tbuckley/cabot-search huggingface dataset:
Abstract 4970: Oxidative phosphorylation as a target in triple negative breast cancer therapy
Authors: Funda Meric-Bernstam, Kurt Evans, Xiaofeng Zheng, Xiaoping Su, Erkan Yuca, Stephen Scott, Argun Akcakanat, Naoto Ueno, Bora Lim, Jennifer Litton, Vicente Valero, Fraser Symmans, Gabriel Hortobagyi, Charles Perou, Debu Tripathy, Guilio Draetta, Joe Marszalek, Ana Maria Gonzalez-Angulo, Stacy Moulder
Journal: Cancer Research (2017)

Abstract Altered cellular metabolism is a hallmark of cancer. It is increasingly recognized that selected tumors are dependent on oxidative phosphorylation (OXPHOS). However, the role of OXPHOS in TNBC is not well understood. We performed RNA sequencing in pre-treatment biopsies from 43 patients with operable triple negative breast cancer (TNBC) who received sequential taxane- and anthracycline-based neoadjuvant chemotherapy. At a median follow-up of 63 months, 14 patients recurred and 12 patients died. At a false discovery rate of 0.05, 33 genes were differentially expressed between the patients who did and did not have a subsequent recurrence. Ingenuity pathway analysis demonstrated that one of the top canonical pathways that differed was higher expression of oxidative phosphorylation signature (p=5.89E-0.7). The patients who recurred had significantly higher levels of mitochondrial genes: MT-ND1 (adjusted p or FDR-BH; q=0.007); MT-ND5 (q=0.03) and MT-ND4 (q=0.04). Further, 21 genes were differentially expressed between patients based on survival, including MT-ND5 (q=0.001); MT-ND4 (q=0.005), MT-ND4L (q=0.015), MT-ND6 (q=0.018), and MT-ATP6 (P=0.03). Top canonical pathway that was differentially expressed based on survival was oxidative phosphorylation (p=9.98E-10). We therefore sought to determine the efficacy of IACS-10759, a novel inhibitor of OXPHOS, in 10 different TNBC patient-derived xenografts representing different gene expression based Lehmann TNBC subtypes. Growth inhibition was observed in multiple subtypes, with regression in one basal-like 1(BL1) 1 model, and stabilization of growth in multiple BL1 and immunomodulatory expression subtypes. Taken together, our data suggests that high OXPHOS is associated with higher recurrence and lower survival. OXPHOS is a promising target in several TNBC subtypes. A Phase I trial of IACS-10759, a potent inhibitor of complex I of oxidative phosphorylation, in leukemia is ongoing and planned in TNBC and other solid tumors. Citation Format: Funda Meric-Bernstam, Kurt Evans, Xiaofeng Zheng, Xiaoping Su, Erkan Yuca, Stephen Scott, Argun Akcakanat, Naoto Ueno, Bora Lim, Jennifer Litton, Vicente Valero, Fraser Symmans, Gabriel Hortobagyi, Charles Perou, Debu Tripathy, Guilio Draetta, Joe Marszalek, Ana Maria Gonzalez-Angulo, Stacy Moulder. Oxidative phosphorylation as a target in triple negative breast cancer therapy [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 4970. doi:10.1158/1538-7445.AM2017-4970
Abstract 4200: Targeting cancer stem cells in serous ovarian carcinoma using RP6530, a dual PI3k δ/γ inhibitor
Authors: Sneha S, Nivetha R, R P. Nagare, Srikant Viswanadha, Swaroop Vakkalanka, T S. Ganesan
Journal: Cancer Research (2017)

Abstract Ovarian cancer is one of the most lethal gynecological malignancies as most patients are diagnosed at an advanced stage and have a poor prognosis. Several studies have prospectively isolated cancer stem cells (CSCs) from samples of tumor from patients with serous adenocarcinoma of the ovary (SOC). This has been achieved by using cell surface antigens or functional assays. Targeting this subpopulation could be critical to overcome drug resistance, recurrence, and hence improve the survival of patients. The PI3K pathway is deregulated in 37% of SOC with PI3Kδ and γ amplified in 16% of tumors (TCGA data). We have used a novel and selective PI3K γ/δ inhibitor (RP6530) with high potency against PI3Kγ (IC50=25 nM) and δ (IC50=33 nM) enzymes and selectivity over α (&amp;gt;300-fold) and β (&amp;gt;100-fold) isoforms. RP6530, an orally active and sensitive small molecule inhibitor, is currently being tested in Phase-1 trials in US and Europe to evaluate its safety and efficacy in patients with hematological malignancies. The objective of this study was to test the efficacy of RP6530 against CSCs of EOC. Spheroids, enriched for CSCs were employed as an approach to evaluate the specific potency of the drug. In the experiments, Salinomycin was used as a control drug that targets CSCs. Initially, we have analyzed 3 cell lines (PEO4, OVCAR-5 and CAOV-2) with and without addition of 5µM RP6530. RP6530 significantly inhibited spheroid formation in PEO4 (0.001) and OVCAR-5 (p&amp;lt;0.05) and CAOV-2 (p&amp;lt;0.01) (mean of ≥3 experiments in triplicate). In cell viability assay, RP6530 had no cytotoxic effect as compared to Cisplatin in any of the cell lines. To evaluate the effect of the compound on CSC, we performed analysis of side population (SP) with Hoechst 33342 at 355 nm by flow cytometry. RP6530 either caused a significant reduction (&amp;gt;50%) in the fraction of SP cells (PEO4 and CAOV-2) or was neutral (OVCAR-5) indicating that the compound preferentially targets CSC in ovarian cancer cell lines. Colony assay revealed significantly lesser number of colonies in RP6530 treated cells. Phosphorylation of Akt that is downstream of PI3 kinase was inhibited in a dose dependent manner in all three cell lines. Evaluation of drugs that are intended to target CSCs is different from that of conventional cytotoxic drugs. Taken together, the results indicate that RP6530 shows potent inhibitory effect on CSCs in ovarian cancer cell lines. Citation Format: Sneha S, Nivetha R, R P. Nagare, Srikant Viswanadha, Swaroop Vakkalanka, T S. Ganesan. Targeting cancer stem cells in serous ovarian carcinoma using RP6530, a dual PI3k δ/γ inhibitor [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 4200. doi:10.1158/1538-7445.AM2017-4200
Abstract 2999: NKG2A checkpoint receptor expression on tumor-infiltrating CD8+ T cells restrains efficacy of immunotherapy
Authors: Thorbald van Hall, Nadine van Montfoort, Sytse Piersma, Marjolein Sluijter, Marij J. Welters, Pascale André, Nicolai Wagtmann, Sjoerd H. van der Burg
Journal: Cancer Research (2017)

Abstract The inhibitory receptor CD94-NKG2A is expressed on subsets of NK cells and cytotoxic CD8+ T cells, but not CD4+ T helper cells. It’s ligand is the non-classical MHC class I molecule HLA-E, commonly over-expressed in human cancers. We previously demonstrated that high HLA-E expression in ovarian carcinoma and NSCLC may neutralize the survival benefit of T cell infiltration, suggesting that NKG2A could represent an immune checkpoint that tumors may exploit for immune evasion. We thus examined NKG2A expression on human and mouse Tumor Infiltrating Lymphocyte (TIL) populations and tested blockade of this receptor in mouse tumor models. Multicolor flow cytometry analysis showed higher frequency of NKG2A+CD8+ T cells in TIL samples obtained from biopsies of human head- and neck- carcinomas (n=17) compared to peripheral blood CD8+ T cells. Frequency of NKG2A+ TIL was higher in patients with measurable immune reactivity to HPV16-viral antigens than in patients without tumor immunity (14.8% vs 4.7%, respectively). Interestingly, only subsets of the NKG2A+ T cells co-expressed other inhibitory receptors, including PD-1 and TIM3, suggesting the existence of a ‘dedicated’ T cell subset for NKG2A. In our mouse tumor models we observed similar findings and, moreover, demonstrated that therapeutic vaccines comprising tumor antigens increased the frequency of NKG2A+-positive CD8+ TIL up to 80%. Similarly, expression of Qa-1, the mouse homologue of HLA-E, on tumor cells also increased after therapeutic vaccination. As a proof of concept that the NKG2A - Qa-1 axis limits the efficacy of immunotherapy, NKG2A blocking antibodies were applied in the TC-1 model together with therapeutic peptide vaccination. Combination treatment with vaccine and NKG2A blockade significantly improved the therapeutic efficacy compared to the vaccine alone, both in terms of survival (P&amp;lt;0.05, median survival 44 vs 31 days) as well as overall response rate, defined as decreased tumor size of more than 30% (93.8% vs 43.8%, respectively). Similar results were obtained in Qa-1-deficient mice, suggesting that Qa-1 on tumor cells is of importance. In conclusion, inhibitory receptor NKG2A is enriched on CD8+ TIL and functions as an immune checkpoint that restrains therapeutic efficacy of a cancer vaccine. Citation Format: Thorbald van Hall, Nadine van Montfoort, Sytse Piersma, Marjolein Sluijter, Marij J. Welters, Pascale André, Nicolai Wagtmann, Sjoerd H. van der Burg. NKG2A checkpoint receptor expression on tumor-infiltrating CD8+ T cells restrains efficacy of immunotherapy [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 2999. doi:10.1158/1538-7445.AM2017-2999
Analysis of reimbursement (R) for next generation sequencing (NGS) on patients' tumors in the context of a personalized medicine program.
Authors: Thomas D. Brown, Mariko Tameishi, Xiaoyu Liu, James Scanlan, J. David Beatty, Charles Drescher, John M. Pagel, Philip Jordan Gold, Shlece Alexander, Lauren K. Summers, Madeleine Brindle, Nina Varghis, James Yates, Kathleen N. Fondren, George Richard Birchfield, David Edwin Dong, Tara L. Benkers, Tanya A. Wahl, Scott David Ramsey, Anna Belinda Berry
Journal: Journal of Clinical Oncology (2017)

6506 Background: R policies for NGS testing vary widely among private and public insurers. While drug costs are the greatest challenge in personalized or precision medicine, cost and R are substantial barriers to genomic profiling with NGS. We examined variation in coverage and R for a cohort of cancer patients (pts) treated at a tertiary oncology center. Methods: An Institutional Review Board approved prospective registration protocol was activated with the objective of establishing a centralized longitudinal clinical, molecular phenotypic, and research data repository for pts diagnosed with cancer. Based on provider assessment of medical necessity, mutations in 68 cancer associated genes were analyzed. Evaluation of R for NGS was performed from Sept, 2014 through Jan, 2017, with use of CPT code 81455. R was analyzed based on: payer type; pt age; localized vs. metastatic disease; and actionability of data. Results: 588 pts with evaluable analytic cases, and NGS testing, with R results shown in the table below. For groups with &gt;= 10 pts: R frequency was highest in managed care programs, either private or Medicare, and least frequent in non-HMO Medicare (p&lt;.001). In pts receiving R, payments by private HMOs were highest (p&lt;.02). NGS results with labelled drug indications were associated with less frequent R (26% vs. 35%; p&lt;.05), and lower payments (mean of $358 vs. $567; p&lt;.02) compared to other NGS results. Younger age was associated with more frequent R (38% in pts &lt;60 years, 24% in pts &gt;= 60 years; p&lt;.005). Neither cancer diagnosis nor stage were significantly associated with R. Conclusions: One third of pts received some R for NGS testing. R was more frequent and higher in managed care programs, both private and Medicare. R was more likely for younger age pts, while actionable NGS results were associated with lower R. These data demonstrate the need for rational, transparent, and consistent R policies, along with a value-based R model for NGS across all payer groups. [Table: see text]
Abstract 768: The utility of a breast cancer registry for improved cancer management in developing countries
Authors: DeAnna McGarity, Brandon Epps, Alexis Maynor, Tania Anderson, Ernest Alema-Mensah, Delroy Fray, Maung Aung, Kisha Holden, James Lillard, Brian Rivers, Derrick Beech
Journal: Cancer Research (2017)

Abstract Background Breast cancer is one of the leading causes of cancer related deaths in the island nation of Jamaica, West Indies. Cancer and other non-communicable diseases have increased in many developing nations in the Caribbean as well as Central and South America. The health systems of these developing countries continue to provide care to patients with limited resources. The use of a breast cancer registry can assist in care coordination of these patients and allow targeted screening and treatment programs in under-resourced environments. Methods In collaboration with the Western Regional Health Authority, a breast cancer registry database was developed in RedCap to provide a comprehensive analysis of breast cancer in under resourced environment. 53 patients from Atlanta were compared to 78 patients from Jamaica These patients were entered into the breast cancer registry from June 1, 2014 to March 31, 2015 by the attending physician and de-identified. Demographics, tumor related factors, treatment, survival and health behavior information was collected by the attending physician. The findings were then analyzed using Statistical Analysis System (SAS) and Data Analysis and Statistical Analysis (STATA): Fisher Exact test, chi-square and multiple regressions. Results The median of patient ages were 61 years old (range 38 - 81 years) for the U.S. patients and 53 years old (range 26 - 84 years old) for Jamaican women. For the U.S. patients, 84% were Black, 4% White, and 12.24% were Latin or Asian. The majority of the patients were diagnosed with stage 1 invasive ductal breast cancer. In contrast, the majority of the Jamaican patients were diagnosed with late-stage breast cancer. Utilizing the data from the breast cancer registry, we were able to identify parishes (counties) with disproportionately high rates of late-staged cancer at the time of diagnosis. Conclusion The use of a disease specific registry can improve care coordination and identify actionable target areas for enhanced screening and treatment. It is our hope to frequent review the dashboards associated with the registry data by providers, medical centers and health systems. This will optimize care coordination and allow timely improvements in cancer diagnosis and management in developing countries. Citation Format: DeAnna McGarity, Brandon Epps, Alexis Maynor, Tania Anderson, Ernest Alema-Mensah, Delroy Fray, Maung Aung, Kisha Holden, James Lillard, Brian Rivers, Derrick Beech. The utility of a breast cancer registry for improved cancer management in developing countries [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 768. doi:10.1158/1538-7445.AM2017-768
Abstract 5238: Structural and biochemical characterization of membrane bound KRAS
Authors: Andrew G. Stephen, Que Van, Marco Tonelli, William Gillette, Dominic Esposito, Ben Niu, Michael Gross, Frank Heinrich, Arvind Ramanathan, Christopher Stanley
Journal: Cancer Research (2017)

Abstract KRAS4b functions as a molecular switch cycling between an active GTP bound state and inactive GDP state. Active KRAS4b binds tightly to RAF1 via its Ras binding domain (RBD), however activation of RAF1 competent for MAPK signal transduction requires membrane bound KRAS4b. Using recombinant farnesylated and methylated KRAS4b (KRAS4b-FMe) we have used a variety of biophysical methodologies including paramagnetic relaxation enhancement NMR, neutron reflectivity, small angle neutron and x-ray scattering and protein footprinting to gain insights into the orientation and structure of KRAS-FMe bound to a membrane. In these experiments we have used Nanodiscs or tethered lipid bilayers composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-choline or -serine (70% POPC 30% POPS). Our data indicate that KRAS-FMe is oriented perpendicular to the membrane with minimal direct contacts to the membrane. The nucleotide bound state does not significantly change the orientation relative to the membrane. We will also present data on the effect of the RBD domain of RAF1 binding to KRAS-FMe at the membrane. Citation Format: Andrew G. Stephen, Que Van, Marco Tonelli, William Gillette, Dominic Esposito, Ben Niu, Michael Gross, Frank Heinrich, Arvind Ramanathan, Christopher Stanley. Structural and biochemical characterization of membrane bound KRAS [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 5238. doi:10.1158/1538-7445.AM2017-5238
Exposure–Response of Veliparib to Inform Phase II Trial Design in Refractory or Relapsed Patients with Hematological Malignancies
Authors: Shailly Mehrotra, Mathangi Gopalakrishnan, Jogarao Gobburu, Jiuping Ji, Jacqueline M. Greer, Richard Piekarz, Judith E. Karp, Keith W. Pratz, Michelle A. Rudek
Journal: Clinical Cancer Research (2017)

Abstract Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated a 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure–response analysis to inform the phase II trial design. Experimental Design: Pharmacokinetic, efficacy, and safety data from 95 patients, who were administered 10 to 100 mg b.i.d. doses of veliparib for either 8, 14, or 21 days with T+C, were utilized for exposure–efficacy (objective response and overall survival) and exposure–safety (≥grade 3 mucositis) analysis. Multivariate cox proportional hazards and logistic regression analyses were conducted. The covariates evaluated were disease status, duration of treatment, and number of prior therapies. Results: The odds of having objective response were 1.08-fold with 1,000 ng/hr/mL increase in AUC, 1.8-fold with &amp;gt;8 days treatment, 2.8-fold in patients with myeloproliferative neoplasms (MPN), and 0.5-fold with ≥2 prior therapies. Based on analysis of overall survival, hazard of death decreased by 1.5% for 1,000 ng/hr/mL increase in AUC, 39% with &amp;gt;8 days treatment, 44% in patients with MPN, while increased by 19% with ≥2 prior therapies. The odds of having ≥grade 3 mucositis increased by 29% with 1,000 ng.h/mL increase in AUC. Conclusions: Despite shallow exposure–efficacy relationship, doses lower than 80 mg do not exceed veliparib single agent preclinical IC50. Shallow exposure–mucositis relationship also supports the 80-mg dose. Based on benefit/risk assessment, veliparib at a dose of 80 mg b.i.d. for at least 14 days in combination with T+C is recommended to be studied in MPN patients. Clin Cancer Res; 23(21); 6421–9. ©2017 AACR.
Erratum: Corrigendum: Protein-structure-guided discovery of functional mutations across 19 cancer types
Authors: Beifang Niu, Adam D Scott, Sohini Sengupta, Matthew H Bailey, Prag Batra, Jie Ning, Matthew A Wyczalkowski, Wen-Wei Liang, Qunyuan Zhang, Michael D McLellan, Sam Q Sun, Piyush Tripathi, Carolyn Lou, Kai Ye, R Jay Mashl, John Wallis, Michael C Wendl, Feng Chen, Li Ding
Journal: Nature Genetics (2017)
Abstract 3201: Therapeutic potential of anti-angiogenic multimodal biomimetic peptide in hepatocellular carcinoma
Authors: Mustafa A. Barbhuiya, Adam C. Mirando, Brian W. Simons, Ghali Lemtiri-Chlieh, Jordan J. Green, Aleksander S. Popel, Niranjan B. Pandey, Phuoc T. Tran
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) related mortality ranks second worldwide and stands one step behind lung cancer. Due to the asymptomatic nature of the cancer, early diagnosis is a major problem. Currently only liver transplantation is curative for early stage hepatocellular cancer. There are other multidisciplinary treatment options like radiation and chemotherapy available for advanced patients. However, chemotherapy resistance is a common problem in the treatment of liver cancer. Newer therapeutics are needed for better management of advanced HCC. Angiogenesis and lymphangiogenesis are processes that are vital for tumorigenesis and metastasis. HCC is known to be a hypervascular tumor and many pro-angiogenic proteins are found significantly overexpressed in HCC. We explored the therapeutic potential of the anti-angiogenic and anti-lymphangiogenic, biomimetic peptide SP2043 developed by our group in HCC. Hepatocellular carcinoma cell lines HuH-7, Hep3b and HepG2 showed significant disruption of cell adhesion and migration following treatment. Furthermore, SP2043 was found to impair microvascular endothelial cell (MEC) tube formation induced by HepG2 tumor conditioned media and to significantly inhibit HepG2 tumor xenograft growth compared to untreated controls. The peptide drug was also found to improve the survival of autochthonous Myc induced HCC in a transgenic mouse model from two weeks to four weeks. We discovered the peptide to be a multi-modal anti-angiogenic drug that also inhibits IGF1R and MET signaling pathways in HCC cell lines. We also found that SP2043 treatment reduced the microvascular density in both subcutaneous and autochthonous liver tumors with reduced tumor cell proliferation and increased apoptosis. This study shows the therapeutic potential of SP2043 in the treatment of hepatocellular carcinoma. Note: This abstract was not presented at the meeting. Citation Format: Mustafa A. Barbhuiya, Adam C. Mirando, Brian W. Simons, Ghali Lemtiri-Chlieh, Jordan J. Green, Aleksander S. Popel, Niranjan B. Pandey, Phuoc T. Tran. Therapeutic potential of anti-angiogenic multimodal biomimetic peptide in hepatocellular 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 3201. doi:10.1158/1538-7445.AM2017-3201