tbuckley/cabot-search huggingface dataset:
630. AAV Transduction of a Truncated Dysferlin Improves Dysferlinopathy
Authors: Telmo Llanga, Bryan Sutton, Nadia Nagy, Matthew Hirsch
Journal: Molecular Therapy (2016)

Dysferlinopathy is a progressive muscular dystrophy caused by the absence of functional Dysferlin. Dysferlin cDNA is over the packaging capacity of adeno-associated viral vectors (AAV), complicating potentially therapeutic gene addition strategies. The use of dual or fragmented AAV vectors, while genetically intriguing, is undesired as these formats demonstrate decreased transduction efficiencies. Therefore, an alternative approach using a panel of smaller dysferlin-like molecules was executed in vitro and in vivo in an AAV vector context. Three of the four "hybrid" dysferlin reading frames produced protein which behaved similar to full length dysferlin in localization studies. Upon AAV vector production, only 1 variant (341) demonstrated intact genome packaging despite final cassettes sizes of approximately 5kb. Intramuscular administration of vectors encoding 341 in dysferlin deficient mice resulted in increased muscle integrity without indications of toxicity. Dysferlin deficient mice receiving AAV9-341 through intravenous injection demonstrated increased rearing activity that was sustained 6 months post-injection. Consistently a trend of decreased muscle damage was observed in these mice. Our data suggest that 341, and additional hybrid dysferlin candidates under evaluation, may find relevance for the treatment of dysferlinopathy.
In vitro activity of sorafenib against imatinib- and sunitinib-resistant kinase mutations associated with drug-resistant GI stromal tumors
Authors: M. C. Heinrich, R. Carden, D. Griffith, C. Liang, A. Marino-Enriquez, A. McKinley, A. Presnell, J. A. Fletcher
Journal: Journal of Clinical Oncology (2009)

10500 Background: Most gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor alpha (PDGFRA) kinases, which are targets of imatinib (front-line therapy) or sunitinib (second-line therapy). Resistance to imatinib (IM) or sunitinib (SU) is commonly associated with the acquisition of secondary kinase mutations. In phase II studies, sorafenib (SOR), which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in GIST patients after failure of IM and SU. We evaluated the in vitro activity of SOR against IM and/or SU resistant kinases. Methods: Kinase mutants were biochemically profiled for SOR, SU, and IM sensitivity by measuring inhibition of kinase phosphorylation after drug treatment in mutant-expressing CHO cells. We also tested the biochemical and cellular activity of SOR and IM against GIST cells derived from IM-resistant tumor clones. Results: SOR had superior potency to IM against IM-resistant KIT secondary mutations involving the ATP binding pocket (V654A, T670I) and the activation loop (D816H, D820A/G, N822K, Y823D). SOR and SU had similar potency against IM-resistant KIT secondary mutations involving the ATP binding pocket. In contrast, SOR had markedly increased potency, compared to SU, against IM-resistant KIT activation loop mutations. Both SOR and SU were more potent than IM against the isolated KIT exon 9 mutation. To confirm these observations in a GIST cellular context, we tested the relative potency of IM and SU against two previously described IM-resistant GIST cell lines (GIST430: exon 11 + V654A, GIST48: exon 11 + D820A). SOR was significantly more potent than IM against KIT in these cell lines. This also correlated with enhanced inhibition of downstream signaling pathways and cellular proliferation. Conclusions: SOR has superior in vitro potency compared with IM or SU against a panel of GIST-relevant mutant kinases. Notably, SOR, unlike SU, is active against most IM-resistant secondary mutations involving the KIT activation loop. Based on these results, we hypothesize that SOR might have superior clinical activity to SU in the setting of imatinib-resistant GIST and should be further evaluated for clinical efficacy in the second-line setting. [Table: see text]
195. Allogeneic CD19-CART Therapy to the Rescue of a Pediatric Patient with Relapsed and Refractory Acute B Lymphoblastic Leukemia
Authors: Lung-Ji Chang, Jian-Ping Zhang, Yu-Chen Liu, Lujia Dong, Tong Wu, Dao-Pei Lu
Journal: Molecular Therapy (2016)

Acute B lymphoblastic leukemia (B-ALL) is a common hematological malignancy in children. Using a fourth generation, safety-switch inserted, chimeric antigen receptor (4SCAR) technology, we have treated more than 200 patients with B-ALL in China, with an overall complete remission rate of more than 80% (ASH 2015). Here we report the case of a 7-year-old girl with a high load of refractory B-ALL, who was heavily pretreated with chemotherapy but relapsed with >80 leukemic blasts in her bone marrow. The patient received CD19-4SCAR T cells generated from her mother's peripheral blood T cells (allo-4SCAR19) for three times at total of 0.76 x106 CART/kg on day 0, 4, and 7, followed by an infusion of autologous 4SCAR19 (auto-4SCAR19) at total of 0.16 x106 CART/kg on day 56, which was derived from the patient's own T cells after her immune recovery. Complete remission was achieved as revealed by bone marrow examination on day 77. Graft versus host disease signs were not observed throughout the days following the infusions, and the syndrome of suspected cytokine storm was generally mild. The only adverse responses were intermittent fever and skin rashes following allo-4SCAR19 infusions which lasted for about 20 days. The outcome of this case suggests that allo-4SCAR19 may be a safe approach in treating B-ALL patients who could not provide their own T cells for CART engineering, and allo-4SCAR19 combined with auto-4SCAR19 is a novel strategy that may rescue chemo-refractory, high-risk and highly immune suppressed leukemia patients.
ACTR-07. EFFICACY OF A NOVEL ANTIBODY-DRUG CONJUGATE (ADC), ABT-414, AS MONOTHERAPY IN EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AMPLIFIED (EGFRamp), RECURRENT GLIOBLASTOMA (rGBM)
Authors: Martin van den Bent, Hui Gan, Andrew Lassman, Priya Kumthekar, Ryan Merrell, Nicholas Butowski, Zarnie Lwin, Tom Mikkelsen, Louis Nabors, Kyriakos Papadopoulos, Marta Penas-Prado, John Simes, Tobias Walbert, Andrew Scott, Erica Gomez, Ho-Jin Lee, Lisa Roberts-Rapp, Hao Xiong, Earle Bain, Kyle Holen, David Maag, David Reardon
Journal: Neuro-Oncology (2016)

Patients (pts) with rGBM have a poor prognosis. EGFRamp is present in ~50% of GBMs. ABT-414 is an ADC that releases a potent toxin, monomethyl auristatin F (MMAF), inside cells with EGFRamp. Here we report the safety and efficacy of ABT-414 monotherapy at the recommended phase 2 dose (RPTD) in EGFRamp, rGBM. M12-356 (NCT01800695) is an open-label, Phase 1 study with three escalation cohorts. Study design and RPTD was reported previously (ASCO Meeting 2015, SNO Meeting 2015). Sixty pts, all with EGFRamp, rGBM, were enrolled as part of the escalation (12 pts) or expansion (48 pts) cohort treated with ABT-414 monotherapy at 1.25 mg/kg. Adults with measurable (RANO), bevacizumab-naïve, rGBMs with EGFRamp confirmed centrally were eligible. As of March 1, 2016, 60 pts with EGFRamp, rGBM underwent treatment. Median age was 58 years (range, 35–80). Pts underwent 1, 2 (43% each) or 3 (13%) prior therapies. The most common treatment emergent adverse events (TEAEs) (≥20% pts) included blurred vision (65%), headache, fatigue (30% each), eye pain and photophobia (28% each). Grade 3/4 TEAEs (>1 pt) were keratitis (13%), corneal epithelial microcysts (8%), blurred vision (5%), dry eye, ulcerative keratitis and reduced visual acuity (3% each). The best RANO responses of 56 pts with complete data were: 3 (5%) partial responses, 24 (43%) stable diseases and 29 (52%) progressive diseases. Median duration of overall response in 3 patients with partial responses was 4.4 months (range, 1.9–5.6). The 6-month progression-free survival (PFS6) estimate was 25.3% [95% CI=14.8, 37.2]. ABT-414 monotherapy displayed frequent but mostly grade 1/2 ocular toxicities. An encouraging PFS6 (25%) was observed in this rGBM population where 56% had ≥2 prior therapies. A global randomized trial of ABT-414, alone or with TMZ, vs. TMZ or lomustine, is underway in EGFRamp, rGBM (NCT02343406).
Clinical implications of low grade dysplasia found during inflammatory bowel disease surveillance: a retrospective study comparing chromoendoscopy and white-light endoscopy
Authors: Joren ten Hove, Erik Mooiweer, Andrea van der Meulen de Jong, Evelien Dekker, Cyriel Ponsioen, Peter Siersema, Bas Oldenburg
Journal: Endoscopy (2016)

Background and study aims Current guidelines recommend the use of pancolonic chromoendoscopy for surveillance of patients with inflammatory bowel disease (IBD). It is currently unknown whether low grade dysplasia (LGD) found using chromoendoscopy carries a similar risk of high grade dysplasia (HGD) or colorectal cancer (CRC) compared with LGD detected using white-light endoscopy (WLE). The aim of this study was to compare the risk of advanced neoplasia, a combined endpoint of HGD and CRC, during follow-up after detection of lesions containing LGD identified with either chromoendoscopy or WLE. Patients and methods A retrospective cohort was established to identify patients who underwent IBD surveillance for ulcerative colitis or colonic Crohn's disease between 2000 and 2014. Subgroups were identified, based on the endoscopic technique (standard definition resolution WLE, high definition resolution WLE or chromoendoscopy). LGD detected in random biopsies was considered invisible LGD. Patients were followed until detection of advanced neoplasia, colectomy, death, or the last known surveillance colonoscopy. Results Of 1065 patients undergoing IBD surveillance, 159 patients underwent follow-up for LGD, which was visible in 133 cases and invisible in 26 cases. On follow-up, five cases of HGD and five cases of CRC were detected. The overall incidence rate of advanced neoplasia was 1.34 per 100 patient-years with a median follow-up of 4.7 years and a median time to advanced neoplasia of 3.3 years. There were no significant differences in the incidence of advanced neoplasia between chromoendoscopy-detected and WLE-detected LGD. Conclusion Advanced neoplasia was found to develop infrequently after detection of LGD in patients undergoing endoscopic surveillance for IBD. LGD lesions detected with either chromoendoscopy or WLE carry similar risks of advanced neoplasia over time.
Abstract 2680: Cyclic AMP signaling in melanoma: Paradoxical downregulation of pCREB upon activation of adenylate cyclase confers resistance to MAPK inhibition
Authors: Carlos I. Rodriguez, Vijayasaradhi Setaluri
Journal: Cancer Research (2015)

Abstract Melanoma, which arises from malignant transformation of melanocytes, has proven to be difficult to treat due its intrinsic and acquired resistance for chemotherapy. Although polymorphisms in the melanocortin receptor 1 (MC1R), which result in impairment of cyclic AMP (cAMP) signaling, are associated with increased risk for melanoma development, the role of cAMP signaling in melanoma, specifically in drug resistance, is not fully understood. Given the importance of cAMP signaling in melanocytes proliferation and differentiation, we investigated the role of cAMP signaling in melanoma cell proliferation, survival and drug resistance. We found that upregulation of cAMP signaling, through activation of adenylate cyclase with forskolin (FSK), has both positive and negative effects on proliferation and survival of melanoma cells. The effect of FSK on melanoma proliferation and survival was not dependent on oncogenic (RAS vs. BRAF) mutation. Moreover, upregulation of cAMP conferred resistance to Selumetinib (AZD6244)-mediated MAPK inhibition by restoring the pERK levels. We also show that FSK-mediated resistance is paradoxically related to a downregulation of phosphorylated cAMP Responsive Element Binding Protein (pCREB), suggesting a CREB-independent mechanism of FSK-induced MAPK reactivation in acquired drug resistance. Citation Format: Carlos I. Rodriguez, Vijayasaradhi Setaluri. Cyclic AMP signaling in melanoma: Paradoxical downregulation of pCREB upon activation of adenylate cyclase confers resistance to MAPK inhibition. [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 2680. doi:10.1158/1538-7445.AM2015-2680
An evaluation of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy on patients with peritoneal carcinomatosis: Final results of a phase II prospective and randomized clinical trial.
Authors: Y. Li, X. Yang, G. Yang, Y. Zhou, Y. Yonrmura
Journal: Journal of Clinical Oncology (2011)

4051 Background: Our phase I study indicates that cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is feasible and may help improve the outcomes of pts with peritoneal carcinomatosis (PC). This randomized and prospective phase II study was to evaluate the efficacy and safety of CRS + IPHC using cisplatin (CDDP) and mitomycin C (MMC) for the PC. Methods: Pts eligibility criteria were: (1) PC from gastric and colorectal cancers without evidence of distant metastasis and expected survival of > 8 wk; (2) age between 25-70 yr old; (3) KPS>50; (4) routine laboratory workup found no significant changes limiting aggressive intervention; (5) good tolerance for major surgery; and (6) written informed consent. After randomization, pts were treated with CRS alone or CRS + IPHC using CDDP 120 mg and MMC 30 mg in 12,000 mL of normal saline at 43±0.5°C for 60-90 min. Survival and safety were studied. Results: A total of 89 pts with PC (68 from gastric cancer and 21 from colorectal cancer) were randomized into CRS group (n=44) and CRS + HIPEC group (n=45). The 2 groups were well-balanced in terms of major demographic data, KPS and PCI. At a median follow-up of 32.5 mo (7-83 mo), the median survival was 6.5 mo (95% CI 5.2-7.8 mo) in CRS group and 13.0 months (95% CI 9.0-17.0 mo) in the CRS + HIPEC group (P=0.001, log rank test). For gastric PC pts, the median survival was 6.5 months (95% CI 4.9-8.2 mo) in CRS group (n=34) and 11.0 mo (95% CI 9.0-12.9 mo) in the CRS+HIPEC group (n=34) (P=0.002, log rank test). For CRC PC pts, the median survival was 7.0 mo (95% CI 3.5-10.5 mo) in CRS group (n=11) and 15.5 mo (95% CI 4.9-26.1 mo) in the CRS+HIPEC group (n=10) (P=0.003, log rank test). HIPEC could increase the median survival by over 60%. No perioperative death occurred. Four pts (10.3%) in the CRS+HIPEC group and 2 (5.0%) pts in the CRS group developed SAE. Conclusions: For PC pts from gastric and colorectal cancers, CRS plus HIPEC with MMC 30 mg and CDDP 120 mg could improve survival with acceptable safety.
ATPS-78PERSONALIZED CHEMOTHERAPY: TREATING BRAIN CANCERS WITH TARGETED NANOSYRINGES
Authors: Martyn Sharpe, David Baskin
Journal: Neuro-Oncology (2015)

The ability of targeted, epitope-specific, drug laden nanosyringes to raise chemotherapeutic levels within cancer cells, but not in non-targeted tissues is a promising avenue for cancer therapy. We have developed a nanosyringe system derived from single wall carbon nanotubes capable of carrying a wide range of drugs/dyes, and these constructs are targeted toward the surface of cancer cells via binding to specific, upregulated, tyrosine kinase receptors. As a technology demonstrator we have focused on a nanosyringe designed to bind to epidermal growth factor receptor EGFR. Targeting of the nanosyringe is achieved by the covalent linkage of multiple EGFR-specific binding peptides to the syringes' outer surface. The lipophilic and hydrophobic core of the nanosyringe is loaded with a wide range of hydrophobic compounds, which only leave the syringe when the construct binds to cell specific antigens and makes contact with the lipophilic and hydrophobic environment of the cell membrane. We can deliver large amounts of hydrophobic chemotherapeutic drugs or fluorescent probes to cancers cells expressing EGFR in vitro and in vivo. Binding of EGFR-targeted nanosyringe to EGFR in living cells causes EGFR homo/heterodimerization and receptor autophosphorylation at signaling residue T678. The phosphorylated receptor recruits adapter proteins inducing the formation of clathrin coated pits and the subsequent internalization of both the receptor and the nanosyringe. Using EGFR-targeted nanosyringes loaded with Nile Red fluorophore, we can rapidly transfer dye into gliomal cells, and both nanosyringe binding and dye transfer is competitive with EGF. Flank and intracranial tumor models of nude mice with gliomal U87-EGFR xenografts show uptake of Nile Red, delivered by nanosyringe, and dye transfer to non-target tissues is below detection thresholds. When loaded with chemotherapeutic drugs, and also with xenobiotic drug transport inhibitors, we can successfully treat a range of cancers, in flank and intracranial tumor models.
Dihydrofolate Reductase Deficiency Is Caused by a Homozygous DHFR Mutation and Leads to Congenital Megaloblastic Anemia and Cerebral Folate Deficiency
Authors: Holger Cario, Desiree E.C. Smith, Henk J. Blom, Harald Bode, Nenad Blau, Karlheinz Holzmann, Ulrich Pannicke, Elisabeth Kohne, Klaus-Michael Debatin, Yvo M. Smulders, Klaus Schwarz
Journal: Blood (2010)
Abstract 311: High-throughput spheroid formation in a 384-well format using magnetic 3D bioprinting
Authors: Hubert Tseng, Jacob A. Gage, William L. Haisler, Glauco R. Souza
Journal: Cancer Research (2015)

Abstract Technical limitations in the rapid and reproducible formation of multicellular tumor spheroids prevent their widespread use in high-throughput screening for cancer research and drug development. Existing systems for spheroid formation require lengthy processing times, and make simple tasks like media exchange and sample retention challenging. An ideal 3D cell culture system would print spheroids rapidly, while being easy to handle and process for high-throughput applications. To address this unmet need, we use magnetic 3D bioprinting for high-throughput spheroid formation. Magnetic 3D bioprinting is based on the principle of magnetizing cells using a magnetic nanoparticle assembly. Once magnetized, these cells can be directed and aggregated using magnetic forces; specifically, magnetized cells can be aggregated into spheroids in 384-well plates. These spheroids can be cultured long-term, and, as they are magnetic, the spheroids can be held down or transferred out of the well, avoiding the technical issues of other 3D systems to retain samples. Moreover, the magnetic nanoparticles have no effect on cell behavior and do not interfere with fluorescence. We demonstrated this method by printing spheroids of HepG2, HCT-116, A549, and PANC-1 cancer cells in 384-well plates. We printed spheroids rapidly (15 min) and reproducibly, with cell numbers as small as 100 cells. We assayed the spheroids by using their contraction over time as an endpoint, which we validated as a toxicity endpoint correlating with cell migration, proliferation, and viability. In running these experiments we also demonstrated that these spheroids are amenable to high-content testing, with multiple experiments being performed on the same spheroid to yield more data per test. Thus, this study introduces magnetic 3D bioprinting for high-throughput spheroid formation, where multicellular tumor spheroids that represent native tumor environments can be rapidly and easily printed for cancer research and compound screening. Citation Format: Hubert Tseng, Jacob A. Gage, William L. Haisler, Glauco R. Souza. High-throughput spheroid formation in a 384-well format using magnetic 3D bioprinting. [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 311. doi:10.1158/1538-7445.AM2015-311
Chystallographic Evidence of Autologous Recognition By a Clonotypic B Cell Receptor in Chronic Lymphocytic Leukemia
Authors: Maria Gounari, Claudia Minici, Marcus Dühren-von Minden, Schneider Dunja, Alkhatib Alabbas, Übelhart Rudolf, Andreas Agathangelidis, Stavroula Ntoufa, Nicholas Chiorazzi, Hassan Jumaa, Kostas Stamatopoulos, Massimo Degano, Paolo Ghia
Journal: Blood (2015)
Phase I and Pharmacokinetics (PK) of DJ-927, an oral taxane, in patients (Pts) with advanced cancers
Authors: S. K. Syed, M. Beeram, C. H. Takimoto, J. Jakubowitz, M. Kimura, M. Ducharme, S. Gadgeel, R. De Jager, E. Rowinsky, P. Lorusso
Journal: Journal of Clinical Oncology (2004)

2028 Background: DJ-927, a novel semi-synthetic taxane and a poor substrate of P-glycoprotein (Pgp), is orally bioavailable and possesses potent anti-tumor activity against Pgp expressing human cancers. Preclinically, DJ-927 is more potent than both paclitaxel and docetaxel. Methods:This first-in-human study assessed the maximum tolerated dose [MTD], dose limiting toxicities [DLT] and PK of DJ-927 administered as a single oral 3-weekly dose. Pts were stratified based on prior therapy into minimally (MP) and heavily (HP) pretreated cohorts. The starting dose of DJ-927, 1.5 mg/m2, was increased in 100% increments until grade 2 toxicities occurred during course 1 and by 50% thereafter, until consistent DLT were observed. Results: To date, 40 pts have received 109 courses [median-2; range 1–8] at the following doses: 1.5 mg/m2 [3], 3 mg/m2 [3], 6 mg/m2 [3], 12 mg/m2 [3], 18 mg/m2 [4], 27 mg/m2 [8], 35 mg/m2 [8] and 40 mg/m2 [8]. Demographics: 23 male / 17 female; median [range] age- 57 [31–81]; PS 0 [7], PS 1 [31], and PS 2 [2]. Primary tumors are colorectal [15], breast [4], pancreas [5], renal cell [3], soft tissue sarcoma [3] and others [10]. Minimal drug-related toxicities were observed at doses 5 days duration [7] and grade 3 thrombocytopenia [4] were the predominant hematological toxicities observed at 40 and 35 mg/m2 doses. Non-hematological toxicities included: transient grade 3 peripheral sensory neuropathy after 3 cycles [1] at 27 mg/m2, grade 3 diarrhea and grade 3 mucositis [1] at 40mg/m2. Minor responses were seen in taxane-refractory breast carcinoma [1] and transitional cell carcinoma of the bladder [1]. Disease stabilization for >3 months was noted in 8 pts. Plasma PK of DJ- 927 were dose proportional over the dose range explored. The Cmax, mean (CV%) 58.83 (70.2) μg/L, AUC (inf) 1792.7 (36.4) h*μg/L), clearance/F 45.93 (48.6) L/h, and terminal half-life 175.5 (38.2) h were seen at 40 mg/m2 dose (8). Conclusions: DJ-927 generates predictable systemic drug exposures and has been well tolerated when orally administered. Dose escalation ceased due to DLT in 2/3 MP + 2/5 HP at 40 mg/m2 and 2/6 MP + 2/2 HP at 35 mg/m2. MTD has been defined as 27 mg/m2 for MP and HP patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Daiichi Pharmaceutical Corp.; MDS Pharma Daiichi Pharmaceutical Corp.; Daiichi, USA; MDS Pharma Daiichi Pharmaceutical Corp.; MDS Pharma Daiichi Pharmaceutical Corp. Daiichi Corp.