bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3816: Reactive oxygen species and ERK2 phosphorylation are required for NSC59984 to induce mutant p53 protein degradation and restore p53 signaling
Authors: Zhang Shengliang , Zhou Lanlan , Dicker David , El-Deiry Wafik S. 
Published: July 2016

Abstract
Tumor suppressor p53 is mutated in over 50% of human cancers. p53 mutation abolishes wild-type p53 function and also endows mutant p53 with a gain-of-function (GOF) that drives tumor growth and drug resistance. Targeting mutant p53 is an attractive strategy for cancer therapy. We recently reported (Zhang et al., Cancer Research, 2015) a small-molecule NSC59984 with dual capabilities to restore p53 signaling and destabilize mutant p53 protein (depleting GOF). We now demonstrate the role of reactive oxygen species (ROS) and ERK2 in the mechanism of action of NSC59984. We observe a sustained-phosphorylation of ERK2 in cancer cells treated with NSC59984. Blockade of ERK2 rescues mutant p53 from NSC59984-mediated degradation, and inhibits restoration of p53 signaling in mutant p53-expressing cells. Thus, sustained ERK2 phosphorylation is required for NSC59984-induced degradation of mutant p53 protein, and depletion of mutant p53 contributes to the restoration of p53 pathway. NSC59984 induces MDM2 phosphorylation that correlates with ERK2 phosphorylation. The effect of NSC59984 on MDM2 phosphorylation is blocked by U0126 and knockdown of ERK2. NSC59984-mediated mutant p53 protein degradation is inhibited by MDM2 knockdown, and enhanced by MDM2 overexpression. Thus, ERK2-dependent MDM2 phosphorylation is a major determinant of NSC59984-mediated mutant p53 degradation. We investigated the role of ROS in the effect of NSC59984 on ERK2 phosphorylation. ROS is induced by NSC59984 and a decrease in ROS by NAC inhibits NSC59984-induced ERK2 phosphorylation, and mutant p53 protein degradation. Increased ROS by BSO treatment enhances the NSC59984 effect on ERK2 phosphorylation, mutant p53 protein degradation and restoration of p53 signaling. We conclude that ROS is required for NSC59984 to sustain ERK2 phosphorylation, which, in turn, is required for NSC59984-induced mutant p53 protein degradation via MDM2. The combination of NSC59984 and BSO synergistically induces cell death in colorectal cancer cells. ROS and ERK2 are two important factors required for NSC59984 to degrade mutant p53 protein, restore p53 signaling and induce cell death. These results provide a rationale for clinical testing of NSC59984 in tumors with high ROS.
Citation Format: Shengliang Zhang, Lanlan Zhou, David Dicker, Wafik S. El-Deiry. Reactive oxygen species and ERK2 phosphorylation are required for NSC59984 to induce mutant p53 protein degradation and restore p53 signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3816.
Abstract 3817: Recombinant stapled proteins for the treatment of chronic myeloid leukemia
Authors: Bruno Benjamin J. , Cornillie Sean P. , Cheatham Thomas E. , Chou Daniel H. , Lim Carol S. 
Published: July 2016

Abstract
The oncoprotein Bcr-Abl is the cause of chronic myeloid leukemia (CML). Current therapies target the tyrosine kinase domain of Bcr-Abl, but due to their non-curative nature, resistance to these drugs is common. Therefore, new treatments are needed for those patients refractive to available therapies. Bcr-Abl homo-oligomerization via its N-terminal coiled coil (CC) domain is required for tyrosine kinase activity. Our previous work has shown that it is possible to inhibit Bcr-Abl activity by targeting the CC domain with a peptidomemetic known as CCmut, delivered as a protein using a cell-penetrating peptide (CPP-CCmut). CPP-CCmut selectively enters leukemic cells and inhibits Bcr-Abl, as seen by Western blot, 7AAD, Annexin V, cell proliferation, and colony forming assays.
This leukemia cell-permeable CPP-CCmut protein domain is our lead compound for CML therapy, but to be translatable to the clinic it must be modified to improve proteolytic stability. For this reason, we created stapled versions of this CPP-CCmut. Stapled peptides are resistant to proteolysis, and are emerging as a viable strategy for disrupting protein-protein interactions in diseases including HIV and cancer. Until recently, peptide stapling required incorporation of unnatural amino acids; therefore these peptides were created via solid-state synthesis. However, the synthesis of the 81 amino acid CPP-CCmut is no trivial matter. The ability to staple a longer sequence such as our protein domain is now possible using thiol-ene coupling. This exciting new chemistry allows for the stapling of recombinant proteins at substituted cysteine residues (instead of stapling substituted unnatural amino acids incorporated into synthetically made peptides). Thiol-ene coupling is used here to staple recombinant CPP-CCmut, and provides a path for translation of our lead compound to the clinic.
Molecular modeling has identified optimal locations for staples on CPP-CCmut, which include 29/36, 36/43, 50/57, 57/64, as well as double staples 29/36-50/57 and 36/43-50/57. These staple locations still allow for dimerization of CPP-CCmut with Bcr-Abl, as indicated by free energy calculations and helicity. The staple locations have also been optimized for maximal coverage from proteolytic degradation.
This work acts as a proof-of-concept that proteins (not just peptides) can be stapled, thus greatly expanding the variety and complexity of stapled proteins for use in the exciting field of targeting protein-protein interfaces to treat disease.
Citation Format: Benjamin J. Bruno, Sean P. Cornillie, Thomas E. Cheatham, Daniel H. Chou, Carol S. Lim. Recombinant stapled proteins for the treatment of chronic myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3817.
Abstract 3818: Therapeutic potential of blocking CCR5 by maraviroc in breast cancer bone metastasis
Authors: Pervaiz Asim , Zepp Michael , Ali Doaa M. , Berger Martin R. , Adwan Hassan 
Published: July 2016

Abstract
Introduction:
Bone metastasis is a highly unfavorable condition observed in up to 70% of the patients with breast cancer. Treatment options for this condition are not curative, but palliative, only, which highlights the need for exploring new therapeutic options. In this study, we propose that targeting a chemokine receptor (CCR5), often upregulated in primary and secondary breast cancers, can contribute to a more successful treatment of breast cancer bone metastasis.
Methodology:
Following the blockage of CCR5 by maraviroc, cytotoxic effects were measured by MTT assay, while the migratory effects were determined by migration and scratch healing assays. Apoptosis related activities were investigated by nuclear staining and western blot analysis. Maraviroc mediated cytostatic changes were analyzed by a ready-made Human Cell Cycle Regulation Panel (Roche, Germany). In vivo experiments were performed by implanting MDA-MB-231 cells via the saphenous artery to the left hind limb of male nude rats (RNU strain) for inducing bone metastasis. Treatment with maraviroc was started from 2nd and 7th day of transplantation in two groups of rats (n = 6/group) designated as A and B, respectively, and was compared with an untreated control group (n = 8 rats).
Results:
CCR5 blockage by maraviroc (concentration &gt; 100μM) induced concentration dependent cytotoxicity in MDA-MB-231 and MCF-7 cells. Maraviroc exposure also showed significant inhibition of migration of the cells, while nuclear staining indicated the condensation/fragmentation of nuclear content. Maraviroc exposure induced significant expression of cleaved caspase 7 and PARP, while real time RT-PCR showed pronounced inhibition of multiple genes (≥2fold) including cyclins, CDKs and their down-stream targets. Treatment of tumor bearing animals, with intra-peritoneal injections of maraviroc (25mg/kg, 3-4 weeks daily), reduced the tumor burden significantly (p &lt; 0.05) in group A (50-75%), while the effects were minimal in group B (&lt;25%). Concomitantly, no signs of toxicity were observed in rats of the two groups.
Conclusion:
CCR5 blockage by maraviroc induces significant anti-neoplastic effects in breast cancer cells. At mechanistic level, these effects included induction of apoptosis and alterations in cell cycle. Considerable inhibition in group A, but minimal inhibition of tumor burden in group B indicates that targeting CCR5 by maraviroc during early stages of breast cancer bone metastasis is a promising treatment option which should be further explored.
Citation Format: Asim Pervaiz, Michael Zepp, Doaa M. Ali, Martin R. Berger, Hassan Adwan. Therapeutic potential of blocking CCR5 by maraviroc in breast cancer bone metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3818.
Abstract 382: Concomitant administration of acid reducing agents can impact the pharmacokinetics of the balanced pan-PI3K and mTOR inhibitor PQR309
Authors: Jorga Karin , Huehn Eva , Fraczkiewicz Grace , Schmitz Debora , Fabbro Doriano , Dimitrijevic Sasa 
Published: July 2016

Abstract
Introduction
Acid reducing agents (ARAs) - such as proton pump inhibitors, H2-antagonists or antacids - are commonly prescribed medications to reduce stomach acidity in cancer patients. Increased gastric pH can significantly impair the dissolution of agents that exhibit pH-dependent solubility, thus possibly reducing their absorption and influence their pharmacokinetics (PK).
PQR309 is a novel oral balanced dual pan-PI3K and mTOR inhibitor currently in clinical development for treatment of solid tumors and hematological malignancies. PQR309 is a weak base and exhibits pH-dependent solubility. Therefore, the assessment of the potential for drug-drug interactions with ARAs is essential to avoid treatment failure in cancer patients.
Methods
GastroPlusTM v.9.0 (Simulations Plus, Inc.) was used to build a physiologically-based absorption and pharmacokinetic (PBPK) model of PQR309. A baseline model was built with the physicochemical properties of the compound and pre-clinical PK data after iv and po administration. The model was then extended using PK data from cancer patients. Volume of distribution and renal clearance were calculated using the Lukacova and fup*GFR methods, respectively. Hepatic clearance was estimated from in vitro clearance obtained in hepatocytes and the intestinal absorption was calculated by the Advanced Compartmental Absorption and Transit (ACATTM) Model.
Results
The parameter sensitivity analysis showed that at fasted stomach pH of ∼1.5, PQR309 is fully dissolved and rapidly absorbed in the upper part of gastrointestinal tract leading to a distinct maximum plasma concentration (Cmax) and a predicted bioavailability of almost 100%. At a stomach pH of 4.0 dissolution is delayed and the absorption shifted towards distal parts of the gastrointestinal tract. The predicted bioavailability is still estimated to be good (&gt; 75%), but the observed plasma concentration time profile is much shallower and the expected Cmax considerably reduced.
Conclusions
Our model predicts that concomitant administration of ARAs can impact PQR309 absorption and change its pharmacokinetic profile. The clinical relevance of this potential drug-drug interaction is unknown. In currently ongoing clinical studies co-medication of PQR309 with ARAs should be avoided until further clinical investigations confirm the model predictions and mitigation strategies are explored.
Citation Format: Karin Jorga, Eva Huehn, Grace Fraczkiewicz, Debora Schmitz, Doriano Fabbro, Sasa Dimitrijevic. Concomitant administration of acid reducing agents can impact the pharmacokinetics of the balanced pan-PI3K and mTOR inhibitor PQR309. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 382.
Abstract 383: In vitro effects of PI3K/mTOR inhibition in canine hemangiosarcoma
Authors: Pyuen Alex A. , Thamm Douglas H. 
Published: July 2016

Abstract
While extremely rare in humans, hemangiosarcoma (HSA) accounts for nearly 2% of canine neoplasia, and is characterized by both aggressive local growth/invasion and a high rate of metastasis. Both canine and human HSA exhibit sustained aberrant PI3K/Akt/mTOR pathway signaling. The purpose of this study was to examine the in vitro effects of a novel dual PI3K/mTOR inhibitor, VDC-597, in canine HSA cells. Three canine HSA cell lines (DEN-HSA, CIN-HSA, and SB-HSA) were employed in multiple in vitro assays. Western analysis evaluated activation (phosphorylation) of key downstream pro-survival proteins in the PI3K/mTOR pathway. Changes in tumor cell growth/apoptosis were assessed using both bioreductive assays (Alamar Blue) and in vitro live-cell imaging (IncuCyte), in the presence and absence of doxorubicin, a standard-of-care cytotoxic drug for canine and human sarcomas, as well as in the presence and absence of U-0126, an inhibitor of the MEK pathway. Migration was assessed using both Boyden chamber and scratch assays, via live-cell imaging (IncuCyte). Matrigel invasion was assessed using traditional Boyden chambers. Finally, ELISA was utilized to quantify relative expression of vascular endothelial growth factor (VEGF). VDC-597 suppressed activation of both Akt and 4eBP1 in canine HSA cells in a dose- and time-dependent fashion, with an IC50 of approximately 0.3 uM, a concentration predicted to be clinically achievable based on preliminary early-phase canine and human studies. VDC-597 dose-dependently reduced proliferation, migration, invasion, and VEGF expression in HSA cells, while promoting tumor cell apoptosis. VDC-597 demonstrated additive antiproliferative effects when combined with doxorubicin and U-0126. Together, these results suggest that inhibitors of the PI3K/Akt/mTOR pathway may act against multiple components of the neoplastic process, including proliferation/apoptosis, chemosensitivity, invasion/migration and angiogenesis, and justify the evaluation of PI3K/mTOR inhibitors in canine, and eventually human, HSA. Experiments to examine the effect of VDC-597 in reducing tumor burden and metastasis in a rodent model are ongoing.
Citation Format: Alex A. Pyuen, Douglas H. Thamm. In vitro effects of PI3K/mTOR inhibition in canine hemangiosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 383.
Abstract 3830: Synthesis and anticancer activity of novel prodigiosin analogs
Authors: Tian Xiaobing , Zhang Shengliang , El-Deiry Wafik S. 
Published: July 2016

Abstract
We recently reported that Prodigiosin is a potent p53 pathway restoring small molecule that acts through p73 and by interfering with p73:mutant p53 protein interaction (Hong et al., Cancer Research, 2014). Prodigiosin is the parent member of the tripyrrole alkaloid family of natural products that shows potent anti-cancer activity against tumors with mutated p53. To improve pharmacological and medicinal properties of Prodigiosin including p73 induction and restoration of the p53 pathway in tumors with mutated p53, two new series of analogs were synthesized. We introduced carboxylic group substituents either directly on the C-ring or on the side-chain of the C-ring. Carboxylic group allowed for further derivatization of Prodigiosin. A number of new analogs have been prepared and tested for their anticancer activity. Preliminary biological activity assay showed that new compounds inhibited cancer cell proliferation from 0.1 μM to 10 μM both in p53 mutated SW480 and wild-type HCT116 colorectal cancer cell lines. Some of the newly synthesized compounds can induce p53 transcriptional reporter activity in p53 mutated SW480 colorectal cancer cells. Our ongoing experiments are focused on the signaling mechanism of apoptosis induced by the new analogs, identification of molecular targets of the compounds, and in vivo studies of Prodigiosin analogues as single agents or in combination with chemotherapy or targeted therapy.
Citation Format: Xiaobing Tian, Shengliang Zhang, Wafik S. El-Deiry. Synthesis and anticancer activity of novel prodigiosin analogs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3830.
Abstract 3839: Vitamin E delta-tocotrienol targets human colon cancer stem cells and inhibits colon cancer metastasis and induces apoptosis
Authors: Husain Kazim , Coppola Domenico , Sebti Said M. , Malafa Mokenge P. 
Published: July 2016

Abstract
Background: Colon cancer is the most commonly diagnosed cancer both in men and women and cause of cancer related deaths worldwide. Treatment for the recurrent and metastatic colon cancer remains a center of clinical attention. Cancer stem cells (CSCs) are suggested to be the only cells within tumor with tumorigenic capacity and implicated in metastasis. We have shown that vitamin E delta-tocotrienol (VEDT) is the most bioactive tocotrienols against cancers. This study aimed to evaluate the effect of VEDT on colon cancer growth, metastatic epithelial to mesenchymal transition (EMT), migration/ invasion/angiogenesis and colon CSCs growth and apoptosis.
Methods: Human colon cancer cells HCT-116 and metastatic colon cancer cells SW-620 and colon CSCs were treated with VEDT (10-100 μM) for 72 h and cell viability recorded. VEDT (50 μM) was used for malignant transformation; migration/invasion, CSCs spheroid formation, and pluripotency were determined. Azoxymethane treated Fisher 344 rats were used as colon carcinogenesis model. They were treated with 1) vehicle control and 2) VEDT (200 mg/kg, orally twice a day) for 20 weeks. After 20 weeks the polyps and tumor formation were recorded.
Results: VEDT significantly inhibited the anchorage-dependent and independent cancer cell growth, migration/invasion and induced apoptosis compared to control. VEDT inhibited the CSC spheroid formation EMT (E-cadherin to vimentin), metastasis (MMP9), angiogenesis (VEGF), CSCs transcription factors (Nanog, Oct4, Sox2 and KLF4) compared to control.
Conclusion: Vitamin E delta-tocotrienol inhibited colon cancer growth and metastasis through inhibition of cancer stem cell pluripotency, EMT, migration, invasion, angiogenesis and induction of apoptosis.
Citation Format: Kazim Husain, Domenico Coppola, Said M. Sebti, Mokenge P. Malafa. Vitamin E delta-tocotrienol targets human colon cancer stem cells and inhibits colon cancer metastasis and induces apoptosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3839.
Abstract 3844: A novel liposomal Clodronate depletes tumor-associated macrophages in primary and metastatic melanoma: anti-angiogenic and anti-tumor effects
Authors: Brignole Chiara , Perri Patrizia , Piaggio Francesca , Pastorino Fabio , Di Paolo Daniela , Emionite Laura , Daga Antonio , Kondylis Vangelis , Pasparakis Manolis , Ribatti Domenico , Ponzoni Mirco 
Published: July 2016

Abstract
The depletion of tumor-associated macrophages (TAMs), involved in different stages of cancer development and progression, is an appealing strategy in cancer therapy.
We developed novel Clodronate-containing liposomes (Clo-Lipo-DOTAP) presenting good physicochemical properties (size distribution, polidispersity index and Z-potential).
In vitro, Clo-Lipo-DOTAP inhibited proliferation, reduced viability and induced apoptosis of a macrophage-like cell line in a dose- and time-dependent manner.
In proof of functionality experiments, Clo-Lipo-DOTAP depleted macrophages in a genetic mouse model of chronic hepatitis and hepatocellular carcinoma leading to a significant reduction of F4/80-positive cells in the liver and spleen of treated mice compared to PBS-treated controls. The number of granulocytes, B and T lymphocytes was not affected.
In B16/F10 subcutaneous melanoma-bearing mice, Clo-Lipo-DOTAP significantly reduced the volume of primary tumors (P &lt; 0.001). Within the tumors, the expression F4/80 and α-SMA was significantly lowered. Plasma levels of IL-10, Mo KC, TNF-α, VEGF and PDGF-bb were statistically decreased. In B16/F10 lung metastatic melanoma model, treatment with Clo-Lipo-DOTAP significantly reduced the number of pulmonary nodules (P &lt; 0.05). F4/80-positive cells and microvessel density were statistically decreased.
In conclusion, the depletion of TAMs in primary and metastatic melanoma presents anti-tumor efficacy via inhibition of angiogenesis and modulation of inflammation related cytokines.
Citation Format: Chiara Brignole, Patrizia Perri, Francesca Piaggio, Fabio Pastorino, Daniela Di Paolo, Laura Emionite, Antonio Daga, Vangelis Kondylis, Manolis Pasparakis, Domenico Ribatti, Mirco Ponzoni. A novel liposomal Clodronate depletes tumor-associated macrophages in primary and metastatic melanoma: anti-angiogenic and anti-tumor effects. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3844.
Abstract 3846: Sensitivity of NOTCH1 mutant T-ALL to ABT-263
Authors: Dastur Anahita , Costa Carlotta , Faber Anthony , Benes Cyril 
Published: July 2016

Abstract
Effective targeted therapies are lacking for refractory and relapsed T-cell Acute Lymphoblastic Leukemia (T-ALL). Analysis of a large cell line screen revealed that NOTCH1 mutant T-ALL cells are sensitive to the Bcl-2/xL inhibitor ABT-263. We show that NOTCH1 inhibits the mTOR complex 1, resulting in low MCL-1 levels and sensitization to ABT-263. Further suppression of mTORC1 using small molecule inhibitors in combination with ABT-263 results in very high levels of apoptosis and tumor regressions in vivo. This suggests new therapeutic opportunities for NOTCH1 mutant T-ALL, including in the setting of gamma-secretase inhibitor (GSI) resistance.
Citation Format: Anahita Dastur, Carlotta Costa, Anthony Faber, Cyril Benes. Sensitivity of NOTCH1 mutant T-ALL to ABT-263. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3846.