WO2018067431A1 - Resensibilisation de cellules cancéreuses résistantes aux médicaments par thérapie combinatoire - Google Patents

Resensibilisation de cellules cancéreuses résistantes aux médicaments par thérapie combinatoire Download PDF

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WO2018067431A1
WO2018067431A1 PCT/US2017/054707 US2017054707W WO2018067431A1 WO 2018067431 A1 WO2018067431 A1 WO 2018067431A1 US 2017054707 W US2017054707 W US 2017054707W WO 2018067431 A1 WO2018067431 A1 WO 2018067431A1
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cancer
cancer cells
cells
avasimibe
combinational therapy
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Ji-Xin Cheng
Junjie Li
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Purdue Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

Definitions

  • This disclosure is related to a combinational therapy that re-sensitizes cancer cells that are resistant to an existing cancer treatment regimen.
  • the combinational therapy provides at least one agent that inhibits cholesterol esterification pathway, which in turn leads to decreased cholesterol ester.
  • the combinational therapy synergizes the chemotherapy or other therapy effects to the resistant cancer cells.
  • Method of identifying re-sensitizing agent is also provided in this disclosure.
  • Cancer drug resistance includes primary and acquired resistance, depending on whether resistance occurs prior or after initial therapy. Numerous attempts have been made to decipher the mechanisms underlying cancer resistance. Dysregulated metabolism, mutation of the molecular targets, bypass of the targeted signaling and many other mechanisms have been revealed.
  • This disclosure provides a combinational therapy to re-sensitize cancer cells that are resistant to an existing cancer treatment regimen.
  • the combinational therapy comprises applying an effective amount of at least one agent to the cancer cells, along with the existing cancer treatment regimen that the cancer cells typically are resistant to in the absence of the agent.
  • the agent re- sensitizes the cancer cells to the existing cancer treatment regimen by inhibiting cholesterol esterification pathway.
  • the combinational therapy treated cancer cells has reduced cholesterol ester level and increased intracellular free cholesterol level that leads to the cancer cells apoptosis.
  • This disclosure further discloses a method to identify a compound that re-sensitize cancer cells that are resistant to an existing cancer treatment regimen.
  • the method comprises:
  • determining the baseline cholesterol ester level in the resistant cancer cells applying at least one compound along with the existing cancer treatment regimen to the cancer cells; measuring the cholesterol ester level in the cancer cells to identify the compound that reduces the base line cholesterol ester level in resistant cancer cells; and confirming the compound causes the resistant cancer cells' death.
  • the aforementioned combinational therapy is used in said cancer cells selected from the group consisting of prostate cancer, pancreatic cancer, myeloid leukemia, melanoma and lung cancer.
  • the aforementioned combinational therapy uses an agent that down regulates PI3K/AKT/mTOR pathway.
  • the aforementioned combinational therapy uses an agent that is an inhibitor to Acyl-coenzyme A: cholesterol acyltransferase isoform 1 (ACAT-1).
  • ACAT-1 cholesterol acyltransferase isoform 1
  • the aforementioned combinational therapy uses an agent that downregulates MAPK and NFKB pathways.
  • the agent in the aforementioned combinational therapy is avasimibe.
  • the existing cancer treatment regimen in the combinational therapy is a chemotherapy drug, a targeted therapy, a hormone therapy, or an immunotherapy.
  • the existing cancer treatment regimen in the combinational therapy is gemcitabine for pancreatic cancer, imatinib for chronic myeloid leukemia, or abiraterone/enzalutamide for castration-resistant prostate cancer.
  • the combinational therapy comprises an agent to chemotherapy drug ratio of about 5: 1 for avasimibe and germcitabine.
  • the combinational therapy comprises an immunotherapy with PD- 1 antibody for melanoma or lung cancer.
  • the cancer cells' cholesterol ester level is determined by
  • This disclosure further provides a combinational therapy to synergize the effect of an existing chemotherapy drug to cancer cells.
  • the combinational therapy comprises applying an effective amount of at least one agent to the cancer cells, along with an existing chemotherapy drug, so that the agent inhibits cholesterol esterification pathway in the cancer cells.
  • the agent used in the combination therapy to synergize the existing chemotherapy drug is an inhibitor to Acyl-coenzyme A: cholesterol acyltransferase isoform 1 (ACAT-1).
  • the agent used in the combination therapy to synergize the existing chemotherapy drug down regulates MAPK and NFKB pathways.
  • the agent used in the combination therapy to synergize the existing chemotherapy drug is avasimibe.
  • FIG. 1 CE accumulation in gemcitabine-resistant pancreatic cancer cells.
  • FIG. a Representative SRS imaging of gemcitabine- sensitive Mia PaCa-2 cells and gemcitabine- resistant G3K cells. Scale bar: 10 ⁇ .
  • Fig. c Representative Raman spectra taken from individual LD in Mia PaCa-2 and G3K cells. The spectra were offset to clarify.
  • FIG. d Quantification of CE percentage out of total lipids in LDs in Mia PaCa-2 and G3K cells.
  • FIG. 2 Avasimibe and gemcitabine synergistically suppressed pancreatic cancer proliferation in vitro.
  • FIG. 3 Avasimibe and gemcitabine synergistically suppressed pancreatic tumor growth in vivo.
  • Fig. a Tumor growth curves of mice treated with saline (control), avasimibe (7.5 mg/kg), gemcitabine (50 mg/kg), or combination of avasimibe (7.5 mg/kg) and gemcitabine (50 mg/kg).
  • Figure 4 Avasimibe resensitizes pancreatic cancer cells to gemcitabine by
  • FIG. a Immunoblotting of ⁇ -actin, Akt, and p-Akt in Mia PaCa-2 and G3K cells.
  • FIG. b Immunoblotting of ⁇ -actin, Akt, and p-Akt in Mia PaCa-2 cells treated with gemcitabine, avasimibe, or combination of both at indicated concentrations for 48 hours.
  • FIG. c Immunoblotting of ⁇ -actin, SREBP-1, Cav-1, Akt, and p-Akt in Mia PaCa-2 cells treated with avasimibe at indicated concentrations for 48 hours.
  • FIG. d Diagram showing the mechanism by which avasimibe overcomes gemcitabine resistance in pancreatic cancer cells.
  • FIG. 5 CE accumulation in chronic myeloid leukemia (CML).
  • CML chronic myeloid leukemia
  • Fig. b Quantification of CE% in leukemia cell lines
  • Fig. c SRS Imaging of Ba/F3 Cells, 4X
  • Fig. d ImageJ quantification by threshold analysis of LD area fraction from SRS imaging in
  • Fig. e Raman spectra of Ba/F3 BCR-ABL variants
  • Fig. f Quantification of CE% in LDs from Ba/F3 Cells.
  • Figure 6 Avasimibe reduces CE in Ba/F3 BCR-ABL ⁇ cells.
  • Fig. a Cells were
  • FIG. a Imatinib (IM) and avasimibe show a significant synergy in K562R cells.
  • FIG. a SRS imaging of K562(5X) and K562R(2X) cells
  • Fig. b CE% in K562 and K562R LDS
  • Fig. c 3D contour plot with colormap of cell lines treated with a 1: 10 constant
  • Figure 8 Combination of avasimibe and imatinib did not show a synergistic effect in naive K562 cells or BCR-ABL dependent imatinib resistant Ba/F3 BCR-ABLT315I cells.
  • Figs. 8a, c 3D Colormap Contour Plot of relative cell viability normalized to no inhibitor of Ba/F3 BCR- ABL 13151 after 72 hour treatment with a 1: 10 constant combination ratio of imatinib to avasimibe measured by Cell Titer Glo.
  • FIGs, b, d Linear plot showing the relative cell viabilities of Ba/F3 BCR-ABL 13151 after 72-hour treatment with avasimibe alone, imatinib alone, and a 1: 10 constant combination ratio of avasimibe to imatinib.
  • Combination index was calculated from the cell viability data by the Chou-Talalay Method.
  • FIG. 10 Imatinib and avasimibe synergistically inhibit K562R tumor xenograft growth in implanted athymic nude mice.
  • FIG. a Tumor volume (mm 3 ) measured by a caliper over the course of treatment for the four treatment groups. Significance was measured by
  • Figure 11 Avasimibe induces downregulation of the MAPK and NF- ⁇ pathways.
  • FIG. a Contour biaxials of pS6 (y-axis) and pCREB (x-axis) gated on pCRKL+ K562R cells examined by mass cytometry. Cells were treated for 0 or 4 hours with 10 ⁇ avasimibe.
  • FIG. b Heatmaps of non-lymphoid CD34 + CD38 " cells from normal bone marrow (NBM) (top), peripheral blood from an imatinib- sensitive patient (middle), and peripheral blood from an imatinib-resistant patient without a BCR-ABL kinase domain mutation (bottom).
  • Each plot represents one of the four stimulation conditions: basal (top left), imatinib (top right), avasimibe (bottom left), and imatinib + avasimibe (bottom right).
  • the contour represents cell density.
  • Fig. d The top left plot shows the cell types in the viSNE map from the same experiment as panels (b) and (c), with each gate overlayed over the other and color-coded.
  • the top right plot shows cell density in the viSNE map with red being the most dense and blue being the least dense. Gating was done using the viSNE map. See supplemental figure S2 for surface marker validation.
  • the first set of four plots show p-p65/NF-KB intensity across the four aforementioned conditions (top), the second set shows pCREB (middle), and the third set shows p-p38/MAPK (bottom).
  • the maps are color-coded for marker signal intensity, with red being the maximum intensity.
  • Figure 12 CE accumulates in castration-resistant patient-derived xenograft (PDX) model and avasimibe shows effects in enzalutamide-resistant MR49F cells.
  • PDX patient-derived xenograft
  • Fig. a SRS images and
  • Fig. b Raman spectra in PDX CRPC tumor tissues.
  • Fig. c Viability assay of MR49F cells treated with enzalutamide or avasimibe at indicated concentrations.
  • Figure 13 Table 1. Synergistic effects of avasimibe and gemcitabine in MiaPaCa2 cells combined at various dose ratios.
  • the term "about” can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range.
  • This aberrant accumulation of CE can be detected through Raman Spectra and was found to be induced by the activated PI3K/AKT/mTOR pathway and mediated by the Acyl- coenzyme A: cholesterol acyltransferase isoform 1 (ACAT-1) enzyme.
  • ACAT-1 cholesterol acyltransferase isoform 1
  • G3K cells were cultured in the same media supplemented with 1 ⁇ gemcitabine to maintain the resistance.
  • MOLM14, RCH-ACV, K562, and Kasumi-2 cell lines were obtained from DSMZ and maintained in RPMI medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, and 0.5% penicillin/streptomycin.
  • Ba/F3 and 32D cells expressing empty vector, BCR-ABL,BCR-ABL T3151 or BCR-ABL kinase dead were maintained in the same medium.
  • K562R cell lines which display EVI resistance in the absence of BCR-ABL mutations, were initially generated by culturing naive K562 cells with FGF2 and imatinib. Resistant K562R cells were maintained in 0.5-1 ⁇ imatinib.
  • Enzalutamide-resistant prostate cancer MR49-F cells were cultured in RPMI 1640 supplemented with 10% FBS and 10 ⁇ enzalutamide. For maintenance, all cells were cultured at 37 °C in a humidified incubator with 5% C0 2 supply. All patient samples were obtained with written consent according to an approved IRB protocol. All CML patient samples had wild-type BCR-ABL. Chemicals including avasimibe, gemcitabine, and imatinib mesylate used in vitro and in vivo studies were purchased from Selleckchem.com.
  • mice All animal experiments were conducted following protocols approved by Purdue Animal Care and Use Committee (PACUC). 4-6 week-old female athymic nude mice (Envigo) were injected with ⁇ 5 x 10 6 MIA PaCa-2 or K562R cells per mouse. One week after tumor cell inoculation, the mice were divided into four groups, control, avasimibe alone, gemcitabine or imatinib along, and combination of avasimibe and gemcitabine or combination of avasimibe and imatinib, with 8 mice in each group. Avasimibe was administered daily by
  • intraperitoneal injection at a dose of 7.5 mg/kg
  • imatinib was administered daily by oral gavage at a dose of 70 mg/kg
  • gemcitabine was administrated once every 3 days by intraperitoneal injection at a dose of 50 mg/kg.
  • SRS Stimulated Raman scattering microscopy was performed with two femto-second laser system. Specifically, a Ti:Sapphire laser (Chameleon Vision, Coherent) with up to 4W (80 MHz, ⁇ 140 fs pulse width) pumps an optical parametric oscillator (OPO, Chameleon Compact, Angewandte Physik & Elektronik GmbH). The pump and Stokes beams were tuned to 830 nm and 1090 nm, respectively. The pump and Stokes pulse trains were collinearly overlapped and directed into a laser-scanning microscope (FV300, Olympus).
  • a Ti:Sapphire laser Chameleon Vision, Coherent
  • 4W 80 MHz, ⁇ 140 fs pulse width
  • OPO optical parametric oscillator
  • the pump and Stokes beams were tuned to 830 nm and 1090 nm, respectively.
  • the pump and Stokes pulse trains were collinearly overlapped and directed into
  • a 60X water-immersion objective lens (UPlanSApo, Olympus) was used to focus the laser into a sample.
  • the typical acquisition time for a 512 x 512 pixels SRL image was 1.12 second. Images were processed using ImageJ.
  • Single-cell protein analysis was performed using a CyTOF2 instrument according to previously published procedures. All metal-conjugated antibodies were purchased from Fluidigm. Cells were treated with ⁇ imatinib for 30 minutes or 10 ⁇ avasimibe for 4 hours. Data analysis was performed using Cytobank as described previously. Further analysis was performed using viSNE.
  • Cells were harvested and lysed in RIPA lysis buffer (Sigma- Aldrich) supplemented with protease and phosphatase inhibitor cocktail. Protein concentration was determined using the Bio-Rad protein assay kit. Protein extraction was subjected to immunoblotting with the antibodies against Akt (Cell Signaling, #4691), p-Akt (Cell Signaling, #4060L), Caveolin-1 (Cell signaling, #3238S), SREBP-1 (Santa Cruz, #sc-13551), and ⁇ -actin (Sigma, A5441). ⁇ - actin was used as loading control for normalization.
  • Akt Cell Signaling, #4691
  • p-Akt Cell Signaling, #4060L
  • Caveolin-1 Cell signaling, #3238S
  • SREBP-1 Santa Cruz, #sc-13551
  • ⁇ -actin Sigma, A5441
  • a gemcitabine-resistant cell line G3K was generated from Mia PaCa-2 cells by continuous culture with gemcitabine (15). Stimulated Raman Scattering (SRS) imaging and Raman spectroscopy were used to assess the lipid and cholesterol content in parent MiaPaCa- 2 and gemcitabine-resistant G3K cells.
  • SRS Stimulated Raman Scattering
  • G3K cells were shown to have significantly higher amount of lipid droplets (LDs) than Mia PaCa-2 cells (Fig. la, b).
  • LDs lipid droplets
  • CE cholesteryl ester
  • avasimibe an inhibitor to ACTAl enzyme, synergizes the effect of gemcitabine to cancer cells.
  • a combination of avasimibe and gemcitabine Mia PaCa-2 cells were treated with avasimibe, gemcitabine alone, or combination of avasimibe and gemcitabine at concentrations with constant ratios.
  • the combinational therapy showed superior inhibitory effects on cell viability, compared to single agent treatments (Fig. 2a).
  • CI combination index
  • This example shows combination effects of Avasimibe and Gemcitabine in xenograft model.
  • a xenograft model derived from Mia PaCa-2 cells was used. Avasimibe and gemcitabine were administrated at doses of 7.5 mg/kg and 50 mg/kg, respectively. While avasimibe and gemcitabine alone suppressed tumor growth, combination of these two compounds sigfinicantly amplified this effect by further inducing a regression of tumors after treatment (Fig. 3a). Notably, no obvious treatment associated body weight loss was observed (Fig. 3b). These data suggest a strong synergistic effect between avasimibe and gemcitabine when administrated together as a combinational therapy.
  • This example shows avasimibe overcomes gemcitabine-resistance by downregulating Akt pathway.
  • Akt pathway has been known as one of the signaling pathways associated with gemcitabine-resistance in pancreatic cancer.
  • This example shows abnormal CE accumulation in chronic myeloid leukemia (CML) is driven by BCR-ABL.
  • CML chronic myeloid leukemia
  • Raman spectral analysis was performed on a variety of well-characterized leukemia cell lines, including MOLM14 (AML), RCH-ACV (ALL), Kasumi-2 (ALL), and K562 (CML) cells.
  • An abnormal accumulation of CE was identified in K562 cells, as evidenced by the peak at Raman shift of 702cm "1 from cholesterol ring vibration (Fig. 5a).
  • Quantitative analysis revealed a 50% level of CE in the lipid droplets of K562 cells, but only around 10% in other cells (Fig. 5b). Considering the correlation between BCR-ABL activation and CE
  • BCR-ABL drives CE accumulation.
  • a murine interleukin-3 dependent pro-B cell line Ba/F3 was used.
  • Ba/F3 cells overexpressing BCR- ABL WT , BCR-ABL 13151 , or empty vector (control) were subjected to SRS imaging to visualize LD accumulation in the three cell lines (Fig. 5c).
  • Ba/F3 cells transfected with empty vector showed no accumulation of LDs, regardless of whether they were stimulated with IL-3 for 48 hours.
  • Ba/F3 BCR-ABL and Ba/F3 BCR-ABL cells had LD accumulation even without IL-3 stimulation (Fig. 5d).
  • these LDs were found to be mainly composed of CE (65- 75%) (Fig. 5e-f).
  • the Ba/F3 control cells could not be spectrally analyzed because there were no detectable LDs.
  • EXAMPLE 7 Avasimibe resensitizes BCR-ABL mutation-independent imatinib-resistant CML in vitro
  • This example shows avasimibe resensitizes BCR-ABL mutation-independent imatinib- resistant CML in vitro.
  • EXAMPLE 9 The combination index (CI) as defined by the Chou-Talalay method indicated a strong synergistic effect between avasimibe and imatinib in K562R cells, but not in K562 or Ba/F3 BCR-ABL T31SI cells.
  • EXAMPLE 10 Avasimibe and imatinib synergistically reduce tumor growth in a xenograft mouse model.
  • This example shows avasimibe and imatinib synergistically reduce tumor growth in a xenograft mouse model.
  • a xenograft mouse model To confirm the synergy between avasimibe and imatinib in vivo, we used a xenograft mouse model. The combination treatment significantly (p ⁇ 0.001) reduced tumor growth as compared to the control (DMSO), imatinib, or avasimibe treated groups (Fig. 10a). Moreover, no significant treatment related body weight loss was observed (Fig. 10b).
  • EXAMPLE 11 Avasimibe induces downregulation of the MAPK and NF- ⁇ pathways.
  • Combination therapy had minimal effect in normal bone marrow.
  • the resistant patient's cells also displayed sensitivity to imatinib as measured by pCRKL levels (canonical downstream target of BCR-ABL).
  • imatinib treatment led to increased levels of p-p65/NF-KB, p-p38, and pCREB.
  • Combination treatment reversed the effect of imatinib leading to decreased phosphorylation of these signaling effectors (Fig. llb-c).
  • mass cytometry data was analyzed using the viSNE algorithm that plots every individual cell in on the tSNE axes according to their similarity to neighboring cells.
  • pNF- ⁇ / ⁇ stimulation due to imatinib was not limited to the primitive CD34 + CD38 ⁇ cell population, but could be generalized to the spectrum of myeloid cells expressing CD34 and CD38, as well as more mature cells of the myeloid lineage including monocytes (Fig. lid). Imatinib-related NF- ⁇ activation was not seen, however, in mature T- Cells, B-Cells, or granulocytes, which is to be expected.
  • Combination therapy was also more effective than avasimibe or imatinib monotherapy across the hematopoietic spectrum in the resistant patient, based upon decreased phosphorylation of p-p65/NF-KB, p-p38/MAPK, and pCREB in all cell types with a stimulation response to imatinib (Fig. lid).
  • Fig. 12a-b shows Avasimibe has high efficacy in suppressing the viability of enzalutamide-resistant prostate cancer MR49F cells (Fig. 12c), suggesting the potential use of avasimibe to overcome enzalutamide resistance in patients with very late-stage prostate cancer.

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Abstract

L'invention concerne une thérapie combinatoire qui fournit au moins un agent pour inhiber la voie d'estérification du cholestérol afin de resensibiliser les cellules cancéreuses résistantes aux médicaments. La thérapie combinatoire synergise la chimiothérapie ou d'autres effets thérapeutiques sur les cellules cancéreuses résistantes. L'invention concerne également une méthode d'identification d'un agent de resensibilisation.
PCT/US2017/054707 2016-10-03 2017-10-02 Resensibilisation de cellules cancéreuses résistantes aux médicaments par thérapie combinatoire WO2018067431A1 (fr)

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KR20210114877A (ko) * 2020-03-11 2021-09-24 연세대학교 산학협력단 항암제 내성 진단 또는 치료용 조성물
KR102503593B1 (ko) 2020-03-11 2023-02-24 연세대학교 산학협력단 항암제 내성 진단 또는 치료용 조성물
US20230302021A1 (en) * 2022-03-23 2023-09-28 Purdue Research Foundation Compositions and methods for treating castration-resistant prostate cancer

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