tbuckley/cabot-search huggingface dataset:
Preliminary phase 2 results of ABT-751 in subjects with advanced renal cell carcinoma (RCC)
Authors: A. E. Hagey, R. A. Figlin, N. Moldawer, J. A. Sosman, K. N. Chi, D. M. Medina, K. A. Meek, P. Cernohous, G. B. Gordon
Journal: Journal of Clinical Oncology (2005)

4603 Background: There is currently no effective adjuvant therapy available for subjects with advanced RCC. ABT-751, an oral antimitotic agent that binds to the colchicine site of β-tubulin and prevents microtubule polymerization, has shown antitumor activity in various human xenograft models. In addition, signs of antitumor activity, consisting mainly of stable disease, were seen in subjects with RCC during phase 1 ABT-751 studies. Methods: This phase 2, open label, multi-center study evaluated safety and efficacy of ABT-751 in subjects with advanced RCC [N = 97: 43 subjects with no prior therapy (NPT), 54 subjects with prior therapy (PT)]. For each cycle, subjects received 200 mg ABT-751 orally once daily for 21 consecutive days followed by a 7-day break. Cycles were repeated until the subject met discontinuation criteria. Safety was assessed by adverse events (AEs) and laboratory evaluations. Time to progression (TTP) was analyzed using Kaplan-Meier methodology. Tumor response was assessed radiographically every 2 cycles using RECIST. Results: The median duration of therapy was 2 cycles (range 1 - 10). AEs were reported in 94/97 subjects, and 31/97 (32%) subjects experienced serious adverse events (SAEs). The most commonly reported AEs were asthenia (69%), constipation (59%), nausea (46%), and anorexia (44%). The most common Grade 3 or 4 AEs considered possibly or probably related to drug were asthenia (7%) and ileus (7%). The most common SAEs were carcinoma (6%) and ileus (6%). Thirteen subjects experienced SAEs considered possibly related to study drug, and the most common were ileus (5%) and diarrhea (2%). The median TTP was 3.8 months (95% CI = 3.6 - 4.1). One partial response was observed, and the subject is ongoing in Cycle 9. Two other subjects are experiencing minor responses (26% and 22% decrease in target lesions; ongoing in Cycles 6 and 9, respectively). To date, 17 subjects have had stable disease for 8 or more cycles (12 NPT and 5 PT), the longest duration being nearly one year. Conclusions: The 21-day dosing regimen appears to have an acceptable safety profile in phase 2 clinical trials. Prolonged stable disease and tumor responses suggest a potential benefit from ABT-751 therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories
A Network Meta-Analysis of Everolimus plus Exemestane versus Chemotherapy in the First and Second Line Treatment of Estrogen Receptor Positive Metastatic Breast Cancer
Authors: D. Generali, S. Venturini, C. Rognoni, O. Ciani, L. Pusztai, S. Loi, G. Jerusalem, A. Bottini, R. Tarricone
Journal: Annals of Oncology (2015)
Margaret McCartney: We don’t need nannying for colds
Authors: Margaret McCartney
Journal: BMJ (2017)

Winter means handkerchiefs, and the NHS’s response this season is a campaign to the tune of the NHS Choir. Sparkling and tuneful, they extol messages to keep warm, stock up on food and hot drinks, and keep an eye out for older members of the community. But they also tell us, “See your local pharmacist at the first sign of a cold.”1 The NHS website repeats this: “Always seek advice from your pharmacist at the first sign of a cough or a cold before it gets more serious.”1

Let’s unpack this. The NHS would like everyone with any symptoms of a cough …
23. SiRNA and CRISPR/Cas9 Mediated Knockout of αENAC
Authors: Aristides Tagalakis, Joost vanHaasteren, Ahmad Aldossary, Luca Rosa, Mustafa Munye, David McCarthy, Stephen Hart
Journal: Molecular Therapy (2016)

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis conductance regulator (CFTR) gene, which encodes for a chloride channel. Loss of CFTR upregulates the epithelial sodium channel (ENaC) causing hyperabsorption of sodium, reducing the watery lining of the lung, leading to impaired mucociliary clearance and enabling inflammatory lung damage. Therefore, inhibition of ENaC has been proposed as a treatment in CF. In this study we are assessing the use of siRNA and CRISPR/Cas9 system as complementary methods of achieving disruption of ENaC expression in airway epithelial cells using receptor-targeted nanocomplexes. We sought to compare the efficiency and persistence of silencing, repeatability of delivery and its toxicity. We assessed silencing of the αENaC subunit by transfecting primary CFBE cells growing in Air-Liquid Interface cultures with siRNA-bearing nanocomplexes and achieved 30% silencing at the mRNA level. We then assessed their silencing efficiency in lungs of normal mice (C57BL/6) delivered by oropharyngeal instillation. Following a single dose, the siRNA formulations achieved ~30% knockdown of mouse αENaC. Following repeated delivery (3 doses at 48h intervals) we found out that 48h after the last administration ~50% silencing was achieved, with no adverse effects (as judged by body weight and histology), whilst following a single administration there was still ~30% silencing 7 days later. An algorithm was used to design 6 different guide RNA targets for αENaC. These were used to transfect cells along with Cas9 and showed varied levels of indel mutation rates in the αENaC gene by the T7 endonuclease I assay although two, T3 and T4, were optimal. In order to increase the amount of indels created we subjected the cells (CFTE and HBE) to sequential transfections of the same target at 48h intervals. This showed an accumulation of indels in cells targeted with T3 at a rate of 33.3% in HBE cells. This correlated with a 60% decrease in ENaC mRNA compared to controls and with 40% after a single dose to 65% decrease in protein levels after three doses. The siRNA-mediated silencing showed that we can repeatedly deliver the formulations with no adverse effects and that the effect of a single dose, although transient, can last for at least 1 week. CRISPR/Cas9 also mediated efficient gene disruption of αENaC, but with the advantage that this knockdown will be permanent in cells where the life span is quite long. Another encouraging finding was the accumulation of gene disruption with both systems when delivered by a non-immunogenic vector. This is very important as CF therapy would need repeated administrations. It is reasonable to anticipate that these systems offer new prospects to CF gene therapy.
Adoptive transfer of short-term cultured tumor-infiltrating lymphocytes (young TIL) in metastatic melanoma patients.
Authors: R. Shapira-Frommer, M. Besser, I. Kuchuk, R. Nave, D. Zippel, A. Treves, A. Nagler, S. Apter, A. Shimoni, R. Yerushalmi, E. Ben-Ami, A. Ben-Nun, G. Markel, O. Itzhaki, R. Catane, J. Schachter
Journal: Journal of Clinical Oncology (2011)

8510 Background: Treatment of metastatic melanoma patients with adoptively transferred Tumor Infiltrating Lymphocytes (TIL) has developed into an effective therapy. The use of unselected, short term cultured (young) TIL simplifies the laboratory production process. Our aim was to explore the effectiveness and toxicity of adoptive young TIL transfer in metastatic melanoma patients (ClinicalTrial.gov NCT00287131). Methods: Patients were eligible if they had progressed on prior IL2 based treatment and had adequate organ function. Amended protocol since 5/10 allowed recruitment of patients with CNS metastasis without major neurologic deficit. Patients received lympho-depleting chemotherapy with CTX and fludarabin before TIL administration followed by high dose bolus IL2 infusion. Results: Sixty five patients were enrolled in the study and Young-TIL cultures were successfully generated for 60 (92%). Ten patients clinically deteriorated during TIL production, resulting in a total drop-out rate of 23% (15/65). 26 of 38 treated and evaluated patients had M1c disease, including two patients with CNS involvement. Overall response rate was 42% (16/38) including 13% CR (n=5) and 29% PR (n=11). Eleven additional patients demonstrated disease stabilization. Median OS was 10 months. There was a significant difference in the median OS of responding and non-responding patients (18 vs. 5 months respectively, p=0.002). Most common grade 3/4 toxicities were neutropenic fever (92%, 35/38) pulmonary congestion (28%), hypotension (9%), diarrhea (9%) and hyperbilirubinemia (9%). All toxicities were transient. Patients were hospitalized on average for 20 days. There was no treatment related mortality. Probability of response was related to short culture duration of TIL (13.9±2.8 vs. 18.4±5.5 days, p=0.005) and higher amount of CD8 cells within the infused TIL population (40.6±17.7 x109 vs. 22.4±17.6 x109 cells, p=0.009). Conclusions: Transfer of Young-TIL can mediate tumor regression in 42% of metastatic melanoma patients with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major impact on cell therapy for melanoma patients.
186. Translating an Optogenetic Gene Therapy Approach for Treatment of Neuropathic Pain in Humans
Authors: Chris Towne, Jesus Aguado, Annie Arguello, Claire Discenza, Tim Galfin, Stephan Gehrke, Sabeena Khan, Michael Kaplitt
Journal: Molecular Therapy (2016)

Optogenetics has been established as a powerful tool to study the central and peripheral nervous systems with its potential for directly treating human disease tantalizingly on the horizon. Optogenetic inhibition of pain in mice has been shown to be effective and provides an attractive initial application. We aim to translate this approach to treat neuropathic pain in humans. Firstly, we demonstrated that the inhibitory opsin, NpHR, delivered by intraneural injections of AAV6 could reduce pain (mechanical allodynia) in a clinically meaningful paradigm i.e. vector delivery after establishment of neuropathic pain in the chronic constriction injury (CCI) model. The inhibitory opsin, iC1C2 (a chloride channel requiring less light than NpHR to pass currents) could also reduce pain in this system. We next tested a surgical approach more amenable to patients than nerve injection. Lumbar puncture is a routine clinical practice and AAV8 delivery by this method results in efficient gene delivery to sensory neurons in rodents, dogs and pigs. We found that intrathecal administration of AAV8 expressing iC1C2 could decrease mechanical allodynia in the CCI mouse model. The magnitude of pain inhibition correlated with transduction levels and only 10% transduction of sensory neurons was required for pain relief. To further validate this approach we utilized a second rodent pain model with translational relevance. The mouse tibia fracture/cast immobilization model of Complex Regional Pain Syndrome (CRPS) presents extreme allodynia and recapitulates human disease effectively. We found that intrathecal delivery of AAV8 encoding iC1C2 following development of the CRPS model resulted in light-mediated pain inhibition. Taken together, our results confirm optogenetic therapy for neuropathic pain as an attractive clinical application of this technology.
Abstract 2093: Regulation of c-Myc expression by aspirin and salicylic acid in colon cancer cells through a novel pathway
Authors: Guoqiang Ai, Rakesh Dachineni, Pratik Muley, Hemachand Tummala, Jayarama B. Gunaje
Journal: Cancer Research (2015)

Abstract Epidemiological studies have demonstrated a significant correlation between regular aspirin use and reduced colon cancer incidence and mortality; however, the exact pathway has not been identified. We hypothesized that aspirin's anti-cancer effect may occur through modulation of c-Myc gene expression. Being a transcription factor, c-Myc controls nearly 15% of the expression of all genes and its activity is highly regulated in normal cells. In many cancers including colon cancer, c-Myc is mutated and constitutively activated which leads to uncontrolled cell proliferation. In the present study, we demonstrate that aspirin and its primary metabolite, salicylic acid, significantly decrease the c-Myc protein levels in colon cancer cells. In total cell lysates, both drugs decreased the levels of c-Myc in a concentration dependent (250 μM to 2500 μM) fashion (up to 70%). Interestingly, greater inhibition was observed in the nucleus than the cytoplasm, and immuno-fluorescence studies further confirmed these observations. Pre-treatment of cells with lactacystin partially reversed the inhibitory effect of both aspirin and salicylic acid, suggesting that 26S proteasomal pathway is involved. Transfection of HCT-116 cells with DDK-tagged c-Myc produced abundant c-Myc protein; but, it was unaffected by aspirin and salicylic acid. In the same lysates, the endogenous c-Myc level were significantly decreased. HPLC analysis showed that aspirin taken up by cells was metabolized to salicylic acid in a time-dependent fashion. This further supports the finding aspirin's inhibitory effect on c-Myc occurs through formation of salicylic acid. Our result suggests that aspirin and salicylic acid regulate c-Myc level at both transcriptional and post-transcription level. Inhibition of c-Myc levels may represent an important pathway by which aspirin exerts its anti-cancer effect and decrease the occurrence of cancer in epithelial tissues. Citation Format: Guoqiang Ai, Rakesh Dachineni, Pratik Muley, Hemachand Tummala, Jayarama B. Gunaje. Regulation of c-Myc expression by aspirin and salicylic acid in colon cancer cells through a novel pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2093. doi:10.1158/1538-7445.AM2015-2093
Abstract SY13-03: Novel targeted therapies in myelodysplastic syndrome
Authors: Benjamin Ebert
Journal: Cancer Research (2015)

Abstract Ubiquitin ligases target specific proteins for degradation, and pharmacologic modulation of ubiquitin ligase activity has the potential for therapeutic efficacy in cancer by altering the abundance of proteins that are required for tumor cell survival. Thalidomide and its derivatives, lenalidomide and pomalidomide, represent the first class of drugs that act by binding and changing the activity of a specific ubiquitin ligase. These compounds bind the CRL4-CRBN ubiquitin ligase, inducing the ubiquitination and consequent degradation of specific protreins. Lenalidomide is a highly effective drug for the treatment of myelodysplastic syndrome (MDS) with del(5q), multiple myeloma, and some additional B cell lymphomas. In multiple myeloma cells, lenalidomide increases the binding of two substrates, IKZF1 and IKZF3, to the CRBN substrate adapter; increases the ubiquitination of these substrates; and causes the targeted degradation of IKZF1 and IKZF3, transcription factors that are essential for the differentiation and survival of plasma cells including multiple myeloma cells. In del(5q) MDS, lenalidomide targets CSNK1A1 for destruction. Haploinsufficiency for CSNK1A1, a gene located within the common deleted region on chromosome 5q, results in selective targeting of the del(5q) clone. Recent studies indicate that lenalidomide, pomalidomide, and thalidomide modulate the CRl4-CRBN ubiquitin ligase in distinct ways, raising the possibility that new molecules may induce degradation of other proteins, creating new therapeutic opportunities. Citation Format: Benjamin Ebert. Novel targeted therapies in myelodysplastic syndrome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY13-03. doi:10.1158/1538-7445.AM2015-SY13-03
A Phase I MMRC Clinical Trial Testing the Combination of Bortezomib and Tipifarnib in Relapsed/Refractory Multiple Myeloma
Authors: Sagar Lonial, Dixil Francis, Chatchada Karanes, Suzanne Trudel, Donna E. Reece, Amrita Krishnan, Marc Buacharern, Renee Smith, Faraz Zaman, Engin Gul, Akari M. Dollard, Donald Harvey, Jonathan Kaufman
Journal: Blood (2008)
Abstract 623: Evaluation of a multiplex biomarker assay for the detection of prostate cancer cells in urine
Authors: Kristen Nickens, Amina Ali, Tatiana Scoggin, Shyh-han Tan, Lakshmi Ravindranath, David McLeod, David Tacha, Isabell Sesterhenn, Albert Dobi, Shiv Srivastava, Gyorgy Petrovics
Journal: Cancer Research (2015)

Abstract Background and Objectives: Over one million men undergo prostate biopsies annually in the US, a majority of them due to elevated serum PSA. More than half of the biopsies turn out to be negative for prostate cancer (CaP). The limitations of PSA test as well as the biopsy procedure have prompted to develop more precise CaP detection assays in urine- (e.g. PCA3, TMPRSS2-ERG) or blood (e.g. PHI, 4K). Here we describe the development and evaluation of a Urine CaP Marker Panel (UCMP) assay for sensitive and reproducible detection of CaP cells in post-digital rectal examination (post-DRE) urine. Methods: The cellular content of the post-DRE urine, was captured on translucent membrane for direct evaluation by microscopy and immunocytochemistry. The membranes placed on Cytoclear microscope slides were used for characterization of prostate epithelial cell by PSA and Prostein or tumor cells by ERG and AMACR protein markers. Immunostained cells were analyzed for quantitative and qualitative features and correlated with biopsy positive and negative status for malignancy. Results: Assay was optimized for single cell capture sensitivity and downstream evaluations by spiking known number of cells from established prostate cancer cell lines, LNCaP and VCaP, into cleared control urine. The cells captured from the post-DRE urine of subjects, obtained prior to biopsy procedure, were co-stained for ERG, AMACR, Prostein and PSA, rendering a whole cell based analysis and characterization. A feasibility cohort of 63 post-DRE urine specimens was assessed. Comparison of the UCMP results with the blinded biopsy results showed an assay sensitivity of 64% (16 of 25) and a specificity of 68.8% (22 of 32) for CaP detection by biopsy. Conclusion: This pilot study assessing a minimally invasive prostate cancer detection assay with single cell sensitivity cell-capture and characterization from the post-DRE urine holds promise for further development of this novel assay platform. Citation Format: Kristen Nickens, Amina Ali, Tatiana Scoggin, Shyh-han Tan, Lakshmi Ravindranath, David McLeod, David Tacha, Isabell Sesterhenn, Albert Dobi, Shiv Srivastava, Gyorgy Petrovics. Evaluation of a multiplex biomarker assay for the detection of prostate cancer cells in urine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 623. doi:10.1158/1538-7445.AM2015-623
111. HSV Vectors Retargeted for Infection of TrkA Receptor-Bearing, Pain-Sensing C-Fibers
Authors: Marco Marzulli, Justus B. Cohen, Bonnie Reinhart, William F. Goins, Joseph C. Glorioso
Journal: Molecular Therapy (2016)

Chronic pain represents a major cause of morbidity and effective pain therapy remains a significant unmet medical need. The standard of care relies primarily on systemic drug therapies that do not target the site of pain sensation. These therapies often have limited effectiveness, deleterious side effects, and ,induce tolerance. Herpes simplex viruses (HSV)-based gene therapy vectors offer an attractive alternative to drug therapy since therapeutic genes can be delivered to sensory nerve afferents where pain is arising. Our goal is to develop a transductionally retargeted HSV vector to selectively deliver therapeutic genes to those neurons activated during chronic pain states. NGF/TRKA signaling mediates the pain response associated with inflammatory hyperalgesia and neuropathic pain conditions, making TrkA-expressing cells an important target for chronic pain gene therapy. To obtain a fully retargeted HSV, the virus attachment/entry component glycoprotein D (gD) can be modified to eliminate recognition of its cognate receptors (HVEM and nectin1) and introduce a new ligand into the N-terminus of gD to allow entry through its corresponding cellular receptor. Therefore, we replaced the signal peptide and HVEM binding domain of gD with pre-pro-(pp) NGF to create a TrkA targeting protein, gD:ppNGF(Y38), that can still bind nectin1. Virus expressing gD:ppNGF(Y38) was propagated on cells expressing nectin1 and purified virus was shown to enter J1.1-2, nectin1-deficient cells, only when transduced with TrkA receptor (J/TrkA cells). To enhance the propagation of these vectors on complementing cells, we developed genetic selection methods to isolate retargeted virus variants that display enhanced entry and spread on J/TrkA cells. We found that a selected variant (J4H) had acquired mutations in other HSV envelope glycoproteins, including one glycoprotein involved in envelope-cell fusion events (gH) and two that were previously shown to contribute to virus spread (gE and gI). Moreover, we show that the gH mutation alone, when introduced into the parental virus backbone, enhances entry and minimally improves virus spread. We are currently investigating the specific phenotypes of the individual gE and gI mutations. A fully TrkA-retargeted J4H-based virus (J4HΔ38), further modified to completely eliminate nectin1-binding, also displays enhanced entry and spread on J/TrkA cells. We are currently testing the J4HΔ38 virus in primary sensory neurons in culture and in infections of animals in vivo. We suggest that the TrkA-vector retargeting will provide a means for transduction of pain sensing C-fibers to more precisely introduce pain-relieving gene products.
ACTR-42. CLINICAL TRIALS OF VAL-083 IN PATIENTS WITH CHEMORESISTANT GLIOBLASTOMA
Authors: Jeffrey Bacha, Richard Schwartz, Anne Steino, John Langlands, Sarath Kanekal, Lorena Lopez, Dennis Brown
Journal: Neuro-Oncology (2016)

Glioblastoma (GBM) is the most common CNS-tumor. Patients with recurrent GBM have few treatment options and dismal prognosis. O6-methylguanine-DNA-methyltransferase (MGMT) is correlated with resistance to standard-of-care treatment with temozolomide and poor patient outcomes. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that readily crosses the blood-brain barrier and has demonstrated MGMT-independent activity in multiple GBM cell-lines and cancer stem cells, in vitro. VAL-083 showed promise against CNS-tumors in prior NCI-sponsored clinical trials. We recently concluded a phase I/II clinical trial studying VAL-083 in recurrent GBM after failing temozolomide and bevacizumab, suggesting potential of VAL-083 to offer clinically meaningful survival benefits and a promising new treatment for GBM patients who have failed or are unlikely to respond to currently available chemotherapeutic regimens. In this phase I/II trial, VAL-083, 40 mg/m2/day x 3 every 21 days was well tolerated and was selected for study in subsequent clinical trials in GBM. These trials include i) a pivotal, randomized Phase 3 study measuring survival outcomes compared to “physician’s choice” control, which, if successful, would serve as the basis for a New Drug Application (NDA) submission for VAL-083. The control arm will consist of a limited number of salvage chemotherapies currently utilized in bevacizumab-failed GBM. ii) A non-comparative, biomarker-driven, Phase 2 study to determine if treatment of MGMT-unmethylated recurrent GBM with VAL-083 improves overall survival at 9 months, compared to reported CCNU control in bevacizumab-naïve patients. iii) A single arm Phase 2 study to confirm the tolerability of DelMar’s dosing regimen in combination with radiotherapy and to explore the activity of VAL-083 in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT-levels. Trial designs and further details will be presented at the meeting. The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM.