bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4809: Combination therapy targeting ribosome biogenesis and mRNA translation provides a novel and potent therapeutic approach to treat MYC-driven malignancy
Authors: Devlin Jennifer R. , Rebello Richard J. , Hannan Katherine M. , Cullinane Carleen , Drygin Denis , Risbridger Gail P. , Furic Luc , Hannan Ross D. , Pearson Richard B. 
Published: July 2016

Abstract
MYC-driven malignancies are associated with elevated rates of ribosome biogenesis and mTORC1/eIF4E-driven protein synthesis suggesting they may be vulnerable to therapeutic strategies that target the ribosome. We investigated the therapeutic efficacy of targeting multiple nodes of the network controlling the ribosome in mouse models of MYC-driven lymphoma (Eì-Myc) and prostate cancer (HI-MYC). Simultaneous inhibition of ribosomal RNA synthesis and repression of protein translation was achieved by utilizing the novel RNA polymerase I inhibitor CX-5461 and PI3K/AKT/mTORC1 and PIM 1 signaling inhibitors.
Combined inhibition of ribosome biogenesis and function significantly improved therapeutic outcomes in lymphoma and prostate cancer models. CX-5461 and Everolimus (mTORC1 inhibitor) co-treatment more than doubled the survival of Eì-Myc lymphoma-bearing mice. While both classes of inhibitor suppress rDNA transcription, they treat MYC-driven malignancy through distinct molecular mechanisms facilitating their combinatorial effects. In contrast to CX-5461, PI3K/AKT/mTOR pathway inhibitors did not activate a nucleolar stress response and p53-dependent apoptosis but instead induce B-lymphoma cell death via the upregulation of the BH3-only protein BMF (Devlin et al Cancer Discovery 2015 Oct 21. pii: CD-14-0673. [Epub ahead of print]). PIM kinase has been shown to regulate eIF4Edriven protein synthesis on prostate cancer cell lines. Co-treatment of HI-MYC mice with CX-5461 and the PIM kinase inhibitor CX-6258 reverted highly invasive disease to low-grade prostate intraepithelial neoplasia.
These findings demonstrate that MYC driven tumors are addicted to multiple regulatory steps associated with ribosome synthesis and function and coordinated targeting of these addictions provides an effective new therapeutic approach to treat MYC driven cancers.
Citation Format: Jennifer R. Devlin, Richard J. Rebello, Katherine M. Hannan, Carleen Cullinane, Denis Drygin, Gail P. Risbridger, Luc Furic, Ross D. Hannan, Richard B. Pearson. Combination therapy targeting ribosome biogenesis and mRNA translation provides a novel and potent therapeutic approach to treat MYC-driven malignancy. [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 4809.
Abstract 4811: Global demethylation with decitabine increases DNA repair and sensitizes melanoma to carboplatin
Authors: Budden Timothy , Davey Ryan J. , Vilain Ricardo E. , Ashton Katie A. , Braye Stephen , van der Westhuizen Andre , Bowden Nikola A. 
Published: July 2016

Abstract
Global genome repair (GGR) is critical for recognizing DNA damage by the chemotherapy agent carboplatin, and triggering apoptotic signalling. XPC is a critical gene in the GGR pathway but in melanoma XPC is not induced in response to carboplatin resulting in extreme resistance. Despite low global methylation levels across the melanoma genome, there is evidence methylation plays a role in suppression of XPC. 5-aza-2’-deoxycytidine (decitabine), is a DNA methyltransferases inhibitor used as a chemotherapy agent that results in global loss of methylation and re-expression of silenced genes. We hypothesised that restoring expression of XPC in melanoma using decitabine could overcome resistance to carboplatin. To confirm low XPC in melanoma tumour tissue, transcript and protein expression from 196 advanced primary and metastatic melanomas was quantified and compared to normal tissue and other cancer types. Melanoma cell lines with low baseline XPC were treated with pharmacological doses of decitabine or carboplatin alone, or in sequential combination. XPC transcript, apoptosis, proliferation, senescence, global and CpG island shore demethylation was quantified. XPC transcript and protein was low in a proportion of melanoma tumours and expression correlated with overall survival. Treatment of melanoma cells with carboplatin alone did not significantly induce XPC expression or increase apoptosis in the majority of melanoma cell lines. Decitabine decreased global methylation (average 44.67% decrease) and increased XPC expression (0.9-3.0 fold increase). Hotspots of demethylation after decitabine treatment in the XPC CpG island shore were detected and could be responsible for the increase in XPC expression. When carboplatin was administered following decitabine, a greater XPC induction (1.5-7.6 fold increase) occurred with significantly increased levels of apoptosis (1.6-2.2 fold increase). This was coupled with a decreased proliferation and the presence of markers of senescence. Knocking down XPC expression with siRNA significantly reduced the effects of combination treatment. The outcomes of this study are evidence that silencing of XPC by methylation is a mechanism of carboplatin resistance in melanoma and sequential combination of decitabine followed by carboplatin may be used to restore GGR function and overcome resistance.
Citation Format: Timothy Budden, Ryan J. Davey, Ricardo E. Vilain, Katie A. Ashton, Stephen Braye, Andre van der Westhuizen, Nikola A. Bowden. Global demethylation with decitabine increases DNA repair and sensitizes melanoma to carboplatin. [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 4811.
Abstract 4837: Design, synthesis, and biological evaluation of thieno[2,3-d] and thieno[3,2-d]pyrimidines as dual acting RTK inhibitors and microtubule targeting antitumor agents
Authors: Gangjee Aleem , Islam Farhana , Quadery Tasdique Mohammad , Mooberry Susan L. , Bastian Anja , Ihnat Michael A. 
Published: July 2016

Abstract
Microtubules, attractive targets for drug development as anticancer agents, play vital roles in multiple aspects of cellular metabolism. These agents have been successfully used in the clinic for the treatment of various cancers. However, the utility of such agents are often limited by the emergence of tumor resistance due to overexpression of P-glycoprotein and/or âIII-tubulin. Tumor angiogenic mechanisms are important for tumor growth and metastasis are inhibited by antiangiogenic agents (AAs). AAs are usually cytostatic, and their utility in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of antiangiogenic agents with antitubulin agents have been particularly successful. Recently, we reported water-soluble tubulin targeting pyrrolo[2,3-d]- and pyrrolo[3,2-d]pyrimidine analogs as antitumor agents, that circumvent drug resistance. These analogs also possess RTK (EGFR, VEGFR2 and PDGFRâ) inhibitory activity. To further explore the activity of these dual RTK/tubulin inhibitors we designed isosteric thieno[2,3-d] pyrimidine and thieno[3,2-d]pyrimidine analogs which increased microtubule depolymerizing potency by 14 to 24-fold (AG95 IC50 = 7.0 ± 2.7 nM, AG370 IC50 = 7.6 ± 2.1 nM) compared with the lead compounds (AG85 IC50 = 96.6 ± 5.3 nM, AG20 IC50 = 183 ± 3.4 nM). Substitution at the 4-anilino position of both these scaffolds were also explored with various moieties to afford the 6-methoxy-tetrahydroquinoline moiety which possess the optimum balance of microtubule depolymerizing activity (AG372 IC50 = 4.3 ± 1.6 nM, AG337 IC50 = 3.4 ± 0.9 nM,) and RTK (EGFR, VEGFR2 and PDGFRâ) inhibitory activity. These two compounds demonstrated excellent inhibition for EGFR (IC50 = 12.6 ± 1.2 nM, 28.5 ± 3.9 nM), VEGFR-2 (25.2 ± 7.2 nM, 216.1 ± 18.6 nM) and PDGFRâ (IC50 = 25.6 ± 7.2 nM, 266.8 ± 35.4 nM) comparable to the standard clinically used agents. These attributes of the 4-N-substituted thieno pyrimidines provides the impetus for further development of these compounds as dual acting targeted antitumor agents.
Citation Format: Aleem Gangjee, Farhana Islam, Tasdique Mohammad Quadery, Susan L. Mooberry, Anja Bastian, Michael A. Ihnat. Design, synthesis, and biological evaluation of thieno[2,3-d] and thieno[3,2-d]pyrimidines as dual acting RTK inhibitors and microtubule targeting antitumor agents. [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 4837.
Abstract 484: Pre-treatment platelet counts as a prognostic factor in stage II and III rectal adenocarcinoma
Authors: Voutsadakis Ioannis , Steele Morgan 
Published: July 2016

Abstract
Background. Thrombocytosis is often associated with malignancies and has been confirmed as an adverse prognostic factor in various cancers. We investigated if pre-treatment elevated platelet counts could provide prognostic information in patients with stage II and III rectal adenocarcinoma that received neo-adjuvant treatment before surgery.
Patients and Methods. Platelet number on diagnosis of stage II and III rectal cancer was evaluated in 51 patients receiving neo-adjuvant treatment and for whom there were complete follow-up data on progression and survival, as well as pathologic outcome at time of surgery. Pathologic response after neo-adjuvant treatment of patients with lower platelet counts (150-300× 109/L) was compared with that of patients with higher platelet counts (&gt;300× 109/L) by the χ2 test. Overall and progression free survival Kaplan-Meier curves of the two groups were constructed and compared with the LogRank test.
Results. A significant difference was present between the two groups in regards to pathologic response with patients with lower platelet counts being more likely to exhibit a good or complete response to neo-adjuvant treatment than patients with higher platelet counts (P = 0.015). There was also a significant difference between the CEA at presentation of patients that exhibited a good or complete response and those that had no response or a minimal to moderate response. Patients with a good or complete response were more likely to present with a CEA of less than 5 (P = 0.00066). There was no significant difference in overall and progression free survival between the two groups (LogRank tests p = 0.42 and p = 0.35, respectively).
Conclusion. In this retrospective analysis of stage II and III rectal cancer patients, platelet counts at the time of diagnosis had prognostic value for neo-adjuvant treatment pathologic effect. Pre-treatment CEA also held prognostic value in regards to treatment effect.
Citation Format: Ioannis Voutsadakis, Morgan Steele. Pre-treatment platelet counts as a prognostic factor in stage II and III rectal adenocarcinoma. [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 484.
Abstract 4840: The role of the metal scaffold in the development of cytotoxic metal complexes
Authors: Glazer Edith C. 
Published: July 2016

Abstract
Multiple cytotoxic metal compounds are known, but structure activity relationships can be difficult to determine in these complex molecules. It is tempting to generalize the activity or off-target effects of the compounds to being related to the identity of the metal, or alternatively, to some specific “active” ligand features, but this is a misleading oversimplification that can slow the development of new therapeutics. In this presentation a systematic study of the impact of the metal center, one specific “active” ligand, and the inactive “coligands” that create the metal scaffold will be presented. There is clear evidence that each component plays a role in both desired and potentially deleterious off-target activities, providing the opportunity to adjust each of these three components independently to generate optimized potential anti-cancer agents.
Citation Format: Edith C. Glazer. The role of the metal scaffold in the development of cytotoxic metal complexes. [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 4840.
Abstract 4847: Discovery, semisynthesis, and structure-activity relationship studies of hirsutinolide derivatives as new STAT3 inhibitors and anti-glioma agents
Authors: Zhang Mingming , Youn Ui Joung , Miklossy Gabriella , Wongwiwatthananukit Supakit , Turkson James , Chang Leng Chee , Sun Dianqing 
Published: July 2016

Abstract
Clinically, natural product has played a pivotal role in anticancer drug discovery and development. Cancer chemotherapy and/or radiotherapy due to glioma treatment are not ideal, frequently cause unwanted adverse effects, and justify further research and development of alternative, novel, safe, and effective agents. In our continued efforts to identify new signal transducer and activator of transcription 3 (STAT3) and antiglioma agents with enhanced efficacy and specificity, we have initiated a collaborative and multidisciplinary natural product drug discovery project and the goal was to isolate, semisynthesize, and evaluate the potential of Vernonia cinerea-derived phytochemicals as STAT3 inhibitors with therapeutic remedy of human glioma and may be even more effective than the existing ones. To date, our preliminary studies have been conducted and resulted in the discovery of a class of sesquiterpene lactone hirsutinolide series with an á,â-unsaturated-ã-lactone ring as new STAT3 inhibitors. Specifically, on the basis of encouraging biological data and to expand the existing structure activity relationship (SAR) of isolated natural hirsutinolide analogues, chemical modifications were performed using conventional Steglich esterification protocol to produce a series of semisynthetic hirsutinolide derivatives in moderate to high yields. Thus far, biological evaluation revealed that several semisynthetic analogues showed low micromolar inhibitory activities against constitutively-active STAT3 and malignant glioma phenotype. SAR showed that a bulky and lipophilic ester functionality at position 13 is essential for STAT3 inhibition as well as whole cell based anticancer activity. A lipophilic side chain at position 8 also plays an important role in anticancer activity and may contribute a detrimental effect on specificity. In addition, the methoxy group at position 1 enhances the cell-type specificity and selectivity. Finally, selected promising lead candidates also demonstrated in vivo efficacy following oral gavage delivery, inhibiting human glioma tumor growth in subcutaneous mouse xenografts. Together, natural and chemically modified hirsutinolide-type sesquiterpene lactones represent a promising natural product class of new anticancer agents for the treatment of malignant human glioma.
Citation Format: Mingming Zhang, Ui Joung Youn, Gabriella Miklossy, Supakit Wongwiwatthananukit, James Turkson, Leng Chee Chang, Dianqing Sun. Discovery, semisynthesis, and structure-activity relationship studies of hirsutinolide derivatives as new STAT3 inhibitors and anti-glioma agents. [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 4847.
Abstract 4851: Second generation 2,3-dihydroimidazo[1,2-c]quinazoline PI3K inhibitors: development of BAY 1082439, a novel balanced PI3Ká / PI3Kâ inhibitor
Authors: Scott William J. , Liu Ningshu , Hägebarth Andreas , Möwes Manfred , Mönning Ursula , Bömer Ulf , Mumberg Dominik , von Nussbaum Franz , Brands Michael , Lafranc Julien 
Published: July 2016

Abstract
The phosphoinositide-3 kinase (PI3K) pathway plays critical roles in cancer cell growth and survival, as well as in intrinsic and acquired resistance to both chemotherapy and targeted agents. These essential roles of PI3K in human cancer have led to the clinical development of PI3K pathway inhibitors. Due to the complexity derived from the existence of various PI3K isoforms (á, ß, ã, ∂), and their differential roles in signal transduction as well as cancer pathology, investigation of PI3K inhibitors with differential isoform activity profiles would allow potential use in novel indications. Mutation or amplification of PIK3CA and/or activation of PI3Ká (e.g., through oncogenic RTKs) are found frequently in a variety of cancers, making this isoform a prime target for anti-cancer therapy. In addition, the role of PI3Kß in PTEN-deficient tumors, as well as in acquired resistance to PI3Ká, has been described. This led to the hypothesis that development of a dual PI3Ká / PI3Kß inhibitor might provide a unique efficacy profile.
The discovery of a novel class of 2,3-dihydroimidazo[1,2]quinazoline PI3K inhibitors, and its optimization to afford the i.v. PI3Ká/∂ inhibitor copanlisib (IC50 ratio of 1:7 in biochemical assays of PI3Ká vs. PI3Kß) has been reported recently. Herein is described the structure-activity relationship (SAR) leading to potent oral 2,3-dihydroimidazo[1,2]quinazoline PI3K inhibitors with balanced PI3Ká and PI3Kß activity, and to the selection of BAY 1082439, as a clinical candidate.
BAY 1082439 has an IC50 ratio of 1:3 in biochemical assays of PI3Ká (4.9 nM) vs. PI3Kâ (15.0 nM). In addition, BAY 1082439 has unique pharmacokinetic (PK) properties with very high plasma free fractions across all species tested (33-50%), large Vss, high clearance and intermediate T1/2. Thus, BAY 1082439 represents a PI3K inhibitor with a novel pharmacological profile, warranting exploration in clinical development. BAY 1082439 is currently being studied in a phase I trial for subjects with advanced malignancies (NCT01728311).
Citation Format: William J. Scott, Ningshu Liu, Andreas Hägebarth, Manfred Möwes, Ursula Mönning, Ulf Bömer, Dominik Mumberg, Franz von Nussbaum, Michael Brands, Julien Lafranc. Second generation 2,3-dihydroimidazo[1,2-c]quinazoline PI3K inhibitors: development of BAY 1082439, a novel balanced PI3Ká / PI3Kâ inhibitor. [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 4851.
Abstract 4858: LADR™: A novel linker activated drug release technology for drug delivery
Authors: Abu Ajaj Khalid , Koester Stephan David , Nollmann Friederike Inga , Waltzer Simon , Fuchs Olga , Warnecke André , Kratz Felix 
Published: July 2016

Abstract
Drug delivery systems in oncology for treating cancer are based on different drug release mechanisms at the tumor site including primarily hydrolytic, reductive, enzymatic and/or acid-sensitive cleavage. Drug carrier conjugates that incorporate an acid-sensitive breaking-point exploit the extra- and intracellular acidic environment of the tumor. Important requirements for acid-sensitive bonds are high stability of the carrier-bound drug in the blood circulation and an effective or sustained release of the active drug in the acidic tumor interstitium and acidic endosomes/lysosomes of tumor cells. In addition, sufficient stability of the acid-sensitive bond is a prerequisite for galenic formulation and reconstitution. As a continuation of our development of aldoxorubicin, an acid-sensitive albumin-binding drug of doxorubicin, which is being clinically assessed in advanced clinical trials (www.cytrx.com), we have set out to design a novel acid-sensitive drug release platform that is applicable to carriers such as serum proteins and antibodies.
The key components of this specific drug delivery system are linkers containing a thiol-binding maleimide group and a substituted aromatic hydrazine to form an acid-cleavable hydrazone bond with suitable carbonyl-containing drugs. For establishing and fine-tuning the pH-dependent release profiles, the aromatic moiety of the linker was substituted with a spectrum of electron-withdrawing groups, and reacted with the anthracyclines doxorubicin and nemorubicin. The resulting hydrazone derivatives were conjugated to the cysteine-34 position of albumin as a model protein. Subsequently, the drug release was determined at physiological and acidic conditions as well as in human plasma. It was discovered that by variation of the electron-withdrawing groups, the pH dependent release of the drug could be substantially varied between 1-50 h in the pH range of 4-5. The technology using these linkers was coined LADR™ (Linker Activated Drug Release) and has the additional advantage that the galenic formulation and reconstitution of LADR™-based drugs is facilitated. We have applied the LADR™ technology to several anticancer drugs such as vinblastine and gemcitabine. In summary, LADR™ is an innovative and versatile linker technology creating a platform for developing acid-sensitive drug carrier conjugates that allow the carrier-bound drug to be released in a controlled manner resulting in sustained exposure to cancer cells.
Citation Format: Khalid Abu Ajaj, Stephan David Koester, Friederike Inga Nollmann, Simon Waltzer, Olga Fuchs, André Warnecke, Felix Kratz. LADR™: A novel linker activated drug release technology for drug delivery. [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 4858.
Abstract 4860: The BTK inhibitor ibrutinib modulates T cell immunity in mouse models and in differentiated human T cells
Authors: Huang Yujun , Hsu Jeff , Sirisawad Mint , Kuo Hsu-Ping , Chang Betty Y. 
Published: July 2016

Abstract
Ibrutinib inhibits Bruton's tyrosine kinase (BTK) and effectively treats B-cell malignancies. Ibrutinib also targets IL-2-inducible T-cell kinase (ITK) and modulates the T-cell receptor signaling pathway. Because ibrutinib enhanced antitumor immunity when combined with anti-PD-L1 in various syngeneic solid tumor and lymphoma models (Sajiv-Barfi, PNAS 2015), we sought to determine the effect of ibrutinib on T-cell function and activation. Using in vitro human primary T-cell activation assays, we found that ibrutinib did not suppress T-cell proliferation but slightly inhibited IFNã production in CD4 and CD8 effector T cells when human peripheral blood mononuclear cells (PBMCs) were stimulated with anti-CD3 and anti-CD28 antibodies. Ibrutinib also inhibited PD-1 expression on human CD8 effector T cells. More strikingly, ibrutinib significantly suppressed naïve murine CD4 T-cell differentiation in vitro into Foxp3+ regulatory T cells (Treg) in the presence of TGF-â. Further, we evaluated the immunomodulatory effect of ibrutinib in tumor-bearing mice. In pancreatic (Pan02) and renal cell carcinoma (Renca) models, we found that single-agent ibrutinib, as well as in combination with standard-of-care agents, effectively inhibited tumor growth. In the syngeneic Renca tumor model, combination ibrutinib treatment significantly reduced CD4+Foxp3+ Treg cells both in the spleen (P &lt; 0.001) and tumor microenvironment (P &lt; 0.05), compared with everolimus alone. Ibrutinib also significantly reduced the percentage of PD-1hi cells among CD8 tumor-infiltrating lymphocytes in A20 lymphoma-bearing mice (P &lt; 0.05). These data demonstrate that ibrutinib, a BTK inhibitor, can suppress immune-inhibitory factors and enhance antitumor immunity in vivo. Ibrutinib may serve as a promising immunomodulatory agent in potentiating current cancer immunotherapy in solid tumors.
Citation Format: Yujun Huang, Jeff Hsu, Mint Sirisawad, Hsu-Ping Kuo, Betty Y. Chang. The BTK inhibitor ibrutinib modulates T cell immunity in mouse models and in differentiated human T cells. [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 4860.