tbuckley/cabot-search huggingface dataset:
Abstract 2188: Targeted delivery of pro-apoptotic peptide using ELP-based carrier for effective cancer therapy in various cancer model
Authors: Sarangthem Vijaya, Rang-Woon Park
Journal: Cancer Research (2017)

Abstract Therapeutic peptides classified as biopharmaceuticals have gained attention as a new generation of cancer therapeutics with enhanced efficiency and diminished toxicity. They often fail to have sufficient effects due to their unsatisfactory pharmacokinetic profiles, which include poor bioavailability, low stability, short half-life, and poor penetration across the biological membrane. Elastin-like polypeptide (ELP)-based drug delivery has been utilized for various applications including cancer therapies for many years. Genetic incorporation of internalization ligands and cell targeting peptides along with ELP polymer enhanced tumor accumulation and retention time as well as stability and activities of the drug conjugates. Herein, we described a unique delivery system comprised of genetically engineered ELP incorporated with multiple copies of IL-4 receptor targeting peptide (AP1) periodically and proapoptotic peptide (KLAKLAK)2 referred to as AP1-ELP-KLAK. It triggered thermal responsive self-assembly into a nanoparticle-like structure at physiological body temperature and stabilized its helical conformation, which is critical for its membrane disrupting activities. Increased IL-4 receptor specific cellular internalization was associated with the enhanced cytotoxic effect of (KLAKLAK)2 peptide. Additionally, multivalent presentation of targeting ligands by AP1-ELP-KLAK significantly enhanced intratumoral localization and prolonged the retention time compared to ELP-KLAK, non-targeted control. Systemic administration of AP1-ELP-KLAK significantly inhibited tumor growth by provoking cell apoptosis in MDA-MB231 breast cancer and B16F10 melanoma tumor xenograft models without any specific organ toxicity. Thus, our newly designed AP1-ELP-KLAK polymer nanoparticle is a promising candidate for effective cancer therapy and due to the simple preparative procedures of ELPs, this platform can be used as a good carrier for tumor-specific delivery of other therapeutics. Citation Format: Sarangthem Vijaya, Rang-Woon Park. Targeted delivery of pro-apoptotic peptide using ELP-based carrier for effective cancer therapy in various cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2188. doi:10.1158/1538-7445.AM2017-2188
Abstract LB-165: Personalized prognostic prediction models for breast cancer recurrence and survival incorporating multidimensional data
Authors: Xifeng Wu, Yuanqing Ye, Carlos H. Barcenas, Wong-Ho Chow, Qing H. Meng, Mariana Chavez Mac Gregor, Michelle Hildebrandt, Hua Zhao, Xiangjun Gu, Yang Deng, Elizabeth A. Wagar, Francisco J. Esteva, Debu Tripathy, Gabriel N. Hortobagyi
Journal: Cancer Research (2017)

Abstract Background: In this study, we developed integrative, personalized prognostic models for breast cancer recurrence and overall survival (OS) that consider receptor subtypes, epidemiological data, quality of life (QoL), and treatment. Methods: 15,314 women with stage I to III invasive primary breast cancer treated at The University of Texas MD Anderson Cancer Center between 1997 and 2012 was used to generate prognostic models by Cox regression analysis including 10,809 women as discovery population (median follow-up: 6.09 years, 1,144 recurrence and 1,627 deaths) and 4,505 women as validation population (median follow-up: 7.95 years, 684 recurrence and 1,095 deaths). Model performance was assessed by calculating the area under the curve (AUC) and calibration analysis and compared with Nottingham Prognostic Index (NPI) and PREDICT. Results: In addition to the known clinical/pathological variables, the model for recurrence included alcohol consumption while the model for OS included smoking status and physical component summary score. The AUCs for recurrence and OS were 0.813 and 0.810 in the discovery and 0.807 and 0.803 in the validation, respectively, compared to AUC of 0.761 and 0.753 in discovery and 0.777 and 0.751 in validation for NPI. Our model further showed better calibration compared to PREDICT. We also developed race-specific and receptor subtype-specific models with comparable AUC. Racial disparity was evident in the distributions of many risk factors and clinical presentation of the disease. Conclusions: Our integrative prognostic models for breast cancer exhibit high discriminatory accuracy and excellent calibration and are the first to incorporate receptor subtype, epidemiological and QoL data. Citation Format: Xifeng Wu, Yuanqing Ye, Carlos H. Barcenas, Wong-Ho Chow, Qing H. Meng, Mariana Chavez Mac Gregor, Michelle Hildebrandt, Hua Zhao, Xiangjun Gu, Yang Deng, Elizabeth A. Wagar, Francisco J. Esteva, Debu Tripathy, Gabriel N. Hortobagyi. Personalized prognostic prediction models for breast cancer recurrence and survival incorporating multidimensional data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-165. doi:10.1158/1538-7445.AM2017-LB-165
Abstract CT095: The selective targeting of myeloid-derived suppressor cells in cancer patients using an agonistic TRAIL-R2 antibody
Authors: George A. Dominguez, Thomas Condamine, Sridevi Mony, Ayumi Hashimoto, Fang Wang, Qin Liu, Andres Forero, Johanna C. Bendell, Robert Witt, Neil Hockstein, Prasanna Kumar, Dmitry I. Gabrilovich
Journal: Cancer Research (2017)

Abstract The goal of this current study was to clinically test the hypothesis that by targeting TRAIL-R2, myeloid-derived suppressor cells (MDSCs) can be selectively eliminated. MDSC) are one of the major contributors to immune suppression in cancer. We previously demonstrated in a preclinical study that MDSCs are sensitive to a TRAIL receptor 2 (TRAIL-R2) agonist. The TRAIL-R2 agonistic antibody (DS-8273a; provided by Daiichi Sankyo, Inc.) was tested in 16 patients with advanced solid cancers or lymphomas enrolled in a phase 1 trial. The antibody (24 mg/kg) was administered IV once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated using flow cytometry and immunohistochemistry. Overall, the treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Furthermore, treatment with DS-8273a resulted in reduction of the elevated numbers of MDSC in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSC rebounded back to the pre-treatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells with decreases in MDSC levels inversely correlating with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSC in 50% of the patients who were able to provide pre- and on-treatment biopsies. In conclusion, targeting TRAIL-R2 using DS-8273a resulted in a temporary elimination of MDSCs without affecting mature myeloid or lymphoid cells, and these data support further use of this antibody in combination with current immmunotherapies of cancer. Citation Format: George A. Dominguez, Thomas Condamine, Sridevi Mony, Ayumi Hashimoto, Fang Wang, Qin Liu, Andres Forero, Johanna C. Bendell, Robert Witt, Neil Hockstein, Prasanna Kumar, Dmitry I. Gabrilovich. The selective targeting of myeloid-derived suppressor cells in cancer patients using an agonistic TRAIL-R2 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT095. doi:10.1158/1538-7445.AM2017-CT095
Abstract 1277: Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with obesity and lifestyle factors on postmenopausal breast cancer risk
Authors: Su Yon Jung, Gloria Ho, Thomas Rohan, Howard Strickler, Jennifer Bea, Jeanette Papp, Eric Sobel, Zuo-Feng Zhang, Carolyn Crandall
Journal: Cancer Research (2017)

Abstract Objectives: Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. Stratifying via obesity and lifestyle modifiers, we evaluated the effects of insulin-like growth factor-I (IGF-I)/insulin resistance (IR)–related traits on breast cancer risk as a mediator or influencing factor in this case-cohort study. Method: Using 75 single-nucleotide polymorphisms (SNPs) in genes related to IGF-I/IR traits and signaling pathways, and data from 1,003 postmenopausal women in Women’s Health Initiative Observation ancillary studies, we assessed the effects of IGF-I/IR-traits (fasting total and free IGF-I, IGF binding protein-3, glucose, insulin, and homeostatic model assessment–insulin resistance) by proportional change estimation. Using traits as mediators of the IGF-I/IR–traits genetic variants-cancer relationship, we partitioned total effect of these genetic variants on cancer risk into two putative mechanisms: 1) indirect (mediated by traits) and 2) direct (through pathways other than traits). For the effects of IGF-I/IR traits on IGF-I/IR signaling pathways–relevant genetic variants–cancer risk, we used the same algorithm as that for mediator, but interpreted as an influential factor. Results: Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E nonusers and users. The mediation effects of IGF-I/IR traits on these SNPs–cancer relationship differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by IGF-I/IR traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways–related genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP–cancer relationship explained by IGF-I/IR traits varied 45-50% between the strata. Conclusions: Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Citation Format: Su Yon Jung, Gloria Ho, Thomas Rohan, Howard Strickler, Jennifer Bea, Jeanette Papp, Eric Sobel, Zuo-Feng Zhang, Carolyn Crandall. Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with obesity and lifestyle factors on postmenopausal breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1277. doi:10.1158/1538-7445.AM2017-1277
Abstract 2069: Overcoming drug resistance by targeting melanoma dedifferentiation through information-theoretic analysis and single cell proteomics
Authors: Yapeng SU, Wei Wei, Lidia Robert, Jennifer Tsoi, Min Xue, Jungwoo Kim, Thomas Graeber, Raphael Levine, Antoni Ribas, James Heath
Journal: Cancer Research (2017)

Abstract Despite impressive initial response of BRAF targeted therapy in mestastic melanoma patients, acquired drug resistance, often times derived from tumor heterogeneity, always limit its clinical outcome. A dedifferentiation process named melanocyte to neural crest transition (MNT) has shown to be critical in the early stage resistance development. The dedifferentiation could induce a whole cell state change resulting a drug tolerant state of melanoma cells, which will lead to initial drug resistance. Mathematic modeling indicates the nature of the transition as results of both stochastic phenotypic transition and non-genetic drug selection, which indicates and further proved that the whole cell state transition should be reversible during drug removal. Information theoretic analysis reduced the dimensional of thousands of gene expression level changes as results of only two unbalanced processes onto a cellular steady state. Reversible transition trajectory defined through two processes indicates it to resemble a critical transition in physical systems. Refined single cell proteomic analysis of those proteins that associate with major unbalanced processes identify the critical points of the transition as early as day6, which cannot be resolved from bulk proteomic measurement. By co-targeting the drivers at the critical points in combination with original brafi targeted drug successfully arrested the transition and induced a sustained tumor growth inhibition in multiple patient-derived melanoma cell lines. This study provides us a noval methodology of mining whole transcriptomic transition with information theoretic analysis to reduce the dimensionality and then using single cell proteomic analysis for refining critical points and driver proteins which eventually rationalized a effective combination therapy to stop the drug resistance development early on. Citation Format: Yapeng SU, Wei Wei, Lidia Robert, Jennifer Tsoi, Min Xue, Jungwoo Kim, Thomas Graeber, Raphael Levine, Antoni Ribas, James Heath. Overcoming drug resistance by targeting melanoma dedifferentiation through information-theoretic analysis and single cell proteomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2069. doi:10.1158/1538-7445.AM2017-2069
Abstract 34: A MET x MET bispecific antibody that induces receptor degradation potently inhibits the growth of MET-addicted tumor xenografts
Authors: John DaSilva
Journal: Cancer Research (2017)

Abstract Aberrant regulation of MET receptor tyrosine kinase signaling is associated with development and progression of various human tumors. Elevated MET signaling during tumorigenesis results from MET amplification, mutation or up-regulation of the ligand, HGF. MET amplification is thought to be a key driver of oncogenesis in non-small cell lung cancers (NSCLC) and oesophagogastric malignancies. In addition, mutations resulting in exon 14 deletion of MET have been described as oncogenic drivers in a subset of NSCLC. Both preclinical and recent clinical results indicate that tumors harboring these genetic alterations respond to MET inhibitors, validating MET as a cancer driver. We have developed a novel bispecific antibody that binds to two distinct epitopes on MET. The METxMET bispecific antibody blocks HGF binding and exhibits very low agonist activity (much weaker than either of its parental antibodies). Furthermore, the METxMET bispecific antibody effectively promotes MET degradation, thereby inhibiting ligand-independent signaling in MET-amplified tumor cells. The METxMET bispecific antibody exhibits strong anti-tumor efficacy in xenograft models harboring MET genetic alterations, either completely inhibiting tumor growth (EBC1 MET-amplified NSCLC) or promoting substantial tumor regression (SNU5 MET-amplified gastric cancer, Hs746T MET-amplified/MET exon 14 skip gastric cancer). Analysis of lysates from SNU5 tumors treated with the METxMET bispecific antibody confirms its ability to effectively promote MET degradation in vivo. Finally, the METxMET bispecific antibody strongly inhibits the growth of a glioblastoma xenograft model (U118) driven by autocrine HGF signaling. In summary, we have generated a novel METxMET bispecific antibody that potently inhibits the growth of MET-dependent tumor xenografts. Our data suggest that antibody-mediated MET degradation may be an effective clinical strategy in tumors harboring MET genetic alterations. Citation Format: John DaSilva. A MET x MET bispecific antibody that induces receptor degradation potently inhibits the growth of MET-addicted tumor xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 34. doi:10.1158/1538-7445.AM2017-34
Abstract 3452: The cohesin subunitSTAG1is a hardwired genetic dependency ofSTAG2mutant cancer cells
Authors: Petra Van Der Lelij, Simone Lieb, Julian Jude, Gordana Wutz, Catarina Pereira, Katrina Falkenberg, Jozef Ban, Heinrich Kovar, Todd Waldman, Francisco Real, Mark Pearson, Norbert Kraut, Jan-Michael Peters, Johannes Zuber, Mark P. Petronczki
Journal: Cancer Research (2017)

Abstract Recent genome analyses have identified recurrent mutations in subunits of the cohesin complex in human cancer. Cohesin is a chromosomal factor that is essential for sister chromatid cohesion and cell division and that contributes to gene regulation and DNA repair. Deleterious mutations in the cohesin subunit STAG2 have been detected in about 20% of bladder cancer, 15% of Ewing sarcoma and 6% of AML/MDS patients. The mechanistic involvement of cohesin mutations in the pathogenesis of human malignancies is currently under active investigation. We hypothesized that the loss of STAG2 could alter the properties and functionalities of the cohesin complex leading to unique vulnerabilities of STAG2 mutant cells. Using CRISPR/Cas9 and RNAi in isogenic solid cancer and leukemic models we identified STAG1, a STAG2 paralog, as a strong and clean genetic vulnerability of STAG2 mutant cells. Mechanistically, STAG1 loss abrogates sister chromatid cohesion specifically in STAG2 mutant but not wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of disease relevant STAG2 mutant but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutant bladder cancer model alleviates the dependence on STAG1. Our results demonstrate that the cohesin subunits STAG1 and STAG2 act redundantly to support sister chromatid cohesion and cell viability in human cells. We have identified STAG1 as a hardwired, context independent vulnerability of STAG2 mutant cancers. Specific synthetic lethalities elicited by recurrent cohesin mutations in human tumors hold the promise for the development of selective therapeutics. Citation Format: Petra Van Der Lelij, Simone Lieb, Julian Jude, Gordana Wutz, Catarina Pereira, Katrina Falkenberg, Jozef Ban, Heinrich Kovar, Todd Waldman, Francisco Real, Mark Pearson, Norbert Kraut, Jan-Michael Peters, Johannes Zuber, Mark P. Petronczki. The cohesin subunit STAG1 is a hardwired genetic dependency of STAG2 mutant cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3452. doi:10.1158/1538-7445.AM2017-3452
Abstract 2370: Depletion of p21-activated kinase 4, PAK4, inhibits cellular proliferation, motility and clonogenicity in oral squamous cell carcinoma
Authors: Felicia F. Chung, Si-Hoey Tan, Vijay J. Raja, Pei Yuen Ng, Ian C. Paterson, Chye Ling Tan, Chee-Onn Leong
Journal: Cancer Research (2017)

Abstract Oral squamous cell carcinoma (OSCC) accounts for 90% of all malignancies in the oral cavity, and is often associated with low survival and poor prognosis. While considerable progress in OSCC treatment has been made, options for targeted therapy remain limited. Thus, it is imperative that new druggable targets are identified and characterized. p21-activated kinase 4 (PAK4) is a member of the PAK family of serine/threonine kinases, which are known modulators of a diverse range of oncogenic pathways including cell proliferation, escape from apoptosis, and anchorage-independent growth. Previous reports have indicated that PAK4 is overexpressed in a subset of invasive OSCC, and is highly associated with poor prognosis. However, the specific role of PAK4 in OSCC has yet to be elucidated. Here, we show that RNAi-mediated depletion of PAK4 conferred reduced clonogenicity, cell motility, and cell proliferation in OSCC cell lines in a cell line-dependent manner. Global proteomic profiling of PAK4-depleted H103 and H357 cells was conducted to identify the molecules and signaling pathways responsive to PAK4 depletion. In addition to reported targets of PAK4 such as CFL1, ACTB, and TUBB6, we observed that p16INK4a, pre-mRNA splicing factors (SRSF2, SRSF5, SRSF6, SLU7), and proteasome activator subunits (PSME1-4) were dysregulated as a result of PAK4 depletion. These results indicate that PAK4 plays a role in promoting OSCC progression by regulating multiple signaling pathways. Of note, there have yet to be any reports describing interactions between PAK4 signaling and mRNA splicing or proteasome activation. Further investigation is thus warranted to further delineate the potential role of PAK4 in regulating these targets. Citation Format: Felicia F. Chung, Si-Hoey Tan, Vijay J. Raja, Pei Yuen Ng, Ian C. Paterson, Chye Ling Tan, Chee-Onn Leong. Depletion of p21-activated kinase 4, PAK4, inhibits cellular proliferation, motility and clonogenicity in oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2370. doi:10.1158/1538-7445.AM2017-2370