tbuckley/cabot-search huggingface dataset:
Prevalence of Cancer at Baseline Screening in the National Cancer Institute Li-Fraumeni Syndrome Cohort
Authors: Phuong L. Mai, Payal P. Khincha, Jennifer T. Loud, Rosamma M. DeCastro, Renée C. Bremer, June A. Peters, Chia-Ying Liu, David A. Bluemke, Ashkan A. Malayeri, Sharon A. Savage
Journal: JAMA Oncology (2017)

<h3>Importance</h3> Establishment of an optimal cancer surveillance program is important to reduce cancer-related morbidity and mortality in individuals with Li-Fraumeni syndrome, a rare, highly penetrant cancer predisposition syndrome. <h3>Objective</h3> To determine the feasibility and efficacy of a comprehensive cancer screening regimen in Li-Fraumeni syndrome, using multiple radiologic techniques, including rapid whole-body magnetic resonance imaging (MRI) and laboratory measurements. <h3>Design, Setting, and Participants</h3> Baseline evaluation of a prospective cancer screening study was conducted from June 1, 2012, to July 30, 2016, at the National Cancer Institute, National Institutes of Health (an academic research facility). Participants included 116 individuals with Li-Fraumeni syndrome with a germline<i>TP53</i>pathogenic variant who were aged 3 years or older at the time of baseline screening and had not received active cancer therapy at least 6 months prior to screening. <h3>Main Outcomes and Measures</h3> Detection of prevalent cancer with multimodal screening techniques and the need for additional evaluation. <h3>Results</h3> Of the 116 study participants, 77 (66.4%) were female; median age was 37.6 years (range, 3-68 years). Baseline cancer screening led to the diagnosis of cancer in 8 (6.9%) individuals (2 lung adenocarcinomas, 1 osteosarcoma, 1 sarcoma, 1 astrocytoma, 1 low-grade glioma, and 2 preinvasive breast cancers [ductal carcinoma in situ]); all but 1 required only resection for definitive treatment. A total of 40 (34.5%) participants required additional studies to further investigate abnormalities identified on screening, with 32 having incidental, benign, or normal findings, resulting in a false-positive rate of 29.6%. Non-MRI techniques, including baseline blood tests, abdominal ultrasonography in children, mammography, and colonoscopy, did not lead to a diagnosis of prevalent cancer in our cohort. <h3>Conclusions and Relevance</h3> This study describes the establishment and feasibility of an intensive cancer surveillance protocol for individuals with Li-Fraumeni syndrome. Prevalent cancers were detected at an early stage with baseline whole-body, brain, and breast MRI. Prospective screening of the participants is under way.
Abstract 5828: Targeting the polyamine-hypusine nexus for the treatment of neuroblastoma
Authors: Andre S. Bachmann, Raid El-Khawaja, Chad Schultz
Journal: Cancer Research (2017)

Abstract The highly conserved and unique post-translational hypusine modification is essential for the activation of a single cellular protein called eukaryotic initiation factor 5A (eIF5A). Hypusination of eIF5A represents an essential mechanism in the control of cell proliferation and has been linked to cancer. The hypusine modification of eIF5A requires the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) and, importantly, uniquely depends on the polyamine spermidine as a selective substrate. Polyamines including spermidine are frequently dysregulated in neoplastic disease and are critical for cell proliferation. Ornithine decarboxylase (ODC) is the sentinel enzyme in polyamine biosynthesis. We pioneered the repurposing of the irreversible ODC inhibitor alpha-difluoromethylornithine (DFMO) for neuroblastoma (NB), a devastating pediatric cancer of the sympathetic nervous system. Our preclinical work was confirmed by other groups and spurred two consortia (NMTRC and NANT) to test DFMO in independent phase I/II NB clinical trials. The oncogene MYCN is commonly amplified in high-risk NB patients and predicts poor prognosis. MYCN directly activates ODC (and eIF5A) and drives NB tumor progression, presumably through the activation of polyamines, but the precise molecular mechanisms are not fully understood. Since spermidine is the only molecule that can activate eI5FA through hypusine modification, we hypothesized that the polyamine-hypusine nexus provides a rational target site to identify new drug combinations that trigger synergistic anti-tumor effects. In this study we found that DFMO combined with DHPS inhibitor GC7 induced synergistic drug reactions in NB at concentrations that are not lethal on their own. While each drug alone at higher concentrations induced p27/Rb-mediated G1/S cell cycle arrest, the combination of both drugs resulted in the induction of programmed cell death (apoptosis). The intracellular free polyamine levels (putrescine, spermidine, and spermine) were quantified by C-18 RP-HPLC and responded directly to drug treatments, suggesting specific drug targeting effects. This dual-pronged drug combination approach that specifically targets the blockade of the unique polyamine/spermidine-dependent hypusine-eIF5A signaling circuit known to be involved in cell proliferation might lead to more effective DFMO treatment options by reducing high DFMO doses currently needed while achieving better therapeutic outcomes in NB. Citation Format: Andre S. Bachmann, Raid El-Khawaja, Chad Schultz. Targeting the polyamine-hypusine nexus for the treatment of neuroblastoma [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 5828. doi:10.1158/1538-7445.AM2017-5828
Abstract 5692: Cross-platform detection and quantification of actionable mutations in cell-free DNA shows high concordance and correlation between next-generation sequencing and droplet digital PCR
Authors: Bryan C. Ulrich, Rebecca J. Nagy, Justin I. Odegaard, Richard B. Lanman, Geoffrey R. Oxnard, Cloud P. Paweletz
Journal: Cancer Research (2017)

Abstract Background: Non-invasive genotyping of cell-free DNA (cfDNA) provides physicians with the ability to identify genomic alterations, evaluate response to treatment, and uncover potential mechanisms of resistance. Here, we analyze the concordance of next-generation sequencing (NGS) and droplet digital PCR (ddPCR) in detecting and quantifying actionable mutations from cfDNA of lung, colorectal, and breast cancer patients. Methods: We studied a cohort of 221 advanced cancer cfDNA samples with completed Guardant360 digital sequencing results. Variant allele frequencies (% AFs) ranged from less than 0.2% to greater than 90% for common driver and resistance mutations. Blinded to plasma NGS results, we performed ddPCR using our validated assays for EGFR L858R, exon19 del, T790M (113 presumed lung cases); BRAF V600E, KRAS G12X (77 colorectal cases); ESR1 D538G, Y537C and PIK3CA H1047R (31 breast cases). Following unblinding, qualitative and quantitative accuracy were compared. Results: Qualitative results (Table 1) show a high concordance between NGS and ddPCR, with 98.3% (576/586) of all assays run being concordant. 9/22 of samples that had an AF below 0.4% were discordant, while only one sample above 0.4% AF was discordant. AFs calculated by NGS and ddPCR were strongly correlated by linear regression (R between 0.951 and 0.999). Notably, the slope of the ddPCR AF versus NGS AF graph for EGFR ex19del was 0.725, which improved to 0.95 with the adoption of an alternate calling method. Conclusions: This interlaboratory comparison of actionable mutations in cfDNA from lung, colorectal, and breast cancers by orthogonal genotyping platforms demonstrates a substantial concordance in detection and quantification between NGS and ddPCR. Our cross-platform study establishes the feasibility of standardization of qualitative and quantitative measurements of cfDNA-detected alterations. Table 1LungEGFR L858REGFR Ex19 delEGFR T790M(n=113)G360+G360-G360+G360-G360+G360-ddPCR+580510530ddPCR-055458456BreastESR1 Y537CESR1 D538GPIK3CA H1047R(n=31)G360+G360-G360+G360-G360+G360-ddPCR+1022020ddPCR-03009029ColorectalBRAF V600EKRAS G12X(n=78)G360+G360-G360+G360-ddPCR+220571ddPCR-055118 Citation Format: Bryan C. Ulrich, Rebecca J. Nagy, Justin I. Odegaard, Richard B. Lanman, Geoffrey R. Oxnard, Cloud P. Paweletz. Cross-platform detection and quantification of actionable mutations in cell-free DNA shows high concordance and correlation between next-generation sequencing and droplet digital PCR [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 5692. doi:10.1158/1538-7445.AM2017-5692
Abstract LB-109: PDeX (Patient Derived eXplant) models to determine the basis for response to targeted agents in prostate cancer
Authors: Ayesha A. Shafi, Matthew J. Schiewer, Renee de Leeuw, Peter A. McCue, Leonard G. Gomella, Costas D. Lallas, Edouard J. Trabulsi, Theresa Hickey, Neelima Shah, Edna Cukierman, Lisa M. Butler, Wayne Tilley, Ganesh Raj, Karen E. Knudsen
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is the most common non-cutanenous cancer and the third leading cause of cancer-related death in American men. Androgen receptor (AR) is a hormone-activated transcription factor that plays an important role in both the development and progression of PCa. Androgen deprivation therapy is a common first-line therapy for disseminated disease. However, virtually all tumors become resistant to such therapy and the tumor recurs. Thus, there is a vital need for the development of novel, more effective drugs. One major hurdle in this aspect is the lack of adequate preclinical models. Current models do not effectively recapitulate the heterogeneity and the microenvironment of human PCa tumors, significantly hindering the ability to accurately predict therapeutic response. Our collaborative group has utilized and characterized a method to culture patient tumors ex vivo, termed Patient Derived eXplant (PDeX). This approach maintains the integrity of the native tumor microenvironment, tumor tissue morphology, and molecular signaling. Importantly, our PDeX model can be manipulated both chemically (drugs/compounds) and genetically (shRNA) in order to determine specific reactions and mechanisms of response on individual tumor growth. Furthermore, with this model we can quantitatively assess drug efficacy on numerous parameters (i.e. AR levels, Ki67 staining, apoptosis screening, and desmoplasmic indices). Data to be discussed will assess the variances in response to AR-directed therapeutics and underlying mechanisms of action, while also utilizing TME characteristics as a means to predict response to therapy. In addition, we can potentially identify clinically relevant subpopulations of patients and molecularly profile their cultured tissue to uncover new pathways for therapeutic intervention. Thus, the PDeX model allows for a comprehensive evaluation of individual tumors in their native microenvironment to ultimately develop more effective therapies. This study will have transformative clinical impact discerning novel metrics for the inclusion of precision medicine for advanced PCa. Citation Format: Ayesha A. Shafi, Matthew J. Schiewer, Renee de Leeuw, Peter A. McCue, Leonard G. Gomella, Costas D. Lallas, Edouard J. Trabulsi, Theresa Hickey, Neelima Shah, Edna Cukierman, Lisa M. Butler, Wayne Tilley, Ganesh Raj, Karen E. Knudsen. PDeX (Patient Derived eXplant) models to determine the basis for response to targeted agents in prostate cancer [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-109. doi:10.1158/1538-7445.AM2017-LB-109
Introduction: Session VII
Authors: Andervont, H. B.
Journal: JNCI Journal of the National Cancer Institute (1954)

Journal Article Introduction: Session VII Get access H. B. Andervont H. B. Andervont Chairman Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 15, Issue 3, December 1954, Pages 773–774, https://doi.org/10.1093/jnci/15.3.773 Published: 01 December 1954
Abstract 3543: Targeting the metabolic mevalonate pathway with statins as anti-breast cancer agents
Authors: Jenna van Leeuwen, Aleksandra Pandyra, Carolyn Goard, Peter J. Mullen, Rosemary Yu, Linda Z. Penn
Journal: Cancer Research (2017)

Abstract The statin family of drugs target the mevalonate pathway and have been used for decades in the control of hypercholesterolemia, however recent evidence suggests these approved agents may also be useful as anti-cancer therapeutics (see our recent Nature Review Cancer article1). For example, statins can trigger tumor-specific apoptosis and two independent pre-op clinical trials in breast cancer, evaluating cholesterol-lowering doses of fluvastatin and atorvastatin, resulted in breast tumor shrinkage due to decreased growth and increased apoptosis. Our hypothesis is that statins have utility as anti-breast cancer agents. To maximize efficacy and speak to personalized medicine, our objectives are to develop biomarkers to distinguish which patients will benefit from the addition of statins to their treatment regimen and how best to use statins in combination with other agents to augment anti-tumor efficacy. To identify biomarkers of statin sensitivity we evaluated fluvastatin activity across a panel of BCa cell lines and showed that the basal, estrogen receptor-negative subtype were significantly sensitive to statin-induced apoptosis. As this included the difficult-to-treat triple negative BCa (TNBCa) we have extended this work and further evaluated a panel of TNBCa cell lines for statin sensitivity. From these results we are identifying features associated with robust apoptosis in response to statin exposure. To identify how best to use statins, we conducted two unbiased screens and have shown that blocking the restorative feedback response to statin exposure potentiates statin-induced apoptosis. This is reversible with exogenous mevalonate, reinforcing that this is an on-target effect. We also identified another approved agent, dipyridamole, as able to potentiate the anti-cancer activity of statins. Mechanistically we have shown that dipyridamole blocks the feedback response to statin exposure. We have extended these studies and shown that the combination of statins and dipyridamole is effective against TNBCa both in vitro and in vivo. Thus, we provide essential pre-clinical data to support the further evaluation of statins and dipyridamole in BCa. Reference: Mullen, P.J. et al. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer. 16, 718-731 (2016). Citation Format: Jenna van Leeuwen, Aleksandra Pandyra, Carolyn Goard, Peter J. Mullen, Rosemary Yu, Linda Z. Penn. Targeting the metabolic mevalonate pathway with statins as anti-breast cancer agents [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 3543. doi:10.1158/1538-7445.AM2017-3543
Abstract LB-307: Dissecting mutual exclusiveness of oncogenic mutations in melanoma
Authors: Raj Kumar, Ching-Ni-Jenny Njauw, Zhenyu Ji, Anpuchchelvi Rajadurai, Hensin Tsao
Journal: Cancer Research (2017)

Abstract Mutual exclusiveness of oncogenes is a general phenomenon in cancer. Specifically in melanoma BRAF and NRAS mutations do not co-exist except a few (0.7%) cases. Here, we are looking for critical exclusive common target(s) of BRAF and NRAS mutations meant for synthetic lethality in melanoma therapy. To specifically evaluate BRAF and NRAS mutation dependent gene regulation in melanoma, mRNA microarray gene expression analysis was performed in melanoma cell lines where growth suppressive and non-suppressive properties depend on mutual targets of BRAFV600E and NRASQ61R/K mutation. We identified the tumor suppressor gene SPRY4 as a novel transcriptional target of second oncogenes BRAFV600E or NRASQ61R/K responsible for suppressive growth phenotype in various melanoma cell lines. Sprouty4 (SPRY4) acts as a feedback suppressor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. It has a role in the regulation of cell growth, motility and progression of various cancer types’ breast cancer, osteosarcoma, endometrial adenocarcinoma, myeloid leukemia including melanoma. Remote inducible expression of either BRAFV600E or NRASQ61R/K enhances the expression of SPRY4 at mRNA and protein level only in poor growth cell lines such as NRASQ61R (Tet-On BRAFV600E: SKmel119, WM1361 and BRAFV600E (Tet-On NRASQ61R: Gmel and MGH-CH-1) but not in NRASQ61R (Tet-On BRAFV600E: SKmel-63), BRAFV600E (Tet-On NRASVQ61R: A375) mutation. In addition, we observed that BRAFV600E expression exhibit constitutive activation of stress pathway signaling that is presumed to induce secondary senescence, as it does in nevi or normal cells. SPRY4 modify second oncogene induced changes such as inhibition of SPRY4 rescues cell growth impaired by BRAF or NRAS mutation expression. Hence, second oncogene enhances SPRY4 expression in part through stress pathway as confirmed by phospho kinase array. These findings suggest that in SPRY4/MAPK/Stress pathway, SPRY4 as a common target of BRAF and NRAS mutations affecting melanoma growth. Citation Format: Raj Kumar, Ching-Ni-Jenny Njauw, Zhenyu Ji, Anpuchchelvi Rajadurai, Hensin Tsao. Dissecting mutual exclusiveness of oncogenic mutations in melanoma [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-307. doi:10.1158/1538-7445.AM2017-LB-307
Abstract 2360: Regulation of the MAPK phosphatase MKP-1 by the E3 ligase GP78 in cancer cells
Authors: Dhonghyo Kho, Gen Sheng Wu
Journal: Cancer Research (2017)

Abstract Mitogen-activated protein kinase (MAPK) phosphatase 1 (DUSP1/MKP-1) is a member of the threonine-tyrosine dual-specificity phosphatase family that is endogenous inhibitor for extracellular signal-regulated protein kinases (ERKs), p38 MAPKs, and JNKs signaling. MKP-1 plays a key role in determining the magnitude and duration of MAPK activation in response to extracellular stimuli. In human cancers, abnormal expression of DUSP1 is associated with tumor development, chemoresistance and prognosis. However, the mechanism by which MKP-1 is regulated is not fully understood. Here, we show that GP78, an E3 ligase, plays an important role in regulation of MKP-1 protein levels. Specifically, we found that MKP-1 interacts with GP78 both in vitro and in vivo. Their interaction occurs between the N-terminal, Rhodanese domain of MKP-1 and C-terminal E3 ligase domain of GP78. We also found that K230, 280, and 289 residues on MKP-1 are responsible for its ubiquitination. Importantly, this interaction causes MKP-1 ubiquitination and subsequent degradation. Furthermore, we showed by overexpression and knockdown studies that GP78 downregulates the level of MKP-1 protein in cancer cells. Therefore, we identify a novel mechanism by which GP78 controls MKP-1 protein levels and suggest that this regulatory mechanism may play an important in cancer. Citation Format: Dhonghyo Kho, Gen Sheng Wu. Regulation of the MAPK phosphatase MKP-1 by the E3 ligase GP78 in 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 2360. doi:10.1158/1538-7445.AM2017-2360
Abstract 5443: Developing a novel miR-15a mimic as a potential therapeutic molecule to eliminate resistant colorectal cancer stem cells
Authors: Andrew T. Fesler, Hua Liu, Ning Wu, Jingfang Ju
Journal: Cancer Research (2017)

Abstract In the last 15 years, it has become well established that microRNA play important roles in cancer biology. Due to their ability to regulate the expression of important target genes, aberrant expression of miRNAs has been linked to cancer development and progression. Based on these important functions, there is great interest in developing miRNA based therapeutics. In colorectal cancer, treatment using 5-flurouracil (5-FU) based chemotherapy has improved patient outcomes. However, there remain challenges associated with chemoresistance and recurrence for patients with advanced stage colorectal cancer. miRNA based therapeutics may represent an potential novel therapeutic option for colorectal cancer therapy either alone or in combination with 5-FU based chemotherapy. miR-15a was of the first miRNAs identified to be associated with cancer, and has been shown to have important roles in several tumor types. miR-15a is downregulated in colon cancer and associated with poor patient prognosis. We have identified several important cancer related targets of miR-15a in colon cancer, including YAP1, DCLK1, BMI1 and BCL2. Through the regulation of these targets, miR-15a expression can be used as a potent inhibitor to reduce colon cancer cell proliferation, invasion and improve sensitivity to 5-FU, as well as decreasing tumor growth in vivo mouse colon tumor models using colon cancer stem cells. In the interest of developing miR-15a based colon cancer therapeutics, we have made a modified miR-15a mimic that shows enhanced abilities to disrupt resistant colon cancer cell proliferation and induction of cell cycle arrest when compared to unmodified miR-15a. Following transfection with miR-15a mimic, cell number was reduced by 84% compared to control and 66% compared to miR-15a precursor. Cell cycle analysis showed that G1/S ratio was increased from 1.07 for control to 2.87 for precursor miR-15a and 7.07 for miR-15a mimic. This miR-15a mimic also maintains its ability to regulate these important target genes in colon cancer stem cells. In mouse models using colon cancer stem cells, miR-15a mimic has demonstrated therapeutic potential by reducing tumor growth. Based on these findings, there is potential that modified miR-15a could be adapted for treatment of patients to improve survival of advanced stage colorectal cancer patients. Citation Format: Andrew T. Fesler, Hua Liu, Ning Wu, Jingfang Ju. Developing a novel miR-15a mimic as a potential therapeutic molecule to eliminate resistant colorectal cancer stem 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 5443. doi:10.1158/1538-7445.AM2017-5443