Medical uses of calcium channel blockers in combination with tumor treating fields (ttfields)

Abstract

This invention describes how reduced viability and tumor size of cancer cells (e.g., glioblastoma cells) can be achieved by applying an alternating electric field of 100-500 kHz (e.g., 200 kHz) to these cancer cells and inhibiting interleukin-11 (IL11) activity, and by administering antifibrotic agents as needed. Inhibition of IL11 activity can be achieved, for example, by reducing IL11 expression, inhibiting IL11 signaling, downregulating IL11, neutralizing IL11, blocking IL11 receptors, administering IL11 antagonists, administering IL11 neutralizing antibodies, or administering IL11 receptor α (IL11Ra) neutralizing antibodies.

Description

[Technical Field]

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 882,813, filed on August 5, 2019, which is incorporated herein by reference in its entirety. [Previous Technology]

[0003] Tumor Treating Fields (TTFields) are low-intensity (e.g., 1-3 V / cm) alternating electric fields in the mid-frequency range (e.g., 100-500 kHz) that inhibit cancer cell growth. This non-invasive treatment targets solid tumors and is described in U.S. Patent 7,565,205, which is incorporated herein by reference in its entirety. TTFields are FDA-approved for the treatment of glioblastoma (GBM) and can be delivered, for example, via the Optune™ system. Optune™ includes an electric field generator and two pairs of transducer arrays (i.e., electrode arrays) placed on the patient's laser head. One pair of electrodes is positioned on the left and right sides of the tumor, and the other pair of electrodes is positioned on the anterior and posterior parts of the tumor. In a preclinical setting, TTFields can be applied in vitro using, for example, the Inovitro™ TTFields benchtop laboratory system. [Summary of the Invention]

[0004] One aspect of the present invention relates to a first method for reducing the viability of cancer cells. The first method includes applying an alternating current electric field to the cancer cells, the alternating current electric field having a frequency between 100 kHz and 500 kHz; and inhibiting IL11 activity.

[0005] In some cases of the first method, the frequency of the alternating electric field is between 180 kHz and 220 kHz. In some cases of the first method, the cancer cells include glioblastoma cells and hepatocytes.

[0006] In some embodiments of the first method, inhibiting IL11 activity includes at least one of reducing IL11 expression, inhibiting IL11 signaling, downregulating IL11, neutralizing IL11, and blocking IL11 receptors. In some embodiments of the first method, inhibiting IL11 activity includes administering at least one of an IL11 antagonist, an IL11 neutralizing antibody, and an IL11 receptor α (IL11Ra) neutralizing antibody.

[0007] In some cases of the first method, the individual is administered a therapeutically effective concentration of a fibrosis inhibitor. In some cases of the second method, administering the fibrosis inhibitor includes administering to the individual at least one of fasudil, pirfenidone, nintedanib, losartan, hyaluronidase, tranilast, and vismodegib. In some cases, the individual is administered at least one of a broad-spectrum tyrosine kinase inhibitor (e.g., sorafenib, sunitinib, and imatinib) at a therapeutically effective concentration.

[0008] Another aspect of the present invention relates to a second method for reducing tumor volume in a living individual. The second method includes applying an alternating current field to the tumor, the alternating current field having a frequency between 100 kHz and 500 kHz; and administering a therapeutically effective concentration of an IL-11 inhibitor to the individual.

[0009] In some cases of the second method, the frequency of the alternating electric field is between 180 kHz and 220 kHz. In some cases of the second method, at least a portion of the application step is performed simultaneously with at least a portion of the feeding step.

[0010] In some cases of the second method, administering the IL11 inhibitor includes administering at least one of an IL11 antagonist, an IL11 neutralizing antibody, and an IL11 receptor α (IL11Ra) neutralizing antibody.

[0011] In some cases of the second method, administering the IL11 inhibitor includes administering at least one of an IL13 antagonist, an IL13 neutralizing antibody, and an IL13 receptor α (IL13Ra) neutralizing antibody.

[0012] In some cases of the second method, the individual is given a therapeutically effective concentration of a fibrosis inhibitor.

[0013] In some cases of the second method, administering the fibrosis inhibitor includes administering to the individual at least one of fasudil, pirfenidone, nintedanib, losartan, hyaluronidase, tranilast and vemodil.

[0014] In some cases, the second method further comprises administering to the individual at a therapeutically effective concentration of at least one of a broad-spectrum tyrosine kinase inhibitor (e.g., sorafenib, sunitinib, and imatinib). The tumor volume may be reduced by at least about 5-fold.

[0015] Another aspect of the present invention relates to a third method for reducing the viability of cancer cells located in a living individual. The third method includes applying an alternating current field to the cancer cells, the alternating current field having a frequency between 100 kHz and 500 kHz; and administering a therapeutically effective concentration of a fibrosis inhibitor to the individual.

[0016] In some cases of the third method, the frequency of the alternating electric field is between 180 kHz and 220 kHz. In some cases of the third method, at least a portion of the application step is performed simultaneously with at least a portion of the dosing step. In some cases of the third method, dosing the fibrosis inhibitor comprises administering to the individual at least one of fasudil, pirfenidone, nintedanib, losartan, hyaluronidase, tranilast, and vemodil.

[0017] In some cases of this third method, administering the fibrosis inhibitor includes administering a calcium channel blocker to the individual. Where necessary, in some of these cases, the calcium channel blocker includes at least one of felodipine, verapamil, diltiazem, and nifedipine.

Implementation Method

[0025] Generally, the electrical conductivity of most tumors is higher than that of the surrounding healthy tissue. This higher conductivity explains the specificity of TTFields for malignant tissues. More specifically, the power loss density of the electric field L is defined by equation (1), where σ is the electrical conductivity of the tissue and |E| is the intensity of the electric field. (Power loss density is measured in milliwatts per cubic centimeter). The higher electrical conductivity σ within tumor tissue will cause a higher power loss density within that specific tissue.

[0026] Clinical data showed a significant increase in interleukin-11 (IL11) expression in tumors from GBM patients treated with TTFields. This data was obtained as follows: GBM tumor samples were obtained before and after treatment with either standard chemoradiotherapy (six patients) or a combination of TTFields and standard chemoradiotherapy (six patients). Gene expression analysis was performed using RNA-seq. Post-treatment performance and the different effects of the control group and TTFields treatment were analyzed using a negative binomial generalized linear model. Raw data were analyzed using DESeq2 software. Differential gene expression analysis was calculated using reads per kilobase million (RPKM) values ​​in the chemoradiotherapy and TTFields treatment groups. Statistical analysis was performed using a negative binomial generalized linear model. Differences in performance before and after treatment for each individual were derived, and the mean net treatment effect for each treatment group was calculated. Differences in treatment effects are expressed as fold changes between the mean net effects of TTFields and the control group. The Benjamin-Hochberg method was used to correct for fold change p-values ​​in multiple comparisons. A list of 712 genes related to immune activity was compiled using general literature, Nanostring's "nCounter® PanCancer immune profiling panel," and ThermoFischer's "Oncomine™ Immune Response" gene list.

[0027] A significant difference in the treatment effect between TTFields and the control group was defined as a fold change >2 or <0.5, where the adjusted p-value was <0.1. The table below presents genes that exhibited significant changes in gene expression. Gene Multiple change FDR P-val' IL11 8.5 0.001 GPR18 5.9 0.071 CD70 5 0.079 CCL26 4.5 0.031 NKG2D 4.2 0.034 T-bet 3.4 0.019 ICOS-L 3.3 0.094 ISG15 3.2 0.035 Fac. XII 3.1 0.032 HGF 3 0.041 GNLY 2.6 0.083 MMP2 2.5 0.036

[0028] Notably, the difference in IL11 expression with TTFields plus chemoradiotherapy (compared to the control group receiving chemoradiotherapy alone) was 8.5-fold. This increase in IL11, without being bound by the operational theory described below, raises two questions.

[0029] The first problem is that IL11 is known to be a fibrotic factor. Therefore, the increase in IL11 associated with TTFields application may lead to extracellular matrix remodeling and fibrosis within tumor tissue. Because fibrosis results in a reduction of both intracellular and extracellular fluid, the conductivity of fibrotic tissue is typically lower than that of non-fibrotic tissue. Therefore, IL11-promoted fibrosis will (over time) reduce the conductivity σ in the tumor, which in turn reduces the power loss density in the tumor as calculated by equation (1), thereby reducing the effectiveness of TTFields. This adverse event chain can be interrupted by inhibiting IL11 activity. More specifically, inhibiting IL11 activity will reduce fibrosis, which allows the conductivity σ to remain higher, thereby allowing the power loss density to remain higher, and thus allowing the effectiveness of TTFields to remain higher.

[0030] The expected effect of interrupting the aforementioned adverse event chain is supported by established experimental evidence that inhibiting IL11 can prevent cardiac and renal fibrosis.

[0031] The second question is that the expression of IL11 in tumors is associated with an invasive phenotype and poor prognosis in a wide range of tumors, including hepatocellular carcinoma, pancreatic cancer, gastric adenocarcinoma, non-small cell lung cancer, breast cancer, endometrial cancer and chondrosarcoma.

[0032] Both of the problems mentioned above can be improved by counteracting the increase in IL11 that occurs when the tumor is exposed to TTFields (e.g., by inhibiting IL11 activity).

[0033] Examples of suitable methods for inhibiting IL11 activity include: reducing IL11 expression, inhibiting IL11 signaling (e.g., by administering Bazedoxifene), downregulating IL11, neutralizing IL11, blocking IL11 receptors, administering IL11 antagonists (e.g., W147A), administering IL11 neutralizing antibodies (e.g., ENx108A, ENx203, or ENx209), and administering IL11 receptor α (IL11Ra) neutralizing antibodies.

[0034] Inhibition of IL11 activity can also be achieved indirectly by an IL11 inhibitor or an IL11 receptor α (IL11Ra) inhibitor. For example, since IL13 is a potent stimulant of both IL11 and IL11Ra, additional examples of suitable methods for inhibiting IL11 activity include: reducing IL13 expression, inhibiting IL13 signaling, downregulating IL13, neutralizing IL13 (e.g., by administering dupilumab), blocking IL13 receptors, administering IL13 antagonists, administering IL13 neutralizing antibodies, and administering IL13 receptor α (IL13Ra) neutralizing antibodies.

[0035] In view of the above, one method for treating tumors and reducing the viability of cancer cells is to apply TTFields to cancer cells and inhibit IL11 activity. This method is expected to improve the efficacy of TTFields treatment by addressing the two problems mentioned above. In vitro, the inhibition of IL11 activity can be achieved by administering a therapeutically effective concentration of an IL11 inhibitor to the individual.

[0036] One alternative method for treating tumors and reducing cancer cell viability is to apply TTFields to cancer cells, which generally inhibit fibrosis. This method is expected to improve the efficacy of TTFields treatment by improving the first problem mentioned above (regardless of whether the second problem mentioned above is improved). More specifically, because the conductivity of fibrotic tissue is typically lower than that of non-fibrotic tissue, IL11-induced fibrosis will (over time) reduce the conductivity σ in the tumor, which in turn reduces the power loss density in the tumor calculated by equation (1), thereby reducing the effectiveness of TTFields. This adverse event chain can be offset by using different methods to inhibit IL11-induced fibrosis.

[0037] In some specific instances, this is achieved using at least one of the following drugs: fasudil, pirfenidone, nintedanib, losartan, hyaluronidase, tranilast, and vemodigine (each of which contains a compound known to inhibit fibrosis). In other specific instances, this is achieved using calcium channel blockers known to inhibit fibrosis (e.g., felodipine, verapamil, diltiazem, and / or nifedipine). In other specific instances, this is achieved using any of a variety of other compounds known to inhibit fibrosis.

[0038] In some specific instances, this can be achieved using at least one antitumor and antifibrotic compound (e.g., sorafenib or any suitable broad-spectrum receptor tyrosine kinase inhibitor (RTKI) such as sunitinib and imatinib). In this case, sorafenib can reduce fibrosis and decrease tumor size, thereby improving tumor response to TTFields treatment.

[0039] In the specific examples described above that rely on inhibiting IL11 activity to suppress fibrosis, the reduction in the degree of fibrosis in such specific examples will allow the conductivity σ to remain high, thereby allowing the power loss density to remain high, thereby allowing the TTFields effect to remain high.

[0040] In vitro, fibrosis can be inhibited by administering a therapeutically effective concentration of fibrosis inhibitor to the individual.

[0041] In the in vitro setting, administration of one or more relevant molecules (e.g., IL11 inhibitors or fibrosis inhibitors) to cancer cells can be performed continuously from the moment the molecule circulates in the patient's body (e.g., after systemic administration) or is introduced into the vicinity of the cancer cells (t1) until the molecule is eliminated or depleted from the patient's body (t2). Therefore, if TTFields are applied to cancer cells between t1 and t2, the application step will be synchronized with at least a portion of the administration step. molecule administration to an individual can be performed using any of a variety of methods, including but not limited to intravenous, oral, subcutaneous, intrathecal, intramuscular, intraventricular, and intraperitoneal administration. Furthermore, the application of an alternating electric field to cancer cells can be performed using the Novocure Optune® system or variants thereof operating at different frequencies.

[0042] In some cases, fibrosis can be reduced using anti-fibrotic and anti-tumor agents. For example, the combination of TTFields and sorafenib is known to synergistically reduce tumor volume in hepatocellular carcinoma N1S1 cells. See U.S. Patent Application Publication 2020 / 0016067; Figure 1. As shown in Figure 1, the combination of TTFields and sorafenib causes a reduction in tumor volume of at least 10-fold.

[0043] The effects of TTFields alone and in combination with sorafenib on fibrosis in N1S1 tumors were evaluated. As assessed by pathologists, the combination of TTFields and sorafenib significantly reduced the fibrosis score compared to TTFields alone. Figures 3A and 3B. The fibrotic area of ​​the tumor was measured by area percentage and fold change, and a similar reduction in fibrosis was observed. Figures 4 and 5.

[0044] Decreased tumor fold size (Fig. 1A) and tumor volume (Fig. 1B) were associated with increased fibrosis scores in tumors treated with TTFields (Figs. 6A to 6B). Decreased tumor fold size and tumor volume were associated with increased fibrosis area (Figs. 6C to 6D).

[0045] In summary, TTFields can be combined with anti-IL11 and / or additional anti-fibrotic agents, as well as agents that can synergistically reduce tumor volume. In some cases, sorafenib can be used to reduce tumor volume and is also used as an anti-fibrotic agent as described herein.

[0046] As used herein, the term "reducing viability of cancer cells" refers to reducing the growth, proliferation, or survival of cancer cells. In some cases, reduced viability of cancer cells includes reducing the survival of cancer cell communities, increasing the cytotoxicity of cancer cells, inducing apoptosis in cancer cells, and reducing the tumor volume of tumors formed by at least some of the cancer cells.

[0047] The term "clonogenic survival" refers to the ability of a single cancer cell to grow into a cancer cell colony. In a phenotype, a "colony" consists of at least fifty cells.

[0048] The term "cytotoxicity" refers to a measure of the ability of a drug or treatment to kill cells.

[0049] The term "apoptosis" refers to the phenomenon known as "programmed cell death," which refers to cell death as part of the controlled cell cycle of cell growth and development.

[0050] As used herein, the term "therapeutically effective concentration" refers to the concentration of a compound sufficient to achieve its intended purpose (e.g., inhibiting IL-11 activity, inhibiting fibrosis, etc.). Example 1 - The combination of TTFields (150 kHz) and sorafenib resulted in a significant reduction in tumor volume in vitro.

[0051] As shown in Figures 1A and 1B and in U.S. Patent Application Publication 2020 / 0016067 (incorporated herein by reference in its entirety), the combination of TTFields and sorafenib at 150 kHz significantly reduced the fold increase in tumor volume in N1S1 hepatocellular carcinoma cells. Tumor volume was measured by MRI. Figures 1A and 1B show the results of the in vitro studies described below regarding N1S1 tumor volume in Sprague Dawley rats treated with heating, TTFields alone, sorafenib alone, and a combination of TTFields and sorafenib. In this experiment, tumor volume was measured using MRI on day 6 (the day before treatment began) and day 14 (the day after treatment ended); and the data points in Figure 1A represent the tumor volume on day 14 divided by the tumor volume on day 6. Therefore, numbers greater than 1 indicate tumor volume increase, and numbers less than 1 indicate tumor shrinkage between day 6 and day 14. In this figure, "*" indicates p < 0.1, "**" indicates p < 0.01, and "****" indicates p < 0.0001. As shown in Figure 1, there was a synergistic reduction in tumor volume after treatment with a combination of TTFields (2.86 V / cm) and sorafenib (10 mg / kg / day). Figure 1B shows the tumor volume. Example 2 - Fibrosis and TTFields Treatment

[0052] Eight-week-old male SD rats (Envigo Ltd., Israel) were anesthetized by intraperitoneal injection of ketamine (75 mg / kg) and xylazine (10 mg / kg) (Figure 2). After loss of postural reflexes, fur was removed from the upper abdominal region using a trimmer. The left lobe of the liver was surgically exposed, and a 10 μl cell suspension containing 50,000 N1-S1 hepatocellular carcinoma cells in an equal volume of serum-free culture medium and Matrigel (CORNING, Bedford, MA) was directly injected into the left lobe using a syringe with a 31-gauge needle. The peritoneal and abdominal muscle incisions were closed with surgical sutures, and the skin was closed with clips. The rats were allowed to recover for 6 days.

[0053] On day 6, all animals underwent their first MRI scan and were randomly assigned to the following treatment groups:

[0054] Group I - Rats were treated with sham heating electrodes and mediator injection.

[0055] Group II - Rats were treated with 150 kHz TTFields and a carrier injection.

[0056] Group III - Rats were treated with sorafenib at a dose of 10 mg / kg / day.

[0057] Group IV - Rats were treated with 150 kHz TTFields and 10 mg / kg / day of sorafenib.

[0058] On day 7, electrodes (TTFields or sham heating) were placed on the animals. Animals were treated with TTFields or sham heating for 6 days. Sorafenib or a control agent was administered via intraperitoneal injection for 5 of the 6 days of treatment. On day 13, all electrodes were removed, and the animals underwent a second MRI and were euthanized on day 14. Tumor volume was determined based on MRI scans on days 7 and 14 after tumor implantation. The MRI system was a Bruker Icon system operating at 1 Tesla, housed in the company's animal facility. Animals were anesthetized with isoflurane and placed prone in rat coils. T2-weighted coronal anatomical images were scanned using RARE sequences and the following parameters after localizer image: TR / TE 1900 / 51 ms, number of slices at 10, slice thickness 1 mm, FOV 55-65 mm, acquisition matrix 140, 8 mean values, acquisition time 4 minutes 18 seconds. Tumor volume was measured using the free ITK-SNAP software version 3.6.0-rc1 after manual tumor segmentation. (t-test; * P < 0.05, ** P < 0.01 and *** P < 0.001) (Figure 1).

[0059] Tumors were collected for histological assessment of fibrosis grade using a semi-quantitative assessment scale. Paraffin blocks were sectioned to a thickness of approximately 4 micrometers. Each section was placed on a glass slide and stained with hematoxylin and eosin (H&E) and Massen trichrome staining (MT). Fibrosis in sections stained with Massen trichrome was analyzed using a rating scale and digital morphology.

[0060] The H&E stained slides were examined by a pathologist, and the presence of pathological changes was scored using a semi-quantitative scoring system (Figures 3 and 3A), as detailed below:

[0061] Grade 0: No symptoms of fibrosis

[0062] Grade 1: Very mild fibrosis symptoms

[0063] Grade 2: Mild fibrosis symptoms

[0064] Grade 3: Moderate fibrosis symptoms

[0065] Level 4: Highly fibrotic

[0066] Level 5: Extremely high degree of fibrosis

[0067] As shown in Figure 3, the L*a*b* color space was used, and color segmentation (MT: fibrillation) of the blue-stained region was performed using MATLAB-based color segmentation. The L*a*b* color space is derived from the CIE XYZ tri-color stimulus values. The L*a*b* space consists of a luminance layer 'L*' or luminance layer, a chromaticity layer 'a*' indicating the position of the color along the red-green axis, and a chromaticity layer 'b*' indicating the position of the color along the blue-yellow axis. Example 3 - Morphological Measurement (Fibrillation Area Magnitude Change, Fibrillation Area Percentage)

[0068] Calculate the percentage of the stained area (Figure 3: upper right) to the whole tissue (Figure 3: upper right + lower left) as shown in Figure 4.

[0069] Morphological analysis of the percentage of fibrosis showed that the tumors from rats that received only TTFields had the highest fibrosis area (34% increase relative to the control group) and the tumors from rats that received only sorafenib (anti-fibrotic) had the lowest fibrosis area (30.4% decrease relative to the control group).

[0070] Compared with the control group, the combination treatment of TTFields and sorafenib resulted in a 20.8% reduction in fibrosis area. These results are summarized in "Fibrosis Area (Fold Change)" (Figure 5). The percentage change in fibrosis area is summarized in Figure 4. Example 4 - Correlation between tumor volume reduction and fibrosis increase in response to TTFields

[0071] Figures 6A to 6D show the correlations between (1) fibrosis score and tumor volume of TTFields-treated tumors (Figure 6A), (2) fibrosis score and tumor fold change of TTFields-treated tumors (Figure 6B), (3) fibrosis area and tumor fold change of TTFields-treated tumors (Figure 6C), and (4) fibrosis area and tumor volume of TTFields-treated tumors (Figure 6D). Unbound by theory, it is believed that reducing fibrosis associated with TTFields treatment makes tumors more susceptible to treatment with TTFields alone, or in combination with IL11 inhibitors, fibrosis inhibitors, or antitumor factor / fibrosis inhibitors (e.g., sorafenib).

[0072] Although the invention has been disclosed with reference to certain specific examples, various modifications, alterations, and changes may be made to the described specific examples without departing from the scope and domain of the invention, as defined in the appended claims. Therefore, it is intended that the invention is not limited to the described specific examples, but may have the full scope defined by the language of the following claims and their equivalents. [Simplified Explanation of the Diagram]

[0018] [Figures 1A to 1B] show the results of an exemplary study that showed that the combination of TTFields and sorafenib at 150 kHz caused a multiple increase in tumor volume and a reduction in tumor volume in N1S1 hepatocellular carcinoma cells.

[0019] [Figure 2] shows illustrative TTFields treatment and administration protocols for four treatment conditions (I, II, III and IV) used to assess fibrosis;

[0020] [Figure 3A] shows an exemplary histopathological assessment of fibrosis-specific Mason trichrome (MT) staining (blue) of processed N1S1 hepatocellular carcinoma tumors, which shows (1) the original image (for fibrosis scoring) (top left), (2) the color segmentation of fibrosis in the MT-stained section, where ROI-blue indicates fibrosis (for area calculation), (3) the whole tissue without fibrosis (for area calculation, red-eosin, bottom left); and (4) the extra-tissue area (bottom right).

[0021] [Figure 3B] shows the fibrosis score for the experiment described in Figure 3A;

[0022] [Figure 4] shows the fibrosis area (%) calculated from the experiment described in Figure 3A for each condition;

[0023] [Figure 5] shows the fibrous area under each condition, expressed as a multiple change, calculated from the experiment described above with respect to Figure 3A; and

[0024] [Figures 6A to 6D] show the correlations between: (1) fibrosis score and tumor volume of tumors treated with TTFields (Figure 6A); (2) fibrosis score and tumor fold change of tumors treated with TTFields (Figure 6B); (3) fibrosis area and tumor fold change of tumors treated with TTFields (Figure 6C); and (4) fibrosis area and tumor volume of tumors treated with TTFields (Figure 6D).

Claims

1. Use of at least one component comprising at least one calcium channel blocker in the preparation of a medicament for treating cancer in an individual, wherein the at least one calcium channel blocker is selected from the group consisting of felodipine, verapamil, diltiazem, nifedipine, and combinations thereof, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, pancreatic cancer, gastric adenocarcinoma, non-small cell lung cancer, breast cancer, endometrial cancer, and chondrosarcoma, wherein the medicament is used in a method comprising the steps of: (1) applying an alternating current electric field to a target area of ​​the individual for a period of time, wherein the frequency of the alternating current electric field is in the range of 100 kHz to 500 kHz; and (2) administering the medicament to the individual.

2. As requested in item 1, wherein at least a portion of step (1) and at least a portion of step (2) are performed simultaneously.

3. As claimed in claim 1, wherein the method further comprises the following steps: (3) administering to the individual at a therapeutically effective concentration of at least one additional component, wherein the at least one additional component comprises at least one ingredient selected from the group consisting of: sorafenib, sunitinib, imatinib, fasudil, pirfenidone, nintedanib, losartan, hyaluronidase, tranilast, vismodegib, and combinations thereof.

4. Use of at least one component comprising at least one calcium channel blocker in the preparation of a medicament for reducing the volume of a tumor in a living individual, wherein the at least one calcium channel blocker is selected from the group consisting of felodipine, verapamil, diltiazem, nifedipine, and combinations thereof, wherein the tumor is selected from the group consisting of hepatocellular carcinoma, pancreatic cancer, gastric adenocarcinoma, non-small cell lung cancer, breast cancer, endometrial cancer, and chondrosarcoma, wherein the medicament is used in a method comprising the steps of: (1) applying an alternating electric field to the tumor for a period of time, wherein the frequency of the alternating electric field is in the range of 100 kHz to 500 kHz; and (2) administering the medicament to the individual.

5. As requested in item 4, wherein at least a portion of step (1) and at least a portion of step (2) are performed simultaneously.

6. As claimed in claim 4, wherein the method further comprises the following steps: (3) administering to the individual at a therapeutically effective concentration of at least one additional component, wherein the at least one additional component comprises at least one ingredient selected from the group consisting of: sorafenib, sunitinib, imatinib, fasudil, pirfenidone, nintedanib, losartan, hyaluronidase, tranilast, vemodil, and combinations thereof.

7. As requested in claim 4, wherein the tumor volume is reduced by at least approximately 5 times.

8. Use of at least one component comprising at least one calcium channel blocker in the preparation of a medicament for reducing the viability of cancer cells distributed in a living individual, wherein the at least one calcium channel blocker is selected from the group consisting of: felodipine, verapamil, diltiazem, nifedipine, and combinations thereof, wherein the cancer cells are cells of cancers selected from the group consisting of: hepatocellular carcinoma, pancreatic cancer, gastric adenocarcinoma, non-small cell lung cancer, breast cancer, endometrial cancer, and chondrosarcoma, wherein the medicament is used in a method comprising the steps of: (1) applying an alternating electric field to the cancer cells for a period of time, wherein the frequency of the alternating electric field is in the range of 100 kHz to 500 kHz; and (2) administering the medicament to the individual.

9. As requested in item 8, wherein at least a portion of step (1) and at least a portion of step (2) are performed simultaneously.

10. As claimed in claim 8, wherein the method further comprises the steps of: (3) administering to the individual at a therapeutically effective concentration of at least one additional component, wherein the at least one additional component comprises at least one ingredient selected from the group consisting of: sorafenib, sunitinib, imatinib, fasudil, pirfenidone, nintedanib, losartan, hyaluronidase, tranilast, vemodil, and combinations thereof.

Images