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| 1 | Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1α in advanced hepatocellular carcinoma显示文摘BACKGROUND Hypoxia-inducible factor 1α(HIF-1α) is a gene that regulates tumor survival,neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma(HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC.AIM To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179.METHODS In the preclinical study of RO7070179 in a HCC xenograft model, the mice wereseparated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment,received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179.RESULTS Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1 b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies(each biopsy was divided into 2 specimens, the tip and the root).CONCLUSION RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity.This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either m RNA level or DCE-MRI within 1 cycle of therapy. | Jennifer Wu Merly Contratto Krishna P Shanbhogue Gulam A Manji Bert H O'Neil Anne Noonan Robert Tudor Ray Lee | 2019 | World Journal of Clinical Oncology2019，10，3： | 2 |
| 2 | New insights into BDNF function in depression and anxiety显示文摘 | MARTINOWICH K MANJI H LU B | 2007 | Nat Neurosci2007，1，9： | 1 |
| 3 | The role of AMPA receptor modulation in the treatment of neuropsychiatric diseases显示文摘 | Zarate C A Manji H K | | 0，，01： | 1 |
| 4 | Endotoxin reduces maximal oxygen consumption in hepatocytes independent of any hypoxic insult显示文摘 | Rosser DM Manji M Cooksley H | | 0，，： | 1 |
| 5 | Status dystonicus:the syndrome and its management显示文摘 | Manji H Howard RS Miller DH | 1998 | Brain1998，1212，： | 1 |
| 6 | Lithium up-regulates the cyto- protective protein Bcl-2 in the CNS in vivo: a role for neurotro- phic and neuroprotective effects in manic depressive illness显示文摘 | Manji H K Moore G J Chen G | 2000 | J Clin Psychiatry2000，61，： | 1 |
| 7 | Toxic neuropathy显示文摘 | Manji H | 2011 | Curr Opin Neurol2011，24，5： | 1 |
| 8 | New insights into BDNF function in depression and anxiety 显示文摘 | Martinowich K Manji H Lu B | 2007 | Nat Neurosci2007，10，9： | 1 |
| 9 | A novel mutation in the nerve-specific 5'UTR of the GJB1 gene causes X- linked Charcot- Marie- Tooth disease 显示文摘 | Murphy SM Polke J Manji H | 2011 | J Peripher Nerv Syst2011，16，： | 1 |
| 10 | New insights into BDNF function in depression and anxiety显示文摘 | Martinowich K Manji H Lu B | 2007 | Nat Neurosci2007，10，9： | 1 |
| 11 | OL, mic exposure of C6 cells to desipramine desensitzes beta- adrmoceptors, but increase KL/KH ration显示文摘 | Manji H K | 1991 | Eur J Pharmacol1991，，206： | 1 |
| 12 | Signaling: cellular insights into the pathophysiology of bipolar disorder 显示文摘 | H Lenox RH | 1999 | Biol Psychiatry1999，46，： | 1 |
| 13 | Extended usage of xylanase enzyme to enhance the bleaching of softwood kraft pulp显示文摘 | Manji A H | 2006 | Tappi J2006，5，1： | 1 |
| 14 | New insights into BDNF function in dep-ression and anxiety显示文摘 | Martinowich K Manji H Lu B | 2007 | Nat neurosci2007，10，9： | 1 |
| 15 | Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents:therapeutic implications显示文摘 | Manji H K Bebchuk J M Moore G J | 1999 | J Clin Psychiatry1999，60，2： | 1 |
| 16 | New insights into BDNF function in depression and anxiety显示文摘 | Martinowich K Manji H Lu B | | 0，，09： | 1 |
| 17 | The cellular neurobiology of depression显示文摘 | MANJI H K DREVETS W C CHARNEY D S | 2001 | Nat Med2001，7，5： | 1 |
| 18 | Novel drugs and therapeutic targets for severe mood disorders显示文摘 | MATHEW S J MANJI H K CHARNEY D S | 2008 | Neuropsychopharmacology2008，33，9： | 1 |
| 19 | Genetic markers of suicidal ideation emerging during citalopram treatment of major depression显示文摘 | Laje G Paddock S Manji H | 2007 | Am J Psychiatry2007，164，： | 1 |
| 20 | Signaling: cellular insights into the patho- physiology of bipolar disorder显示文摘 | Manji H Lenox RH | 1999 | Biol Psychiatry1999，46，10： | 1 |
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