bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C240: The synthetic parasite-derived peptide GK1 increases survival in a preclinical mouse melanoma model.
Authors: Vera Aguilera Jesus , Perez Torres Armando , Vera Aguilera Carlos , Monterverde Suarez Diego , Moreno Aguilera Eduardo , Hernaiz Leonardo Juan Carlos , Estrada Barcenas Daniel 
Published: August 2014

Abstract
Purpose: The therapeutic efficacy of a synthetic parasite-derived peptide GK1, an immune response booster, was evaluated in a mouse melanoma model. This melanoma model correlates with human stage IIb melanoma, which is treated with wide surgical excision, a parallel study employing a surgical treatment was carried out as an instructive goal.
Experimental Design: C57BL/6 mice were injected subcutaneously in the flank with 2×105 B16-F10 murine melanoma cells. When the tumors reached 20 mm3, mice were separated into two different groups: the GK1 group, treated weekly with peritumoral injections of GK1 (10 μg/100 μl of sterile saline solution); and the control group, treated weekly with an antiseptic peritumoral injection of 100 μl of sterile saline solution without further intervention. All mice were monitored daily for clinical appearance, tumor size, and survival. Surgical treatment was performed in parallel when the tumor size was 20 mm3 (group A), 500 mm3 (group B) and greater than 500 mm3 (group C).
Results: The GK1 peptide effectively increased the mean survival time by 9.05 days, corresponding to an increase of 42.58%, and significantly delayed tumor growth from day 3 to 12 of treatment. In addition, tumor necrosis was significantly increased (P&lt;0.05) in the treated mice. The overall survival rates obtained with surgical treatment at 6 months were 83.33% for group A, 40% for group B and 0% for group C, with significant differences (P&lt; 0.05) among the groups.
Conclusions: The GK1 peptide demonstrated therapeutic properties in a mouse melanoma model, as treatment resulted in a significant increase in the mean survival time of the treated animals (42.58%). The potential for GK1 to be used as a primary or adjuvant component of chemotherapeutic cocktails for the treatment of experimental and human cancers remains to be determined, and surgical removal remains as a challenge for any new experimental treatment of melanoma in mouse models.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C240.
Citation Format: Jesus Vera Aguilera, Armando Perez Torres, Carlos Vera Aguilera, Diego Monterverde Suarez, Eduardo Moreno Aguilera, Juan Carlos Hernaiz Leonardo, Daniel Estrada Barcenas. The synthetic parasite-derived peptide GK1 increases survival in a preclinical mouse melanoma model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C240.
Abstract C246: SH-4-54, a novel small-molecule inhibitor of STAT3, demonstrates significant anti-tumor activity against multiple myeloma.
Authors: Li Zhi Hua , Haftchenary Sina , Croucher Danielle , Gunning Patrick T. , Trudel Suzanne 
Published: August 2014

Abstract
Aberrant STAT3 signaling is prevalent in hematologic malignancies such as Multiple Myeloma (MM) and is recognized as a master regulator of tumor processes such as survival, angiogenesis, and drug resistance. Significant efforts have therefore focused on therapeutic targeting of STAT3 as an anti-cancer strategy. Based on rational structure-based design, we present pre-clinical findings for a newly developed small molecule STAT3 inhibitor, SH-4-54. SH-4-54 was designed to block the SH2 domain of STAT3 by mimicking its native phosphopeptide binding sequence and in turn prevent phosphorylation (activation) and disrupt transcriptionally active STAT3:STAT3 dimerization. SH-4-54 has been shown to have a KD for STAT3 protein of 300 nM by surface plasmon resonance and inhibits STAT3 SH2 domain-phosphopeptide interactions as assessed by a fluorescence polarization assay.
The anti-MM activity of SH-4-54 was assessed using MTT assays against a panel of molecularly heterogeneous human myeloma cell lines (HMCLs), revealing potent and broad effects on cell viability with 10/15 HMCLs displaying IC50 values &lt; 10 μM. Moreover, SH-4-54 induced apoptotic responses in HMCLs as evidenced by increased Annexin V staining. Promising results were observed for the effects of SH-4-54 on primary patient-derived myeloma cells. Using flow cytometric analysis of CD138 as a marker of myeloma cells and Annexin V staining, SH-4-54 was found to significantly reduce the percentage of CD138+/Annexin V negative, viable myeloma cells, while displaying little to no toxicity against the non-malignant (CD138−) cell fraction. Supporting the predicted molecular mechanisms of SH-4-54 activity, immunoblot analysis revealed that SH-4-54 inhibits constitutive STAT3 phosphorylation, but does not alter STAT3 protein levels. Furthermore, using HMCLs engineered to express a STAT3-driven luciferase reporter construct, SH-4-54 was found to significantly reduce STAT3 transcriptional activity, and consistently induce a reduction in proteins that encode STAT3 target genes such as c-Myc.
Taken together, our results highlight the promising therapeutic potential of SH-4-54 and support the continued development of targeted therapies for MM with a focus on aberrant STAT signaling.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C246.
Citation Format: Zhi Hua Li, Sina Haftchenary, Danielle Croucher, Patrick T. Gunning, Suzanne Trudel. SH-4-54, a novel small-molecule inhibitor of STAT3, demonstrates significant anti-tumor activity against multiple myeloma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C246.
Abstract C291: Targeting SDF-1 (CXCL12) pathway to inhibit the recurrence of breast cancer brain metastases after whole-brain irradiation.
Authors: Chernikova Sophia , Ahn G-One , Liu Shie-Chau , Stafford Jason , Brown J. Martin 
Published: August 2014

Abstract
The presence of tumor-associated macrophages (TAMs) in tumors strongly correlates with poor outcome. At least one lineage of TAMs originates from the peripheral bone marrow-derived mononuclear cells. We have previously reported that bone marrow-derived CD11b+ myeloid cells contribute to tumor regrowth after irradiation by homing to the irradiated site, where they aid in restoring tumor vasculature. We have also shown that inhibiting the recruitment of CD11b+ monocytes/macrophages by blocking the SDF-1 (CXCL12)-CXCR4 axis prevents or delays recurrence of mouse and rat glioblastoma after irradiation. We further demonstrate that TAMs in the irradiated glioblastoma could be detected in vivo by magnetic resonance (MR) imaging of iron oxide nanoparticles phagocytosed by TAMs. Radiation remains one of the major modalities for treatment of breast cancer brain metastases (BCBMs). We hypothesized that inhibition of SDF-1 mediated neovasculogenesis may be as useful for treatment of BCBMs as it is for treatment of glioblastoma. In this study, brain metastases from MDA-MB-231-BR3 cells injected through intra-carotid artery in nude mice were detected by bioluminescence imaging. SDF-1 activity was inhibited using Spiegelmer NOX-A12. Treatment with NOX-A12 began immediately after irradiation, and continued every second day until the end of the experiment. We show that combination of NOX-A12 with 12Gy resulted in marked delay of metastatic regrowth after irradiation compared to 12Gy alone and a doubling of the survival time of the mice. Detection of TAMs using MR imaging of iron oxide nanoparticles is under way.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C291.
Citation Format: Sophia Chernikova, G-One Ahn, Shie-Chau Liu, Jason Stafford, J. Martin Brown. Targeting SDF-1 (CXCL12) pathway to inhibit the recurrence of breast cancer brain metastases after whole-brain irradiation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C291.
Abstract CN01-03: Prospects for miRNA- and lncRNA-based cancer therapeutics.
Authors: Agami Reuven 
Published: August 2014

Abstract
The past decade has witnessed a swift advance in the identification of microRNAs and elucidation of their function. In particular, miRNAs were found to present cancer-specific expression patterns, but also to encompass causative roles in cancer development and in resistance to therapy. This fundamental biological research has led to the initiation of clinical trials testing oligonucleotide-based therapies inhibiting or mimicking microRNAs. With their simple design, scalability, and systemic delivery to the body, oligonucleotide-based therapy seems easier and faster to develop, improve, and put to practice than gene and drug-based therapies. The outcome of ongoing clinical trials will determine how valuable microRNAs are as therapeutic targets.
In contrast to microRNAs, the research field of the long noncoding RNA (lncRNA) is only starting to emerge. Their recent identification, long size, typical low expression level, and excessive structure delayed progress. Principally, lncRNAs can be divided into two types; those that are spliced and polyadenylated and therefore are relatively more stable, and those that are not, and thus are very labile. While the first group may have trans and cis functions, the second mostly exert a local activity on the chromatin of neighboring genes. I will present principle examples related to the tumor suppressor p53 pathway in humans. Altogether, it appears that lncRNAs can be as powerful as microRNAs in controlling essential cellular processes. However, a dedicated preclinical investigation of lncRNAs is required to characterize and understand how they function in order to discover the best ways to control their function. Only when such pronounced fundamental understanding is achieved can we start implementing lncRNAs in therapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN01-03.
Citation Format: Reuven Agami. Prospects for miRNA- and lncRNA-based cancer therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN01-03.
Abstract CN06-04: Reversible tolerance to anticancer drugs.
Authors: Settleman Jeffrey E. 
Published: August 2014

Abstract
A variety of pathway-targeted inhibitors have recently proven to provide significant clinical benefit to genotype-defined subsets of cancer patients. However, these agents are not curative due to the relatively rapid acquisition of drug resistance in virtually all cases. In some patients, specific mutational mechanisms of acquired drug resistance have been identified, prompting the discovery and development of second-generation therapeutics that can overcome these resistance mechanisms. In addition to such genetic resistance mechanisms, our preclinical modeling studies of acquired drug resistance have revealed the heterogeneous nature of "clonal" tumor-derived cell lines, and the existence of subpopulations of cells with distinct vulnerabilities to treatments that effectively kill the vast majority of cells in the population. This seemingly stochastic spontaneous acquisition of distinct phenotypes within cancer cell populations is reversible, and therefore non-genetic in nature. We find that this stochastic switch is associated with distinct chromatin states, and that cells exhibiting the drug "tolerant" state display sensitivities to a variety of agents that are largely ineffective against the bulk population of cells. We have also found evidence that the drug-tolerant switch is analogous to the epithelial-mesenchymal transition, which is also spontaneously reversible and associated with distinct drug sensitivities. These findings highlight the dynamic nature of clonal heterogeneity within cancer cell populations and point to a likely need to co-target multiple distinct cellular states within a tumor population to effectively eradicate cancer cells and minimize the likelihood of acquired drug resistance and tumor recurrence.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN06-04.
Citation Format: Jeffrey E. Settleman. Reversible tolerance to anticancer drugs. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN06-04.
Abstract PL01-01: Using synthetic lethality to find effective combination therapies for cancer.
Authors: Bernards René 
Published: August 2014

Abstract
Cancer remains difficult to treat, even with the new generation of targeted cancer drugs. By far the most formidable obstacle is the rapid emergence of therapy resistance. Indeed, many of the new cancer drugs elicit powerful initial responses, leading to dramatic effects on "progression free survival," but far less long-term benefit is seen in terms of overall survival. Combination therapies can help fight therapy resistance, but with an arsenal of over 1000 cancer drugs in clinical development, the number of possible combinations seems nearly endless. In my laboratory we employ functional genetic screens to find powerful combinations of cancer drugs by exploiting the concept of "synthetic lethality." Using RNA interference-based genetic screens with collections of shRNAs that target druggable gene families, we search for genes whose inactivation is particularly synergistic with clinically-relevant cancer drugs. Such screens can identify drug combinations that are far more powerful than the sum of the two single agents. We aim to understand the molecular rationale for the observed synergy between two cancer drugs. Once we have insight into the molecular mechanism, we aim to bring such rationally-designed combinations to the cancer clinic as soon as possible through our clinical collaborations in our comprehensive cancer center. As a second approach, we use genome wide loss-of-function genetic screens in cancer cells that are sensitive to the drug-of-interest to search for genes whose down-regulation confers resistance to the drug-of-interest. Such genetic screens can identify novel mechanisms of drug resistance. This in turn may suggest strategies that help prevent drug resistance. Examples of genetic screens that help to optimize the treatment of cancer will be presented.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL01-01.
Citation Format: René Bernards. Using synthetic lethality to find effective combination therapies for cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL01-01.
Abstract PL02-02: The genetic basis of kidney cancer: A metabolic disease.
Authors: Linehan W. Marston 
Published: August 2014

Abstract
Much of what is known about the genetic basis of kidney cancer has been learned from the study of inherited forms of kidney cancer, including von Hippel-Lindau (VHL) (clear cell kidney cancer, the VHL gene), hereditary papillary renal carcinoma (type 1 papillary kidney cancer, the MET gene), Birt-Hogg-Dubé (BHD) (chromophobe kidney cancer, the FLCN gene), hereditary leiomyomatosis and renal cell carcinoma (HLRCC, the fumarate hydratase gene), and SDH-RCC (the succinate dehydrogenase genes). Study of these disease gene pathways has shown that kidney cancer is fundamentally a metabolic disease. Each of the known kidney cancer genes affects the cell's ability to sense changes in oxygen, iron, nutrients or ATP. This is most clearly illustrated in fumarate hydratase (FH) and succinate dehydrogenase (SDH) deficient kidney cancer. FH-deficient kidney cancer, an extremely aggressive form of type 2 papillary kidney cancer, is characterized by a metabolic shift to aerobic glycolysis and impaired oxidative phosphorylaton, decreased AMPK, fumarate-induced impairment of dioxygenases (such as prolyl hydroxylase), resulting in increased stability of HIF and DNA and histone methylation, glutamine dependent reductive carboxylation and a fumarate-mediated activation of the Nrf2 pathway. SDH-deficient kidney cancer is characterized by a metabolic shift to aerobic glycolysis, a profound impairment of oxidative phosphorylation and a glutamine-dependent reductive carboxylation pathway for lipid biosynthesis. Clinical trials are currently underway targeting the metabolic basis of FH-deficient kidney cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL02-02.
Citation Format: W. Marston Linehan. The genetic basis of kidney cancer: A metabolic disease. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL02-02.
Abstract PL02-03: Ras-induced macropinocytosis: Metabolic adaptation to signaling in the absence of adequate nutrients.
Authors: Thompson Craig B. 
Published: August 2014

Abstract
Under conditions of an abundant supply of extracellular glucose and glutamine, cancer cells synthesize lipids, nucleic acids, and non-essential amino acids from these precursors. However, when cancer grows to exceed its vascular supply, cells must adapt to lower availability of essential nutrients and oxygen. This past year we have seen a significant breakthrough in the discovery of novel mechanisms by which cancer cells adapt to metabolic stress. It was previously determined that glutamine-dependent lipid synthesis could support de novo lipid synthesis under hypoxia but metabolic tracing studies uncovered that over 50% of lipids used in phospholipid biosynthesis in hypoxic cells come from exogenous sources. We were able to determine that hypoxia-induced macropinocytosis facilitates the uptake and incorporation of unsaturated phospholipids to maintain effective unsaturated lipid levels under conditions in which stearoyl-CoA desaturase is inhibited by oxygen limitation. Follow up studies, in collaboration with others, have demonstrated that this property of cellular scavenging of extracellular macromolecules is induced in a Ras-dependent fashion in transformed cells and provides a potent mechanism by which Ras-transformed cells can adapt to metabolic stress in their environment. How these insights can be used to develop novel therapeutic strategies to address Ras-induced tumors will be discussed.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL02-03.
Citation Format: Craig B. Thompson. Ras-induced macropinocytosis: Metabolic adaptation to signaling in the absence of adequate nutrients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL02-03.
Abstract PL02-04: IDH mutations and tumorigenicity.
Authors: Wang F. , Travins J. , DeLaBarre B. , Penard-Lacronique V. , Schalm S. , Hansen E. , Straley K. , Kernytsky A. , Liu W. , Gliser C. , Yang H. , Gross S. , Artin E. , Saada V , Mylonas E. , Quivoron C. , Popovici-Muller J. , Saunders J. O. , Salituro F. G. , Yan S. , Murray S. , Wei W. , Gao Y. , Dang L. , Dorsch M. , Agresta S. , Schenkein D. P. , Biller S. A. , Su S. M. , Botton S. de , Yen Katharine E. 
Published: August 2014

Abstract
Mutations in the isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes are present in ∼20% of acute myeloid leukemia, and cause a neomorphic enzyme activity that results in the production of 2-hydroxyglutarate (2HG). Mutational and epigenetic profiling of a large patient cohort of acute myeloid leukemia (AML) has revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and impaired hematopoietic differentiation.
To further investigate the intrinsic effect of 2HG on hematopoietic proliferation and differentiation, we transfected an erythroleukemia cell line (TF-1) with either IDH1 or IDH2 mutant alleles. These cells overexpress the mutant enzyme, have high levels of 2HG, and exhibit GM-CSF independent growth. Consistent with clinical observations, overexpression of the IDH mutant proteins led to hypermethylation of both histones and DNA. These results suggest that mutations in IDH1/2 could lead to epigenetic rewiring of cells that could facilitate the gain of function phenotype. We are currently studying the global and specific effects of IDH1/2 mutant overexpression to gain a broader understanding of the biological consequence of the IDH1/2 gain of function mutations.
We have also generated mutation selective molecules that are capable of inhibiting IDHm enzymes. Upon compound treatment in vitro, we are able to reverse hypermethylation of both histones and DNA and induce cellular differentiation in IDHm cell lines and primary human IDHm AML patient samples(1, 2). These data suggest that an inhibitor of IDH1/2 mutations could correct the altered gene expression patterns seen in IDH1/2 mutant AML tumors leading to a profound effect on hematopoietic differentiation, proliferation and tumor growth.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL02-04.
Citation Format: F. Wang, J. Travins, B. DeLaBarre, V. Penard-Lacronique, S. Schalm, E. Hansen, K. Straley, A. Kernytsky, W. Liu, C. Gliser, H. Yang, S. Gross, E. Artin, V Saada, E. Mylonas, C. Quivoron, J. Popovici-Muller, J. O. Saunders, F. G. Salituro, S. Yan, S. Murray, W. Wei, Y. Gao, L. Dang, M. Dorsch, S. Agresta, D. P. Schenkein, S. A. Biller, S. M. Su, S. de Botton, Katharine E. Yen. IDH mutations and tumorigenicity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL02-04.
Abstract PL03-01: Working together to identify new epigenetic targets for cancer.
Authors: Bountra Chas 
Published: August 2014

Abstract
During my presentation, I will discuss: 1) how we are pooling the expertise and infrastructure of several big pharmas, with the disease and clinical expertise, and patients resources in academia, to accelerate novel target identification; 2) novel epigenetic targets which are worth further exploration; 3) how these efforts are facilitating science and proprietary programmes, including the creation of new biotechs; 4) our plans to establish human disease platforms for novel epigenetic target prioritization.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL03-01.
Citation Format: Chas Bountra. Working together to identify new epigenetic targets for cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL03-01.