tbuckley/cabot-search huggingface dataset:
Targeted combination therapy with fulvestrant (FUL) for second-line (2L) treatment of hormone receptor-positive (HR+) advanced breast cancer (ABC).
Authors: Ingrid A. Mayer, Ruth O'Regan, Noah Saul Kornblum, Kimberly L. Blackwell
Journal: Journal of Clinical Oncology (2017)

e12527 Background: FUL is the recommended 2L treatment for patients whose HR+ ABC progressed after aromatase inhibitor (AI) therapy. In first line ABC adding targeted therapy, eg. cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) palbociclib or ribociclib, or mammalian target of rapamycin inhibitor (mTORi) everolimus (EVE), to endocrine therapy (ET) has shown superior efficacy vs ET alone. The use of similar strategies to delay disease progression on ET in the 2L setting is an area of active research. Methods: PubMed and ClinicalTrials.gov were searched for trials investigating FUL + targeted therapies in 2L HR+ ABC. Search terms: (advanced OR metastatic) AND (breast cancer) AND (FUL OR faslodex) AND (2L OR relapse OR refractory OR resistant OR progression). Efficacy, adverse events (AEs) and quality of life were assessed. Results: 28 studies of FUL + targeted therapies in 2L ABC were found. Key randomized trials include 8 studies exploring FUL + CDK4/6i: palbociclib, ribociclib or abemaciclib. Palbociclib + FUL significantly improved progression-free survival (PFS) vs FUL in 2L HR+ ABC (p &lt; 0.0001; PALOMA-3), AEs were manageable. Assessment of FUL + ribociclib (MONALEESA-3) or FUL + abemaciclib (MONARCH-2) in 2L HR+ ABC is ongoing. Ten studies are evaluating FUL + phosphatidylinositol 3-kinase (PI3K)/AKT/mTORi in 2L HR+ ABC. FUL + EVE significantly prolonged PFS vs FUL (p = 0.02; PrECOG 0102). Two trials evaluated buparlisib (pan-PI3K inhibitor [PI3Ki]) + FUL in HR+ ABC post-AI (BELLE-2) and post-mTORi (BELLE-3). In both trials, buparlisib + FUL improved PFS vs FUL in patients with PIK3CA-mutated tumors, FUL alone led to a poor response in this subgroup. However, pictilisib (pan-PI3Ki) + FUL did not improve PFS vs FUL even in the PIK3CA-mutated subgroup (FERGI). Ongoing phase 3 trials are exploring FUL + alpelisib (α-specific PI3Ki; SOLAR-1) or FUL + taselisib (β-sparing PI3Ki; SANDPIPER) in PIK3CA-mutant HR+ ABC. Pts who have progressed on AI, CDK4/6i or (neo)adjuvant chemotherapy are eligible for these studies. Data on FUL + other targeted therapies will also be discussed. Conclusions: Addition of targeted therapy to FUL demonstrates promising efficacy beyond first line.
IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions
Authors: Chang-Han Lee, Gabrielle Romain, Wupeng Yan, Makiko Watanabe, Wissam Charab, Biliana Todorova, Jiwon Lee, Kendra Triplett, Moses Donkor, Oana I Lungu, Anja Lux, Nicholas Marshall, Margaret A Lindorfer, Odile Richard-Le Goff, Bianca Balbino, Tae Hyun Kang, Hidetaka Tanno, George Delidakis, Corrine Alford, Ronald P Taylor, Falk Nimmerjahn, Navin Varadarajan, Pierre Bruhns, Yan Jessie Zhang, George Georgiou
Journal: Nature Immunology (2017)
Abstract NTOC-105: RUXOLITINIB SENSITIZES OVARIAN CANCER CELLS TO LOW–DOSE PACLITAXEL THERAPY
Authors: Patrick Reeves, Mojgan Abbaslou, Mark C. Poznansky
Journal: Clinical Cancer Research (2017)

Abstract In ovarian cancer chemotherapy initially reduces tumor burden; however, &amp;gt;70% of patients experience tumor recurrence, creating a need for additional therapies. We evaluated the ability of Ruxolitinib, a FDA approved JAK 1/2 kinase inhibitor, as a potential adjunctive therapy for paclitaxel treatment of ovarian cancer. Using murine ID8 and human TOV-112D ovarian cancer cells we tested the ability of Ruxolitinib alone and in combination with low-dose paclitaxel to limit cell proliferation and colony formation in vitro. Additionally, using flow cytometry we assessed the capacity of paclitaxel to induce the expression of cell surface markers associated with stemness and the cellular stress response. We next determined if Ruxolitinib could reduce paclitaxel-induced expression of stemness and stress markers. Finally daily administration of Ruxolitinib, both alone and in combination with a single low-dose administration of paclitaxel, was tested for the capacity to reduce tumor growth and extend survival using the syngeneic ID8 luciferase-expressing model of ovarian cancer in C57Bl/6 mice. Our in vitro data demonstrate that Ruxolitinib can sensitize both murine ID8 and human TOV-112D cells to low concentrations of paclitaxel, as evidenced by a significant reduction of cell proliferation and colony formation. We find that pre-incubation with Ruxolitinib is sufficient to sensitize cells to subsequent incubation with paclitaxel. Paclitaxel-induced expression of stemness and stress markers (SCA-1, GRP78 and CD133) is reduced by co-incubation with Ruxolitinib. In vivo, Ruxolitinib plus administration of a single low-dose paclitaxel treatment is sufficient to limit tumor growth and significantly extend median survival from in mice bearing ID8 ovarian cancer tumors (Control 59days vs Ruxolitinib-paclitaxel 77 days). Together, these data indicate that Ruxolitinib can increase the susceptibility of both murine and human ovarian cancer cells to reduced concentrations paclitaxel chemotherapy in vitro and that combination therapy with Ruxolitinib and a single low-dose paclitaxel administration extends survival in mice. Our data provide important pre-clinical data to support the use of Ruxolitinib to enhance the efficacy of paclitaxel therapy for patients with ovarian cancer. Citation Format: Patrick Reeves PhD, Mojgan Abbaslou MD, Mark C. Poznansky MD PHD. RUXOLITINIB SENSITIZES OVARIAN CANCER CELLS TO LOW–DOSE PACLITAXEL THERAPY [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-105.
Thrombotic Thrombocytopenic Purpura Associated With Pegylated Interferon Alfa-2a Use in a Patient With Polycythemia Vera
Authors: Radhika Gangaraju, Soo J. Kim, Jing-Fei Dong, Sabina Swierczek, Josef T. Prchal
Journal: Journal of the National Comprehensive Cancer Network (2017)

Pegylated interferon alfa-2a (pegIFNa) is being increasingly used for treatment of myeloproliferative neoplasms; however, its side effects, including autoimmune complications, are not unusual. We report on a 47-year-old woman with polycythemia vera (PV) treated with pegIFNa and in complete hematologic remission who developed thrombotic thrombocytopenic purpura (TTP). To our knowledge, thrombotic microangiopathy has been reported as a side effect of interferon (IFN) use in patients with hepatitis and chronic myeloid leukemia, but not in those with PV. Our patient had a low ADAMTS13 level due to an inhibitor, which normalized after withholding pegIFNa and initiating treatment for TTP with therapeutic plasma exchange and corticosteroids. She experienced refractory TTP, necessitating treatment with rituximab and splenectomy. Postsplenectomy, she developed a high platelet count, warranting the need to restart treatment for PV. However, JAK2V617F allelic burden by real-time PCR was 0.7%, indicating that the increased platelet count was likely secondary to splenectomy. Therefore, we elected to monitor her counts and JAK2V617F allelic burden closely. With this case report, we hope to alert treating physicians that TTP should be considered as a complication of pegIFNa therapy in PV and that prompt discontinuation of the drug with necessary treatment should be instituted to prevent fatal complications.
Sickle Cell Disease Patients with Systemic Lupus Erythematosus Exhibit Quantitative and Qualitative Impairments in Circulating B Regulatory Cells
Authors: Amal Al-Naamani, Ahmed Al-Yarabi, Nasser Ambu-Ali, Tahar Al-Shabibi, Zahra Al-Qarni, Nasra Al-Obaidani, Hamad Khan, Juma K Al-Kaabi, Jalila Al-Shekaili, Amar Oukil, Sulaiman Ali Al-Hashmi, Alya Al-Ansari, Fahad Al-Zadjali, Murtadha K. Al-Khabori, Khalil Al-Farsi, Mohammed N. Alhuneini, Yasser Wali, Salam Al-Kindi, Mohamed-Rachid Boulassel
Journal: Blood (2016)
Utilization, trend and impact of neoadjuvant endocrine therapy compared to neoadjuvant chemotherapy in postmenopausal breast cancer patients: Analysis of the National Cancer Data Base.
Authors: Alina Basnet, Dongliang Wang, Abirami Sivapiragasam
Journal: Journal of Clinical Oncology (2017)

578 Background: Three small prospective trials that compared the efficacy of neoadjuvant endocrine therapy (NET) to neoadjuvant chemotherapy (NCT) showed no statistically significant difference. We report the differences in utilization of NET and NCT using National Cancer Data Base (NCDB) and their trend, response rates (RR) and breast conservation rates (BCR). Methods: A retrospective review of hormone receptor positive breast cancer patients ≥ 50 yrs without metastasis using NCDB was performed (2004-2014). Patients underwent NET or NCT prior to definitive surgery. Utilization pattern, practice trend, RR and BCR between NET and NCT was assessed using univariate and multivariate logistic analysis. Results: Out of 2,246,279 breast cancer patients reported in NCDB, 38,632 met our inclusion criteria. 9178 received NET and 29,454 received NCT. On multivariate analysis NET use was higher in academic vs community centers [Odds ratio (OR) 1.355, 95% CI 1.270-1.445], age &gt;70 vs &lt; 70 (OR 6.603, 95% CI 6.110-7.137) and high vs low Charlson Deyo comorbidity index (OR 1.817, 95% CI 1.548-2.133). NET use was lower in black vs white (OR 0.790, 95% CI 0.712- 0.875), tumors with higher vs lower grade (OR 0.153, 95% CI 0.138-0.169), higher vs lower T stage (OR 0.372, 95% CI 0.340-0.407), higher vs lower N stage (OR 0.274, 95% CI 0.243-0.310) and private vs no insurance (OR 0.600, 95% CI 0.509- 0.707), (all p&lt;0.0001). A significant upward trend in utilization of NET was observed from year 2011 (25.9%) compared to before (22.2%), p&lt;0.0001. RR was significantly higher for patients receiving NCT (90.5%) compared to NET (77.2%), with an [adjusted OR (aOR) 2.413; 95% CI 2.116-2.752], however the BCR was superior in the NET group (50.0%) compared to NCT group (31.1%) with (aOR 1.676; 95% CI 1.567-1.794). Conclusions: Our study is the first to compare NET and NCT utilization and their efficacy using NCDB database. Our results have shown striking differences in outcome among these two strategies as compared to other prospective trials. Despite high RR, more patients underwent mastectomy in the NCT group. We also see a steady upward trend in usage of NET from year 2011.
Abstract 103: MiR-4261 Controls Endothelial Cells Angiogenesis
Authors: Qiulian Zhou, Dongchao Lv, Qi Sun, Ping Chen, Yihua Bei, Junjie Xiao
Journal: Circulation Research (2015)

Myocardial infarction (MI) is among major causes of morbidity and mortality associated with coronary artery disease. Angiogenesis improves tissue perfusion and cardiac repair after MI. Therefore, angiogenesis is considered to be a novel therapeutic way for ischemic heart diseases. MicroRNAs (miRNAs, miRs) have been reported to play important roles in regulating post-ischemic neovascularization. The current study aims at investigating the role of miR-4261 in angiogenesis. We found that miR-4261 mimics increased, while miR-4261 inhibitors decreased the proliferation of human umbilical vein endothelial cells (HUVEC) using EdU incorporation assay (17.25%±1.31% vs 30.91%±0.92% in nc-mimics vs mir-4261-mimics, 17.91%±1.36% vs 8.51%±0.82% in nc-inhibitor vs mir-4261-inhibitor, respectively) and CCK-8 assays (0.84±0.04 vs 1.38±0.04 in nc-mimics vs mir-4261-mimics, 0.80±0.02 vs 0.72±0.01 in nc-inhibitor vs mir-4261-inhibitor, respectively). The wound healing assay showed that miR-4261 mimic transfection resulted in a significant increase in the migration of HUVEC compared to that of the negative controls while miR-4261 inhibition had the opposite effects. Tube formation assays showed that HUVEC transfected with miR-4261 mimics increased the number of tubes formed (57.25±2.56 vs 81.5±2.53 in nc-mimics vs mir-4261-mimics, respectively), while miR-4261 inhibitor-transfected cells had the opposite effect (56.55±0.45 vs 41.38±0.52 in nc-inhibitor vs mir-4261-inhibitor, respectively). These results indicate that miR-4261 play an important role in regulating angiogenesis. However, it remains unknown which target gene mediated the effects of miR-4261. Thus, it will be of great interest to further investigate the molecular mechanisms of miR-4261 in the proliferation, migration, and tube formation of HUVEC in vitro. MiR-4261 could be a potential therapeutic target to enhance angiogenesis.
More Rigorous Study Needed Before Claiming No Harm of Blood Glucose Test Strip Limits for Patients Using Insulin—Reply
Authors: Tara Gomes, Baiju R. Shah, Muhammad M. Mamdani
Journal: JAMA Internal Medicine (2017)

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Combined therapeutic effects of bortezomib and fenretinide on neuroblastoma cell growth and apoptosis
Authors: Gabriella Pagnan, Daniela Di Paolo, Roberta Carosio, Fabio Pastorino, Chiara Brignole, Danilo Marimpietri, Monica Loi, Annalisa Pezzolo, Federica Piccardi, Michele Cilli, Mirco Ponzoni
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3266 

The proteasome inhibitor bortezomib was able to inhibit cell growth and angiogenesis in neuroblastoma (NB). Bortezomib has been shown to induce synergistic activity when combined with several other antineoplastic agents. Here, we assayed a putative increased antitumor activity of bortezomib if delivered to NB cells together with fenretinide (HPR), a synthetic retinoic acid used as apoptotic agent in a variety of cancers, including NB.    Different NB cell lines were tested for sensitivity to bortezomib and HPR, given alone or in different dose-and time-dependent combination schedules. Cell proliferation, cell viability and apoptosis were evaluated by measuring 3H-thymidine incorporation, trypan blue staining, DNA fragmentation and western-blot analysis. Angiogenesis was assessed by the chick embryo chorioallantoic membrane (CAM) assay. A mouse orthotopic model that mimics the growth and spread of NB in humans was used to examine in vivo sensitivity.    Incubation with 2,5 μM HPR caused >50% inhibition of NB cell growth when cells were treated with 5 nM bortezomib at 24 hours: these doses correspond to at least the half concentration necessary to have the same results when both drugs were administered alone. The inhibition of cell proliferation was associated to a marked G1 and G2/M cell cycle arrest with a nearly complete depletion of S phase by the combined treatment. NB cell death, triggered by the combination of the two drugs, occurs with apoptosis features via ER stress and suppression of the unfolded protein response that is translated in the sequential activation of different genes related to these processes (i.e. GRP78, caspase-4, GADD 153, p-JNK). Tumor-bearing mice treated with HPR plus bortezomib lived statistically significantly longer than mice treated with each single drug. CAM analysis and histological evaluation of primary tumors evidenced that the combined therapeutic effects are mainly due to the increased antitumor activity more than to the anti-angiogenic potential of each drug.    Our findings provide the rationale for design a new therapeutic strategy to treat NB based on this pharmacological combination.
Recombinant Poliovirus for Cancer Immunotherapy
Authors: Matthias Gromeier, Smita K. Nair
Journal: Annual Review of Medicine (2018)

Mechanisms to elicit antiviral immunity, a natural host response to viral pathogen challenge, are of eminent relevance to cancer immunotherapy. “Oncolytic” viruses, naturally existing or genetically engineered viral agents with cell type-specific propagation in malignant cells, were ostensibly conceived for their tumor cytotoxic properties. Yet, their true therapeutic value may rest in their ability to provoke antiviral signals that engage antitumor immune responses within the immunosuppressive tumor microenvironment. Coopting oncolytic viral agents to instigate antitumor immunity is not an easy feat. In the course of coevolution with their hosts, viruses have acquired sophisticated strategies to block inflammatory signals, intercept innate antiviral interferon responses, and prevent antiviral effector responses, e.g., by interfering with antigen presentation and T cell costimulation. The resulting struggle of host innate inflammatory and antiviral responses versus viral immune evasion and suppression determines the potential for antitumor immunity to occur. Moreover, paradigms of early host:virus interaction established in normal immunocompetent organisms may not hold in the profoundly immunosuppressive tumor microenvironment. In this review, we explain the mechanisms of recombinant nonpathogenic poliovirus, PVSRIPO, which is currently in phase I clinical trials against recurrent glioblastoma. We focus on an unusual host:virus relationship defined by the simple and cytotoxic replication strategy of poliovirus, which generates inflammatory perturbations conducive to tumor antigen-specific immune priming.
A Serendipitous Scientist
Authors: Robert J. Lefkowitz
Journal: The Annual Review of Pharmacology and Toxicology (2017)

Growing up in a middle-class Jewish home in the Bronx, I had only one professional goal: to become a physician. However, as with most of my Vietnam-era MD colleagues, I found my residency training interrupted by the Doctor Draft in 1968. Some of us who were academically inclined fulfilled this obligation by serving in the US Public Health Service as commissioned officers stationed at the National Institutes of Health. This experience would eventually change the entire trajectory of my career. Here I describe how, over a period of years, I transitioned from the life of a physician to that of a physician-scientist; my 50 years of work on cellular receptors; and some miscellaneous thoughts on subjects as varied as Nobel prizes, scientific lineages, mentoring, publishing, and funding.
Abstract NTOC-119: VCP INHIBITORS INDUCE ENDOPLASMIC RETICULUM (ER) STRESS AND SYNERGISTICALLY KILL OVARIAN CANCER CELLS IN COMBINATION WITH SALUBRINAL OR MIFEPRISTONE
Authors: Prabhakar Bastola, Frank J. Schoenen, Jeremy Chien
Journal: Clinical Cancer Research (2017)

Abstract Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been linked to several cellular functions including endoplasmic reticulum associated degradation (ERAD), cell division, golgi-membrane reassembly and autophagy. Recent studies have indicated VCP as one of the vulnerabilities in ovarian cancer. Here, we show that treatment with CB-5083, an orally bioavailable compound derived from previously identified quinazoline scaffold-based VCP inhibitor ML240, contributes to cytotoxicity in high-grade serous or clear cell ovarian cancer cell lines. CB-5083 treatment results in increased unfolded protein response (UPR), accumulation of cell cycle proteins as a result of inhibition of proteosomal degradation, cell cycle arrest at G1, and subsequent cell death mediated by both intrinsic and extrinsic apoptotic pathways. These results support an emerging concept that ER stress pathway can be therapeutically targeted in ovarian cancer. Since CB-5083 induces CHOP-dependent apoptosis, we tested the extent to which VCP inhibitors act synergistically with salubrinal, a compound that inhibits GADD34 and enhances eIF2α phosphorylation. Results from Sulforadamine B and clonogenic assays indicate that VCP inhibitors and salubrinal act synergistically across various concentrations of drug combination. Based on recent studies indicating that mifepristone, a steroidal antagonist to progesterone and glucocorticoid, induce ER stress and subsequent cell death, we also tested the potential drug synergies between VCP inhibitors and mifepristone. Our results indicate these drugs act synergistically across various concentrations in ovarian cancer cells. Analysis of TCGA RNA-sequencing datasets indicate VCP expression is down-regulated in cisplatin-resistant tumor samples compared to cisplatin-sensitive cancer. This data is consistent with the fact that tumors with lower expression of VCP shows significant association with poor progression-free survival and overall survivor. Finally, our results indicate that cells with lower expression of VCP are more sensitive to VCP inhibitors than those with higher expression. Considering that cisplatin-resistant tumor samples have lower expression of VCP, VCP inhibitors may be a good therapeutic candidate to treat cisplatin-resistant ovarian cancer. Collectively, our results provide evidence that VCP inhibitors can be used as a single agent and can be synergized with compounds that prolong or induce ER stress in ovarian cancer. Citation Format: Prabhakar Bastola, Frank J. Schoenen, Jeremy Chien. VCP INHIBITORS INDUCE ENDOPLASMIC RETICULUM (ER) STRESS AND SYNERGISTICALLY KILL OVARIAN CANCER CELLS IN COMBINATION WITH SALUBRINAL OR MIFEPRISTONE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-119.
Blockage of intracellular proton extrusion with proton pump inhibitor induces apoptosis in gastric cancer
Authors: Marie Yeo, Dong-Kyu Kim, Hee Jin Park, Sung Won Cho, Jae Youn Cheong, Kwang Jae Lee
Journal: Clinical Cancer Research (2007)

A36  Background & Aims: To survive in an ischemic microenvironment with a lower extracellular pH, ability to up-regulate proton extrusions is critical and well developed for cancer cell survival. Gastric H+/K+-ATPase exchanges luminal K+ for cytoplasmic H+ and is the enzyme primarily responsible for gastric acidification. Based on the fact that blocking the clearance of acidic metabolites are known to induce the cell death, we hypothesized that proton pump inhibitor (PPI), one of gastric H+/K+-ATPase inhibitors frequently used to treat acid-related diseases, could inhibit growth of tumor cells. Methods: Genomic DNA fragmentation, TUNEL assay, and annexin V staining were done to reveal whether PPI induced apoptosis in gastric cancer cells. MAPK activation and heat shock protein expression were determined by immunoblot with specific antibodies to reveal the selective induction of cell death with PPI. The anti-tumor effect of PPI was evaluated in vivo by xenograft model of nude mice. Results:Following PPI treatment, apoptotic cell death was seen selectively in cancer cells and was accompanied with ERK deactivation and p38 activation. By contrast, normal gastric mucosal cells showed the resistance to PPI-induced apoptosis through by the overexpression of anti-apoptotic regulators including HSP70 and HSP27. In a xenograft model of nude mice, administration of PPI significantly inhibited tumorigenesis and induced large-scale apoptosis of tumor cells. Conclusions: PPI selectively induced in vivo and in vitro apoptotic cell death in gastric cancer, suggesting that proton pump inhibitors (PPIs) could be extensively used for selective anti-cancer effects