations to a PARP inhibitor.
Citation Format: Bo Rueda, Celeste Digloria, Tracilyn Hall, Rosemary Foster, Darrell Borger, Whitfield Growdon. PI3K inhibition induces homologous repair defects in endometrioid endometrial cancer patient derived xenografts leading to synergistic anti-tumor activity with PARP inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2666. doi:10.1158/1538-7445.AM2015-2666
Abstract 2672: Characterization of the enhanced potency of PI3K inhibitor taselisib (GDC-0032) in PI3K mutant cell lines and models
Authors: Edgar Kyle A. , Nannini Michelle , Hong Rebecca , Eigenbrot Charlie , Schmidt Stephen , Young Amy , Sampath Deepak , Wallin Jeffrey J. , Friedman Lori S. 
Published: August 2015

Abstract
Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene or loss of the tumor suppressor PTEN. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis; thus PI3K is a promising therapeutic target with multiple inhibitors in clinical trials. The current study investigates preclinical mechanism of action of taselisib (GDC-0032), a novel, oral, selective inhibitor of PI3K alpha sparing inhibition of PI3K beta. In preclinical studies, taselisib demonstrates greater potency in cancer cell lines harboring activating PI3K alpha mutations vs wild-type lines. Taselisib induces tumor growth arrest and regressions at tolerated doses in xenograft and patient-derived xenograft (PDX) tumor models bearing PI3K alpha mutations. Notably, taselisib is distinguished from other PI3K inhibitors by enhanced potency in PI3K alpha mutant isogenic cells compared to parental cells. Pathway inhibition and apoptosis are associated with the enhanced activity of taselisib in PI3K alpha mutant cells. Other PI3K inhibitors, including PI3K alpha selective and pan-PI3K inhibitors, do not achieve the same level of activity in PI3K alpha mutant cell lines. Taselisib is more effective at maintaining suppression of the signaling pathway upon activation of Receptor Tyrosine Kinases (RTKs), such as after alleviation of negative feedback within the pathway. Additionally, a screen to evaluate secreted factors contributing to pan-PI3K inhibitor resistance was carried out in SW48 parental and PI3Kα H1047R isogenic cells. Growth factor ligands for the EGFR family were found to reduce the activity of PI3K inhibitors. Taken together, taselisib offers greater preclinical activity in PI3K alpha mutant cells when compared to other PI3K inhibitors, which may indicate a wider therapeutic index.
Citation Format: Kyle A. Edgar, Michelle Nannini, Rebecca Hong, Charlie Eigenbrot, Stephen Schmidt, Amy Young, Deepak Sampath, Jeffrey J. Wallin, Lori S. Friedman. Characterization of the enhanced potency of PI3K inhibitor taselisib (GDC-0032) in PI3K mutant cell lines and models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2672. doi:10.1158/1538-7445.AM2015-2672
Abstract 2680: Cyclic AMP signaling in melanoma: Paradoxical downregulation of pCREB upon activation of adenylate cyclase confers resistance to MAPK inhibition
Authors: Rodriguez Carlos I. , Setaluri Vijayasaradhi 
Published: August 2015

Abstract
Melanoma, which arises from malignant transformation of melanocytes, has proven to be difficult to treat due its intrinsic and acquired resistance for chemotherapy. Although polymorphisms in the melanocortin receptor 1 (MC1R), which result in impairment of cyclic AMP (cAMP) signaling, are associated with increased risk for melanoma development, the role of cAMP signaling in melanoma, specifically in drug resistance, is not fully understood. Given the importance of cAMP signaling in melanocytes proliferation and differentiation, we investigated the role of cAMP signaling in melanoma cell proliferation, survival and drug resistance. We found that upregulation of cAMP signaling, through activation of adenylate cyclase with forskolin (FSK), has both positive and negative effects on proliferation and survival of melanoma cells. The effect of FSK on melanoma proliferation and survival was not dependent on oncogenic (RAS vs. BRAF) mutation. Moreover, upregulation of cAMP conferred resistance to Selumetinib (AZD6244)-mediated MAPK inhibition by restoring the pERK levels. We also show that FSK-mediated resistance is paradoxically related to a downregulation of phosphorylated cAMP Responsive Element Binding Protein (pCREB), suggesting a CREB-independent mechanism of FSK-induced MAPK reactivation in acquired drug resistance.
Citation Format: Carlos I. Rodriguez, Vijayasaradhi Setaluri. Cyclic AMP signaling in melanoma: Paradoxical downregulation of pCREB upon activation of adenylate cyclase confers resistance to MAPK inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2680. doi:10.1158/1538-7445.AM2015-2680