WO2012049439A1 - Traitement du cancer/inhibition de métastases - Google Patents

Traitement du cancer/inhibition de métastases Download PDF

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Publication number
WO2012049439A1
WO2012049439A1 PCT/GB2010/001906 GB2010001906W WO2012049439A1 WO 2012049439 A1 WO2012049439 A1 WO 2012049439A1 GB 2010001906 W GB2010001906 W GB 2010001906W WO 2012049439 A1 WO2012049439 A1 WO 2012049439A1
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cells
ranolazine
hypoxia
riluzole
under
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PCT/GB2010/001906
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English (en)
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Mujstafa Bilgin Ali Djamgoz
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Imperial Innovations Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • Progression of metastatic cancer is generally considered as comprising five phases, as follows:
  • Proliferation namely increase in the number of cancer cells to form a primary tumour of increasing size.
  • Ranolazine and riluzole are both known for the treatment of cardiac conditions. It is further known that each of them differentially affects the magnitude of the transient and persistent parts of the VGSC currents, the effect being in a dose- dependent manner. High doses of these drugs completely block the VGSC currents. Doses of these, or any other drug, which would have the effect of completely blocking VGSC currents in cardiac tissue would be fatal to the patient because the heart requires these currents in order to carry out its function.
  • metastatic behaviour is inhibited or reduced in cancer by administering ranolazine or riluzole, or another substance, at an appropriate dosage to inhibit or reduce the persistent pan ot tne VGSC current without blocking, or at least without completely blocking, the transient part.
  • ranolazine or riluzole or another substance
  • metastasis in cancer may be inhibited or reduced in this way without having to administer doses of drugs which would be fatal.
  • riluzole or ranolazine
  • riluzole is administered at a dosage level which will inhibit the persistent part of the VGSC current without blocking or completely blocking the transient part and without directly causing cell death.
  • metastatic behaviour may be inhibited or reduced without causing cell death may be a significant advantage since recent work has suggested that treating cancer by killing the cells may, at least in some cases, be counterproductive in the sense that whilst there will be a short term benefit, the cancer will nevertheless return and proliferate.
  • the invention provides the possibility of inhibiting or preventing metastatic behaviour without the potential problems which may arise from actually killing the cancer cells.
  • ranolazine or riluzole at various dosage levels can increase the adhesiveness of the cells and/or reduce one or more of the lateral motility, transverse migration and invasiveness of the cells.
  • a compound, composition or other substance which is used or intended to be used, in an appropriate dose, to inhibit or reduce the persistent part of the VGSC in metastatic cancer cells whilst leaving the transient part unaffected or only partially reduced, for inhibiting or reducing metastasis, preferably without directly causing cell death.
  • Figure 1 is a schematic representation of a timeline for cancer progression from primary tumorigenesis to formation of secondary tumours (metastases);
  • Figure 3 (a) is a sketch illustrating the current through VGSC's, showing both the transient and persistent parts of the current and also showing the current under both normoxic and hypoxic conditions;
  • Figure 3 (b) is a sketch illustrating the effect of differing concentrations of ranolazine on the VGSC current components
  • Figure 3 (c) is a sketch illustrating the effect of differing concentrations of riluzole on the VGSC current components
  • Figure 4 is a schematic illustration of a cell adhesion measuring apparaius lor measuring the adhesion of cells singly;
  • Figure 5 is a schematic illustration of apparatus used for measuring the lateral motility of cells;
  • view (a) is a plan view from above of a cell culture dish containing a semi-confluent layer of cells;
  • view (b) is a schematic side sectional view of the plated cells;
  • Figure 6 is a schematic side sectional view of apparatus used for measuring the transverse migration of cells
  • Figure 7 is a schematic side sectional view of apparatus used for measuring the invasiveness of cells
  • Figure 1 1 is a histogram showing the dose-dependent effect of ranolazine on the transverse migration of MDA-MB-231 cells under normoxia and hypoxia;
  • Figure 13 is a series of histograms showing the dose-dependent effect of ranolazine on the invasiveness of MDA-MB-231 cells that have been pre-treated with ranolazine for different durations under hypoxia;
  • view (a) is a histogram showing the effect of 5 ⁇ ranolazine for cells treated only for 24 hours during the assay (i.e., no pre-treatment);
  • view (b) is a histogram showing the effect of 5 ⁇ ranolazine for cells pre-treated with the drug for 72 hours;
  • view (c) is a histogram showing the effect of 25 ⁇ ranolazine for cells treated only for 24 hours during the assay (i.e., no pre-treatment);
  • view (d) is a histogram showing the effect of 5 ⁇ ranolazine for cells pre-treated with the drug for 48 hours, and
  • view (e) is a histogram showing the effect of 5 ⁇ ranolazine for cells pre-treated with the drug for
  • Figure 16 is a histogram showing the dose-dependent effect of ranolazine on the transverse migration of rat strongly metastatic prostate cancer Mat-LyLu cells under normoxia and hypoxia;
  • Figure 17 is a histogram showing the dose-dependent effect of ranolazine on the invasiveness of Mat-LyLu cells under normoxia and hypoxia;
  • Figure 1 8 is a histogram showing the lack of effect of ranolazine on the proliferation of Mat-LyLu cells under normoxia and hypoxia;
  • Figure 19 is a histogram showing the lack of effect of ranolazine on the viability of Mat-LyLu cells under normoxia and hypoxia;
  • Figure 20 is a histogram showing the dose-dependent effect of riluzole on the lateral motility of MDA-MB-23 1 cells under normoxia and hypoxia;
  • Figure 21 is a histogram showing the dose-dependent effect of riluzole on the transverse migration of MDA-MB-231 cells under normoxia ana nypoxia;
  • Figure 22 is a histogram showing the dose-dependent effect of riluzole on the invasiveness of MDA-MB-231 cells under normoxia and hypoxia;
  • Figure 23 is a pair of histograms showing the comparative effect on the invasiveness of MDA-MB-23 1 pre -treated with 5 ⁇ riluzole for >72 hours under hypoxia;
  • view (a) is a histogram showing the effect of 5 ⁇ riluzole for cells treated only for 24 hours during the assay (i.e., no pre-treatment);
  • view (b) is a histogram showing the effect of 5 ⁇ riluzole for cells pre-treated with the drug for 72 hours;
  • Figure 24 is a histogram showing the dose-dependent effect of riluzole on the growth of MDA-MB-231 cells under normoxia
  • Figure 25 is a histogram showing the dose-dependent effect of riluzole on the viability of MDA-MB-23 1 cells under normoxia
  • Figure 26 is a histogram showing the dose-dependent effect of riluzole on the invasiveness of Mat-LyLu cells under normoxia and hypoxia;
  • timeline 101 is a representation of three successive phases in the development of a tumour, namely a phase 102 prior to the development of cancerous cells, a phase 103 following phase 102 during which the genesis of cancer cells takes place and a phase 104, following phase 103, during which the cancerous cells proliferate so as to form a growing tumour.
  • the proliferation phase 104 may begin soon after the genesis phase 103 begins.
  • reference number 200 represents a portion of an organ such as a breast or a prostate. Healthy cells 201 of the breast or prostate are shown as supported on a basement membrane 202 and surrounding a cancerous tumour 203, which is assumed to have gone through the genesis phase 103 and into the proliferation phase 104.
  • Certain cells 204 of the cancerous tumour 202 are shown as detaching from the tumour 203 and passing through a degraded region 202a of the basement membrane 202 into adjacent region 205 of the organ containing the tumour 203, which region may comprise mainly collagen fibres.
  • Cancer cells 206 which have become detached from the tumour and have passed through the basement membrane 202, are shown passing through the region 205 towards a blood vessel 207.
  • a cancerous cell 208 is shown migrating through the wall of the blood vessel 207 into the bloodstream 209.
  • Reference number 214 represents dormant cancerous cells which have simply settled in or adjacent to the wall of the blood vessel 207.
  • a known drug such as ranolazine or riluzole, previously used for inhibiting or reducing the persistent part of the VGSC current without eliminating the peak part is used for inhibiting or reducing metastatic behaviour in cancer, especially breast or prostate cancer.
  • Curve 304 shows a pulse of VGSC current under hypoxic conditions.
  • the peak part 305 of the current under hypoxic conditions is smaller than the peak part 301 under normoxic conditions, but the persistent part 306 under hypoxic conditions is greater than the persistent part 303 under normoxic conditions.
  • the difference between these curves under hypoxic and normoxic conditions is relevant, as will become clear from consideration of experimental results which are described below, because many of the cells in a cancerous tumour are hypoxic due to their partial isolation, by other cancerous cells, from the blood circulation system.
  • FIG. 3(c) A similar effect with increasing doses of riluzole can be seen from Figure 3(c), in which solid line curve 308 represents the magnitude of the transient part of the current plotted against increasing doses of riluzole and the broken line curve 310 represents the magnitude of the persistent part of the current.
  • Therapeutically acceptable doses of riluzole for human beings include the range from 1 ⁇ to 10 ⁇ .
  • the reduction in the magnitude of the persistent part of the current is substantially more than the reduction in the magnitude of the transient part.
  • the curves of Figure 3(b) and 3(c) are sketches to illustrate the currents rather than being based upon the specific experimental results.
  • FIG 4 is a schematic illustration of the single-cell adhesion measurement apparatus (SCAMA) first described in the paper by Palmer et al. (2008).
  • SCAMA single-cell adhesion measurement apparatus
  • Human breast cancer cells from the MDA-MB-231 cell line were plated at a density of 2.5 x 10 4 cells/ml and left to settle in a cell culture dish 401 for 48 hours prior to measurements. Medium was removed and 2 ml of the drug under study was applied for 10 minutes. Adhesion was measured using a glass micropipette 402 connected to a vacuum pump 403 via plastic tubing 404. The tip of the micropipette was drawn to about 20pm (range, 17-24 ⁇ ) tip diameter. The vacuum pump was used to create negative pressure inside a reservoir 405 so that the negative pressure could be applied to the tip of the micropipette by pressing the thumb to the open end of a sealable T-piece 406. The cells were observed using a 20* microscope objective 407 under the illumination of a lamp 408. The pressure was measured using a digital manometer 409 connected to a computer 410 via a RS232 cable 41 1.
  • the micropipette 402 was positioned on the periphery of a single cell.
  • the negative pressure was applied to the cell under investigation and, at the exact moment that the cell was observed to be detached from the culture dish 401 , the pressure was released by opening the T-piece 406.
  • the negative pressure required to detach the cell was recorded on the computer as a pressure spike.
  • the peak of the spike (“detachment negative pressure" (DNP)) was used as a measure of the cell's adhesiveness. Using this technique, several recordings could be made from a single dish within minutes.
  • hypoxia was chemically induced by application of hydrogen peroxide (1-500 ⁇ ) for the final 24 hours before testing.
  • the pharmacological agent was washed off, fresh medium was added and the plate was incubated for a further 10 minutes prior to re-measurement. Each treatment was carried out on at least two dishes of cells, at least 100 cells per dish were measured, and the experiment was repeated three times (with corresponding controls).
  • Figure 5(a) is a plan view from above of a cell culture dish 501 having a semi-confluent layer of cells 502 on its surface, the cells being in an aqueous medium 503.
  • FIG. 6 shows a schematic side sectional view of a migration chamber 601 having a Transwell® insert 602 separating the chamber into two sections which, for convenience, will be referred to as the upper 603 and lower 604 sections of the chamber.
  • the insert 602 has a migration filter membrane 605 in its base with 8 ⁇ pores 606 extending therethrough.
  • Cells 607 were plated at a density of 2 x 10 4 /ml on the filter membrane 605 and placed under a growth medium 608 containing 1 % foetal bovine serum (FBS).
  • FBS foetal bovine serum
  • a chemotactic gradient was created across the filter membrane 605 by placing growth medium 609 containing 10% FBS in the lower section 604 of the chamber.
  • Figure 7 is a schematic side sectional view of an invasion chamber 701 having a Transwell® insert 702 separating the chamber into upper 703 and lower 704 sections.
  • the insert 702 has a migration filter membrane 705 in its base with 8 ⁇ pores 706 extending therethrough.
  • a layer 707 of MatrigelTM is shown coating the filter membrane 705.
  • Cells 708 were plated at a density of 2 x 10 4 /ml onto the MatrigelTM layer 707 in 24-well plates (Becton-Dickinson) according to the manufacturers' instructions. 50 ⁇ MatrigelTM was seeded at a 1 :7 dilution ( 10 mg/ml stock) onto the inserts and left overnight. Prior to seeding with the cells the MatrigelTM was rehydrated using medium with no additions. This medium was removed prior to seeding the cells.
  • the number of cells invading to the underside of the insert 702 was determined using crystal violet staining. Invaded cells were fixed for 1 5 minutes with ice- cold methanol. Then 0.5 % crystal violet (in 25 % methanol) was added for 1 5 minutes. The inserts were swabbed again and then washed in water and allowed to dry. Cells were then counted using twelve separate fields of view per insert (x200 magnification). If the difference in the average number of cells invading the two control inserts was more than 40 %, the experiment was rejected.
  • hypoxia was induced chemically by application of hydrogen peroxide (1 - 500 ⁇ ) for 24 hours.
  • Human breast cancer cells from the MDA-MB-231 cell line were plated in a cell culture dish at a density of 2.5 x 10 4 cells/ml and left to settle for 48 hours prior to measurements.
  • the cells were subjected to hydrogen peroxide concentrations of ⁇ ⁇ , ⁇ and ⁇ ⁇ and the negative pressure required to detach cells from the bottom of the cell culture dish was measured. At each concentration of hydrogen peroxide, measurements were taken on at least two dishes of cells for at least 100 cells per dish. The experiment was repeated three times and the measurements of detachment negative pressure are presented in Figure 8 as means ⁇ SEM.
  • the data point 801 shows that cells exposed to hydrogen peroxide at a concentration of ⁇ ⁇ had a mean detachment negative pressure of approximately -9%
  • data point 802 shows that cells exposed to hydrogen peroxide at a concentration of 10 ⁇ had a mean detachment negative pressure of approximately -14%
  • data point 803 shows that cells exposed to hydrogen peroxide at a concentration of ⁇ ⁇ had a mean detachment negative pressure of approximately -20%.
  • Single-cell adhesion was measured using the technique described above and illustrated in Figure 4 for human MDA-MB-231 cells exposed to different concentrations of ranolazine and under normoxic and hypoxic conditions.
  • Ranolazine increased the substrate adhesion of cells under normoxia in a dose dependent manner.
  • the dose-dependent increase in the adhesion of cells was even more marked under hypoxia - See Figure 9.
  • the vertical axis represents a measure of the adhesion of cells.
  • Block 1 105 is the result obtained for the control sample (without drug) for MDA- MB-231 cells under conditions of hypoxia. From a comparison of blocks 1 101 and 1 105 it can be seen that hypoxia increased transverse migration.
  • the vertical axis represents relative values for invasiveness of the measured cells, with a reference point for nonnal invasiveness being represented by the control sample (block 1201 ) of MDA-MB-23 1 cells under normoxia and without drug, normalised to 100%.
  • the set of results for experiments conducted under normoxia is plotted on the left- hand side and the set of results for experiments conducted under hypoxia is plotted on the right-hand side.
  • the concentration of ranolazine used increases from left to right.
  • Example 6 Effects of ranolazine on the invasiveness of MDA-MB-231 cells under normoxia and hypoxia pre-treatment of the cells
  • block 1301 represents the invasiveness result obtained under control conditions (no drug) for cells invading over the 24 hour duration of the assay (i.e., effectively no pre-treatment was used).
  • Block 1302 represents the invasiveness result for cells treated with 5 ⁇ ranolazine and invading over the 24 hour duration of the assay (no pre-treatment). The effect on invasiveness of cells treated with 5 ⁇ ranolazine was not statistically significant.
  • block 1303 represents the invasiveness result obtained under control conditions (no drug) for cells invading over the 24 hour duration of the assay (i.e., effectively no pre-treatment was used).
  • Block 1304 represents the invasiveness result for cells pre-treated with 5 ⁇ ranolazine for 72 hours and invading over the 24 hour duration of the assay. There was a very significant reduction in the invasiveness of cells pre-treated with 5 ⁇ ranolazine for 72 hours.
  • Figure 13(c) to (e) show the effect of 25 ⁇ ranolazine (ran) on invasion of MDA-MB-231 cells under conditions of hypoxia in vitro.
  • the histograms indicate the number of MDA-MB-23 1 cells invading following treatment with 25 ⁇ ranolazine for different periods in comparison to corresponding control conditions
  • block 1305 represents the invasiveness result obtained under control conditions (no drug) for cells invading over the 24 hour duration of the assay (i.e., effectively no pre-treatment was used).
  • Block 1306 represents the invasiveness result for cells treated with 25 ⁇ ranolazine and invading over the 24 hour duration of the assay (no pre-treatment). Cells treated with 5 ⁇ ranolazine were less invasive than untreated cells in a statistically significant way.
  • block 1307 represents the invasiveness result obtained under control conditions for cells maintained for 24 hours without drug and invading over the following 24 hours prior to measurement.
  • Block 1308 represents the invasiveness result for cells pre-treated for 24 hours with 25 ⁇ ranolazine and invading over the following 24 hours prior to measurement.
  • Cells pre-treated with 25 ⁇ ranolazine for 24 hours before commencing the 24 hour long assay were significantly less invasive than untreated cells.
  • block 309 represents the invasiveness result obtained under control conditions for cells maintained for 48 hours without drug and invading over the following 24 hours prior to measurement.
  • Block 1310 represents the invasiveness result for cells pre-treated for 48 hours with 25 ⁇ ranolazine and invading over the following 24 hours prior to measurement. Cells pre-treated with 25 ⁇ ranolazine for 48 hours before commencing the 24 hour long assay were again significantly less invasive than untreated cells.
  • the number of "cells invading" in the histograms of Figures 13(c) to (e) denotes the average of cell number counted in 24 randomly chosen fields of view from two separate experiments.
  • pre-treatment of the cells with ranolazine led to a statistically significant reduction in their invasiveness.
  • Such pre-treatment of the cells with the drug in an in vitro test is considered to be representative of in vivo treatment, where the patient receives a continual therapeutic dose of the drug.
  • Example 8 Effects of ranolazine on the viability of MDA-MB-231 cells under normoxia
  • Rat prostate cancer cells from the Mat-LyLu cell line were treated with different concentrations of ranolazine under normoxia, and hypoxia.
  • the migration of the cells was measured after treating them with no drug (control) and ranolazine at concentrations of 20 ⁇ , 50 ⁇ and 300 ⁇ .
  • the results are shown in Figure 16 as blocks 1601, 1603, 1604 and 1605, respectively.
  • Increasing the concentration of ranolazine reduced the transverse migration of the cells at concentrations of ranolazine of 20 ⁇ and 50 ⁇ .
  • the effect of ranolazine on transverse migration at a concentration of 300 ⁇ was not statistically significant.
  • Figure 1 7 also includes results for an additional pair of controls, labelled in the drawing as blocks 1 702 and 1707.
  • additional controls cells were exposed to the toxin tetrodotoxin (TTX) whose binding site is located at the pore opening of the VGSC.
  • the TTX measurement is a positive control confirming that sodium channel activity is indeed contributing (potentiating) the metastatic cell behaviour under investigation.
  • TTX toxin tetrodotoxin
  • the vertical axis represents the total cell number in a plated sample, with a reference point for normal growth being represented by the control sample (blocks 1801 ) of Mat-LyLu cells under normoxia and without drug normalised to 100%.
  • the control sample blocks 1801
  • the set of results for experiments conducted under normoxia is plotted on the left-hand side and the search of results for experiments conducted under hypoxia is plotted on the right-hand side.
  • the concentration of ranolazine used increases from left to right. Note that the term "growth" includes cell proliferation and cell death.
  • block 2601 shows the invasion index for the control sample of Mat-LyLu cells under normoxia and without drug, normalised to 100%.
  • Block 2604 is the corresponding control sample (without drug) for Mat-LyLu cells under conditions of hypoxia. From a comparison of blocks 2601 and 2604 it can be seen that hypoxia increased invasion in a statistically significant way.

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Abstract

L'invention concerne des substances et des méthodes de réduction ou de prévention d'un comportement métastatique dans une cellule cancéreuse exprimant les canaux sodiques VGSC, au moyen d'au moins une réduction partielle de la partie persistante du courant des canaux sodiques sensibles à la tension sans éliminer la partie transitoire. L'inhibition des comportements cellulaires métastatiques tels que la capacité de détachement, la motilité latérale, la migration transverse et l'invasivité est démontrée à l'aide des médicaments connus que sont la ranolazine et le riluzole.
PCT/GB2010/001906 2010-10-13 2010-10-13 Traitement du cancer/inhibition de métastases WO2012049439A1 (fr)

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Cited By (2)

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WO2013037800A1 (fr) * 2011-09-13 2013-03-21 Pierre Fabre Medicament Utilisation de la 3-(r)-[3-(2-methoxyphenylthio)-2-(s)-methyl-propyl]amino-3,4-dihydro-2h-1,5-benzoxathiepine pour le traitement du cancer et en particulier pour la prevention et/ou le traitement des metastases cancereuses
WO2018146313A1 (fr) * 2017-02-10 2018-08-16 Celex Gmbh Traitement du cancer et suppression des métastases

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WO2013037800A1 (fr) * 2011-09-13 2013-03-21 Pierre Fabre Medicament Utilisation de la 3-(r)-[3-(2-methoxyphenylthio)-2-(s)-methyl-propyl]amino-3,4-dihydro-2h-1,5-benzoxathiepine pour le traitement du cancer et en particulier pour la prevention et/ou le traitement des metastases cancereuses
CN103764142A (zh) * 2011-09-13 2014-04-30 皮埃尔法布雷医药公司 3-(r)-[3-(2-甲氧基苯硫基)-2-(s)-甲基-丙基]氨基-3,4-二氢-2h-1,5-苯并巯氧杂卓用于治疗癌症特别是用于预防和/或治疗癌症转移的用途
JP2014526485A (ja) * 2011-09-13 2014-10-06 ピエール、ファーブル、メディカマン 癌を治療するための、特に、癌転移を予防および／または治療するための、３−（ｒ）−［３−（２−メトキシフェニルチオ）−２−（ｓ）−メチル−プロピル］アミノ−３，４−ジヒドロ−２ｈ−１，５−ベンゾオキサチエピンの使用
CN103764142B (zh) * 2011-09-13 2015-11-25 皮埃尔法布雷医药公司 3-(r)-[3-(2-甲氧基苯硫基)-2-(s)-甲基-丙基]氨基-3,4-二氢-2h-1,5-苯并巯氧杂卓用于治疗癌症特别是用于预防和/或治疗癌症转移的用途
AU2012307437B2 (en) * 2011-09-13 2017-01-12 Pierre Fabre Medicament Use of 3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro- 2H-1,5-benzoxathiepine for treating cancer and in particular for preventing and/or treating cancer metastases
US9603835B2 (en) 2011-09-13 2017-03-28 Pierre Fabre Medicament Use of 3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine for treating cancer and in particular for preventing and/or treating cancer metastases
WO2018146313A1 (fr) * 2017-02-10 2018-08-16 Celex Gmbh Traitement du cancer et suppression des métastases
AU2018218341B2 (en) * 2017-02-10 2023-07-06 Celex Oncology Innovations Limited Treatment of cancer and inhibition of metastasis

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