36 results on '"Pilat MJ"'
Search Results
2. Lack of food effect on single-dose pharmacokinetics of brivanib, and safety and efficacy following multiple doses in subjects with advanced or metastatic solid tumors.
- Author
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Lorusso P, Shapiro GI, Hurwitz H, Pilat MJ, Chemidlin J, Kollia G, Syed S, Fischer B, and Masson E
- Published
- 2011
3. NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors.
- Author
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Cecchini M, Walther Z, Wei W, Hafez N, Pilat MJ, Boerner SA, Durecki DE, Eder JP, Schalper KA, Chen AP, and LoRusso P
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- Humans, Irinotecan therapeutic use, Benzimidazoles adverse effects, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Neoplasms drug therapy, Antineoplastic Agents therapeutic use
- Abstract
Purpose: Veliparib is a PARP inhibitor (PARPi) with activity in BRCA 1/2/ PALB2 -deficient tumors. Preclinical observations reveal topoisomerase inhibitors like irinotecan are synergistic with PARPi irrespective of homologous recombination deficiency (HRD), potentially expanding the role for PARPi., Experimental Design: NCI 7977 was a multicohort phase I clinical trial evaluating the safety and efficacy of multiple dose schedules of veliparib with irinotecan for solid tumors. In the intermittent veliparib cohort, escalating doses of veliparib were given twice daily at dose level (DL) 1 (50 mg) and DL 2 (100 mg) days 1-4 and 8-11 with irinotecan 100 mg/m
2 days 3 and 10 in 21-day cycles., Results: Fifteen patients enrolled, 8 of 15 (53%) received ≥4 prior systemic treatments. At DL1, 1 of 6 patients experienced a dose-limiting toxicity (DLT) of diarrhea. At DL2, 9 patients were treated, with 3 unevaluable for DLT, and 2 of 6 evaluable patients experienced a DLT of grade 3 neutropenia. Irinotecan 100 mg/m2 and veliparib 50 mg twice daily was the MTD. No objective responses were observed, although 4 patients had progression-free survival >6 months., Conclusions: The MTD of intermittent veliparib is 50 mg twice daily days 1-4 and 8-11 with weekly irinotecan 100 mg/m2 days 3 and 10 every 21 days. Multiple patients experienced prolonged stable disease irrespective of HRD and prior irinotecan. However, due to the toxicities with higher dose intermittent veliparib and irinotecan, this schedule was determined too toxic for further development and the arm was closed prematurely., Significance: The combination of intermittent veliparib with weekly irinotecan was deemed too toxic for further development. Future PARPi combinations should focus on agents with nonoverlapping toxicities to improve tolerability. The treatment combination showed limited efficacy with prolonged stable disease observed in multiple heavily pretreated patients, but no objective responses were seen., (© 2023 The Authors; Published by the American Association for Cancer Research.)- Published
- 2023
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4. Multicenter Phase II Trial of the PARP Inhibitor Olaparib in Recurrent IDH1- and IDH2 -mutant Glioma.
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Fanucci K, Pilat MJ, Shyr D, Shyr Y, Boerner S, Li J, Durecki D, Drappatz J, Puduvalli V, Lieberman FS, Gonzalez J, Giglio P, Ivy SP, Bindra RS, Omuro A, and LoRusso P
- Subjects
- Humans, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Isocitrate Dehydrogenase genetics, Neoplasm Recurrence, Local drug therapy, Brain Neoplasms drug therapy, Glioma drug therapy, Antineoplastic Agents adverse effects
- Abstract
Purpose: Isocitrate dehydrogenase ( IDH ) 1 and IDH2 mutations ( IDH1/2 mt) are frequent in glioma. Preclinical studies suggest IDH1/2 mts confer "BRCAness" phenotype, a vulnerability that can be targeted through PARP inhibition. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients with IDH1/2 mt gliomas., Methods: Patients with recurrent, contrast-enhancing IDH1/2 mt gliomas were enrolled in a two-step phase II trial; the primary endpoint was overall response rate per Response Assessment in Neuro-Oncology (RANO) criteria. Olaparib 300 mg orally twice daily was given., Results: A total of 15 evaluable patients were enrolled. Histology was astrocytoma ( N = 12) and oligodendroglioma ( N = 3). Most toxicities were grade 1 or 2. Best response was stable disease (SD) in 9 (60%) patients. Median progression-free survival (PFS) was 3.63 months and median overall survival was 20.7 months. For patients with SD, median PFS was 5.53 months; 4 patients had SD for >6 months. Among patients with best response progressive disease ( N = 6), 5 had grade 4 tumor and 4 had known CDKN2A alteration. PFS was 5.23 months for grades 2 or 3 tumors ( N = 10) versus 1.8 months for grade 4 ( N = 5; P = 0.0013)., Conclusion: The study did not meet the prespecified response-based activity threshold for moving to step 2. However, prolonged SD was observed in patients with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select populations. Grade 4 tumors per 2021 World Health Organization classification defined by histology or CDKN2A alteration derived no benefit from this drug, highlighting the usefulness of this classification for future patient stratification and trial design., Significance: A single-arm phase II trial of olaparib in IDH -mutant glioma demonstrated clinically significant prolonged SD for select patients with grade 2/3 disease, suggesting potential benefit of olaparib in IDH -mutant gliomas., Competing Interests: Y. Shyr reports grants from NIH/NCI during the conduct of the study; grants from NIH outside the submitted work. S. Boerner reports grants from NCI-CTEP and Rising Tide Foundation during the conduct of the study. D. Durecki reports grants from NIH/NCI UM1CA186689 during the conduct of the study. J. Drappatz reports other from Pfizer, GSK, Gilead, and Vertex outside the submitted work. V. Puduvalli reports personal fees and other from Servier and Novocure, other from Karyopharm, and personal fees from Orbus therapeutics during the conduct of the study; other from Amarin and Gilead outside the submitted work. F.S. Lieberman reports grants from ABTC during the conduct of the study; grants from Novocure, Chimerix, Blue Diamond Therapeutics, and Abbvie outside the submitted work. J. Gonzalez reports other from AstraZeneca outside the submitted work. P. Giglio reports grants from NCI during the conduct of the study; other from Vanguard Funds; grants from BioMimetix, Denovo Biopharma, Institut de Recherches Internationales Servier, Novocure, and Prelude Therapeutics outside the submitted work. R.S. Bindra reports a patent to 62/344,678 pending. A. Omuro reports grants from Arcus Biosciences; personal fees from Pyramid, Merck, Kiyatec, and Ono outside the submitted work. P. LoRusso reports other from AbbVie, Agios, Five Prime, GenMab, Halozyme, Roche-Genetech, Genentech, CytomX, Takeda, Sotio, Cybrexa, Agenus, Tyme, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin Pharmaceutical, Kineta, Zentalis, Molecular Templates, ABL Bio, SK Life Science, STCube Pharmaceuticals, Bayer, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, Roivant, and NeuroTrials outside the submitted work. No disclosures were reported by the other authors., (© 2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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5. Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial.
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LoRusso PM, Sekulic A, Sosman JA, Liang WS, Carpten J, Craig DW, Solit DB, Bryce AH, Kiefer JA, Aldrich J, Nasser S, Halperin R, Byron SA, Pilat MJ, Boerner SA, Durecki D, Hendricks WPD, Enriquez D, Izatt T, Keats J, Legendre C, Markovic SN, Weise A, Naveed F, Schmidt J, Basu GD, Sekar S, Adkins J, Tassone E, Sivaprakasam K, Zismann V, Calvert VS, Petricoin EF, Fecher LA, Lao C, Eder JP, Vogelzang NJ, Perlmutter J, Gorman M, Manica B, Fox L, Schork N, Zelterman D, DeVeaux M, Joseph RW, Cowey CL, and Trent JM
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- Adult, Aged, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Pilot Projects, Prospective Studies, Melanoma, Cutaneous Malignant, Benzimidazoles administration & dosage, Genomics, Melanoma drug therapy, Melanoma genetics, Melanoma metabolism, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Skin Neoplasms metabolism
- Abstract
Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that may be considered for future studies. Our results highlight the complexity and heterogeneity of metastatic melanomas, as well as how the lack of response in this trial may be associated with limitations including monotherapy drug selection and the dearth of available single and combination molecularly-driven therapies to treat BRAFV600wt metastatic melanomas., Competing Interests: These commercial affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2021
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6. Impact of Type of Healthcare Experience Before Physician Assistant School Admission on PANCE Score.
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Lolar S, Pilat MJ, and Welch RD
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- Adult, Clinical Competence, Clinical Decision-Making, Female, Humans, Male, Pilot Projects, Retrospective Studies, Young Adult, Academic Success, Certification standards, Physician Assistants education
- Abstract
Background: The physician assistant (PA) profession is based on a strong foundation of previous healthcare experience (HCE). It is unclear if HCE requiring more autonomous decision-making equates to a higher likelihood of success as a PA student. The purpose of this study was to determine if there is a correlation between type of pre-PA program HCE and success as determined by Physician Assistant National Certifying Examination (PANCE) scores., Method: This retrospective, observational study included PA students (single institution) who took the PANCE (n=188). Self-reported HCE was used to classify students into two broad groups based on locally derived criteria: Group A (less autonomy: such as medical assistant, nursing assistant) and Group B (more autonomy: paramedic, registered nurse, etc.). A linear mixed model was fit to assess the association between the primary outcome, PANCE, and HCE group., Results: Group A (n=124) and Group B (n=64) had similar baseline PANCE scores (mean 497 vs 499; p=0.26). After adjusting for included predictors in the model, Group A was associated with lower PANCE scores but this did not reach statistical significance (p=0.7) and there was no association with number of HCE hours (p=0.77)., Conclusion: There was no statistically significant association between type of pre-PA program HCE and PANCE.
- Published
- 2020
7. Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors.
- Author
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Shapiro GI, LoRusso P, Kwak E, Pandya S, Rudin CM, Kurkjian C, Cleary JM, Pilat MJ, Jones S, de Crespigny A, Fredrickson J, Musib L, Yan Y, Wongchenko M, Hsieh HJ, Gates MR, Chan IT, and Bendell J
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- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Azetidines adverse effects, Azetidines pharmacokinetics, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Class I Phosphatidylinositol 3-Kinases genetics, Female, GTP Phosphohydrolases genetics, Humans, Indazoles adverse effects, Indazoles pharmacokinetics, Male, Membrane Proteins genetics, Middle Aged, Mitogen-Activated Protein Kinase Kinases genetics, Neoplasms genetics, Neoplasms metabolism, Phosphoinositide-3 Kinase Inhibitors adverse effects, Phosphoinositide-3 Kinase Inhibitors pharmacokinetics, Piperidines adverse effects, Piperidines pharmacokinetics, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacokinetics, Proto-Oncogene Proteins p21(ras) genetics, Sulfonamides adverse effects, Sulfonamides pharmacokinetics, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Azetidines administration & dosage, Indazoles administration & dosage, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Neoplasms drug therapy, Phosphoinositide-3 Kinase Inhibitors administration & dosage, Piperidines administration & dosage, Protein Kinase Inhibitors administration & dosage, Sulfonamides administration & dosage
- Abstract
Purpose We investigated the combination of the MEK inhibitor, cobimetinib, and the pan-PI3K inhibitor, pictilisib, in an open-label, phase Ib study. Experimental Design Patients with advanced solid tumors were enrolled in 3 dose escalation schedules: (1) both agents once-daily for 21-days-on 7-days-off ("21/7"); (2) intermittent cobimetinib and 21/7 pictilisib ("intermittent"); or (3) both agents once-daily for 7-days-on 7-days-off ("7/7"). Starting doses for the 21/7, intermittent, and 7/7 schedules were 20/80, 100/130, and 40/130 mg of cobimetinib/pictilisib, respectively. Nine indication-specific expansion cohorts interrogated the recommended phase II dose and schedule. Results Of 178 enrollees (dose escalation: n = 98), 177 patients were dosed. The maximum tolerated doses for cobimetinib/pictilisib (mg) were 40/100, 125/180, and not reached, for the 21/7, intermittent, and 7/7 schedules, respectively. Six dose-limiting toxicities included grade 3 (G3) elevated lipase, G4 elevated creatine phosphokinase, and G3 events including fatigue concurrent with a serious adverse event (SAE) of diarrhea, decreased appetite, and SAEs of hypersensitivity and dehydration. Common drug-related adverse events included nausea, fatigue, vomiting, decreased appetite, dysgeusia, rash, and stomatitis. Pharmacokinetic parameters of the drugs used in combination were unaltered compared to monotherapy exposures. Confirmed partial responses were observed in patients with BRAF-mutant melanoma (n = 1) and KRAS-mutant endometrioid adenocarcinoma (n = 1). Eighteen patients remained on study ≥6 months. Biomarker data established successful blockade of MAP kinase (MAPK) and PI3K pathways. The metabolic response rate documented by FDG-PET was similar to that observed with cobimetinib monotherapy. Conclusions Cobimetinib and pictilisib combination therapy in patients with solid tumors had limited tolerability and efficacy.
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- 2020
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8. A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma.
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Goncalves PH, Heilbrun LK, Barrett MT, Kummar S, Hansen AR, Siu LL, Piekarz RL, Sukari AW, Chao J, Pilat MJ, Smith DW, Casetta L, Boerner SA, Chen A, Lenkiewicz E, Malasi S, and LoRusso PM
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- Adult, Aged, Carcinoma, Adenoid Cystic genetics, Chromatin Assembly and Disassembly, Female, Gene Regulatory Networks, Histone Deacetylase Inhibitors adverse effects, Humans, Hydroxamic Acids adverse effects, Male, Middle Aged, Mutation, Neoplasm Metastasis, Neoplasm Recurrence, Local genetics, Pharmacogenomic Variants, Salivary Gland Neoplasms genetics, Vorinostat, Exome Sequencing, Young Adult, Carcinoma, Adenoid Cystic drug therapy, Histone Deacetylase Inhibitors administration & dosage, Hydroxamic Acids administration & dosage, Neoplasm Recurrence, Local drug therapy, Salivary Gland Neoplasms drug therapy
- Abstract
Purpose: Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial., Methods: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients., Results: Thirty patients were enrolled. Median age of patients was 53 years (range 21-73). Median number of cycles was 5 (range 1-66). Lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic events (n = 2) and fatigue (n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC., Conclusion: Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.
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- 2017
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9. Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors.
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LoRusso PM, Li J, Burger A, Heilbrun LK, Sausville EA, Boerner SA, Smith D, Pilat MJ, Zhang J, Tolaney SM, Cleary JM, Chen AP, Rubinstein L, Boerner JL, Bowditch A, Cai D, Bell T, Wolanski A, Marrero AM, Zhang Y, Ji J, Ferry-Galow K, Kinders RJ, Parchment RE, and Shapiro GI
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzimidazoles adverse effects, Camptothecin adverse effects, Camptothecin pharmacokinetics, Camptothecin therapeutic use, Cell Cycle Proteins metabolism, DNA Repair genetics, Female, Histones metabolism, Humans, Irinotecan, Male, Middle Aged, Nuclear Proteins metabolism, Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Poly(ADP-ribose) Polymerases drug effects, Benzimidazoles pharmacokinetics, Benzimidazoles therapeutic use, Camptothecin analogs & derivatives, Neoplasms drug therapy, Poly(ADP-ribose) Polymerase Inhibitors pharmacokinetics, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use
- Abstract
Purpose: PARP is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor-mediated DNA damage. This phase I study determined the MTD, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib, an orally bioavailable PARP1/2 inhibitor, in combination with irinotecan., Experimental Design: Patients with advanced solid tumors were treated with 100 mg/m(2) irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily oral dosing of veliparib (10-50 mg) occurred on days 3 to 14 (cycle 1) and days -1 to 14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1)., Results: Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m(2) irinotecan (days 1 and 8) combined with veliparib 40 mg twice daily (days -1-14) on a 21-day cycle. Of 31 response-evaluable patients, there were six (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared with irinotecan alone., Conclusions: Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination. Clin Cancer Res; 22(13); 3227-37. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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10. Pilot Trial of Selecting Molecularly Guided Therapy for Patients with Non-V600 BRAF-Mutant Metastatic Melanoma: Experience of the SU2C/MRA Melanoma Dream Team.
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LoRusso PM, Boerner SA, Pilat MJ, Forman KM, Zuccaro CY, Kiefer JA, Liang WS, Hunsberger S, Redman BG, Markovic SN, Sekulic A, Bryce AH, Joseph RW, Cowey CL, Fecher LA, Sosman JA, Chapman PB, Schwartz GK, Craig DW, Carpten JD, and Trent JM
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- Aged, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Female, Humans, Male, Melanoma diagnosis, Middle Aged, Phenotype, Pilot Projects, Treatment Outcome, Melanoma drug therapy, Melanoma genetics, Molecular Targeted Therapy, Mutation, Proto-Oncogene Proteins B-raf genetics
- Abstract
Targeted therapies and immunotherapies have led to significant improvements in the treatment of advanced cancers, including metastatic melanoma. However, new strategies are desperately needed to overcome therapeutic resistance to these agents, as well as to identify effective treatment approaches for cancer patients that fall outside major targetable mutational subtypes (e.g., non-V600 BRAF melanoma). One such strategy is to extend the paradigm of individually tailored, molecularly targeted therapy into a broader spectrum of melanoma patients, particularly those bearing tumors without commonly recognized therapeutic targets, as well as having failed or were ineligible for immunotherapy. In this nontreatment pilot study, next-generation sequencing (NGS) technologies were utilized, including whole genome and whole transcriptome sequencing, to identify molecular aberrations in patients with non-V600 BRAF metastatic melanoma. This information was then rationally matched to an appropriate clinical treatment from a defined pharmacopeia. Five patients with advanced non-V600 BRAF metastatic melanoma were enrolled. We demonstrated successful performance of the following during a clinically relevant time period: patient tumor biopsy, quality DNA/RNA extraction, DNA/RNA-based sequencing for gene expression analysis, analysis utilizing a series of data integration methodologies, report generation, and tumor board review with formulated treatment plan. Streamlining measures were conducted based on the experiences of enrolling, collecting specimens, and analyzing the molecular signatures of patients. We demonstrated the feasibility of using NGS to identify molecular aberrations and generate an individualized treatment plan in this patient population. A randomized treatment study utilizing lessons learned from the conduct of this pilot study is currently underway., (©2015 American Association for Cancer Research.)
- Published
- 2015
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11. A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors.
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Hong DS, Kurzrock R, Naing A, Wheler JJ, Falchook GS, Schiffman JS, Faulkner N, Pilat MJ, O'Brien J, and LoRusso P
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- Aged, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Diarrhea chemically induced, Epoxy Compounds adverse effects, Epoxy Compounds pharmacokinetics, Female, Humans, Infusions, Intravenous, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, Macrolides adverse effects, Macrolides pharmacokinetics, Male, Maximum Tolerated Dose, Middle Aged, Nausea chemically induced, Neoplasms metabolism, RNA Splicing drug effects, RNA, Messenger metabolism, Spliceosomes, Vision Disorders chemically induced, Vomiting chemically induced, Antineoplastic Agents administration & dosage, Epoxy Compounds administration & dosage, Macrolides administration & dosage, Neoplasms drug therapy
- Abstract
The aim of this study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of E7107 in patients with advanced solid tumors. Patients in this phase I, open-label, single-arm, dose-escalation study had metastatic or locally advanced solid tumors and received E7107 as a 30-minute intravenous infusion at doses of 0.6, 1.2, 1.8, 2.4, 3.2, 4.3, and 5.7 mg/m(2). Twenty-six patients were enrolled in the study. At 5.7 mg/m(2), two patients experienced dose-limiting toxicities including diarrhea, vomiting, dehydration, and myocardial infarction on Days 1-3 following E7107 administration. Three additional patients were recruited at the lower dose and all six patients tolerated E7107 4.3 mg/m(2) with no dose-limiting toxicities. The maximum tolerated dose of E7107 was therefore 4.3 mg/m(2). The most common drug-related adverse events were nausea, vomiting, and diarrhea. Vision loss was experienced by two patients at Cycles 2 and 7, each patient receiving 3.2 mg/m(2) and 4.3 mg/m(2), respectively. This resulted in the study being put on clinical hold. Pharmacokinetic analysis showed that E7107 was rapidly distributed with a moderate elimination half-life (6-13 h) and high clearance. Exposure to E7107 was dose-related. The best tumor response was stable disease in eight patients. E7107 is a unique first-in-class molecule. The incidence of two cases of vision loss probably related to E7107 led to study discontinuation.
- Published
- 2014
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12. Effect of coadministration of ketoconazole, a strong CYP3A4 inhibitor, on pharmacokinetics and tolerability of motesanib diphosphate (AMG 706) in patients with advanced solid tumors.
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Lorusso P, Heath EI, McGreivy J, Sun YN, Melara R, Yan L, Malburg L, Ingram M, Wiezorek J, Chen L, and Pilat MJ
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- Aged, Cross-Over Studies, Cytochrome P-450 CYP3A, Drug Administration Schedule, Female, Humans, Indoles adverse effects, Indoles pharmacokinetics, Ketoconazole administration & dosage, Male, Middle Aged, Niacinamide administration & dosage, Niacinamide adverse effects, Niacinamide pharmacokinetics, Oligonucleotides, Cytochrome P-450 CYP3A Inhibitors, Indoles administration & dosage, Ketoconazole pharmacology, Neoplasms drug therapy, Niacinamide analogs & derivatives
- Abstract
Motesanib diphosphate is a novel angiogenesis inhibitor selectively targeting vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor and stem cell factor receptor. The purpose of this phase 1b, drug-drug interaction study was to investigate the effect of ketoconazole, a strong inhibitor of the cytochrome P450 3A4 isoenzyme, on the pharmacokinetics and tolerability of motesanib diphosphate. Fourteen patients with advanced solid tumors refractory to standard treatment were enrolled and received motesanib diphosphate 50 mg once daily from day 1 through 15. Patients were randomized to receive a single oral dose of ketoconazole 400 mg either on day 8 (Sequence 1; n = 7) or day 15 (Sequence 2; n = 7), while pharmacokinetic samples were collected. After completion of this part (day 16), 13 patients received an escalated once-daily dose of motesanib diphosphate 125 mg. Evaluable pharmacokinetic data (n = 12) suggest that ketoconazole modestly increased motesanib exposure. The motesanib area under the concentration-time curve (AUC) from 0 to 24 h increased by 86% (90% CI, 1.50-2.29; P < 0.001) and the maximum plasma concentration (C (max)) by 35% (90% CI, 1.12-1.64; P = 0.02), compared with motesanib diphosphate administration alone. The tolerability profile (with or without ketoconazole coadministration) was consistent with that from other motesanib diphosphate monotherapy studies. Treatment-related adverse events were mild to moderate and commonly included fatigue (50% of patients), hypertension (43%), diarrhea (21%), dizziness (14%), paresthesia (14%), and vomiting (14%). Hypertension was the most common related grade 3 event (21%). No grade 4 or 5 treatment-related adverse events occurred.
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- 2008
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13. Effect of food on the pharmacokinetic behavior of the potent oral taxane BMS-275183.
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Bröker LE, Valdivieso M, Pilat MJ, Deluca P, Zhou X, Parker S, Giaccone G, and Lorusso PM
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- Adult, Aged, Body Surface Area, Fasting, Female, Humans, Male, Middle Aged, Solubility, Therapeutic Equivalency, Antineoplastic Agents pharmacokinetics, Bridged-Ring Compounds pharmacokinetics, Dietary Fats pharmacokinetics, Food, Taxoids pharmacokinetics
- Abstract
Purpose: BMS-275183 is a potent oral paclitaxel analogue that previously showed promising activity. The goal of the present trial was to investigate whether food affects the pharmacokinetics of BMS-275183. Additionally, we evaluated its pharmacokinetic variability using flat-fixed dosing compared with dosing individualized by body surface area (BSA)., Patients and Methods: The patients were treated with 200 mg of BMS-275183 under fasting condition (A), after a standard low-fat meal (B), or after a high-fat meal (C). The patients were randomized to one of six treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA). The fourth (D) and consecutive weekly doses were normalized by BSA and consisted of 200 mg/m(2). Pharmacokinetic sampling was done up to 72 hours after the first four doses and analyzed with a validated liquid chromatography/mass spectrometry assay., Results: A total of 31 patients were treated. Pharmacokinetic data were available for 26 patients (A and C), 24 patients (B), and 21 patients (D). Compared with administration under fasted conditions, a decrease of 39% and 63% in the maximal observed drug concentration was observed when BMS-275183 was administered after a low-fat and a high-fat meal, respectively. There was no change in systemic exposure as measured by the area under the plasma concentration versus time curve extrapolated to infinity (AUC(inf)). No apparent relationship was observed between AUC(inf) and BSA for either the 200 mg or the 200 mg/m(2) regimen. BMS-275183 was well tolerated with grade 3 and 4 toxicity in eight patients. One partial response was observed in a non-small cell lung cancer patient., Conclusions: Food intake does not affect the pharmacologic exposure to BMS-275183. BMS-275183 can be given orally by flat dosing instead of BSA-normalized dosing.
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- 2008
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14. Vascular disrupting agents.
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Pilat MJ and Lorusso PM
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- Animals, Flavonoids pharmacology, Ligands, Tubulin metabolism, Xanthones pharmacology, Angiogenesis Inhibitors pharmacology, Neoplasms blood supply
- Abstract
It has been well established that a functioning vascular supply is essential for solid tumor growth and metastases. In the absence of a viable vascular network, tumors are unable to grow beyond a few millimeters and therefore remain dormant. Initiation of angiogenesis allows for continued tumor growth and progression. Targeting tumor vasculature, either by inhibiting growth of new tumor blood vessels (antiangiogenic agents) or by destroying the already present tumor vessels (vascular disrupting agents; VDA), is an area of extensive research in the development of new antitumor agents. These two groups differ in their direct physiological target, the type or extent of disease that is likely to be susceptible, and the treatment schedule. VDAs target the established tumor blood vessels, resulting in tumor ischemia and necrosis. These agents show more immediate effects compared to antiangiogenic agents and may have more efficacy against advanced bulky disease. VDAs can be divided into two groups--ligand-bound and small molecule agents. Both VDA groups have demonstrated antitumor effects and tumor core necrosis, but consistently leave a thin rim of viable tumor cells at the periphery of the tumor. More evidence suggests VDAs will have their greatest effect in combination with conventional chemotherapy or other modes of treatment that attack this outer rim of cells.
- Published
- 2006
- Full Text
- View/download PDF
15. Vascular targeting agents.
- Author
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Pilat MJ, McCormick J, and LoRusso PM
- Subjects
- Clinical Trials as Topic, Humans, Neoplasms drug therapy, Neovascularization, Pathologic drug therapy, Tubulin drug effects, Tubulin Modulators, Angiogenesis Inhibitors therapeutic use, Antineoplastic Agents therapeutic use, Neoplasms blood supply
- Abstract
The role of the vascular network of a tumor has been the focus of much recent research. Angiogenesis, or the growth of new tumor blood vessels, was initially the main target in the development of novel antitumor agents. More recently, new therapeutic strategies have been designed to destroy established tumor blood vessels. These vascular targeting agents (VTAs) exert their action by producing a rapid shutdown of tumor blood flow, resulting in ischemia and tumor cell necrosis. VTAs can be broadly divided into biologic agents and small molecules. In contrast to the biologic agents, drug-based vascular targeting molecules have developed much further, with many clinical trials ongoing. Evidence suggests that VTAs may be useful as single agents but can be more effective when used in combination with other therapeutic regimens.
- Published
- 2004
- Full Text
- View/download PDF
16. Droplet charging for wet scrubbers.
- Author
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Pilat MJ and Lukas JC
- Subjects
- Aerosols, Particle Size, Static Electricity, Water chemistry, Air Pollutants isolation & purification, Air Pollution prevention & control
- Abstract
Water droplet charge/mass of wet scrubbers was measured over the direct charging applied potential range of 0-20 kV, 30-70 pounds per square inch gauge (206.8-482.6 kPa) water pressure, and with spiral, impingement, and whirl nozzles. The measured charge/mass ranged from -0.0005 to 0.2 microcoulomb/gm and was directly related to the applied voltage. The water charge/mass was a function of the spray nozzle, with the smaller orifice lower-flow nozzles having the higher charge/mass.
- Published
- 2004
- Full Text
- View/download PDF
17. Decreased galectin-3 expression in prostate cancer.
- Author
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Pacis RA, Pilat MJ, Pienta KJ, Wojno K, Raz A, Hogan V, and Cooper CR
- Subjects
- Antigens, Differentiation analysis, Antigens, Differentiation genetics, Blotting, Western, Cell Line, Galectin 3, Humans, Immunohistochemistry, Male, Prostate cytology, Prostatic Neoplasms chemistry, Prostatic Neoplasms genetics, Tumor Cells, Cultured, Antigens, Differentiation biosynthesis, Gene Expression Regulation, Neoplastic, Prostate pathology, Prostatic Neoplasms pathology
- Abstract
Background: Galectin-3 is a carbohydrate-binding protein whose level of expression has been shown to be correlated with metastatic potential in a number of different tumor types. The purpose of this investigation was to examine galectin-3 expression in several tumorigenic and nontumorigenic prostate cell lines and prostate tissue samples., Methods: The expression of galectin-3 in cell lines and tissue samples was evaluated by tissue immunohistochemistry and Western blot analysis., Results: Human cell lines PC-3M, PC-3, DU-145, PrEC-1, and MCF10A demonstrated the presence of galectin-3. Galectin-3 was not detected in TSU-pr1 and LNCaP by Western blot analysis. We furthered our studies by examining a series of human prostate tissue samples for expression of galectin-3. Overall, approximately 60-70% of the normal tissue examined demonstrated heterogenous expression of galectin-3. In stage II tumors, however, there was a dramatic decrease in galectin-3 expression in both PIN and tumor sections, with only 10.5% (2/19) of these samples expressing this protein. Stage III tumors also demonstrated a decreased expression of galectin-3, although this downregulation was not as dramatic, with 35% of PIN samples and 52% of tumor tissue expressing galectin-3 (P < 0.01)., Conclusions: These data demonstrate that galectin-3 is downregulated in prostate cancer. The altered downregulation pattern of galectin-3 observed between tumor stages suggests different roles for galectin-3 in the progression of prostate cancer., (Copyright 2000 Wiley-Liss, Inc.)
- Published
- 2000
- Full Text
- View/download PDF
18. The study of gemcitabine in combination with other chemotherapeutic agents as an effective treatment for prostate cancer.
- Author
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Muenchen HJ, Quigley MM, Pilat MJ, Lehr JE, Brumfield SK, Mahoney M, and Pienta KJ
- Subjects
- Animals, Antimetabolites, Antineoplastic therapeutic use, Antineoplastic Agents therapeutic use, Carboplatin toxicity, Cell Division drug effects, Cell Survival drug effects, Deoxycytidine therapeutic use, Deoxycytidine toxicity, Drug Synergism, Estramustine toxicity, Etoposide toxicity, Humans, Male, Paclitaxel toxicity, Rats, Tumor Cells, Cultured, Gemcitabine, Antimetabolites, Antineoplastic toxicity, Antineoplastic Agents toxicity, Deoxycytidine analogs & derivatives, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology
- Abstract
Background: Gemcitabine has demonstrated clinical activity against several common cancers. Our studies examine the ability of gemcitabine, both alone and in combination with other chemotherapeutic agents, to inhibit the in vitro and in vivo growth of several prostate cancer cell lines., Materials and Methods: Cultures of LNCaP, PC-3 or MLL cells were exposed to either gemcitabine or other appropriate agents for specified amounts of time. Cells were lysed and nuclei counted utilizing a Coulter Counter. For in vivo experiments, animals were injected with 1 x 10(5) MLL cells subcutaneously into the right flank. Animals were treated as indicated for 14 days. Tumors were then excised, weighed and measured., Results: In both human (PC-3 and LNCaP) and rat prostate (MLL) cancer cell lines our studies demonstrated gemcitabine had a strong effect in vitro, with an IC50 of approximately 500 nM in the human lines and 10 nM in MLL cells. In vivo, studies using the Dunning prostate cancer model in Copenhagen rats resulted in a dose response inhibition of tumor growth, with an 80% decrease in tumor size in rats treated with gemcitabine at 10 mg/kg., Conclusions: Our results demonstrated the potent activity of gemcitabine against prostate cancer in the Dunning rat model and suggest the addition of paclitaxel may not aid in this activity.
- Published
- 2000
19. Signaling network of paclitaxel-induced apoptosis in the LNCaP prostate cancer cell line.
- Author
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Panvichian R, Orth K, Pilat MJ, Day ML, Day KC, Yee C, Kamradt JM, and Pienta KJ
- Subjects
- Caspases physiology, Cell Cycle Proteins metabolism, Cyclin B metabolism, Cyclin B1, Dose-Response Relationship, Drug, HeLa Cells, Humans, Male, Tumor Cells, Cultured, Antineoplastic Agents, Phytogenic pharmacology, Apoptosis drug effects, Paclitaxel pharmacology, Prostatic Neoplasms pathology
- Abstract
Objectives: To attempt to identify the relationship of the key regulator molecules in paclitaxel-induced apoptosis using two metastatic cell lines: the human prostate carcinoma LNCaP line and the cervical carcinoma HeLa cell line., Methods: Both LNCaP and HeLa cells were continuously exposed to clinically achievable concentrations of paclitaxel and observed for activation of programmed cell death as measured by cytotoxic dose-response curves, poly(adenosine diphosphate-ribose) polymerase cleavage, bcl-2 phosphorylation, and the activation of caspase-7 (interleukin-1 beta converting enzyme (ICE)-LAP3)., Results: Initially, we asked whether paclitaxel-induced bcl-2 phosphorylation is triggered by the spindle assembly checkpoint via an active cdc2 kinase-dependent pathway and whether phosphorylation of endogenous bcl-2 is the signal that activates cell death machinery. Paclitaxel-induced G2/M cell cycle arrest correlated with cdc2 kinase activity and bcl-2 phosphorylation. Olomoucin, a specific inhibitor of cyclin-dependent kinases, inhibited bcl-2 phosphorylation. On the basis of these studies, we then investigated whether bcl-2 was phosphorylated in a cell cycle-dependent fashion. Analysis of synchronized HeLa cells demonstrated that endogenous bcl-2 is phosphorylated in a G2/M cell cycle-dependent manner without apoptosis., Conclusions: Our results indicate that the events associated with paclitaxel-induced cytotoxicity are connected to each other and represent the signaling network of paclitaxel-induced mitotic arrest and cell death. In addition, we confirmed that the death-decision of paclitaxel-induced apoptosis is not mediated by bcl-2 phosphorylation and believe that this decision may be mediated by the activated spindle assembly checkpoint.
- Published
- 1999
- Full Text
- View/download PDF
20. The isolation and characterization of epithelial cells from canine prostate.
- Author
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Lehr JE, Pilat MJ, and Pienta KJ
- Subjects
- Acid Phosphatase analysis, Animals, Antigens, Viral, Tumor genetics, Biomarkers, Cell Division, Cell Line, Cell Line, Transformed, Dog Diseases epidemiology, Dog Diseases pathology, Dogs, Humans, Karyotyping, Keratins analysis, Male, Prostatic Neoplasms epidemiology, Prostatic Neoplasms pathology, Prostatic Neoplasms veterinary, Recombinant Proteins biosynthesis, Simian virus 40 genetics, Transfection, Cell Culture Techniques methods, Epithelial Cells cytology, Prostate cytology
- Abstract
Background: Prostate cancer causes approximately 40,000 deaths in the United States annually (1,2). Adenocarcinoma of the prostate occurs primarily in two species: human and dog (3,4). Although less common in dogs, the etiologic factors responsible for spontaneous canine prostate cancer are presumably the same as for humans. Given the similar etiology and epidemiology of the disease among the two species, a model of canine prostate epithelial cells would be a powerful tool to study the disease., Methods: Prostate epithelial cells were isolated from a sexually intact, adult beagle, and primary cultures established. Epithelial clones were immortalized by transfection with the Simian Virus 40 large T-antigen cDNA. Cells were characterized using immunohistochemical techniques., Results: The immortal prostate epithelial cell line expresses cytokeratin-18, and prostatic acid phosphatase, markers specific for prostate epithelial cells. K-9PE-I, a stable, fast growing, canine prostate epithelial cell line is available for further study., Conclusions: A cell based model of canine prostate epithelium was isolated, immortalized, and characterized. The cell line will be available for further study of prostate disease.
- Published
- 1998
21. Paclitaxel-associated multimininucleation is permitted by the inhibition of caspase activation: a potential early step in drug resistance.
- Author
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Panvichian R, Orth K, Day ML, Day KC, Pilat MJ, and Pienta KJ
- Subjects
- Apoptosis drug effects, CDC2 Protein Kinase physiology, Enzyme Activation drug effects, Humans, Tumor Cells, Cultured, Antineoplastic Agents, Phytogenic pharmacology, Caspases physiology, Cell Nucleus drug effects, Drug Resistance, Neoplasm, Paclitaxel pharmacology
- Abstract
The chemotherapeutic agent paclitaxel disrupts microtubule dynamics causing mitotic arrest, which leads to cell death. However, in paclitaxel-resistant tumor cells, treatment with paclitaxel induces abnormal progression through prophase resulting in a multimininucleated phenotype. Multimininucleation and subsequent polyploidization have been correlated with paclitaxel resistance. Paclitaxel treatment of HeLa cells resulted in cell death via typical activation of the apoptotic machinery, whereas treatment of the relative paclitaxel-resistant prostate cancer cell line PC-3 induced an attenuated caspase activation and multimininucleation. The multimininucleated phenotype could be mimicked in HeLa cells treated with paclitaxel and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), a peptide caspase inhibitor. Interestingly, we observed no discernible difference in the pattern of cdc-2 kinase activation or phosphorylation of bcl-2-like proteins in PC-3 and HeLa cells treated with paclitaxel, which demonstrated that these molecules could not be used as indicators for the degree of caspase activation. In this study, we establish a connection between relative paclitaxel resistance, caspase attenuation/inhibition, and the multimininucleated phenotype.
- Published
- 1998
22. A model to study c-myc and v-H-ras induced prostate cancer progression in the Copenhagen rat.
- Author
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Lehr JE, Pienta KJ, Yamazaki K, and Pilat MJ
- Subjects
- Animals, Carcinogenicity Tests, Cell Division genetics, Cell Transplantation, Epithelial Cells pathology, Gene Expression Regulation, Neoplastic, Immunohistochemistry, Keratins metabolism, Male, Mice, Mice, Nude, Neoplasm Transplantation, Rats, Tumor Cells, Cultured, Genes, myc, Genes, ras, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Normal rat prostate epithelial cells (EPYP-1) were isolated and immortalized with the Simian Virus-40 (SV40) large T-antigen, and transfected with the v-H-ras (EPYP-1-ras) and the c-myc oncogenes (EPYP-1-myc; EPYP-1-ras-myc) to serially create a step-wise model of tumor development in the rat prostate. Pronounced morphological differences were observed between EPYP-1 and the transfected sublines. The immortal epithelial cells (EPYP-1) maintained a cuboidal shape with orderly, contact mediated inhibition of growth. Oncogene transfected clones displayed a spindle shaped structure with multiple overlapping pseudopodia. Transfected cells also exhibited a greater degree of dysplasia, loss of contact inhibition growth and the upregulation of an epithelial tumor marker, cytokeratin-18. All cells exhibited anchorage independent and androgen independent growth. In vivo, EPYP-1 cells and EPYP-1-myc and formed slowly growing non-metastatic, benign tumors in immune compromised mice, while EPYP-1-ras and EPYP-1-ras-myc transfected cells produced rapidly growing, malignant tumors in similar animals. This model augments the hypothesis that tumor initiation and progression can be caused by as few as two discrete genetic events. In addition, the "normal" rat prostate epithelium and transfected daughter cell lines represent a tumor model system with distinct, well understood genetic alterations: activation of ras and myc. This model will be a valuable addition to the current cell lines used in the investigation of prostate cancer carcinogenesis.
- Published
- 1998
23. Examination of the DNA methylation properties in nontumorigenic and tumorigenic breast epithelial cell lines.
- Author
-
Pilat MJ, Schwab ED, Yao KL, and Pienta KJ
- Subjects
- Breast cytology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Cell Line, Transformed, Chromatography, High Pressure Liquid, DNA isolation & purification, DNA metabolism, DNA Modification Methylases biosynthesis, DNA, Neoplasm isolation & purification, DNA, Neoplasm metabolism, Dinucleoside Phosphates analysis, Epithelial Cells cytology, Epithelial Cells metabolism, Female, Humans, Tumor Cells, Cultured, Breast metabolism, Breast Neoplasms genetics, DNA Methylation
- Abstract
Molecular changes in the progressive state of tumorigenesis often include altered patterns of DNA methylation. Utilizing a series of breast epithelial cell lines, the overall 5-methylcytosine content in genomic DNA demonstrated an overall decrease when comparing two malignant cell lines (MCF-7 and T47D) with a mortal cell line (MCF 1 2M) and several derivative cell lines of the immortalized MCF10 cultures (MCF10A,-2A, -5A, A1neoT2, and 139B6). Further investigation on the methylation status of these cells lines indicated no difference in DNA methyltransferase activity, both at a protein and mRNA levels, in the nontumorigenic cell lines examined while activity was 3-10 fold higher in the tumorigenic lines (MCF7, T47D, SkBr3, MB-MDA-231, -468). Examination of the CpG island in the 5' promoter region of the estrogen receptor gene indicates that this region is unmethylated in the mortal and immortal nontumorigenic lines as well as the tumorigenic lines examined, with the exception of the estrogen receptor negative breast cell line MB-MDA-468 which appears to be partially methylated at this site. These results indicate methylation of this CpG island does not account for the inactivation of the estrogen receptor gene in immortalized nontumorigenic breast cells, suggesting another mechanism of transcriptional inactivation of ER in this environment.
- Published
- 1998
24. The effect of amiloride on the metastatic properties of prostate cancer in the Dunning rat model.
- Author
-
Pilat MJ, Lehr JE, Quigley MM, and Pienta KJ
- Subjects
- Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Male, Neoplasm Invasiveness, Neoplasm Metastasis prevention & control, Prostatic Neoplasms pathology, Rats, Treatment Outcome, Tumor Cells, Cultured, Amiloride therapeutic use, Antineoplastic Agents therapeutic use, Prostatic Neoplasms drug therapy
- Abstract
Most deaths from cancer result from the metastatic spread of the disease. The antidiuretic amiloride has been shown to inhibit tumor growth and metastasis in several tumor systems. The object of these studies was to examine the effect on the in vitro and in vivo tumor growth and metastasis in the MatLyLu subline of the Dunning model of rat prostate cancer. In vitro, amiloride was found to have cytotoxic effects only at high concentrations, with an IC50 of 100 microg/ml. In vitro analysis of the ability of amiloride to inhibit invasion of MLL cells demonstrated that this drug was ineffective at all concentrations examined. In vivo, amiloride did not inhibit tumor growth or metastases development. Our studies demonstrate that amiloride does not have activity in this model of prostate cancer and suggest it may not be an appropriate therapy for the treatment of prostate cancer.
- Published
- 1998
- Full Text
- View/download PDF
25. Hormone resistance in prostate cancer.
- Author
-
Pilat MJ, Kamradt JM, and Pienta KJ
- Subjects
- Androgen Antagonists therapeutic use, Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Gene Expression, Humans, Male, Mice, Neoplasms, Hormone-Dependent drug therapy, Neoplasms, Hormone-Dependent radiotherapy, Palliative Care, Prostatic Neoplasms radiotherapy, Receptors, Androgen physiology, Salvage Therapy, Androgens physiology, Neoplasms, Hormone-Dependent pathology, Prostatic Neoplasms drug therapy
- Published
- 1998
- Full Text
- View/download PDF
26. Crystal structure, receptor binding, and gene regulation of 2- and 4-nitroestradiols.
- Author
-
Palomino E, Heeg MJ, Pilat MJ, Hafner M, Polin L, and Brooks SC
- Subjects
- Cell Line, Crystallography, X-Ray, Estradiol chemistry, Estradiol genetics, Humans, Molecular Structure, Transcriptional Activation, Estradiol metabolism, Gene Expression Regulation, Receptors, Estrogen metabolism
- Abstract
Crystal structures of 2-nitroestradiol and 4-nitroestradiol showed two different molecular conformations for each compound. The crystal structure of 4-nitroestradiol, as well as that of 4-nitroestrone-3-methyl ether, displayed a nitro group in which the oxygens were perpendicular to the aromatic ring and were this nonconjugating. On the other hand, the nitro-oxygens in 2-nitroestradiol were periplanar, with the aromatic ring permitting conjugating. This latter structure bound to estrogen receptor with 1/1000th the affinity of estradiol and was inefficient in gene stimulation. 4-Nitroestradiol possessed a relative binding affinity 40-fold greater than that of the 2-nitro derivative and actively induced responsive genes at a concentration of 10(-8) M. Whereas binding affinity can be explained primarily by polar groups and skeletal structure, gene induction may be linked to electronic induction in ring A that causes a requisite electronegative isopotential around the molecule. This electronegative characteristic also produces conformational changes in the alicyclic backbone of the estrogen, specially ring B, which could interfere with the molecular fit of the nitroestradiols with estrogen receptor.
- Published
- 1996
- Full Text
- View/download PDF
27. The effects of omega-3 and omega-6 fatty acids on in vitro prostate cancer growth.
- Author
-
Pandalai PK, Pilat MJ, Yamazaki K, Naik H, and Pienta KJ
- Subjects
- Animals, Cell Division drug effects, Drug Screening Assays, Antitumor, Fatty Acids, Omega-3 metabolism, Fatty Acids, Omega-6, Fatty Acids, Unsaturated metabolism, Humans, Linolenic Acids pharmacology, Male, Prostatic Neoplasms drug therapy, Rats, Fatty Acids, Omega-3 pharmacology, Fatty Acids, Unsaturated pharmacology, Prostatic Neoplasms pathology
- Abstract
Dietary intake of essential fatty acids (EFA) may play a role in prostate cancer cell proliferation. Epidemiological studies have demonstrated that men whose dietary intake is high in omega-3 fatty acid (FA) composition have a lower incidence of clinical prostate cancer, suggesting that external factors such as diet may play an important role in development and growth of prostate cancer. Furthermore, in prostate cancer cell lines, omega-6 and omega-3 FAs have demonstrated promotional and inhibitory effects respectively. To investigate the effects of dietary fats on nontumorigenic prostate cell growth we conducted in vitro studies with human metastatic PC-3, LNCaP and TSU prostate cell lines, the rat metastatic Mat-Ly-Lu cell line and rat non-metastatic epithelial cell lines EPYP1, EPYP2 and EPYP3. Cell lines were treated with linoleic acid (LA), an omega-6 FA (n-6), as well as linolenic (LLA) and eicosapentaenoic (EPA) acids, which are both omega-3 FAs (n-3). All cell lines were treated with 10% and 0.5% serum supplemented media plus fatty acid for comparison. Our results demonstrate that linoleic acid(n-6) has promotional effects at doses of 1-100ng/ml in all cell lines with the exception of EPYPl. Experiments with linolenic acid (n-3) demonstrated consistent growth promotion in all cell lines examined with the exception of the EPYP2 cell line in which there was no significant effect. EPA had no effect in culture media supplemented with 10% serum, while in media containing 0.5% serum this FA demonstrated significant promotion in all human lines. Previous studies have indicated that EPA should inhibit human prostate cancer growth in vitro, however our results demonstrated promotion at low concentrations (lng/ml). At higher concentrations, EPA did inhibit prostate cell growth. These data indicate low levels of dietary fat, regardless of composition, may play a role in prostate cancer proliferation and could be an avenue for therapeutic intervention.
- Published
- 1996
28. Reverse transcriptase- polymerase chain reaction (RT-PCR) to detect prostate cancer micrometastasis in the blood.
- Author
-
Yao KL, Pilat MJ, and Pienta KJ
- Subjects
- Forecasting, Humans, Male, Neoplasm Metastasis, Prostatic Neoplasms blood, Prostatic Neoplasms pathology, RNA-Directed DNA Polymerase, Sensitivity and Specificity, Biomarkers, Tumor blood, Polymerase Chain Reaction methods, Prostatic Neoplasms genetics
- Published
- 1996
- Full Text
- View/download PDF
29. Characterization of the estrogen receptor transfected MCF10A breast cell line 139B6.
- Author
-
Pilat MJ, Christman JK, and Brooks SC
- Subjects
- Actins genetics, Breast Neoplasms etiology, Cathepsin D genetics, Cell Line, Estradiol pharmacology, Female, Humans, RNA, Messenger analysis, Receptors, Estrogen analysis, Receptors, Estrogen physiology, Transfection, Breast metabolism, Receptors, Estrogen genetics
- Abstract
There has been increasing evidence which suggests that abnormal expression of the estrogen receptor (ER) protein in nonmalignant breast tissue may be important in the carcinogenic process. To examine the effects of ER expression in immortalized nonmalignant mammary epithelial cells, an expression vector containing human ER cDNA was transfected into the ER negative human breast cells, MCF10A. Characterization of a clone stably expressing ER, 139B6, provided evidence for the regulated synthesis of a functional ER capable of binding estradiol-17 beta (E2) and undergoing processing. Expression of the ER gene did not enable E2 to stimulate endogenous genes [progesterone receptor (PgR), pS2, cathepsin D and TGF alpha] which normally respond to estrogens in breast cancer cells. The ER in 139B6 cells was, however, capable of inducing expression of an ERE-regulated reporter gene, indicating its ability to interact with transcriptional machinery. Furthermore, cultures in log growth displayed a slight increase in doubling time in the presence of E2. These results indicate that ER expression alone is not sufficient to induce a transformed phenotype. Thus, the 139B6 cell line should provide a new model for determining what additional changes lead to increased growth potential in response to E2 and for exploring how E2 itself may help bring about changes leading to progression of preneoplastic breast epithelial cells.
- Published
- 1996
- Full Text
- View/download PDF
30. Differential induction of pS2 and cathepsin D mRNAs by structurally altered estrogens.
- Author
-
Pilat MJ, Hafner MS, Kral LG, and Brooks SC
- Subjects
- Base Sequence, DNA, Estradiol chemistry, Gene Expression, Humans, Molecular Sequence Data, Molecular Structure, RNA, Messenger drug effects, Transcription, Genetic, Trefoil Factor-1, Tumor Cells, Cultured, Tumor Suppressor Proteins, Cathepsin D genetics, Estradiol pharmacology, Neoplasm Proteins genetics, Proteins, RNA, Messenger biosynthesis
- Abstract
The influence of structural alterations to the estradiol-17 beta (E2) molecule on the induction of pS2 and Cathepsin D (Cath D) mRNAs has been examined by Northern analysis of RNA extracted from MCF-7 cells. Exposure of cultures to estratriene did not affect the level of expression of these estrogen-responsive genes. Addition of one hydroxyl group to estratriene at either of the hydroxylated positions of E2 (3-phenolic or 17 beta) yielded monohydroxyestrogens which stimulated the synthesis of Cath D and pS2 mRNAs to a level comparable to that induced by 10(-10) M E2 and displayed a decrease in activity at the higher concentrations (10(-8) - 10(-7) M) similar to that of the parent estrogen. Both of these genes were induced maximally by estrogens with D-ring alterations. Movement of the phenolic hydroxyl group of E2 to other positions on the A-ring yielded ligands which were highly discriminatory in the induction of these messages. 1-Hydroxyestratrien-17 beta-ol was capable of stimulating maximal synthesis of both pS2 and Cath D mRNAs when added to cultures of MCF-7 cells at a concentration of 10(-8) M. Placement of the phenolic hydroxyl at position 4 greatly diminished the induction of these two estrogen-responsive genes. On the other hand, positioning the A-ring hydroxyl group on carbon 2 yielded a ligand which brought about the induction of one gene (pS2) but was marginally effective in the induction of Cath D mRNA synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1993
- Full Text
- View/download PDF
31. The effect of particle size distribution on light transmittance measurement.
- Author
-
Ensor DS and Pilat MJ
- Subjects
- Mathematics, Models, Theoretical, Optics and Photonics, Absorption, Aerosols, Light
- Published
- 1971
- Full Text
- View/download PDF
32. Calculation of smoke plume opacity from particulate air pollutant properties.
- Author
-
Ensor DS and Pilat MJ
- Subjects
- Mathematics, Methods, Smoke analysis, Air Pollution analysis
- Published
- 1971
- Full Text
- View/download PDF
33. Application of gas-aerosol adsorption data to the selection of air quality standards.
- Author
-
Pilat MJ
- Subjects
- Adsorption, Aerosols, Drug Synergism, Gases, Air, Air Pollution
- Published
- 1968
- Full Text
- View/download PDF
34. Cascade impactor for sizing particulates in emission sources.
- Author
-
Pilat MJ, Ensor DS, and Bosch JC
- Subjects
- Aerosols, Evaluation Studies as Topic, Kinetics, Air Pollution, Equipment and Supplies
- Published
- 1971
- Full Text
- View/download PDF
35. Size distribution of atmospheric giant particles.
- Author
-
Noll KE and Pilat MJ
- Subjects
- Aerosols, Washington, Air Pollution
- Published
- 1971
- Full Text
- View/download PDF
36. Optical efficiency factors for concentric spheres.
- Author
-
Pilat MJ
- Abstract
Extinction, scattering, and absorption efficiency factors for a concentric sphere of a nonlight absorbing nucleus (m = 1.5) and an absorbing shell (m = 1.95 - 0.66i) were calculated based on the theory of Aden and Kerker. For small size parameters (v < 1), the magnitude of the extinction efficiency factor is markedly affected by the shell thickness. An approximating equation, based on the Rayleigh light scattering equation, is presented which relates the increase of the extinction efficiency factor of an absorbing sphere over the extinction efficiency factor of a nonabsorbing sphere to the pertinent variables (refractive index and size parameter).
- Published
- 1967
- Full Text
- View/download PDF
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