tbuckley/cabot-search huggingface dataset:
Abstract 330: SGK1 activation is essential for PI3K-dependent tumor development
Authors: Arturo Orlacchio, Antonio Di Cristofano
Journal: Cancer Research (2017)

Abstract The PI3K signaling cascade is frequently activated in human cancer, with AKT being commonly considered its major transforming conduit. Conditional deletion of Pten in the mouse thyroid epithelium induces constitutive activation of the PI3K pathway, which causes thyroid hyperplasia at birth that progresses to invasive and metastatic follicular carcinoma. Concomitant loss of p53 or activation of KRAS dramatically accelerates the development of aggressive and lethal tumors. The PDK1 kinase plays a key role in the PI3K signaling cascade, directly activating, in a PI3K-dependent manner, not only AKT but also a set of additional AGC kinases, including, S6K, PKC, and SGK. Using in vivo, ex vivo, and in vitro genetic and pharmacological approaches, we now show that AKT activation is not sufficient to transform thyroid epithelial cells. Concomitant activation of additional PDK1-dependent pathways is absolutely required to develop neoplastic lesions in vivo, and to induce cell proliferation ex vivo, in mouse models based on Pten loss, alone and in combination with additional genetic alterations. In particular, we show that one member of the SGK family, SGK1, is an essential mediator of the transformation process downstream of PI3K. Genetic and pharmacological SGK1 inhibition strongly reduces cell proliferation in Pten-/-and PIK3CA-mutant cell lines. Moreover we show that concomitant SGK inhibition significantly increases the efficacy of inhibitors targeting AKT or PI3K. Taken together, our data identify an essential and druggable signaling cascade that critically cooperates with AKT activation to transform thyroid epithelial cells. Citation Format: Arturo Orlacchio, Antonio Di Cristofano. SGK1 activation is essential for PI3K-dependent tumor development [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 330. doi:10.1158/1538-7445.AM2017-330
Abstract 2388: Low grade gliomas exhibit distinct patterns of epigenetic aging associated with prognostic molecular subtype
Authors: Peter Liao, Jill Barnholtz-Sloan
Journal: Cancer Research (2017)

Abstract Background: Low grade gliomas make up a significant proportion of malignant brain tumors and possess a high degree of heterogeneity, highlighting a need for clinically useful markers for prognosis and further biologic investigation. We used an existing model of biological age based upon DNA methylation to characterize epigenetic age in low grade gliomas (LGG) according to existing molecular classifications and assessed the prognostic utility of epigenetic age. Methods: We analyzed the full TCGA LGG cohort consisting of 516 patients; 216 grade 2 and 241 grade 3 tumors. Age at diagnosis ranged from 14-87 years with median age 43. We calculated “DNA methylation age” (DNAm age) based upon 353 CpG probes according to the epigenetic clock developed by Steve Horvath, and calculated age acceleration according to the DNAm age of tumor tissue relative to reported chronological age of patient at diagnosis. DNAm age was assessed for prognostic value using Cox proportional hazards regression. Age acceleration differences were assessed across LGG molecular classification methods using the Wilcoxon Ranked Sum test. Results: DNAm age remained highly correlated with chronological age in LGG tumor tissue (cor=0.58, p&amp;lt;0.001), with an average age acceleration of 33.5y. DNAm age was weakly positively correlated with mutational burden (cor=0.12, p=0.01). Higher DNAm age was positively associated with survival independent of chronologic age and Karnofsky Performance Score (p=0.003), but not when IDH mutation status was included into the Cox proportional hazards model. Further investigation showed that DNAm age acceleration was associated with IDH mutation status and was significantly increased in IDH-mutant compared to IDH-wt tumors (95% CI= 18.6-28.8y) as well as MGMT-promoter methylated versus unmethylated cases (95%CI= 18.1- 28.9y). No significant DNAm changes were observed across histological subtype or grade. Conclusions: Although the regulation of DNAm age in cancers remains poorly understood, significant association of DNAm age acceleration with prognostically useful molecular subtypes in LGGs underscores biological differences that cannot be discerned in LGGs based upon histological classification. This association suggests that LGGs may provide an avenue for investigating DNAm age, molecular subtype, and their relation to tumor behavior and clinical prognosis. Citation Format: Peter Liao, Jill Barnholtz-Sloan. Low grade gliomas exhibit distinct patterns of epigenetic aging associated with prognostic molecular subtype [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 2388. doi:10.1158/1538-7445.AM2017-2388
Abstract 4654: The primary study of the correlation between mRNA expression and protein phosphorylation of epidermal growth factor receptor EGFR in colorectal and breast cancer cell lines
Authors: Hongwei Wang, Catherine Ma, Yuan Zhou
Journal: Cancer Research (2017)

Abstract The EGFR family is a group of receptor tyrosine kinases that mediates cell proliferation, migration, and differentiation. Activation of EGFR signaling is triggered by ligand-binding induced receptor dimerization. The dimerization activates the intracellular kinase domains of the receptor, resulting in autophosphorylation of C-terminal tail and the initiation of downstream signaling. EGFR overexpression is correlated with more aggressive clinical indications in multiple types of cancer, including colon, breast, lung, and head and neck carcinoma. Clinical studies show that EGFR-directed therapeutic approaches improved better outcomes of metastatic lung, colorectal, and head and neck cancers. Predictive biomarkers are being developed to deliver personalized therapies. Therefore, it is important to determine the protein as well as molecular biomarker expression for selecting targeted therapies. Here we present a panel cancer cell lines to examine EGFR expressions at a molecular biomarker level (mRNA) as well as a protein level of phosphorylated EGFR(pS1060). Colon cancer cell lines HT29, HCT116, SW620, as well as the breast cancer cell line SKBR3, were cultured and processed onto formalin-fixed paraffin-embedded (FFPE) CellMax pellets. Expression levels of EGFR mRNA in the FFPE slides were examined with RNAScope technology to visualize single RNA molecules per cell by using probes specifically against EGFR. Expression of phosphorylated EGFR was examined by the phosphospecific EGFR (pS1070) antibodies by using immunohistochemistry (IHC). EGFR mRNA expression was detected in HT29 and HCT 116 cells showing strong punctuated signals in the cytoplasm. However, no EGFR mRNA signals were detected in SW620 cells. Breast cancer cell line SKBR3 showed abundant EGFR mRNA expression. Phosphorylated EGFR were found in the cell HT29, HCT 116 and SKBR3 cells with membrane staining pattern. No phosphorylated EGFR was observed in SW620 cells using Immunochemistry staining. Together, our results demonstrated that the EGFR mRNA expression is correlated to the phosphorylation of EGFR in these cancer cell lines. We concluded that the EGFR mRNA probes, phosphorylated EGFR antibodies, and/or the cell lines can be served as the control-references for clinical biomarker screening. Citation Format: Hongwei Wang, Catherine Ma, Yuan Zhou. The primary study of the correlation between mRNA expression and protein phosphorylation of epidermal growth factor receptor EGFR in colorectal and breast cancer cell lines [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 4654. doi:10.1158/1538-7445.AM2017-4654
Abstract 4174: The impact of catechol estrogen metabolism on the proliferation rate and Docetaxel (DOC) resistance in hormone-responsive cancers
Authors: Mai F. Tolba, Hany Omar, Ayman M. Noreddin
Journal: Cancer Research (2017)

Abstract Estrogen-responsive cancers such as breast cancer (BC) and prostate cancer (PC) are on the top of the most commonly diagnosed cancers in USA. Docetaxel (DOC) is considered the first-line of therapy for both metastatic BC and castration-resistant PC. However, its use in therapeutically effective doses is associated with significant toxic reactions and tumor resistance. Estrogens (E2) play an important role in the development and progression of both malignancies. Of special importance is that the catechol E2 metabolite, 4-hydroxyestradiol (4-OHE2) enhances the proliferation of both breast and prostate normal epithelial cells. The goal of this work is to investigate the relationship between catechol-E2 metabolism and cancer cells proliferation and response to DOC. Methods: The cells were exposed to serial concentrations of E2 and 4OHE2 (0.001-10 µM) to assess their effect on cells’ growth rate over 24-92 h. Cell proliferation assays were utilized to assess the density of viable cells at different time points. Cytotoxicity assays were performed to evaluate the median inhibitory concentration (IC50) of DOC alone or in the presence of 4OHE2. Results: Exposure of the estrogen receptor (ER)-positive BC cell line MCF-7 to 0.1 µM of 17-β-hydroxyestradiol (E2) for 3 days significantly boosted the cell proliferation rate compared to control group by about 27% (P&amp;lt;0.05). Exposure of MCF-7 cells to the catechol estrogen metabolite 4-hydroxyestradiol (4OHE2) at 0.1µM for 3 days significally enhanced cell growth by about 31% (P&amp;lt;0.001). Similarly, exposure of the androgen independent, ER-positive- advanced stage PC cells PC-3 to E2 (1 µM, 3 days) significantly enhanced the growth rate by 37% (P&amp;lt;0.05). Moreover, our data showed that simultaneous exposure to 4OHE2 significantly antagonized the cytotoxic activity of DOC with subsequent increase in the IC50 of DOC by 18 folds (P&amp;lt;0.006). Conclusion: these results indicate that altered E2 metabolism with subsequent accumulation of 4-OHE2 can enhance the proliferation rate of E2-responsive cancers in addition to hindering the cytotoxic activity of DOC with subsequent reduction in DOC potency. Further research is in progress to assess the potential merit of modulating the clearance of catechol E2 as a strategy to improve the cancer response to DOC. (This project is supported by Fulbright Scholar grant FY15/16 and L’Oreal-UNESCO for Women in Science-Levant and Egypt award for MFT). Citation Format: Mai F. Tolba, Hany Omar, Ayman M. Noreddin. The impact of catechol estrogen metabolism on the proliferation rate and Docetaxel (DOC) resistance in hormone-responsive cancers [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 4174. doi:10.1158/1538-7445.AM2017-4174
Abstract 1601: Anti-tumor effect of GAGomer-mediated intra-tumoral IL-2 expression following systemic administration
Authors: Genia Alpert, David Altreuter, Sunil Anamandla, Arlyssa Birt, Guy Cinamon, Keren Cohen Merimi, Orli Even Or, Nir Gefen, Nadia Gurvich, Jeno Gyuris, Lorena Lerner, Adi Mondshine, Hong Wang
Journal: Cancer Research (2017)

Abstract Cancer immunotherapies are revolutionizing cancer treatment. Unfortunately, a large proportion of patients with solid tumors do not respond to currently available immune-therapeutics. The lack of response is due to a variety of mechanisms tumors adopt to avoid immune mediated clearance. The multiplicity of immunosuppressive mechanisms operational in the tumor microenvironment may not be overcome by single agents and require interventions at multiple control points. However, systemic exposure to combinations of immunoregulators may result in severe, dose limiting, acute and chronic toxicities that might be prevented if the effect of these agents is focused to the tumor microenvironment. We are engaged in the discovery of a novel class of immuno-oncology drugs aimed at maximizing the effect of immunoregulatory molecules in the tumor microenvironment and minimizing systemic adverse effects. These drugs incorporate plasmids, engineered to program tumor cells to produce and secrete immune-regulatory proteins, within hyaluronic acid (HA) coated lipid nanoparticles, called GAGomers, which specifically target tumor cells that overexpress activated HA receptors (GAG-pDNA). GAG-pDNA based therapeutics promise highly potent but localized activation of the immune system exclusively in the tumor microenvironment following systemic administration, leading to the destruction of tumor cells by activated immune cells without debilitating toxic side effects. To demonstrate the feasibility of the GAG-pDNA approach we have incorporated a plasmid directing the expression of murine IL-2 into GAGomers (GAG-pIL2) and assessed the anti-tumor activity of the construct after systemic delivery into tumor bearing mice. GAG-pIL2 administration resulted in statistically significant inhibition of tumor growth, which correlated with elevated IL-2 levels in the tumor and increased infiltration of T-cells into the tumor microenvironment. These experiments demonstrate the feasibility of programming tumor cells using GAG-pDNA to produce and secrete immunoregulatory molecules into the tumor microenvironment and trigger robust anti-tumor immune responses. Citation Format: Genia Alpert, David Altreuter, Sunil Anamandla, Arlyssa Birt, Guy Cinamon, Keren Cohen Merimi, Orli Even Or, Nir Gefen, Nadia Gurvich, Jeno Gyuris, Lorena Lerner, Adi Mondshine, Hong Wang. Anti-tumor effect of GAGomer-mediated intra-tumoral IL-2 expression following systemic administration [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 1601. doi:10.1158/1538-7445.AM2017-1601
A phase II study of imatinib mesylate as adjuvant treatment for curatively resected high-risk localized gastrointestinal stromal tumors
Authors: B. Kang, J. Lee, M. Ryu, S. Im, S. Park, W. Kang, T. Kim, D. Oh, K. Jung, Y. Kang
Journal: Journal of Clinical Oncology (2009)

e21515 Background: In our previous study, the presence of c-kit mutation as well as tumor size and mitotic count was an independent poor risk factor for relapse after curative resection of primary localized GIST. The patients with all the 3 poor risk factors had only 30% of 2 year relapse free survival rate (RFSR). (Kim, et al. Clin Cancer Res, 2004) It is also well known that c-kit exon 11 mutant GISTs respond better to imatinib treatment than the other mutant or wild type GISTs. Therefore, the patients who have primary localized GISTs with large size, high mitotic count, and c-kit exon 11 mutation may be the best candidate of adjuvant imatinib treatment. In this phase II study, we have evaluated the efficacy and safety of adjuvant imatinib for this patient group. Methods: Patients who underwent complete resection of a primary GIST with 1) c-kit exon 11 mutation, and 2) ≥10 mitoses/50 HPF, or tumor size ≥10 cm, or ≥5 mitoses/50 HPF and tumor size ≥5 cm were eligible. Patients received imatinib 400mg p.o. daily until recurrence of disease, intolerable toxicities, or for 2 years. The primary end point was relapse-free survival (RFS). Results: A total of 47 patients from 4 centers in Korea were enrolled. The median age was 57.0 years. Stomach was the most common primary site (n=31). Median primary tumor size was 7.5cm and median mitoses index was 12/50 HPF. With a median follow-up of 26.9 months, the median RFS and overall survival (OS) have not yet been reached. RFSR was 97.7% at 1-year and 92.7% at 2-years. Six relapses (12.8%) were documented among the 47 patients. The treatments were generally well tolerated. Grade 3–4 toxicities included neutropenia 27.7%, rash 8.5%, constipation 4.3%, anorexia 2.1%, vomiting 2.1%, and pruritis 2.1%. There were no episode of febrile neutropenia and treatment-related death. Conclusions: Postoperative adjuvant imatinib for 2 years were safe and could prolong the RFS in patients with high-risk of recurrence following complete surgical resection of the primary GIST. However, it remains unknown if this benefit in RFS can be translated into OS benefit. So, further follow-up is needed with comparison of OS with historical controls who could be use imatinib after recurrence. [Table: see text]
Abstract 424: Landscape of somatic mutations in drug-resistant acute myeloid leukemia
Authors: Samuli Eldfors, Mika Kontro, Yevhen Akimov, Olli Kallioniemi, Kimmo Porkka, Caroline Heckman
Journal: Cancer Research (2017)

Abstract Introduction: Most patients with acute myeloid leukemia (AML) initially respond to cytarabine-anthracycline induction chemotherapy. However, in many patients, the disease recurs in a lethal drug-resistant form. Somatic mutations underlying the pathogenesis of AML have been extensively characterized by sequencing of newly diagnosed AMLs. However, the mutations driving therapy resistance and disease progression at relapse have not been well characterized. In this study, we have exome sequenced a cohort of relapsed and refractory AMLs and compared the landscape of somatic mutations at relapse to diagnosis phase AMLs to identify mutations that contribute to therapy resistance and disease progression. Materials and Methods: We performed exome sequencing of diagnosis phase AMLs (n=70) and relapsed or primary refractory AMLs (n=54). Patients with AML M3 subtype were excluded from the study. Paired diagnosis and relapse samples were available from 27 patients. A skin biopsy was used as the germline control. Nine patients had received an allogeneic hematopoietic stem cell transplant before relapse. Somatic mutations were called using varscan2 and copy number aberrations using copyCat. Since the identification of large insertions from next-generation sequencing data remains challenging using existing algorithms, FLT3 internal tandem duplications (FLT3-ITDs) were identified using a novel custom algorithm optimized for FLT3-ITD detection. Population variants were filtered out to remove donor-derived germline variants in chimeric post-transplant relapse samples. Results: Comparison of somatic mutation frequencies in diagnosis and relapse and refractory samples showed that on average relapsed tumors have a higher number of driver mutations than tumors at diagnosis. WT1, TP53, CBL, IDH1 and PTPN11 were mutated at a higher frequency in relapsed samples than at diagnosis, with 13 %, 11 %, 11 %, 9 % and 9 % of relapsed or refractory samples and 4 %, 6 %, 3 %, 4 % and 7 % of diagnosis mutated respectively. Analysis of paired diagnosis-relapse samples showed that in patients with WT1, CBL or PTPN11 mutation at diagnosis the second allele is frequently mutated or lost due to uniparental disomy occurring at relapse. Conclusions: On average relapsed AMLs have a higher number of driver mutations than diagnosis phase AMLs indicating that acquisition of additional driver mutations contributes to relapse. AMLs frequently acquire additional mutations in the same genes and pathways that already harbored mutations at diagnosis. Citation Format: Samuli Eldfors, Mika Kontro, Yevhen Akimov, Olli Kallioniemi, Kimmo Porkka, Caroline Heckman. Landscape of somatic mutations in drug-resistant acute myeloid leukemia [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 424. doi:10.1158/1538-7445.AM2017-424
Abstract SY29-02: Novel mechanisms of PARP inhibitor resistance
Authors: Alan D. D'Andrea
Journal: Cancer Research (2017)

Abstract Large-scale genomic studies have demonstrated that approximately 50% of high-grade serous ovarian cancers (HGSOCs) harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. The most commonly altered HRR genes are BRCA1 and BRCA2, followed by other Fanconi anemia genes including FANCN/PALB2, FANCO/RAD51, FANCJ/BRIP, and FANCA. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to platinum analogues, topoisomerase inhibitors, and PARP-inhibitors (PARPi). The synthetic lethal interaction with PARPi is being exploited therapeutically in diverse clinical contexts and most notably in ovarian cancer, where the PARPi olaparib is FDA approved for use in patients with germline BRCA1/2 mutations. PARP inhibitor resistance has already emerged as a vexing clinical problem for the treatment of BRCA1/2-deficient tumors. The most prevalent mechanism of PARPi resistance is secondary events that cancel the original HRR alteration and restore HRR proficiency. However, PARPi resistance may still develop without restoration of HRR proficiency via disruption of multiple proteins, such as PTIP or CHD4, that leads to replication fork (RF) stabilization. Importantly, this latter mechanism—namely, the restoration of RF stability—appears to be a highly prevalent mechanism of PARP inhibitor resistance in vitro and in vivo, particularly in tumor cells with an underlying BRCA2 deficiency. Due to their underlying deficiency in BRCA2 and inability to generate RAD51 nucleofilaments, these tumor cells are unable to restore HRR mechanisms. Instead, these cells acquire PARP inhibitor resistance by limiting the nucleolytic degradation of their stalled replication forks. We have recently made the surprising observation that BRCA2-deficient tumors can become resistant to PARPi by downregulating the expression of the polycomb repressive complex PRC2, a methyltransferase complex containing EZH2, SUZ12, EED, and RbAp48. Importantly, downregulation of PRC2 results in the reduced recruitment of the nuclease MUS81 to the RF, thereby providing a novel mechanism of RF protection and PARPi resistance. A molecular understanding of PARP inhibitor resistance mechanisms may allow the generation of a new class of drugs or a repurposing of existing drugs, which may reverse this resistance and extend the use of PARP inhibitors to more tumor types. Citation Format: Alan D. D'Andrea. Novel mechanisms of PARP inhibitor resistance [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 SY29-02. doi:10.1158/1538-7445.AM2017-SY29-02