| Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer. | |
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MedLine Citation:
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PMID: 22547163 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). PATIENTS AND METHODS: In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients' biopsies were collected pre-treatment and on Cycle (C) 1, Day (D) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels. Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. RESULTS: Salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. Salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. CONCLUSION: The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA. |
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Authors:
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Daniel Laheru; Preeti Shah; N V Rajeshkumar; Florencia McAllister; Gretchen Taylor; Howard Goldsweig; Dung T Le; Ross Donehower; Antonio Jimeno; Sheila Linden; Ming Zhao; Dongweon Song; Michelle A Rudek; Manuel Hidalgo |
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Publication Detail:
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Type: Clinical Trial, Phase I; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-05-01 |
Journal Detail:
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Title: Investigational new drugs Volume: 30 ISSN: 1573-0646 ISO Abbreviation: Invest New Drugs Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-10-31 Completed Date: 2013-04-04 Revised Date: 2013-04-18 |
Medline Journal Info:
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Nlm Unique ID: 8309330 Medline TA: Invest New Drugs Country: United States |
Other Details:
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Languages: eng Pagination: 2391-9 Citation Subset: IM |
Affiliation:
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Department of Medical Oncology, Skip Viragh Center for Pancreatic Cancer Research and Patient Care, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting- Blaustein Cancer Research Building, Room 4M09, Baltimore, MD 21231, USA. laherda@jhmi.edu |
| Data Bank Information | |
Bank Name/Acc. No.:
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ClinicalTrials.gov/NCT00867230 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenocarcinoma
/
drug therapy*,
metabolism,
pathology Adult Aged Aged, 80 and over Animals Antineoplastic Agents / administration & dosage, blood, pharmacokinetics Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics, therapeutic use* Deoxycytidine / administration & dosage, analogs & derivatives, pharmacokinetics Farnesol / administration & dosage, analogs & derivatives, blood, pharmacokinetics Female Humans Male Mice Mice, Nude Middle Aged Mitogen-Activated Protein Kinases / metabolism Pancreatic Neoplasms / drug therapy*, metabolism, pathology Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins c-akt / metabolism Salicylates / administration & dosage, blood, pharmacokinetics Tumor Burden / drug effects Xenograft Model Antitumor Assays ras Proteins / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P30 CA006973/CA/NCI NIH HHS; P30 CA006973/CA/NCI NIH HHS; R21 CA126058/CA/NCI NIH HHS; UL1 RR 025005/RR/NCRR NIH HHS; UL1 RR025005/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/KRAS protein, human; 0/Proto-Oncogene Proteins; 0/Salicylates; 0/farnesylthiosalicylic acid; 103882-84-4/gemcitabine; 4602-84-0/Farnesol; 951-77-9/Deoxycytidine; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.6.5.2/ras Proteins |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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