tbuckley/cabot-search huggingface dataset:
Functional Delivery of Lipid-Conjugated siRNA by Extracellular Vesicles
Authors: Aisling J. O’Loughlin, Imre Mäger, Olivier G. de Jong, Miguel A. Varela, Raymond M. Schiffelers, Samir El Andaloussi, Matthew J.A. Wood, Pieter Vader
Journal: Molecular Therapy (2017)

Extracellular vesicles (EVs) are cell-derived, membranous nanoparticles that mediate intercellular communication by transferring biomolecules, including proteins and RNA, between cells. As a result of their suggested natural capability to functionally deliver RNA, EVs may be harnessed as therapeutic RNA carriers. One major limitation for their translation to therapeutic use is the lack of an efficient, robust, and scalable method to load EVs with RNA molecules of interest. Here, we evaluated and optimized methods to load EVs with cholesterol-conjugated small interfering RNAs (cc-siRNAs) by systematic evaluation of the influence of key parameters, including incubation time, volume, temperature, and EV:cc-siRNA ratio. EV loading under conditions that resulted in the highest siRNA retention percentage, incubating 15 molecules of cc-siRNA per EV at 37°C for 1 hr in 100 μL, facilitated concentration-dependent silencing of human antigen R (HuR), a therapeutic target in cancer, in EV-treated cells. These results may accelerate the development of EV-based therapeutics. Extracellular vesicles (EVs) are cell-derived, membranous nanoparticles that mediate intercellular communication by transferring biomolecules, including proteins and RNA, between cells. As a result of their suggested natural capability to functionally deliver RNA, EVs may be harnessed as therapeutic RNA carriers. One major limitation for their translation to therapeutic use is the lack of an efficient, robust, and scalable method to load EVs with RNA molecules of interest. Here, we evaluated and optimized methods to load EVs with cholesterol-conjugated small interfering RNAs (cc-siRNAs) by systematic evaluation of the influence of key parameters, including incubation time, volume, temperature, and EV:cc-siRNA ratio. EV loading under conditions that resulted in the highest siRNA retention percentage, incubating 15 molecules of cc-siRNA per EV at 37°C for 1 hr in 100 μL, facilitated concentration-dependent silencing of human antigen R (HuR), a therapeutic target in cancer, in EV-treated cells. These results may accelerate the development of EV-based therapeutics.
Driver Somatic Mutations and Transplantation Decision Making in Patients with Myelodysplastic Syndrome
Authors: Marianna Rossi, Matteo Giovanni Della Porta, Andrea Bacigalupo, Massimo Bernardi, Bernardino Allione, Maria Teresa van Lint, Pietro Enrico Pioltelli, Paola Marenco, Alberto Bosi, Maria Teresa Voso, Simona Sica, Maria Cuzzola, Emanuele Angelucci, Anna Gallì, Silvia Zibellini, Ettore Rizzo, Chiara Milanesi, Benedetto Bruno, Fabio Ciceri, Francesca Bonifazi, Armando Santoro, Emilio Paolo Alessandrino, Alessandro Rambaldi, Mario Cazzola
Journal: Blood (2016)
Interim analysis of perioperative modified FOLFIRINOX (mFOLFIRINOX) in resectable pancreatic cancer (PC).
Authors: Michael Cecchini, Ronald R Salem, Wajih Zaheer Kidwai, Jeremy S. Kortmansky, Neal A. Fischbach, Abhijit Patel, Howard S. Hochster, Jill Lacy
Journal: Journal of Clinical Oncology (2017)

393 Background: The mortality of patients (pts) with resectable PC is &gt; 70% with surgery and adjuvant therapy. Based on the favorable results of our prospective phase II study of mFOLFIRINOX in locally advanced PC (Stein SM et al. Br J Cancer. 2016), we are conducting a single arm open-label phase II trial to evaluate the efficacy of peri-operative mFOLFIRINOX in resectable PC. Here we report our interim results. Methods: Pts with untreated resectable PC were treated with 6 cycles of mFOLFIRINOX every 2 weeks before and after surgical resection. Pre-op FDG-PET and CT scans were obtained at baseline and after 3 and 6 cycles, respectively. After study treatment pts were followed with serial CT scans and CA 19-9 levels. We performed our validated test for circulating tumor DNA (ctDNA) at baseline and multiple time points thereafter. Results: At our interim analysis, 19 pts are enrolled; 1 pt withdrew consent after 1 cycle and is not included. Baseline characteristics: median age 64; male 12; median CA-19 94 (range 0.8-1926); head of pancreas tumor 14; biliary stent 9; ECOG 0 17. Two pts received &lt; 6 cycles pre-op for reasons other than progression or treatment-related adverse events (AEs). Response by RECIST for the 17 pts who received ≥ 3 pre-op cycles was: CR/PR 1 (6%), SD 15 (88%) (8 with minor response defined as 10-30% decrease in target lesion), and PD 1 (6%). Six of 14 pts (43%) who received FDG-PET scans had &gt; 50% decrease in SUV. At present, 2 pts have yet to complete 6 pre-op cycles. Fifteen pts have undergone surgical exploration, and 2 were not deemed resectable during exploration due to peritoneal implants and adhesions from chronic pancreatitis. Thirteen of 16 (82%) underwent resection; 12 (92%) were R0; 2 (15%), 5 (39%), and 6 (46%) pts had pathologic stage I, IIA, and IIB disease, respectively. 4 pts developed disease recurrence and died. AEs were not different than we previously reported and were manageable with protocol-mandated dose adjustments. Conclusions: Our interim analysis suggests that perioperative mFOLFIRINOX for resectable PC is feasible and associated with a 92% rate of R0 resection. Accrual will continue to 46 pts, and analysis of efficacy endpoints and correlative studies including ctDNA are ongoing. Clinical trial information: NCT02047474.
Intercalating and maintenance use of gefitinib plus chemotherapy versus chemotherapy alone in selected advanced NSCLC(ISCAN,CTONG-1102): A multicentre, open-label, randomised, phase 3 study.
Authors: Shun Lu, Hong Jian, Wei Li, Ma Zhi Yong, Jian Jin Huang, Jifeng Feng, Yong Song, Beili Gao, Huili Zhu, Min Tao, Chong Bai, Ma Shenglin, Hongming Pan, Shukui Qin, Dong Hua
Journal: Journal of Clinical Oncology (2015)

8042 Background: This study investigated whether intercalating and maintenance use of gefitinib and chemotherapy improves clinical outcomes versus chemotherapy alone in selected patients with advanced NSCLC after receiving two cycles of chemotherapy with stable disease. Methods: We undertook an open-label, randomized, phase 3 trial at 14 centers in China. We assigned previously untreated patients in China who had stage IIIB or IV pulmonary adenocarcinoma and who were nonsmokers and EGFR mutation status unknown to firstly receive two cycles of gemcitabine plus carboplatin(GC). The patients with stable disease were randomly assigned (1:1) to receive gefitinib on days 15 to 25 of a 4-week cycle of GC or a 4-week cycle of GC alone. In the absence of disease progression, chemotherapy was continued for a maximum of four cycles, after which time patients continued to receive gefitinib or observation until disease progression or unacceptable toxicity. The primary end point was progression-free survival. Secondary end points included overall survival and safety. The trial is registered at ClinicalTrials.gov, number NCT01404260, and has completed enrolment. Results: 109 patients were randomly assigned to receive intercalating and maintenance use of gefitinib plus chemotherapy and 110 to receive chemotherapy alone. 109 in the intercalating and maintenance group and 109 in the chemotherapy alone group were included in analysis of the primary endpoint. Median progression-free survival was significantly longer in intercalating and maintenance use of gefitinib-treated patients than in those on chemotherapy alone(10.0 vs 4.4 months; hazard ratio 0.475, 95% CI 0.349-0.646; p < 0.0001). The addition of gefitinib to chemotherapy was well tolerated. Conclusions: Intercalating and maintenance use of gefitinib plus gemcitabine/carboplatin led to a significant improvement in PFS for advanced pulmonary adenocarcinoma Chinese patients with nonsmoking and EGFR mutation status unknown after receiving two cycles of gemcitabine/ carboplatin with stable disease. Clinical trial information: NCT01404260.
Phase 1 study assessing dovitinib (TKI258) on the pharmacokinetics of caffeine, diclofenac, omeprazole, and midazolam in patients with advanced solid tumors.
Authors: Ding Wang, Raymond P. Perez, Rebecca Anne Moss, Shu Yang, Xiaoming Cui, Massimiliano Quadrigli, Jeffrey W. Scott, Fadi S. Braiteh
Journal: Journal of Clinical Oncology (2014)

2581 Background: Dovitinib (TKI258) is an oral tyrosine kinase inhibitor targeting kinases involved in tumor cell proliferation and survival, including FGFR, VEGFR, PDGFR, c-KIT, and FLT3. In vitro, dovitinib induced CYP1A2, CYP2C9, and CYP2C19 activity and increased the mRNA level of CYP3A4. Here, we evaluated the impact of dovitinib on the pharmacokinetics (PK) of caffeine, diclofenac, omeprazole, and midazolam, the probe drugs metabolized by these cytochrome P450 isoforms. Methods: Patients (pts) ≥ 18 years of age with advanced solid tumors were given a cocktail of oral caffeine (100 mg), diclofenac (25 mg), omeprazole (20 mg), and midazolam (2 mg) on days 1 and 13, and dovitinib (500 mg oral once daily, 5 days on/2 days off) starting on day 2. Blood PK samples for each probe were collected predose and for 24 hours after drug cocktail dosing. Area under the curve (AUC) and maximum concentration (Cmax) values were log-transformed and analyzed with a linear mixed-effects model. Following the drug-drug interaction phase, pts were allowed to continue dovitinib at the same dose and schedule. Results: Of 58 pts screened, 39 were treated, of which 28 and 26 pts were evaluable for PK analysis for drug interaction with caffeine and the remaining probe drugs, respectively. Dovitinib decreased the exposure (AUC and Cmax) of caffeine and omeprazole, decreased the Cmaxof diclofenac, but increased the exposure of midazolam (Table). The most common adverse events regardless of study drug relationship were diarrhea (69%), fatigue (69%), nausea (64%), and vomiting (62%). Conclusions: Dovitinib is a strong inducer of CYP1A2, a moderate inducer of CYP2C19, and has limited impact on CYP2C9. Different from in vitro data, dovitinib is a moderate inhibitor of CYP3A4/5 in humans. Clinical trial information: NCT01596647. Dovitinib + drug:drug alone Geometric mean ratio (90% CI) Caffeine Omeprazole Diclofenac Midazolam Enzyme tested CYP1A2 CYP2C19 CYP2C9 CYP3A4 AUClast 0.04 (0.03-0.05) 0.39 (0.28-0.56) 1.07 (0.86-1.34) 2.63 (2.25-3.08) AUCinf 0.06 (0.04-0.08) 0.39 (0.28-0.55) 1.19 (0.94-1.50) 2.91 (2.31-3.66) Cmax 0.20 (0.17-0.24) 0.49 (0.35-0.70) 0.65 (0.47-0.90) 1.52 (1.33-1.75)
Test of weight gain prevention intervention in stage II and III breast cancer patients receiving neoadjuvant chemotherapy
Authors: K. Basen-Engquist, H. Y. Perkins, C. L. Carmack Taylor, D. C. Hughes, J. L. Jovanovic, B. K. Arun, J. L. Murray
Journal: Journal of Clinical Oncology (2009)

e20523 Background: Weight gain is common in women with breast cancer and is worrisome, as may affect prognosis and risk of other chronic diseases. This randomized study pilot tested a weight gain prevention intervention for breast cancer patients receiving neoadjuvant chemotherapy. Methods: Breast cancer patients receiving neoadjuvant chemotherapy were randomized to a weight gain prevention intervention or a usual care control arm. The intervention used a body acceptance approach, which emphasized changes in diet (low energy density food) and exercise behavior (resistance training) rather than focusing on weight loss. It was administered in weekly sessions delivered in-person and by telephone. Assessments were done at baseline, mid-chemotherapy, pre-surgery, after surgical recovery, after a 9 week post-surgical booster intervention, and 6 months after surgery. The data on weight changes from baseline (T0) to mid-chemotherapy (T1) and presurgery (T2) is presented. Results: 33 participants were randomized the intervention (n=16) or usual care (n=17). Three control participants withdrew before assessments were done. Of the 30 remaining women, 70% had stage II and 30% had stage III breast cancer. Their mean age was 49.7 (SD=12.2), and half were premenopausal. Mean BMI was 29.3 (SD=6.1) and 70% were physically inactive. The sample was diverse with regard to self-reported ethnicity (57% white, 27% African-American, 7% Hispanic, 10% other). Change in weight from T0 to T1 was -0.9 kg in the intervention group and +1.4 kg in the usual care group (n=27, p=0.126); from T0 to T2 the change was -2.0 kg in the intervention group and +0.8 kg in the usual care group (n=20, p=0.056). When weights from a chart review were used for patients with missing assessments the T0 to T2 changes were -2.9 kg for the intervention group and 0 kg for the usual care group (n=30, p=0.065). Conclusions: Based on a preliminary analysis, there was a trend approaching statistical significance for weight loss from a diet and exercise intervention based on the body acceptance approach compared to a usual care control group. These results indicate this intervention should be tested in a larger randomized controlled trial. No significant financial relationships to disclose.
Aldehyde Dehydrogenase-Activity Purifies Multiple Hemangiogenic Lineages That Accelerate Vascularization of Ischemic Tissue through Paracrine Support of Neovessel Formation.
Authors: Krysta D. Levac, Debra L. Robson, Marian J. Neelamkavil, Sarah A. Hohm, Benjamin J. Capoccia, Daniel C. Link, Jan A. Nolta, David A. Hess
Journal: Blood (2007)
Results from a phase I study of enzalutamide in combination with docetaxel in men with prostate cancer.
Authors: Mark T. Fleming, Dana E. Rathkopf, Jackie Gibbons, Amy C. Peterson, Alison Hannah, David Forer, Howard I. Scher, Michael J. Morris
Journal: Journal of Clinical Oncology (2013)

5066 Background: Enzalutamide (ENZA) is a novel androgen receptor (AR) inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (DOC). DOC also prolongs survival in mCRPC and also appears to have anti-tumor effects mediated through the androgen-receptor axis, providing a compelling rationale for combining the two agents. CYP3A4 plays a role in DOC clearance and is induced by ENZA. We therefore conducted a phase I study to explore the PK and safety profiles of this combination. Methods: This study (NCT01565928) evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m 2 ) by 1-h infusion every 3 weeks with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: Twenty-two pts were enrolled, 4 did not receive 2 full doses of DOC. As of 21 Sept 2012, preliminary PK and C1 and C2 safety data were available from 15 pts. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC&lt;1000/mm 3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone.Final PK and updated tolerability and efficacy data beyond Cycle 2 will be presented. Conclusions: In mCRPC pts, ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.
HER2 mutations in lung adenocarcinoma: A report from the Lung Cancer Mutation Consortium (LCMC).
Authors: Rathi Narayana Pillai, Madhusmita Behera, Lynne D Berry, Michael R. Rossi, Mark G. Kris, Paul A. Bunn, Fadlo Raja Khuri, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2014)

8060 Background: A variety of somatic mutations and gene rearrangements have been described in patients with lung adenocarcinoma. The Lung Cancer Mutation Consortium (LCMC) tested for the presence of 10 driver mutations in over 1,000 patients with metastatic adenocarcinoma of the lung. Methods: Tumor specimens were assessed for diagnosis and adequacy; multiplexed genotyping utilizing SNaPshot or Sequenom was performed, and mutations were recorded in GeneInsight database. We reviewed the LCMC database for patients tested for HER2 mutations and accessed clinical characteristics, including age and stage at diagnosis, sex, smoking status, treatment history, sites of metastatic disease, and vital status. We conducted an exploratory analysis to compare survival of HER2 mutated patients treated with HER2 targeted therapies to those who did not receive targeted therapies. Results: Of the 920 patients tested for human epidermal growth factor receptor-2 (HER2) mutation, 24 patients (2.6%) had exon 20 insertion mutations. The mutation was located at exon 20 insertion at codon 775 in all patients; 1 patient also had concurrent MET amplification. The median age was 62 (37-84) and the majority were never smokers (71%). Nearly 70% had advanced stage disease at the time of diagnosis. There was a slight predominance of females (n=14) over males (n=10). The median survival for patients that received HER2 targeted therapies (n=12) or not (n=12) was 18.3 months and 16.4 months respectively. HER2- targeted therapies included dacomitinib (n=5), dacomitinib and crizotinib (n=1), neratinib (n=2), trastuzumab (n=1), lapatanib and trastuzumab (n=1), and STA-9090 (n=1). At last assessment of vital status, 50% (6/12) of the patients treated with targeted therapy were alive as compared to only 33% (4/12) of the remainder. The overall survival for HER2 mutated patients was worse than that for overall LCMC cohort in which median survival with genotype directed therapies was 3.5 years versus 2.4 years without targeted therapy. Conclusions: HER2 mutations were detected in 2.6% of patients with lung adenocarcinoma. There was a favorable survival trend among patients that received HER2 targeted therapies.
Differential Expression of Genes Associated with Oncogene-Induced Senescence and Senescence Associated Secretory Phenotype in the Absence of Differential Expression of High Molecular Risk Genes and Genes Associated with JAK-STAT Pathway in Sorted Cells of Patients with Polycythemia Vera and Primary Myelofibrosis
Authors: Chieh Lee Wong, Andrew Innes, Baoshan Ma, Gareth Gerrard, Zainul Abidin Norziha, Soon Keng Cheong, Chooi Fun Leong, Ping Chong Bee, Jameela Sathar, Siew Fen Lye, Letizia Foroni, Tim Aitman, Liming Liang, Jesus Gil, Michael Laffan
Journal: Blood (2016)
An analysis of target-specific patient resource utilization in NSCLC clinical trials.
Authors: Neeta Somaiah, George R. Simon
Journal: Journal of Clinical Oncology (2012)

e18112 Background: A plethora of targeted agents are currently being evaluated in patients with NSCLC. The number of targeted agents exceeds the number of targets leading to many targeted agents being evaluated against similar targets. The identification of new targets are likely to increase exponentially in the near future given the numerous currently ongoing molecular profiling efforts. The objective of this analysis is to estimate the target-specific patient resource utilization and its impact on routine clinical care. Methods: A comprehensive search for molecularly targeted agents in clinical testing that have accrued or are accruing NSCLC patients were performed by using publically available search engines and databases. Agents were grouped according to the primary target and the phase of development. We computed the number of patients allocated to completed and ongoing phase III NSCLC trials for advanced NSCLC alone. Results: There are more than 30 categories of molecular targets accruing NSCLC patients in clinical trials. By conservative estimates, approximately 215 agents are currently undergoing clinical testing. The median number of agents per target is 7 (range 2 (HIF-1α and PDGFRα) – 24 (EGFR)). There are 7 EGFR inhibitors and 10 VEGFR inhibitors that were evaluated in phase III trials; with 36,093 and 20,313 stage IV NSCLC patients enrolled or to be enrolled in these trials, respectively. No more than 2 agents per target have been FDA approved for NSCLC to date. Further details of the analyses will be more comprehensively presented at the meeting. Conclusions: Patient resource utilization is unevenly distributed across targets. The optimal number of targeted agents to be evaluated per target remains to be defined. More emphasis on identifying new targets and targeting these with limited number of optimal agents may accelerate the advancement of the field and the impact on patient care.
Combined activity of the cancer metabolism inhibitor MPC-8640 and 5-fluorouracil in xenograft models.
Authors: Vijay R. Baichwal, Chad Bradford, J. Scott Patton, Leslie Reeves, Lynn DeMie, Lori Fotheringham, Orvelin Roman, Thomas B Douce, Brita Brown, Robert O. Carlson
Journal: Journal of Clinical Oncology (2012)

e13581 Background: Nicotinamide (Nam) phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step in NAD biosynthesis from Nam. Nampt inhibition causes NAD depletion, inhibition of ATP synthesis and cell death. MPI-0487316 is a selective Nampt inhibitor with potent tumoricidal activity against cancer cell lines of diverse origin. MPC-8640, an orally bioavailable prodrug of MPI-0487316, induces regressions in xenograft models. Combining Nampt inhibitors with 5-fluorouracil (5-FU) results in synergistic tumoricidal activity in cells. We have explored the combination of MPC-8640 with 5-FU in a colon carcinoma xenograft model. Methods: In vitro studies were done in HCT-116 human colon carcinoma cells. Cell viability was measured by determining ATP levels. Xenograft studies were done with cells implanted subcutaneously into athymic mice (nu/nu). MPC-8640 was dosed orally at 12 to 48 mg/kg daily on Days 1-7 and 15-21. 5-FU was dosed intraperitoneally, weekly at 100 mg/kg. Results: MPI-0487316 showed synergistic tumoricidal activity in vitro with 5-FU. In xenograft studies, the prodrug MPC-8640, at 12, 24 and 36 mg/kg, resulted in tumor growth inhibition (TGI) of 64%, 98% and 91%, respectively, at the end of dosing on Day 22 and tumor regression of 5%, when dosed at 48 mg/kg. In the 36 and 48 mg/kg group, 20% and 10% of the mice, respectively, had no detectable tumors by the end of the study on Day 42. In another study, mice were given 5-FU or MPC-8640 as single agents or in combination. Combining 5-FU with MPC-8640 at 24 mg/kg resulted in 45% tumor regression on Day 21 compared to TGI of 88% and 78% for MPC-8640 or 5-FU, respectively, dosed as single agents. Similarly, combining 5-FU and MPC-8640 at 32 mg/kg resulted in 83% tumor regression on Day 21 compared to TGI of 86% and 78% for MPC-8640 and 5-FU, respectively, dosed as single agents. The combinations of 5-FU and MPC-8640 were well-tolerated with &lt;10% change in median body weight. Conclusions: A combination of MPC-8640 with 5-FU causes tumor regression in a colon carcinoma xenograft model and is more effective than either agent dosed alone. Thus, MPC-8640 may have potential for treating cancers as a single agent or in combination with antimetabolites.