Methods and compositions for treating cancer in taxane-resistant patients

Abstract

Methods and compositions are provided for treating cancer in a taxane-resistant patient, comprising administering an effective amount of a taxane, either simultaneously or sequentially, with a P-gp inhibitor, such as ritonavir or a pharma- ceutically acceptable salt thereof. Also provided are methods and compositions for reversing taxane resistance in a patient, comprising administering an effective amount of a P-gp inhibitor, such as ritonavir or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] The present invention relates to tumor chemotherapy with taxanes, and more particularly to methods and compositions for treating cancer in taxane-resistant patients using a combination of a P-gp inhibitor, such as ritonavir, and a taxane. [Background technology]

[0002] The treatment of cancer involves a wide variety of modalities. Treatments include surgery, radiation therapy, chemotherapy, immunotherapy, and cell therapy. Often, cancer treatment involves a combination of different modalities consisting of a combination of different therapeutic drugs. As part of first-line chemotherapy, taxanes such as docetaxel and cabazitaxel are widely used in the treatment of various cancers.

[0003] Docetaxel is a cytotoxic drug. Its primary mechanism of action is thought to be interference with microtubule assembly and disassembly, resulting in inhibition of mitotic cell division. The recommended dose is 75-100 mg / m2 of body surface area. 2 Docetaxel is administered intravenously every 3 weeks with doses ranging from 0.1 to 1.0 mg / kg / day. Docetaxel is used to treat a variety of cancers, including breast, lung, prostate, gastric, head and neck, and ovarian cancers. Docetaxel can be administered intravenously as a chemotherapy agent and is approved and used to treat a variety of solid tumors. Patients have shown variable responses to treatment. Improved means and methods for using docetaxel to treat cancer have been proposed. In particular, docetaxel can be administered in combination with cytochrome P450 isoenzyme CYP3A inhibitors, improving the safety profile of docetaxel compared to standard docetaxel therapy.

[0004] For example, US Pat. No. 5,999,663 provides pharmaceutical compositions and methods for the treatment of neoplastic diseases, including a combination of a taxane and a CYP3A4 inhibitor. US Pat. No. 5,999,663 provides cancer treatment with docetaxel by controlling plasma levels. US Pat. No. 5,999,663 provides combination treatment of solid tumors with docetaxel and a CYP3A inhibitor. However, while taxanes such as docetaxel and cabazitaxel have the potential to benefit patients and improve lifespan and quality of life, continued use of taxanes such as docetaxel and cabazitaxel may result in the development of taxane resistance in patients, limiting the effectiveness of taxanes in cancer treatment. In addition, some patients may have difficulty in treating taxanes from the beginning, for example because of their inherent high resistance. Therefore, it is highly desirable to provide new means of cancer treatment in taxane-resistant patients. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2009 / 027644 A2 [Patent Document 2] WO2020 / 127606 A1 [Patent Document 3] WO2020 / 127607 A1 Summary of the Invention

[0006] Surprisingly, the inventors have discovered that a patient's resistance to treatment with taxanes can be alleviated, substantially overcome, at least partially reversed, or substantially reversed by administration of a P-gp inhibitor, namely, ritonavir. Ritonavir is also used to sensitize or resensitize cells to taxanes. Examples of such taxanes include docetaxel, cabazitaxel, paclitaxel, pharmaceutically acceptable salts or esters thereof, and combinations thereof, for the treatment of cancer. Examples of such cancers include solid tumors, gastric cancer, breast cancer, head and neck cancer, lung cancer, and prostate cancer.

[0007] In a first embodiment, the present invention provides a method of treating cancer in a taxane-resistant patient, the method comprising administering an effective amount of a taxane, either simultaneously or sequentially, with ritonavir or a pharma- ceutically acceptable salt thereof.

[0008] In a second embodiment, the present invention provides a method of reversing taxane resistance in a patient comprising administering an effective amount of ritonavir, or a pharma- ceutically acceptable salt thereof.

[0009] In a third embodiment, the present invention provides a taxane for use in combination therapy with ritonavir, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer in a taxane-resistant patient.

[0010] In a fourth embodiment, the present invention provides ritonavir, or a pharma- ceutically acceptable salt thereof, for use in reversing taxane resistance in a patient.

[0011] In a fifth embodiment, the present invention provides a method for sensitizing or re-sensitizing cells to taxanes in the treatment of cancer, comprising administering an effective amount of ritonavir, or a pharma- ceutically acceptable salt thereof.

[0012] In a sixth embodiment, the present invention provides ritonavir, or a pharma- ceutically acceptable salt thereof, for use in sensitizing or re-sensitizing cells to taxanes in the treatment of cancer.

[0013] In a seventh embodiment, the present invention provides a kit comprising at least one pharmaceutical composition comprising a taxane and at least one pharmaceutical composition comprising a P-gp inhibitor, such as ritonavir, for use in treating cancer in a taxane-resistant patient.

[0014] In an eighth embodiment, the present invention provides a method for treating cancer comprising a combination of a P-gp inhibitor, such as ritonavir, and a taxane. The method comprises: Measuring the expression of ABCB1 (P-gp) in the patient; Optionally, comparing the expression of ABCB1 (P-gp) to a reference level; Optionally, determining the dosage of a P-gp inhibitor based on the expression level of ABCB1 (P-gp) measured in the subject; administering a combination of a P-gp inhibitor and a taxane. [Brief description of the drawings]

[0015] Specific embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which: [Figure 1] FIG. 1 shows docetaxel resistance in the DU145 prostate cancer cell line. [Diagram 2] FIG. 2 shows docetaxel resistance in the 22Rv1 prostate cancer cell line. [Diagram 3] FIG. 3 shows the expression of P-gp protein in docetaxel-resistant prostate cancer cells. [Figure 4]FIG. 4 shows a scatter plot comparing the key genes of DU-145 DOC10 and DU-145 against 22Rv1 DOC8 and 22Rv1. The top right panel shows genes that are upregulated in both pairs. The top left panel shows genes that are upregulated in DU-145 and downregulated in the 22Rv1 pair. The bottom right panel shows genes that are upregulated in 22Rv1 and downregulated in the DU-145 pair. The bottom left panel shows genes that are downregulated in both pairs. [Diagram 5] FIG. 5 shows that ritonavir reverses docetaxel resistance in castration-resistant DU-145 DOC10 prostate cancer cells (clonogenic assay). [Figure 6] FIG. 6 shows that the combination of ritonavir and docetaxel induces synergistic effects in docetaxel-resistant DU-145 DOC10 prostate cancer cells (clonogenic assay). [Figure 7] FIG. 7 shows that ritonavir also reverses docetaxel resistance in 22Rv1 DOC8-resistant prostate cancer cells. [Figure 8] FIG. 8 shows that the combination of ritonavir and cabazitaxel induces a synergistic effect in parental DU-145 prostate cancer cells. [Figure 9] FIG. 9 shows that the combination of ritonavir and cabazitaxel induces synergistic effects in docetaxel-resistant DU-145 DOC10 prostate cancer cells. [Figure 10] FIG. 10 shows that ritonavir reverses cabazitaxel resistance in docetaxel-resistant DU145 DOC10 prostate cancer cells. [Figure 11] FIG. 11 shows that the combination of ritonavir and cabazitaxel induces synergy in docetaxel-resistant 22Rv1 DOC8 prostate cancer cells. [Figure 12] FIG. 12 shows that ritonavir reverses cabazitaxel resistance in docetaxel-resistant 22Rv1 DOC8 prostate cancer cells. [Figure 13]FIG. 13 shows that elacridar reverses docetaxel resistance in castration-resistant DU-145 DOC10 prostate cancer cells. [Figure 14] FIG. 14 shows that elacridar and docetaxel exhibited synergistic effects in docetaxel-resistant DU-145 DOC10 prostate cancer cells (clonogenic assay). [Figure 15] FIG. 15 shows that elacridar reverses docetaxel resistance in castration-resistant 22Rv1 DOC8 prostate cancer cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] In a first embodiment, the present invention provides a method of treating cancer in a taxane-resistant patient comprising administering an effective amount of a taxane, either simultaneously or sequentially, with ritonavir or a pharma- ceutically acceptable salt thereof. In a second embodiment, the present invention provides a method of reversing taxane resistance in a patient, comprising administering an effective amount of ritonavir, or a pharma- ceutically acceptable salt thereof.

[0017] Here, the terms "taxane-resistant patient" and "taxane resistance" may refer to either initial resistance (e.g., a patient who does not respond to taxanes initially due to naturally high Pg-p expression) or acquired resistance (e.g., a patient whose efficacy of the taxane decreases over time after prolonged use of the taxane for more than three months or with increasing taxane dosage).

[0018] Acquired resistance to one taxane can lead to acquired resistance to other taxanes. For example, prolonged use of docetaxel (e.g., 3 months or more) can lead to acquired resistance to other taxanes, such as docetaxel and / or cabazitaxel.

[0019] Acquired resistance in cancer cells following exposure to taxanes is associated with IC 50 It can be identified by observing an increase in IC 50The increase in value may be, for example, greater than about a 10-fold increase, such as greater than about a 20-fold increase, or greater than about a 100-fold increase.

[0020] Drug-resistant cell lines (either innately resistant or acquiredly resistant) can be identified by the upregulation of genes associated with metabolic or homeostasis pathways, particularly ABCB1 (P-glycoprotein), compared to parental untreated cells. For example, ABCB1 (P-glycoprotein) can be upregulated by about 1000-fold or more, about 2000-fold or more, or about 3000-fold or more.

[0021] Preferably, the method is for treating cancer, and ritonavir or a pharma- ceutically acceptable salt thereof is administered simultaneously or sequentially with an effective dose of a taxane.

[0022] For example, the cancer may comprise a solid tumor.For example, the cancer may be selected from the group consisting of gastric cancer, breast cancer, head and neck cancer, lung cancer and prostate cancer.Preferably, the cancer is prostate cancer.These methods may also comprise determining whether the cancer responds to treatment by measuring the responsiveness of DU-145 or 22Rv1 cell line to an effective dose of taxane, either simultaneously or sequentially with ritonavir or its pharmaceutically acceptable salt.

[0023] Advantageously, ritonavir and / or the taxane can be administered orally, thereby improving the means and methods of cancer treatment with an improved safety profile compared to standard treatments of taxanes such as docetaxel, while at the same time allowing control to obtain effective antitumor levels of taxane exposure. Alternatively, ritonavir and / or the taxane can be administered intravenously.

[0024] The taxane may be selected from the group consisting of docetaxel, cabazitaxel, pharmaceutically acceptable salts or esters thereof, and combinations thereof. Preferably, the taxane is docetaxel, or a pharmaceutically acceptable salt or ester thereof. Other taxanes contemplated include paclitaxel.

[0025] Ritonavir is administered in a weekly dose of about 50 mg to about 1200 mg, for example, about 200 mg to about 400 mg.

[0026] Alternatively, ritonavir may be administered in a daily dosage of about 50 mg to about 1200 mg, for example, about 100 mg to about 200 mg.

[0027] The taxane is administered in a weekly dose of about 30 mg to about 500 mg, for example, docetaxel or cabazitaxel, and is administered in a weekly dose of about 30 mg to about 500 mg, for example, about 40 mg to about 100 mg, or about 40 mg to about 50 mg.

[0028] Alternatively, the taxane may be administered in a daily dosage of about 0.1 mg to about 100 mg, for example, the taxane is docetaxel or cabazitaxel and is administered in a daily dosage of about 0.1 mg to about 100 mg, for example, about 40 mg to about 50 mg.

[0029] For example, ritonavir is administered at a dosage of about 50 mg to about 1200 mg per day, such as about 100 mg to about 200 mg, and the taxane is administered at a dosage of about 0.1 mg to about 100 mg per day, such as about 40 mg to about 50 mg, and the daily doses of ritonavir and taxane may be taken at the same or different times of day. In another example, ritonavir is administered at a weekly dosage of about 50 mg to about 1200 mg, such as about 200 mg to about 400 mg, and the taxane is administered at a weekly dosage of about 30 mg to about 500 mg, such as about 40 mg to about 100 mg or about 40 mg to about 50 mg. It is noted that the weekly doses of ritonavir and taxane may be taken on the same or different days.

[0030] In a third embodiment, the present invention provides a taxane for use in combination therapy with ritonavir or a pharmaceutically acceptable salt thereof to treat cancer in taxane-resistant patients. Preferably, ritonavir or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with the taxane. For example, the cancer may comprise a solid tumor. For example, the cancer may be selected from the group consisting of gastric cancer, breast cancer, head and neck cancer, lung cancer, and prostate cancer. Preferably, the cancer is prostate cancer.

[0031] This use also includes determining whether the cancer responds to treatment by measuring the responsiveness of DU-145 or 22Rv1 cell lines to effective doses of the combination therapy. Advantageously, ritonavir and / or taxanes can be administered orally, which provides an improved means and method of cancer treatment with an improved safety profile compared to standard treatments of taxanes such as docetaxel, while at the same time providing control to obtain effective antitumor levels of taxane exposure. Alternatively, ritonavir and / or taxanes can be administered intravenously.

[0032] The taxane may be selected from the group consisting of docetaxel, cabazitaxel, pharmaceutically acceptable salts or esters thereof, and combinations thereof. Preferably, the taxane is docetaxel, or a pharmaceutically acceptable salt or ester thereof. Other taxanes contemplated include paclitaxel.

[0033] Ritonavir is administered in a weekly dose of about 50 mg to about 1200 mg, for example, about 200 mg to about 400 mg. Alternatively, ritonavir may be administered in a daily dose of about 50 mg to about 1200 mg, for example, about 100 mg to about 200 mg.

[0034] The taxane is administered in a weekly dose of about 30 mg to about 500 mg, for example, docetaxel or cabazitaxel, and is administered in a weekly dose of about 30 mg to about 500 mg, for example, about 40 mg to about 100 mg, or about 40 mg to about 50 mg. Alternatively, the taxane may be administered in a daily dosage of about 0.1 mg to about 100 mg, for example, the taxane is docetaxel or cabazitaxel and is administered in a daily dosage of about 0.1 mg to about 100 mg, for example, about 40 mg to about 50 mg.

[0035] For example, ritonavir is administered at a dosage of about 50 mg to about 1200 mg per day, such as about 100 mg to about 200 mg, and the taxane is administered at a dosage of about 0.1 mg to about 100 mg per day, such as about 40 mg to about 50 mg, and the daily doses of ritonavir and taxane may be taken at the same or different times of the day. In another example, ritonavir is administered in a weekly dosage of about 50 mg to about 1200 mg, such as about 20 mg to about 400 mg, and the taxane is administered in a weekly dosage of about 30 mg to about 500 mg, such as about 40 mg to about 100 mg or about 40 mg to about 50 mg, where the weekly dosages of ritonavir and taxane may be taken on the same or different days.

[0036] In a fourth embodiment, the present invention provides ritonavir, or a pharma- ceutically acceptable salt thereof, for use in reversing taxane resistance in a patient. Preferably, said use is for treating cancer in a taxane-resistant patient, and ritonavir is administered simultaneously or sequentially with an effective amount of the taxane. For example, the cancer may comprise a solid tumor. For example, the cancer is selected from the group consisting of gastric cancer, breast cancer, head and neck cancer, lung cancer, and prostate cancer. Preferably, the cancer is prostate cancer.

[0037] This use includes determining whether a cancer responds to treatment by measuring the responsiveness of DU-145 or 22Rv1 cell lines to an effective dose of a taxane, either simultaneously or sequentially with ritonavir or a pharma- ceutical acceptable salt thereof. Advantageously, ritonavir and / or taxanes can be administered orally, which provides an improved means and method of cancer treatment with an improved safety profile compared to standard treatments of taxanes such as docetaxel, while allowing control to obtain effective antitumor levels of taxane exposure. Alternatively, ritonavir and / or taxanes can be administered intravenously.

[0038] The taxane may be selected from the group consisting of docetaxel, cabazitaxel, pharmaceutically acceptable salts or esters thereof, and combinations thereof. Preferably, the taxane is docetaxel, or a pharmaceutically acceptable salt or ester thereof. Other taxanes contemplated include paclitaxel.

[0039] Ritonavir is administered in a weekly dose of about 50 mg to about 1200 mg, for example, about 200 mg to about 400 mg. Alternatively, ritonavir may be administered in a daily dose of about 50 mg to about 1200 mg, for example, about 100 mg to about 200 mg.

[0040] The taxane is administered in a weekly dose of about 30 mg to about 500 mg, for example, docetaxel or cabazitaxel, and is administered in a weekly dose of about 30 mg to about 500 mg, for example, about 40 mg to about 100 mg, or about 40 mg to about 50 mg. Alternatively, the taxane may be administered in a daily dosage of about 0.1 mg to about 100 mg, for example, the taxane is docetaxel or cabazitaxel, administered in a daily dosage of about 0.1 mg to about 100 mg, for example, about 40 mg to about 50 mg.

[0041] For example, ritonavir is administered at a dosage of about 50 mg to about 1200 mg per day, such as about 100 mg to about 200 mg, and the taxane is administered at a dosage of about 0.1 mg to about 100 mg per day, such as about 40 mg to about 50 mg, and the daily doses of ritonavir and taxane may be taken at the same or different times of the day.

[0042] In another example, ritonavir is administered in a weekly dosage of about 50 mg to about 1200 mg, e.g., about 200 mg to about 400 mg, and the taxane is administered in a weekly dosage of about 30 mg to about 500 mg, e.g., about 40 mg to about 100 mg or about 40 mg to about 50 mg, and the weekly dosages of ritonavir and taxane may be taken on the same or different days.

[0043] In a fifth embodiment, the present invention provides a method of sensitizing or re-sensitizing cells to taxanes in the treatment of cancer, the method comprising administering an effective amount of ritonavir or a pharma- ceutically acceptable salt thereof. The taxane may be selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof. Preferably, the taxane is docetaxel. Other taxanes contemplated include paclitaxel.

[0044] In a sixth embodiment, the present invention provides ritonavir, or a pharma- ceutically acceptable salt thereof, for use in sensitizing or re-sensitizing cells to taxanes in the treatment of cancer. The taxane may be selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof. Preferably, the taxane is docetaxel. Other taxanes contemplated include paclitaxel.

[0045] In a seventh embodiment, the present invention provides a kit comprising at least one pharmaceutical composition comprising a taxane and at least one pharmaceutical composition comprising a P-gp inhibitor, said kit being used for treating cancer in a taxane-resistant patient. The taxane may be selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof. Preferably, the taxane is docetaxel. Other taxanes contemplated include paclitaxel.

[0046] The P-gp inhibitor may be selected from the group consisting of ritonavir, elacridar, and combinations thereof, or pharma- ceutically acceptable salts thereof. Preferably, the P-gp inhibitor is ritonavir. The kit may also include instructions for simultaneous or sequential use of the pharmaceutical compositions to treat cancer in a taxane-resistant patient.

[0047] In an eighth embodiment, the present invention provides a method for treating cancer comprising a combination of a P-gp inhibitor and a taxane, the method comprising: Measuring the expression of ABCB1 (P-gp) in the patient; Optionally, comparing the expression of ABCB1 (P-gp) to a reference level; Optionally, determining the dosage of a P-gp inhibitor based on the expression level of ABCB1 (P-gp) measured in said subject (patient); Preferably, the method includes administering a combination of a P-gp inhibitor and a taxane, at a dosage based on the expression level of ABCB1 (P-gp) measured in said subject.

[0048] The taxane may be selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof. Preferably, the taxane is docetaxel. Other taxanes contemplated include paclitaxel. The P-gp inhibitor may be selected from the group consisting of ritonavir, elacridar, and combinations thereof, or pharma- ceutically acceptable salts thereof. Preferably, the P-gp inhibitor is ritonavir.

[0049] Furthermore, in any of the above embodiments of the present invention, the following features are provided. Oral administration of the taxane and / or ritonavir (or other P-gp inhibitors) to a subject can include any route via the mouth that introduces or delivers the drug to a subject to perform its intended function. Pharmaceutical compositions suitable for oral administration include liquids, tablets, or capsules. The capsules and tablets may be enterically coated, in which case the taxane and / or ritonavir is released from the capsule or tablet in the intestine. The capsules and tablets can be formulated as sustained release formulations, such that the taxane and / or ritonavir (or other P-gp inhibitors) is released during, for example, the residence in the intestinal tract, for example, over several hours or more. Thus, the tablets and capsules can be formulated to release the drug gradually. The tablets and capsules can be formulated to release the drug in the stomach or intestine. The tablets and capsules can be formulated to release the drug in the stomach or intestine. Administration includes self-administration and administration by another person. The pharmaceutical composition of the present invention can include taxane and / or ritonavir (or other P-gp inhibitors), or its pharma- ceutically acceptable salts and esters, together with any pharma- ceutically acceptable carrier, adjuvant or vehicle.Formulations and / or pharmaceutical compositions suitable for oral administration include those described in WO2009027644, WO2010020799, and Moes et al., Drug Deliv.Transl.Res.2013, which are incorporated herein by reference in their entirety.Any formulation suitable for oral administration can be considered.

[0050] The present invention is not limited to oral administration of taxanes and / or ritonavir (or other P-gp inhibitors). Administration of taxanes and / or ritonavir (or other P-gp inhibitors) via the gastrointestinal tract is contemplated. Thus, enteral administration can be considered instead of oral administration. Preferably, enteral administration takes the form of capsules, tablets, and suppositories. Administering taxanes and / or ritonavir (or other P-gp inhibitors) via suppositories can be advantageous because it improves bioavailability compared to oral administration. This is because, in the case of oral administration, taxanes and / or ritonavir (or other P-gp inhibitors) are delivered to the liver via the portal vein after passing through the gastrointestinal tract. Enteral administration avoids the barrier of metabolizing taxanes and / or ritonavir (or other P-gp inhibitors) during first pass. Any enteral administration is sufficient as long as it avoids peak levels and provides effective plasma levels.

[0051] The taxane and ritonavir (or other P-gp inhibitors) can be administered simultaneously. It is understood that simultaneous administration can include administration of separate pharmaceutical formulations. For example, one pharmaceutical formulation suitable for oral administration contains the taxane and another pharmaceutical formulation contains ritonavir (or other P-gp inhibitors). The pharmaceutical formulation containing ritonavir (or other P-gp inhibitors) is preferably administered orally. It is understood that simultaneous administration can consist of one pharmaceutical formulation containing both the taxane and ritonavir (or other P-gp inhibitors). As used herein, simultaneous means that the taxane or ritonavir (or other P-gp inhibitors) is administered within about 20 minutes, more preferably within 15 minutes, more preferably within 10 minutes, even more preferably within 5 minutes, and most preferably within 2 minutes of administration of the ritonavir (or other P-gp inhibitors) or taxane. In general, it is preferred that ritonavir (or other P-gp inhibitors) be administered orally at the same time as the oral taxane, as this provides the greatest compliance with self-administration by treated subjects.

[0052] Alternatively, the taxane and ritonavir (or other P-gp inhibitor) can be administered separately and / or sequentially, preferably within about 60 minutes of each other. If administered separately, ritonavir (or other P-gp inhibitor) is preferably administered before the taxane, more preferably within about 60 minutes before the taxane is administered. The recommended dosage for taxanes, such as docetaxel, is 75 mg / m every 3 weeks. 2 to 100 mg / m 3 (milligrams of docetaxel per square meter of subject's body surface area). For non-small cell lung, breast, gastric, head and neck, or prostate cancer, the recommended dose is 75 mg / m every 3 weeks. 2 The recommended dose is 35 mg / m per week. 2 The level of taxane exposure in tumor tissue may be defined herein as the area under the curve obtained when the taxane is administered intravenously, and may correspond to the effective standard of care for the taxane. It is understood that the above method does not define the actual tissue taxane level, since the taxane is measured in plasma. The standard of care for the taxane, as used herein, may be defined as the recommended dose of the taxane administered intravenously.

[0053] The area under the curve (AUC; ng*h / mL) is measured within the first 48 hours after taxane administration. During this period, the taxane concentration in plasma is measured at several time points, and the surface area under the curve can be calculated from the plotted values. The plasma level of the taxane can be measured by methods known in the art (Hendrikx et al., J. Chrom. B, 2011), including liquid chromatography and mass spectrometry. Since plasma is a blood component, it is understood that instead of measuring the taxane in plasma, the level of the taxane can be measured in whole blood or serum. The taxane measurements herein, such as peak levels and areas under the plasma concentration time curve (AUC for short), are defined relative to (blood) plasma, but can be easily recalculated to the corresponding peak levels in whole blood or serum. For example, the AUC may be in the range of 500-2500ng*h / mL, e.g., at least 500ng*h / mL, at least 600ng*h / mL, at least 800ng*h / mL, at least 1000ng*h / mL, or at least 1200ng*h / mL. For example, the AUC may be up to 2500ng*h / mL, up to 2250ng*h / mL, up to 2000ng*h / mL, up to 1800ng*h / mL, up to 1700ng*h / mL, or up to 1500ng*h / mL. For example, the AUC may be in the range of 800-1400ng*h / mL. Herein, the terms plasma concentration time curve, area under the curve, or AUC are used interchangeably and refer to the area under the curve (ng*h / mL) for the first 48 hours following administration of the taxane. For example, these doses can be achieved with 50 mg of a taxane such as docetaxel given orally twice daily (eg, 30 mg in the morning and 20 mg in the evening) once a week.

[0054] Preferably, there is provided a taxane or ritonavir (or other P-gp inhibitor) for use according to the invention described herein when the cancer is a solid tumor. Preferably, the use of the taxane or ritonavir is when the solid tumor is non-small cell lung cancer, gastric cancer, breast cancer, head and neck cancer or prostate cancer. The solid tumors are preferred since taxanes such as docetaxel have been shown to be highly effective against these cancers.

[0055] Most preferably, the cancer is prostate cancer. Prostate cancer may be treated with hormone therapy, such as androgen deprivation therapy. Prostate cancer may not respond to hormone therapy, and such prostate cancer is called hormone refractory prostate cancer (HRPC). Prostate cancer may respond to hormone therapy, and such prostate cancer is called hormone sensitive prostate cancer (HSPC). Such patients may have metastasis, and may develop metastasis during treatment. Such cancers are called mHRPC or mHSPC (m indicates metastatic). Treatment of prostate cancer may include castration surgery. In any case, prostate cancer is generally accompanied by a reduction in testosterone in the body to very low levels. As shown in the examples, the clearance of taxanes measured in plasma is clearly increased in patients with mCRPC compared to patients with solid tumors that are not mCRPC. Such patients have very low testosterone levels. Patients who receive intravenous taxanes at the same time as androgen deprivation therapy at an early stage of the disease experience more toxicity compared to prostate cancer patients who receive intravenous taxanes at a later stage of the disease. Thus, in the treatment of prostate cancer using hormone therapy including androgen inhibitors, a decrease in taxane plasma concentration due to increased taxane clearance can also be expected, but such increased clearance must first be confirmed after the initiation of hormone therapy. Thus, in the early stages of treatment of prostate cancer, the dosage of taxane and / or ritonavir (or other P-gp inhibitor) is adjusted to compensate for the relatively low plasma levels in prostate cancer patients compared to mCRPC patients. Conversely, the plasma level of taxane may need to be confirmed first. For example, a first oral dosage of taxane combined with ritonavir (or other P-gp inhibitor) according to the present invention is administered, and the plasma concentration (such as AUC) of taxane is measured to confirm that the same dosage suitable for mCRPC can be administered. In any case, the dosage suitable for mCRPC may also be suitable for HSPC, HRPC, mHRPC, mHSPC, or CRPC (i.e., non-metastatic). In a preferred embodiment, the dosage suitable for mCRPC is also selected for the treatment of mHSPC.

[0056] In a preferred embodiment, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). The dosing interval and / or dosage of the taxane and / or ritonavir (or other P-gp inhibitor) can be selected to provide a desired taxane exposure level in the tumor tissue, which is equivalent or at least equivalent to the standard of care of docetaxel. For example, docetaxel or ritonavir (or other P-gp inhibitor) may be used in a combination therapy, where docetaxel is administered orally once a week, where the exposure level of docetaxel may be equivalent to the standard of care that results in an area under the curve of 600-1800ng*h / mL, more preferably 1000-1500ng*h / mL.

[0057] In some embodiments, the weekly dose of ritonavir and / or taxane may be split so that the subject takes, for example, a first dose in the morning and a second dose in the evening once a week. This may lower the peak levels of the drug in the plasma, which may help reduce side effects. It may also increase the systemic exposure time of the drug. For example, ritonavir and / or taxane may be administered twice a day every week. This means that ritonavir and / or taxane are administered twice a day, for example, within an 8-16 hour interval, every week. Thus, administration of ritonavir and / or taxane may be done three times a day, twice a day, or once a day, every 2 days, every week, every 2 weeks, every 3 weeks, or any other suitable dosing interval. Combinations of these dosing regimens may also be used, for example, ritonavir and / or taxane may be administered twice a day every week, every 2 weeks, or every 3 weeks.

[0058] For example, in one embodiment, for the treatment of solid tumors, docetaxel is orally administered at a dose of 50mg every week.This administration is preferably performed on a schedule of twice a day once a week.Therefore, a schedule of twice a day administration every week for the treatment of solid tumors is provided herein for the treatment of solid tumors.In this schedule, docetaxel is administered once a week, and the first administration is administered at a dose of 30mg docetaxel together with 100mg ritonavir, and the second administration is administered at a dose of 20mg docetaxel together with 100mg ritonavir.

[0059] In another embodiment, for the treatment of solid tumors, docetaxel is orally administered at a dose of 40mg every week.This administration is preferably performed on a schedule of twice a day every week.Therefore, a schedule of twice a day every week for the treatment of solid tumors is provided herein for the treatment of solid tumors.In this schedule, docetaxel is administered one day a week, and the first administration is administered at a dose of 20mg docetaxel together with 200mg ritonavir, and the second administration is administered at a dose of 20mg docetaxel together with 100mg ritonavir.

[0060] In one embodiment, a twice-daily weekly docetaxel schedule is provided for the treatment of cancer, in which docetaxel is administered once a week with 30 mg of docetaxel and 200 mg of ritonavir in the first dose and 20 mg of docetaxel and 200 mg of ritonavir in the second dose. In another embodiment, a twice-daily weekly docetaxel schedule is provided for the treatment of cancer, in which docetaxel is administered once a week with 20 mg of docetaxel and 200 mg of ritonavir in the first dose and 20 mg of docetaxel and 200 mg of ritonavir in the second dose. In yet another embodiment, a twice-daily weekly docetaxel schedule is provided for the treatment of cancer. In this schedule, docetaxel is administered one day per week, with the first dose being 20 mg docetaxel in combination with 100 mg ritonavir, and the second dose being 20 mg docetaxel in combination with 100 mg ritonavir. In another embodiment, a twice daily weekly dosing schedule is provided for the treatment of cancer, in which docetaxel is administered one day per week, with the first dose being 20 mg docetaxel in combination with 200 mg ritonavir, and the second dose being 20 mg docetaxel in combination with 100 mg ritonavir.

[0061] In a further embodiment, docetaxel is orally administered at a dose of 50mg weekly in the treatment of mCRPC. Such administration is preferably performed on a twice-daily weekly schedule. The ritonavir dose for mCRPC patients should be adjusted to obtain a prescribed AUC. Thus, a twice-daily weekly schedule is provided herein for the treatment of mCRPC. In that schedule, docetaxel is orally administered on the same day at a dose of 30mg docetaxel and 200mg ritonavir in the first dose, and at a dose of 20mg docetaxel and 100mg ritonavir in the second dose.

[0062] The taxane concentration in the subject can be controlled prior to treatment and / or monitored and controlled during treatment after oral administration of the taxane and ritonavir (or other P-gp inhibitor). Such monitoring and control can alternatively (or additionally) be performed by measuring the taxane in plasma. Such monitoring and control can also be performed by monitoring side effects. Taxane clearance in the subject can vary for unknown reasons. Thus, monitoring the taxane concentration in the subject during treatment allows the dosage of the taxane to be adjusted to maintain the taxane concentration in the subject at an appropriate level. Monitoring side effects also aids in this. If the area under the curve is measured, the appropriate dosage of the combination of ritonavir (or other P-gp inhibitor) and taxane that achieves the desired exposure level of the tumor tissue can be determined. For example, the first application may result in too large an increase in the area under the curve, resulting in undesirable side effects. The second application achieves the defined area under the curve, providing the defined exposure level of the tumor tissue while significantly reducing side effects.

[0063] Thus, the present invention can include the steps of: - co-administering a taxane and ritonavir (or other P-gp inhibitor); - measuring the plasma level of a taxane in the subject; - optionally comparing the level of the taxane with a reference level; - determining a dosage of the taxane for subsequent co-administration of the ritonavir (or other P-gp inhibitor) and the taxane; -thereafter co-administering ritonavir (or other P-gp inhibitor) and a taxane.

[0064] Measuring the plasma level of the taxane after the first administration can ensure that the dosage (of both ritonavir (or other P-gp inhibitor) and taxane) selected for the first administration is the appropriate dosage. Conversely, if the plasma levels are too high or too low, the dosage of the subsequent combination of ritonavir (or other P-gp inhibitor) and taxane may be adjusted. The dosage of either ritonavir (or other P-gp inhibitor) or taxane, or both ritonavir (or other P-gp inhibitor) and taxane may be adjusted. Thus, the dosage of ritonavir (or other P-gp inhibitor) may remain the same for the first administration and subsequent doses, and the dosage of taxane may be adjusted to compensate for the increase or decrease in the plasma level of the taxane. Thus, in such methods of treatment that include measuring the plasma level of the taxane, ritonavir (or other P-gp inhibitor) is administered at a predetermined dosage. Alternatively, the taxane dose may remain the same for the first and subsequent doses, and the ritonavir (or other P-gp inhibitor) dose adjusted to compensate for increases or decreases in the plasma levels of the taxane. Adjusting the taxane dose to eradicate tumor cells is preferred.

[0065] Thus, throughout treatment, at least subsequent taxane dosages of the combination of ritonavir (or other P-gp inhibitors) and taxane are sufficient to obtain the desired taxane exposure level in tumor tissue, which may be equivalent or at least equivalent to the standard of care for the taxane. Preferably, the method of treating cancer includes multiple administrations of the combination of ritonavir (or other P-gp inhibitors) and taxane, measuring the level of taxane after each administration to determine the taxane dosage for subsequent combination administrations of ritonavir (or other P-gp inhibitors) and taxane. Thus, if the subject's taxane concentration increases compared to the reference level, the dosage of the taxane is decreased, and if the taxane concentration decreases compared to the reference level during treatment, the dosage of the taxane is increased compared to the previously administered dosage.

[0066] In another embodiment, the present invention may include the following steps. - measuring the expression of ritonavir (or other P-gp inhibitors) in the subject; - optionally comparing the expression of ritonavir (or other P-gp inhibitors) with a reference level; - determining a dosage of ritonavir (or other P-gp inhibitor) based on the expression level of ritonavir measured in the subject; - administering the determined dosage of a combination of ritonavir (or other P-gp inhibitor) and a taxane; The taxane dosage is characterized as being sufficient to achieve a level of tumor tissue exposure to the taxane comparable to standard of care taxane treatment.

[0067] Since the expression of ritonavir (or other P-gp inhibitors) in a subject may affect the dosage of taxane administered to obtain a sufficient exposure level, measuring the expression of ritonavir (or other P-gp inhibitors) has the advantage of taking into account possible variability between subjects. This can be done before starting treatment. The expression of ritonavir (or other P-gp inhibitors) in a subject can be measured by known means, but also by measuring the plasma level of ritonavir (or other P-gp inhibitors) or other indirect methods. Knowing the appropriate dosage of ritonavir (or other P-gp inhibitors) before starting treatment allows the desired exposure level of docetaxel to be obtained in the subject immediately after starting treatment. Thus, in a preferred embodiment, in the method according to the invention, the step of measuring the expression, the optional subsequent step of comparing, and the step of determining the dosage of ritonavir (or other P-gp inhibitors) are carried out before the first administration of the combination of ritonavir (or other P-gp inhibitors) and taxane.

[0068] In yet a further embodiment, a kit is provided for use in the methods and uses described herein for the combination of a taxane with a P-gp inhibitor, such as ritonavir or elacridar. In one embodiment, a kit is provided that includes a pharmaceutical composition. The kit includes a taxane for oral administration and a pharmaceutical composition including a P-gp inhibitor, such as ritonavir or elacridar. In another embodiment, a kit is provided that includes a pharmaceutical composition including a taxane for oral administration and a pharmaceutical composition including a P-gp inhibitor, such as ritonavir or elacridar. The kit is for the treatment of solid tumors, particularly non-small cell lung cancer, gastric cancer, breast cancer, head and neck cancer or prostate cancer, more particularly mCRPC. In yet another embodiment, a kit is provided that includes a pharmaceutical composition including a taxane and a pharmaceutical composition including a P-gp inhibitor, such as ritonavir or elacridar, for use in the combination therapy defined in any one of the methods and uses of the invention described herein.

[0069] The pharmaceutical compositions of the present invention may comprise a taxane, or a pharma- ceutically acceptable salt or ester thereof, and / or ritonavir (or other P-gp inhibitor) or a pharma- ceutically acceptable salt or ester thereof, together with any pharma- ceutically acceptable carrier, adjuvant or vehicle.

[0070] As used in the description of the invention, the clauses and clauses appended to the claims, the singular forms "a", "an" and "the" are used interchangeably and are intended to include the plural forms and to apply to each meaning unless the context clearly indicates otherwise. Additionally, as used herein, "and / or" refers to all possible combinations of one or more of the listed items, and also includes the absence of a combination when interpreted alternatively ("or"). The term "about" as used herein will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If the use of the term is not clear to a person of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the term. EXAMPLES

[0071] overview In the first study, the protein expression levels of P-gp in parental and docetaxel-resistant prostate cancer cell lines (DU-145, DU-145 DOC10, 22Rv1, and 22Rv1 DOC8) were evaluated by Western blot analysis. The study consisted of five parts. In the first part, the protein expression levels of P-gp in parental and docetaxel-resistant cell lines were evaluated by Western blot analysis. Then, cabazitaxel monotherapy was evaluated for its anticancer activity against the four cell lines using a 3D clonogenic assay to determine concentrations for subsequent combination studies. The anticancer activity of three-drug combinations, docetaxel + elacridar, docetaxel + tonavir, and cabazitaxel + ritonavir, was investigated using a 3D clonogenic assay in an 8 × 2 matrix layout combining eight concentrations of the first compound and two concentrations of the second compound. Colony counts based on image analysis were used as readouts. Data analysis used the Bliss independent approach to identify additive / synergistic / antagonistic effects. A clear upregulation of P-gp (MDR1) protein expression was observed in the resistant cell lines compared to the corresponding parental cell lines. This was consistent with the results of a previous study, which showed that both resistant cell lines overexpressed mdr-1 mRNA by RNA-Seq.

[0072] Ritonavir and elacridar have been shown to inhibit P-gp and were tested in combination with docetaxel to determine their effect on reversing docetaxel resistance. At a ritonavir concentration of 31.6 μM, the relative IC 50 The value decreased from 0.219 μM to 0.0026 μM (84-fold), and a strong synergistic effect was observed at the intermediate concentration of docetaxel. Ritonavir at 100 μM completely inhibited tumor colony formation, and no additional effect was seen in combination with docetaxel.

[0073] In the combination of docetaxel + / - elacridar, synergy was observed in the docetaxel-resistant cell lines 22Rv1 DOC8 and DU-145 DOC10, but not in the parental cell line DU-145. Thus, the effect of ritonavir observed in previous studies could be reproduced by elacridar, strongly suggesting that inhibition of P-gp is responsible for the resistance-reversing effect.

[0074] Next, the anticancer activity of cabazitaxel monotherapy against the four cell lines was studied using a 3D clonogenic assay and IC 50 Cabazitaxel inhibited tumor cell proliferation in a concentration-dependent manner in all four cell lines, with IC50 values ​​higher in docetaxel-resistant cell lines compared to the parental cell lines. 50 14.5-fold higher relative IC for 22Rv1 compared to 22Rv1 50 In the case of DU-145 DOC8, IC 50 The shift in values ​​was 2.7-fold. Thus, resistance to docetaxel also led to reduced sensitivity to cabazitaxel.

[0075] Strong synergy was observed in the combination of cabazitaxel + / - ritonavir in the docetaxel-resistant cell line 22Rv1 DOC8, but no or low synergy was observed in the parental cell line and U-145 DOC10. In 22Rv1 DOC8, resistance to cabazitaxel was completely reversed by ritonavir.

[0076] Experimental Method For single agent efficacy experiments, a stock stock solution of cabazitaxel was prepared by dissolving the compound powder in DMSO at a concentration of 10 mM. From this stock solution, a working stock solution of 0.1 mM (330x the highest tested concentration) was prepared. This solution was aliquoted and stored at -20°C. On each day of the experiment, a frozen aliquot of the working stock solution was thawed and stored at room temperature before and during treatment. First, serial half-log dilutions of the working stock solution were prepared in DMSO. These dilutions were then diluted 1:22 into cell culture medium in the intermediate dilution plate. Finally, 10 μl taken from the intermediate dilution plate was transferred to 140 μl / well of the final assay plate. Thus, the DMSO working stock was diluted 1:330 and the DMSO concentration in the assay was 0.3% v / v.

[0077] For combination experiments, working stock solutions of docetaxel, ritonavir, elacridar, and cabazitaxel were prepared in DMSO at 660-fold concentrations of the highest test concentration used. Aliquots of this stock solution were stored at -20°C. On each day of the experiment, frozen aliquots of the working stock solutions were thawed and stored at room temperature before and during treatment. First, the 660-fold concentrated working stocks were diluted 1:2 in DMSO (for monotherapy controls) or mixed with equal volumes of the combined working stocks (for drug combinations). These 330-fold concentrated solutions were then diluted to various dilutions in DMSO to create an 8 × 2 matrix of combination allocations. The DMSO dilutions were further diluted 1:22 in cell culture medium (IMDM, supplemented with 20% (v / v) fetal bovine serum, 50 μg / ml gentamicin) in intermediate dilution plates. Finally, 10 μl from the intermediate dilution plate was transferred to 140 μl of cells and medium per well in the final assay plate, so that the DMSO dilutions used for single and combination treatments were diluted 1:330 and the DMSO concentration in the assay was 0.3% v / v.

[0078] DU-145 DOC10 was generated from DU-145, and 22Rv1 DOC8 was generated from 22Rv1. 22Rv1 was obtained from the American Cell Culture Collection (ATCC, Rockville, MD, USA), and DU-145 was obtained from the National Cancer Institute (NCI, Bethesda, MD, USA).

[0079] Tumor cell lines were cultured in RPMI 1640 medium (Biochrom) supplemented with 10% (v / v) fetal bovine serum and 50 μg / ml gentamicin in a humidified atmosphere of 5% CO2 at 37 °C. Docetaxel-resistant sublines were cultured in the presence of 8 nM (22Rv1) or 10 nM docetaxel (DU-145). Cells were routinely passaged 1-2 times per week and maintained in culture for up to 20 passages. For the assay, cells were harvested using TrypLE and the percentage of viable cells was measured with a CASY T cell counter (OMNI Life Science).

[0080] Clonogenic assays were performed in a 96-well plate format using ultra-low attachment plates. For each test, cells were prepared and assay plates were set up as follows: each test well contained a layer of semi-solid medium containing tumor cells (50 μl) and a second layer of medium supernatant with or without test compound (100 μl). The cell layer was 2 × 10 cells / well. 3 From 3×10 3Tumor cells were plated at 50 μg / well in cell culture medium (IMDM, supplemented with 20% (v / v) fetal bovine serum, 50 μg / ml gentamicin, and 0.4% (w / v) agar). After 24 h, the soft agar layer was covered with 90 μl of the same culture medium without agar, serially diluted in DMSO and transferred to cell culture medium, after which 10 μl of control medium or test compound was added and left on the cells for the duration of the experiment (continuous exposure, 100 μl drug overlay). Each plate contained six untreated control wells and six drug-treated groups. Duplicate values ​​were obtained by testing a single value per condition on one plate. Cultures were incubated at 37 °C and 7.5% CO2 in a humidified atmosphere for 13 days, and colony growth was closely monitored using an inverted microscope. During this period, tumor growth resulted in colonies >50 μm in diameter (area >2000 μm 2 At the time of maximum colony formation, surviving colonies were stained with a sterile aqueous solution of 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyltetrazolium chloride (INT, 1 mg / ml, 25 μL / well) for 48 h, and the number of colonies was counted using an automated image analysis system (Cell Insight NXT, Thermo Scientific or Bioreader 5000 V-alpha, BIO-SYS GmbH).

[0081] Results and Discussion As shown in Figure 1, DU-145 prostate cancer cells exposed to docetaxel for 3 months had an IC 50 Acquired resistance was observed, with an approximate 20-fold increase in β-blockers. Cell resistance was confirmed in a 3D culture (clone formation assay) set-up. Resistance to docetaxel was more pronounced in a 2D set-up (21-fold) than in a 3D set-up (3.3-fold).

[0082] As shown in Figure 2, 22Rv1 prostate cancer cells exposed to docetaxel for 3 months had an IC 50Acquired resistance was observed, with values ​​increasing by more than 100-fold. Cell resistance was confirmed in a 3D culture (clone formation assay) set-up. Resistance to docetaxel was more pronounced in a 2D set-up (105-fold) than in a 3D set-up (42-fold).

[0083] As shown in Figure 3, overexpression of P-glycoprotein (P-gp protein) is observed in docetaxel-resistant prostate cancer cells. Extremely high P-gp protein overexpression is observed in DU-145 DOC10 cells. P-gp protein overexpression is also observed in 22RV1 DOC8 cells. High overexpression of P-gp (MDR-1) mRNA is also observed in DU-145 DOC10 cells (3287-fold overexpression compared to parental cells) and 22Rv1 DOC8 cells (2772-fold overexpression). 22RV1 DOC8 cells express less P-gp protein than DU-145 DOC10, despite being much more resistant to docetaxel (134-fold and 22-fold in 2D culture conditions, respectively). This also suggests that in patients with naturally high or overexpressed P-gp protein expression, incipient resistance to taxanes may exist.

[0084] As shown in Figure 4, in both drug-resistant cell lines DU-145 DOC10 and 22Rv1 DOC8, the most upregulated gene was ABCB1 (P-glycoprotein) (3287-fold in DU145 DOC10 and 2773-fold in 22Rv1 DOC8), again suggesting that in patients with naturally high or overexpressed P-gp protein expression, incipient resistance to taxanes may exist.

[0085] Therefore, it was concluded that docetaxel resistance in DU-145 and 22Rv1 prostate cancer cell lines appears to be primarily driven by distinct gene expression and functional pathway responses. Some overlap was identified in the responses of the two cell lines, which may suggest a common resistance-related mechanism. P-glycoprotein was the most overexpressed gene in both cell lines.

[0086] Ritonavir is an inhibitor of P-glycoprotein. As shown in Figure 5 and the table below, ritonavir reverses docetaxel resistance in castration-resistant DU-145 DOC10 prostate cancer cells (clonogenic assay). 10 μM ritonavir reverses docetaxel resistance in castration-resistant DU-145 DOC10 prostate cancer cells (Clonogenic assay). 50 Addition of 10 μM ritonavir to resistant cells resulted in a 3.4-fold decrease in IC 50 =2.9nM) and has the same sensitivity (IC 50 = 2.8 nM), demonstrating reversal of resistance. [Table 1]

[0087] As shown in Figure 6, ritonavir and docetaxel acted synergistically in docetaxel-resistant DU-145 DOC10 prostate cancer cells (clonogenic assay). 10 μM ritonavir increased the sensitivity to docetaxel (IC 50 The combination of 10 μM ritonavir and 3 nM docetaxel produced a strong synergistic effect in DU-145 DOC10-resistant cells, in contrast to parental cells.

[0088] Ritonavir also reverses docetaxel resistance in 22Rv1 DOC8-resistant prostate cancer cells, as shown in Figure 7 and the table below. In resistant cells, a strong synergistic effect was observed with the combination of 32 μM ritonavir and moderate concentrations of docetaxel (3.16 nM to 316 nM), demonstrating that resistance can be reversed by ritonavir. [Table 2]

[0089] As shown in Figure 8, ritonavir and cabazitaxel cause synergistic effects in parental DU-145 prostate cancer cells. Ritonavir inhibits the proliferation of DU-145 at concentrations above 10 μM. The combination of 10 μM ritonavir and 0.3 nM cabazitaxel has synergistic effects in DU145 cells.

[0090] As shown in Figure 9, ritonavir and cabazitaxel induce a synergistic effect in docetaxel-resistant DU-145 DOC10 prostate cancer cells. Ritonavir inhibits the proliferation of DU145 DOC10 at concentrations of 10 μM or higher. The combination of 10 μM ritonavir and 1 nM cabazitaxel has a synergistic effect in DU-145 DOC10-resistant cells.

[0091] As shown in Figure 10 and the table below, ritonavir reverses cabazitaxel resistance in docetaxel-resistant DLI145 DOC10 prostate cancer cells. 10 μM ritonavir reverses cabazitaxel resistance in docetaxel-resistant DLI145 DOC10 prostate cancer cells, increasing sensitivity to docetaxel (IC 50 Addition of 10 μM ritonavir to resistant cells resulted in a 2.5-fold decrease in IC 50 =0.6nM) and has the same sensitivity (IC 50 = 0.6 nM), demonstrating reversal of resistance. [Table 3]

[0092] As shown in Figure 11, ritonavir and cabazitaxel induced synergy in docetaxel-resistant 22Rv1 DOC8 prostate cancer cells. The combination of 32 μM ritonavir with 1, 3, and 10 nM cabazitaxel results in synergy in 22Rv1 DOC8-resistant cells.

[0093] As shown in Figure 12 and the table below, ritonavir reverses cabazitaxel resistance in docetaxel-resistant 22Rv1 DOC8 prostate cancer cells. 32 μM ritonavir reverses cabazitaxel resistance in docetaxel-resistant 22Rv1 DOC8 prostate cancer cells by increasing sensitivity to docetaxel (IC 50 Addition of 32 μM ritonavir to resistant cells resulted in a 14-fold decrease in the IC 50 =0.7nM) and has the same sensitivity (IC 50 = 0.7 nM), demonstrating reversal of resistance. [Table 4]

[0094] As shown in Figure 13 and the table below, elacridar reverses docetaxel resistance in castration-resistant DU-145 DOC10 prostate cancer cells. Elacridar at 0.3 and 1 μM reverses docetaxel resistance in castration-resistant DU-145 DOC10 prostate cancer cells, increasing sensitivity to docetaxel (IC 50 Addition of 0.3 and 1 μM elacridar to resistant cells induced a 6- to 7-fold decrease in IC 50 =1.1nM) and has almost the same sensitivity (IC 50 = 1.9 nM and 1.6 nM), demonstrating reversal of resistance. [Table 5]

[0095] As shown in Figure 14, elacridar and docetaxel exhibited synergistic effects in docetaxel-resistant DU-145 DOC10 prostate cancer cells (clonogenic assay). The combination of 0.3 or 10 μM elacridar with 3 or 10 nM docetaxel produced strong synergistic effects in DU-145 DOC10-resistant cells. No synergy was observed in parental DU-145 cells.

[0096] As shown in Figure 15 and the table below, elacridar reverses docetaxel resistance in castration-resistant 22Rv1 DOC8 prostate cancer cells. 0.3 and 1 μM elacridar reversed docetaxel resistance in castration-resistant 22Rv1 DOC8 prostate cancer cells by increasing sensitivity to docetaxel (IC 50 Addition of 0.3 and 1 μM elacridar to resistant cells induced a 100-fold decrease in the IC 50 =1.3nM) and has the same sensitivity (IC 50 = 1.4 and 1.3 nM), demonstrating reversal of resistance. [Table 6]

[0097] The above embodiments have been described by way of example only. Many other embodiments falling within the scope of the claims will be apparent to those skilled in the art. Thus, although the present invention has been described in connection with the preferred embodiment in the various figures, it is understood that other similar embodiments may be used, or modifications or additions may be made to the described embodiment, to perform the same functions of the present invention without departing from the spirit and scope of the present invention. Thus, the present invention should not be limited to a single embodiment, but rather should be construed broadly and extensively in accordance with the description of the appended claims.

[0098] Features described above in relation to any aspect or embodiment of the present invention are disclosed herein in relation to all other aspects and embodiments.Similarly, any combination of two or more of the above individual features or elements may be present in any aspect or embodiment.For the sake of brevity, not all possible features and combinations are listed in relation to all aspects and embodiments, but they are expressly contemplated and hereby disclosed.

Claims

1. A method for treating cancer in a taxane-resistant patient comprising administering an effective amount of a taxane, either simultaneously or sequentially, with ritonavir or a pharma- ceutically acceptable salt thereof.

2. SUMMARY OF THE DISCLOSURE A method for reversing taxane resistance in a patient comprising administering an effective amount of ritonavir or a pharma- ceutically acceptable salt thereof.

3. 3. The method of claim 2, for treating cancer, wherein ritonavir or a pharma- ceutically acceptable salt thereof is administered simultaneously or sequentially with an effective amount of a taxane.

4. 4. The method of claim 1 or 3, wherein the cancer comprises a solid tumor.

5. 5. The method of claim 1, 3 or 4, wherein the cancer is selected from the group consisting of gastric cancer, breast cancer, head and neck cancer, lung cancer and prostate cancer.

6. 6. The method of claim 5, wherein the cancer is prostate cancer.

7. 6. The method of claim 5, comprising determining whether the cancer responds to treatment by measuring the responsiveness of DU-145 or 22Rv1 cell lines to an effective dose of a taxane, either simultaneously or sequentially with ritonavir or a pharma- ceutically acceptable salt thereof.

8. 10. The method according to any one of the preceding claims, characterized in that ritonavir and / or taxane are administered orally.

9. 10. The method according to any one of the preceding claims, characterized in that ritonavir and / or taxane are administered intravenously.

10. The taxane is characterized in that it is selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof.

13. A method according to any one of the preceding claims.

11. 2. The method of any one of the preceding claims, wherein the taxane is docetaxel, or a pharma- ceutically acceptable salt or ester thereof.

12. 2. The method according to any one of the preceding claims, wherein ritonavir is administered in a weekly dose of about 50 mg to about 1200 mg.

13. The method according to any one of claims 1 to 11, characterized in that ritonavir is administered in a daily dosage of about 50 mg to about 1200 mg.

14. 10. The method of any one of the preceding claims, wherein the taxane is administered in a weekly dose of about 30 mg to about 500 mg.

15. The method according to any one of claims 1 to 13, wherein the taxane is administered in a daily dosage of about 0.1 mg to about 100 mg.

16. 12. The method of any one of claims 1 or 3-11, wherein ritonavir is administered in a dosage amount of about 50 mg to about 1200 mg per day and the taxane is administered in a dosage amount of about 0.1 mg to about 100 mg per day, and the daily dosages of ritonavir and taxane may be taken at the same or different times of day.

17. 12. The method of any one of claims 1 or 3-11, wherein ritonavir is administered in a weekly dosage of about 50 mg to about 1200 mg and the taxane is administered in a weekly dosage of about 30 mg to about 500 mg, and wherein the weekly dosages of ritonavir and taxane may be taken on the same or different days.

18. A taxane for use in combination therapy with ritonavir, or a pharma- ceutically acceptable salt thereof, to treat cancer in a taxane-resistant patient.

19. 19. The method of claim 18, wherein ritonavir or a pharma- ceutically acceptable salt thereof is administered simultaneously or sequentially with the taxane.

20. 20. The taxane for use according to claim 18 or 19, characterized in that the cancer comprises a solid tumor.

21. The taxane for use according to any one of claims 18 to 20, characterized in that the cancer is selected from the group consisting of gastric cancer, breast cancer, head and neck cancer, lung cancer and prostate cancer.

22. 22. The taxane for use according to claim 21, characterized in that the cancer is prostate cancer.

23. 22. The method of claim 21, wherein said use comprises determining whether said cancer responds to treatment by measuring the responsiveness of DU-145 or 22Rv1 cell lines to an effective dose of combination therapy.

24. The taxane for use according to any one of claims 18 to 23, characterized in that the ritonavir and / or the taxane are administered orally.

25. The taxane for use according to any one of claims 18 to 24, characterized in that the ritonavir and / or the taxane are administered intravenously.

26. The taxane for use according to any one of claims 18 to 25, characterized in that the taxane is selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof.

27. The taxane for use according to any one of claims 18 to 26, characterized in that said taxane is docetaxel or a pharma- ceutically acceptable salt or ester thereof.

28. The taxane for use according to any one of claims 18 to 27, characterized in that ritonavir is administered in a weekly dose of about 50 mg to about 1200 mg.

29. The taxane for use according to any one of claims 18 to 27, characterized in that ritonavir is administered in a daily dose of about 50 mg to about 1200 mg.

30. The taxane is administered in a weekly dosage of about 30 mg to about 500 mg. Taxanes for use according to any of claims 18 to 29

31. The taxane is administered in a daily dosage of about 0.1 mg to about 100 mg. A taxane for use according to any one of claims 18 to 29.

32. 28. The taxane for use according to any one of claims 18 to 27, wherein ritonavir is administered in a dosage of about 50 mg to about 1200 mg per day and said taxane is administered in a dosage of about 0.1 mg to about 100 mg per day, and the daily dosages of ritonavir and said taxane can be taken at the same or different times of the day.

33. 28. The taxane for use according to any one of claims 18 to 27, characterized in that ritonavir is administered in a weekly dosage of about 50 mg to about 1200 mg and said taxane is administered in a weekly dosage of about 30 mg to about 500 mg, and the weekly dosages of ritonavir and said taxane can be taken on the same or different days.

34. Ritonavir, or a pharma- ceutically acceptable salt thereof, used to reverse taxane resistance in a patient.

35. 35. Ritonavir, or a pharma- ceutically acceptable salt thereof, according to claim 34, for use in the treatment of cancer in a taxane-resistant patient, wherein the ritonavir is administered concomitantly or sequentially with an effective amount of the taxane.

36. 36. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to claim 35, characterized in that the cancer comprises a solid tumor.

37. 37. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to claim 35 or 36, characterized in that the cancer is selected from the group consisting of gastric cancer, breast cancer, head and neck cancer, lung cancer, and prostate cancer.

38. 38. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to claim 37, characterized in that the cancer is prostate cancer.

39. 38. The method of claim 37, comprising determining whether the cancer responds to treatment by administering ritonavir or a pharma- ceutical acceptable salt thereof, either simultaneously or sequentially, and measuring the responsiveness of DU-145 or 22Rv1 cell lines to an effective dose of a taxane, said method comprising administering ritonavir or a pharma- ceutical acceptable salt thereof, either simultaneously or sequentially, and determining whether the cancer responds to treatment.

40. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 34 to 39, characterized in that the ritonavir and / or the taxane are administered orally.

41. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 34 to 40, characterized in that the ritonavir and / or the taxane are administered intravenously.

42. 42. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 34 to 41, characterized in that the taxane is selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof.

43. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 34 to 42, characterized in that the taxane is docetaxel, or a pharma- ceutically acceptable salt or ester thereof.

44. 44. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 34 to 43, characterized in that ritonavir is administered in a weekly dose of about 50 mg to about 1200 mg.

45. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 34 to 43, characterized in that ritonavir is administered in a daily dose of about 50 mg to about 1200 mg.

46. 46. ​​Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 35 to 45, characterized in that the taxane is administered in a weekly dose of about 30 mg to about 500 mg.

47. 46. ​​Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 35 to 45, characterized in that the taxane is administered in a daily dosage of about 0.1 mg to about 100 mg.

48. 44. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 35 to 43, characterized in that the ritonavir is administered in a dosage of about 50 mg to about 1200 mg per day and the taxane is administered in a dosage of about 0.1 mg to about 100 mg per day, the daily doses of ritonavir and taxane can be taken at the same or different times of the day.

49. 44. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use according to any one of claims 35 to 43, wherein ritonavir is administered in a weekly dose of about 50 mg to about 1200 mg and said taxane is administered in a weekly dose of about 30 mg to about 500 mg, and wherein the weekly doses of ritonavir and said taxane can be taken on the same or different days.

50. 20. A method for sensitizing or re-sensitizing cells to taxanes in the treatment of cancer comprising administering an effective amount of ritonavir or a pharma- ceutically acceptable salt thereof.

51. 51. The method of claim 50, wherein the taxane is selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof.

52. Ritonavir, or a pharma- ceutically acceptable salt thereof, for use in sensitizing or resensitizing cells to taxanes in the treatment of cancer.

53. 53. Ritonavir for use according to claim 52, characterized in that the taxane is selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof.

54. A kit having at least one pharmaceutical composition comprising a taxane and at least one pharmaceutical composition comprising a P-gp inhibitor, characterized in that the kit is used for treating cancer in a taxane-resistant patient.

55. 55. The kit of claim 54, wherein the taxane is selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof.

56. 56. The kit according to claim 54 or 55, characterized in that the P-gp inhibitor is selected from the group consisting of ritonavir, elacridar and combinations thereof, or pharma- ceutically acceptable salts thereof.

57. A kit according to any one of claims 54 to 56, characterized in that it contains instructions for the simultaneous or sequential use of the pharmaceutical compositions for treating cancer in a taxane-resistant patient.

58. 1. A method of treating cancer comprising a combination of a P-gp inhibitor and a taxane, measuring the expression of ABCB1 (P-gp) in the patient; Optionally, comparing the expression of ABCB1 (P-gp) to a reference level; Optionally, determining the dosage of said P-gp inhibitor based on the expression level of ABCB1 (P-gp) measured in said patient; administering a combination of said P-gp inhibitor and said taxane; The method includes:

59. 59. The method of claim 58, wherein the taxane is selected from the group consisting of docetaxel, cabazitaxel, pharma- ceutically acceptable salts or esters thereof, and combinations thereof.

60. 60. The method according to claim 58 or 59, characterized in that the P-gp inhibitor is selected from the group consisting of ritonavir, elacridar and combinations thereof, or pharma- ceutically acceptable salts thereof.

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