Compositions and methods for treatment with combination of alternating electric field and FGF inhibitor

Abstract

Disclosed is a method of treating a subject in need thereof, comprising: applying an alternating electric field at a frequency to a target site of the subject in need thereof for a period of time; and administering one or more FGF inhibitors or FGFR inhibitors to a subject in need thereof. Disclosed is a method for increasing the sensitivity of a cell to an alternating electric field, comprising: applying an alternating electric field to a cell at a frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby increasing the sensitivity of the cell to the alternating electric field. Disclosed is a method of increasing cytotoxicity in a cell, comprising: applying an alternating electric field to the cell at a frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby increasing cytotoxicity in the cell. Disclosed is a method for maintaining or enhancing the sensitivity of a cell to an alternating electric field, comprising: applying an alternating electric field to a cell at a frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby maintaining or enhancing the sensitivity of the cell to the alternating electric field. In some aspects, maintaining or enhancing the sensitivity of cells to an alternating electric field is the same as reducing the resistance of cells to an alternating electric field.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 353,559 filed on June 18, 2022, U.S. Provisional Patent Application No. 63 / 499,842 filed on May 3, 2023, and U.S. Provisional Patent Application No. 63 / 504,093 filed on May 24, 2023, each of which is incorporated herein by reference in its entirety. Background Art

[0003] Fibroblast growth factor (FGF) signaling pathways regulate many cellular processes, such as cell proliferation, apoptosis, angiogenesis, migration, invasion, and metastasis. FGF / FGF receptors (FGFRs) exert their physiological functions by regulating their downstream targets. Chemical inhibitors, antibodies, and natural drugs of FGF / FGFRs can be used to block the FGF signaling pathway. Therefore, targeting FGF / FGFRs may be an effective approach in combination with tumor treating fields (TTFields) to treat cancer patients. Summary of the invention

[0004] Disclosed are methods for treating a subject in need thereof, comprising: applying an alternating electric field at a certain frequency to a target site of the subject in need thereof for a period of time; and administering one or more FGF inhibitors or FGFR inhibitors to the subject in need thereof.

[0005] Disclosed is a method for increasing the sensitivity of cells to an alternating electric field, comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cells, thereby increasing the sensitivity of the cells to the alternating electric field.

[0006] Disclosed is a method for increasing cytotoxicity in a cell, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby increasing the cytotoxicity in the cell.

[0007] Disclosed is a method for maintaining or enhancing the sensitivity of a cell to an alternating electric field, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby maintaining or enhancing the sensitivity of the cell to the alternating electric field. In some aspects, maintaining or enhancing the sensitivity of the cell to the alternating electric field is the same as reducing the resistance of the cell to the alternating electric field.

[0008] Additional advantages of the disclosed methods and compositions will be set forth in part in the following description and in part will be understood from the description or may be learned by practice of the disclosed methods and compositions. The advantages of the disclosed methods and compositions will be realized and obtained by the elements and combinations particularly pointed out in the appended claims. It should be understood that both the foregoing general description and the following detailed description are merely exemplary and explanatory and do not limit the invention as claimed. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the disclosed methods and compositions and, together with the description, serve to explain the principles of the disclosed methods and compositions.

[0010] Figure 1 is a block diagram of a system for applying an alternating electric field.

[0011] Figure 2 Figure 3. Cytokine secretion profiles following TTField application as measured using a human cytokine array. Cytotoxic effects were observed 3 days after TTField treatment at optimal cytotoxic frequency. A2780 and H1299 cell counts relative to control cells 3 days after TTField application at optimal cytotoxic frequencies of 200 kHz and 150 kHz, respectively.

[0012] Figure 3A and Figure 3B Shown in ( Figure 3A )A2780 cell line (TTField frequency of 200kHz) and ( Figure 3B ) Cytokine array results for upregulated expression of FGF-19, FGF-7, and basic FGF (FGF-basic) in the H1229 cell line (TTField frequency of 150kHz) after 3 days of in vitro application of TTFields. Spot images of human cytokine array membranes for TTField-treated cells and a control group for all three FGF targets basic FGF, FGF 7, and FGF 19 are shown. Quantification of the pixel density of the cytokine array membrane is shown in the figure. The figure includes the average of two biological replicates for each target.

[0013] Figure 4A and Figure 4B Shown are the results of a mouse cytokine array as an in vivo experiment to validate FGF21 upregulation. Figure 4A ) Experimental design of in vivo ovarian cancer model. Female mice were treated with TTField for 10 days compared with the control sham heat group. Figure 4B) Mouse cytokine array membrane spot images of TTField-treated mice and control sham-treated mice. The figure shows the quantification of FGF21 pixel density from cytokine array membrane spots.

[0014] Figure 5 The response to TTFields in different glioblastoma stem cell (GSC) cell lines is shown. Cytotoxic effects were observed on 6 GBM biopsy samples (SRA4, SRC1, SRC2, SRB2, SRA5, and SRB3) after 3 days of TTField treatment at a frequency of 200kHz. Bars represent the mean ± SD of three different experiments.

[0015] Figure 6 Increased mRNA expression of FGFR1 after application of TTField is shown. FGFR1 mRNA levels in SRC1 and SRC2 glioblastoma stem cells were quantified by qPCR after 3 days of treatment with TTField (200kHz). Results are expressed as the fold change of FGFR1 expression in cells treated with TTField relative to FGFR1 expression in cells not treated with TTField.

[0016] Figure 7 TTField application was shown to induce mRNA expression of FGFR1, which was inhibited by the addition of FGFR1 inhibitors. Pemigatininb (PMGB) is a FGFR inhibitor. SRC1 and SRC2 were treated with PMGB (125nM) and TTField (200kHz) simultaneously for 3 days. Results are expressed as the fold change of FGFR1 expression in cells treated with TTField relative to FGFR1 expression in control cells.

[0017] Figure 8 Cell survival to TTField in the presence of FGFR1 inhibitor is shown. Cytotoxic effects were observed on 5GBM biopsy samples (SRA4, SRC1, SRC2, SRB2 and SRA5) after 3 days of TTField (200kHz) and PMGB (125nM) treatment.

[0018] Fig. 9 Cell survival to TTField in the presence of FGFR1 inhibitor is shown. Cytotoxic effects were observed on 5GBM biopsy samples (SRA4, SRC1, SRC2, SRB2 and SRA5) after 3 days of TTField (200kHz) and PMGB (125nM) treatment. DETAILED DESCRIPTION

[0019] The disclosed methods and compositions may be understood more readily by reference to the following detailed description of specific embodiments and embodiments included therein and the accompanying drawings and their preceding and following descriptions.

[0020] It is to be understood that unless otherwise stated, the disclosed methods and compositions are not limited to specific synthetic methods, specific analytical techniques or specific reagents, and may vary as such. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0021] Materials, compositions, and components are disclosed that can be used in, can be used in conjunction with, can be used to prepare, or are products of the disclosed methods and compositions. These and other materials are disclosed herein, and it should be understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed, while specific references to each different individual and collective combination and arrangement of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. Thus, if a class of molecules A, B, and C and a class of molecules D, E, and F are disclosed, and examples AD of the combined molecules are disclosed, then each is considered individually and collectively even if each is not individually listed. Thus, in this example, each of the combinations AE, AF, BD, BE, BF, CD, CE, and CF is specifically contemplated and should be considered disclosed from the disclosure of A, B, and C; D, E, and F; and the example combination AD. Likewise, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, subsets of AE, BF, and CE are specifically contemplated and should be considered disclosed from the disclosure of A, B, and C; D, E, and F; and example combination AD. This concept applies to all aspects of this application, including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are various additional steps that can be performed, it should be understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and each such combination is specifically contemplated and should be considered disclosed.

[0022] A. Definition

[0023] It should be understood that the disclosed methods and compositions are not limited to the specific methods, protocols and reagents described, as these may vary. It should also be understood that the terminology used herein is only for the purpose of describing specific embodiments and is not intended to limit the scope of the present invention, which is limited only by the appended claims.

[0024] It must be noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an FGF inhibitor" or "an FGFR inhibitor" includes a plurality of such inhibitors and reference to "the inhibitor" refers to one or more inhibitors and equivalents thereof known to those skilled in the art, and so forth.

[0025] As used herein, a "target site" is a specific site or location in or present in a subject or patient. For example, a "target site" may refer to, but is not limited to, a cell (e.g., a cancer cell), a cell group, an organ, a tissue, or a tumor. Thus, the phrase "target cell" may be used to refer to a target site, wherein the target site is a cell. In some aspects, a "target cell" may be a cancer cell. In some aspects, organs that may serve as target sites include, but are not limited to, the brain. In some aspects, cells or cell groups that may be target sites or target cells include, but are not limited to, cancer cells (e.g., ovarian cancer cells). In some aspects, a "target site" may be a tumor target site.

[0026] A "tumor target site" is a site or location in or present in a subject or patient that includes or is adjacent to one or more cancer cells, previously included one or more tumor cells, or is suspected of including one or more tumor cells. For example, a tumor target site may refer to a site or location in or present in a subject or patient that is susceptible to metastasis. In addition, a target site or tumor target site may refer to a site or location of resection of a primary tumor in or present in a subject or patient. In addition, a target site or tumor target site may refer to a site or location adjacent to resection of a primary tumor in or present in a subject or patient.

[0027] As used herein, "alternating electric field" and "alternating electric fields" refer to very low intensity, directional, medium frequency alternating electric fields delivered to a subject, a sample obtained from a subject, or delivered to a specific location (e.g., a target site such as a cell) in a subject or patient. In some aspects, the alternating electric field can be unidirectional or multidirectional. In some aspects, the alternating electric field can be delivered by two pairs of transducer arrays that produce perpendicular fields within the target site. For example, for Optune TM The system (alternating electric field delivery system) has one pair of electrodes located at the left and right sides (LR) of the target site and another pair of electrodes located at the anterior and posterior sides (AP) of the target site. The electric field circulates between these two directions (i.e., LR and AP) to ensure targeting of the largest range of cell orientations.

[0028] As used herein, an "alternating electric field" applied to a tumor target site may be referred to as a "tumor treating field" or "TTField." TTFields have been established as an anti-mitotic cancer treatment modality because they interfere with normal microtubule assembly during metaphase and ultimately destroy cells during telophase, cytokinesis, or subsequent interphase. TTFields target solid tumors and are described in U.S. Pat. No. 7,565,205, which is incorporated herein by reference in its entirety for its teachings of TTFields.

[0029] In vivo and in vitro studies have shown that the efficacy of TTField therapy increases with increasing electric field strength. Therefore, optimization of array placement on a subject can be performed using the criteria of the Optune system to increase the intensity in a target location or target cell. Array placement optimization can be performed using "rules of thumb" (e.g., placing the array as close to the target site or target cell as possible on the subject), measurements describing the patient's body geometry, target site size, and / or target site or cell location. The measurements used as input can be derived from imaging data. Imaging data is intended to include any type of visual data, such as single photon emission computed tomography (SPECT) image data, X-ray computed tomography (X-ray CT) data, magnetic resonance imaging (MRI) data, positron emission tomography (PET) data, data that can be captured by optical instruments (e.g., cameras, charge-coupled device (CCD) cameras, infrared cameras, etc.), and the like. In certain embodiments, the image data may include 3D data (e.g., point cloud data) obtained or generated from a 3D scanner. Optimization can rely on an understanding of how the electric field is distributed within the target site or target cells based on array position and, in some aspects, account for variations in the distribution of electrical properties within different patient heads.

[0030] The term "subject" refers to a target of administration, such as an animal. Thus, the subject of the disclosed method can be a vertebrate, such as a mammal. For example, the subject can be a human. The term does not indicate a particular age or sex. Subject can be used interchangeably with "individual" or "patient". For example, a subject of administration can refer to a recipient of an alternating electric field. For example, a subject of administration can be a subject with ovarian cancer or lung cancer.

[0031] "Treatment" refers to the administration or application of a therapeutic agent, such as an alternating electric field and a vector, to a subject, such as a human or other mammal (e.g., an animal model), that has cancer or has an increased susceptibility to developing cancer, to prevent or delay progression of the disease or infection, or to partially or completely reverse the effects of the cancer. For example, treating a subject with glioblastoma may include delivering a therapeutic agent to the subject's cells.

[0032] "Prevention" means minimizing or reducing the chance of a subject developing cancer.

[0033] As used herein, the terms "administering" and "dosing" refer to any method of providing a FGF or FGFR inhibitor directly or indirectly to a target site of a subject. Such methods are well known to those skilled in the art, and include, but are not limited to, oral administration, transdermal administration, inhalation administration, intranasal administration, topical administration, intravaginal administration, ocular administration, intraauricular administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injection administration, such as intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration may be continuous or intermittent. In various aspects, the preparation may be administered therapeutically; i.e., for the treatment of cancer. In further various aspects, the preparation may be administered prophylactically; i.e., for the prevention of cancer. In one aspect, a technician may determine an effective dose, an effective regimen, or an effective route of administration in order to treat a subject. In some aspects, administration includes exposure or application. Therefore, in some aspects, exposing a target site or subject to an alternating electric field or applying an alternating electric field to a target site or subject refers to applying an alternating electric field to a target site or subject.

[0034] “Optional” or “optionally” means that the subsequently described event, circumstance or material can or cannot occur or exist, and that the description includes instances where the event, circumstance or material occurs or exists and instances where it does not.

[0035] Ranges can be expressed herein as from "about" a particular value and / or to "about" another particular value. When expressing such ranges, it is also specifically considered and considered that a range from a particular value and / or to another particular value is disclosed, unless otherwise specified in the context. Similarly, when a value is expressed as an approximation by using the antecedent "about", it should be understood that the particular value forms another specifically considered embodiment, unless otherwise specified in the context, the embodiment should be considered disclosed. It should also be understood that the endpoints of each range are both crucial when related to and independent of another endpoint, unless otherwise specified in the context. Finally, it should be understood that all individual values ​​and sub-ranges of values ​​contained in the clearly disclosed range are also specifically considered, and should be considered disclosed, unless otherwise specified in the context. Regardless of whether some or all of these embodiments are clearly disclosed in a particular case, the foregoing applies.

[0036] Unless otherwise defined, all technical and scientific terms used in this article have the same meanings as those generally understood by those skilled in the art to which the disclosed method and composition belong. Although any methods and materials similar or equivalent to those described herein can be used for the implementation or testing of the methods and compositions herein, particularly useful methods, devices and materials are as described. The publications cited herein and the materials to which they are cited are hereby specifically incorporated by reference. Nothing herein should be construed as admitting that the present invention has no right to precede the disclosed content due to existing inventions. It is not recognized that any reference constitutes prior art. The discussion of the reference states what its author claims, and the applicant reserves the right to question the accuracy and relevance of the cited documents. It should be clearly understood that although many publications are mentioned herein, such a reference does not constitute an admission that any of these documents form part of the common general knowledge of the art.

[0037] Throughout the description and claims of this specification, the word "comprise" and variations of the word (e.g., "comprising" and "comprises") mean "including but not limited to", and are not intended to exclude, for example, other additives, components, integers or steps. In particular, in a method described as including one or more steps or operations, each step is specifically considered to include what is listed (unless the step includes a limiting term, such as "consisting of"), which means that each step is not intended to exclude, for example, other additives, components, integers or steps not listed in the step.

[0038] B. Alternating electric field

[0039] The methods disclosed herein include alternating electric fields. In some aspects, the alternating electric field used in the methods disclosed herein is a tumor treatment field. In some aspects, the alternating electric field can vary depending on the cell type or condition to which the alternating electric field is applied. In some aspects, the alternating electric field can be applied by one or more electrodes placed on the subject's body. In some aspects, there can be two or more pairs of electrodes. For example, the array can be placed on the front / back and side of the patient and can be used with the systems and methods disclosed herein. In some aspects, in the case of using two pairs of electrodes, the alternating electric field can alternate between multiple pairs of electrodes. For example, a first pair of electrodes can be placed on the front and back of the subject, a second pair of electrodes can be placed on either side of the subject, and then an alternating electric field can be applied, and the alternating electric field can alternate between the front and back electrodes and then applied to the side electrodes.

[0040] In some aspects, the frequency of the alternating electric field is between 100kHz and 500kHz. In some aspects, the frequency of the alternating electric field is between 50kHz and 1MHz. The frequency of the alternating electric field can also be but not limited to between 50kHz and 500kHz, between 100kHz and 500kHz, between 25kHz and 1MHz, between 50kHz and 190kHz, between 25kHz and 190kHz, between 180kHz and 220kHz, or between 210kHz and 400kHz. In some aspects, the frequency of the alternating electric field can be that the electric field is 50kHz, 100kHz, 150kHz, 200kHz, 250kHz, 300kHz, 350kHz, 400kHz, 450kHz, 500kHz or any frequency therebetween. In some aspects, the frequency of the alternating electric field is about 200kHz to about 400kHz, about 250kHz to about 350kHz, and can be about 300kHz.

[0041] In some aspects, the field intensity of the alternating electric field can be between 0.5V / cm RMS and 4V / cm RMS. In some aspects, the field intensity of the alternating electric field can be between 1V / cm RMS and 4V / cm RMS. In some aspects, different field intensities (e.g., between 0.1V / cm RMS and 10V / cm) can be used. In some aspects, the field intensity can be 1.75V / cm RMS. In some embodiments, the field intensity is at least 1V / cm RMS. In some aspects, the field intensity can be 0.9V / cm RMS. In other embodiments, a combination of multiple field intensities is applied, such as combining two or more frequencies simultaneously, and / or applying two or more frequencies at different times.

[0042] In some aspects, the alternating electric field can be applied at various intervals ranging from 0.5 hours to 72 hours. In some aspects, different durations (e.g., between 0.5 hours and 14 days) can be used. In some aspects, the application of the alternating electric field can be repeated periodically. For example, the alternating electric field can be applied every day for two hours.

[0043] In some aspects, exposure can last for at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours or at least 72 hours or more of continuous exposure. In some aspects, exposure can last for at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours or at least 72 hours or more of cumulative exposure hours. For example, in some aspects, exposure can occur at different times in a few days, weeks or months. In some aspects, the patient applies an alternating electric field at least 50%, 60%, 70%, 80% or 90% of the treatment time.

[0044] In some aspects, the application of the alternating electric field can be continuous or discontinuous. For example, in some aspects, brief interruptions in the application of the alternating electric field can occur to allow the subject to shower or otherwise rest from the therapy. In some aspects, regardless of any brief interruptions in the application of the alternating electric field, the subject receives the alternating electric field for at least 50%, 60%, 70%, 80%, 90% of the treatment time.

[0045] The disclosed methods include applying one or more alternating electric fields to a cell or a subject. In some aspects, an alternating electric field is applied to a target site or a tumor target site. When an alternating electric field is applied to a cell, this can generally refer to applying an alternating electric field to a subject including the cell. Therefore, applying an alternating electric field to a target site of a subject results in applying an alternating electric field to the cell.

[0046] C. FGF / FGFR inhibitors

[0047] As used herein, FGF inhibitors are compositions that bind to FGF proteins, peptides or nucleic acids encoding FGF and prevent FGF from interacting or binding with one or more FGFRs. In some respects, FGF inhibitors specifically inhibit or reduce the expression of FGF. In some respects, FGF inhibitors specifically bind nucleic acids encoding FGF. In some respects, "specificity" refers to inhibitors that are selective for FGF or FGFR, rather than non-selective inhibitors for a variety of receptors. For example, in some respects, disclosed FGF or FGFR inhibitors are selective for FGF or FGFR, and do not inhibit a second receptor, such as VEGFR. In some respects, the IC50 of the inhibitor that specifically inhibits FGF or FGFR to at least one of FGF1, 2, 3 or 4 or FGFR1, 2, 3 or 4 can be less than 30nM, less than 20nM, less than 10nM, less than 5nM, less than 1nM. For example, the IC50 of pemigatinib is significantly lower than that of lenvatinib (a non-selective inhibitor) (Kommalapati et al., Cancers. 2021 June 13; 13(12): 2968).

[0048] In some respects, FGF is FGF-21, FGF-19, FGF-7 or basic FGF. In some respects, FGF inhibitor can be small molecule, peptide, protein, antibody or nucleic acid (such as siRNA). The example of FGF inhibitor includes but is not limited to soluble FGFR (such as soluble FGFR3) and soluble decoy receptor (such as FGF-Trap, it is a kind of soluble decoy receptor fusion protein in conjunction with FGF-2).

[0049] As used herein, FGFR inhibitor is to be combined with FGFR protein, peptide or nucleic acid encoding FGFR and prevent FGFR from interacting with one or more FGF or the composition of combination. In some respects, FGFR inhibitor specificity inhibits or reduces the expression of FGFR. In some respects, FGFR inhibitor specificity binds the nucleic acid encoding FGFR. In some respects, FGFR is FGFR1, FGFR2, FGFR3 or FGFR4. In some respects, FGFR inhibitor can be small molecule, peptide, protein, antibody or nucleic acid (such as siRNA). In some respects, FGFR inhibitor can be one or more inhibitors listed in Table 1.

[0050] Table 1: Examples of FGFR inhibitors.

[0051] Compound Target BAY 1179470 FGFR2 FPA144 FGFR2 PRO-001 FGFR3 RG7444 FGFR3 SSR128129E FGFR AZD4547 FGFR1-3 BAY1163877 FGFR BGJ398 FGFR1-3 CH5183284 FGFR1-3 Erdafitinib FGFR LY2874455 FGFR Roblitinib FGFR4 Infigratinib (BGJ398) Selective FGFR inhibitors for FGFR1 / 2 / 3 SSR128129E FGFR1 PD-166866 FGFR1 ASP5878 FGFR1, 2, 3, and 4 H3B-6527 FGFR4 NSC12 FGF2 / FGFR BO-264 Blocking the function of FGFR3-TACC3 Fisogatinib (BLU-554) FGFR1 / 4 FIIN-2 Pan-FGFR Futibatinib (TAS-120) FGFR1 / 2 / 3 / 4 BLU9931 FGFR4 <![CDATA[Pemigatinib (INCB054828 ) > FGFR1 / 2 / 3 / 4 Zoligratinib (Debio-1347) FGFR1 / 2 / 3 / 4 Alofanib (RPT835) FGFR2 PRN1371 FGFR1 / 2 / 3 / 4 Ferulic acid FGFR1 / 2 Derazantinib (ARQ-087) FGFR1 / 2 / 3 / 4

[0052] D. Composition

[0053] Compositions and formulations are disclosed, which include one or more FGF inhibitors or FGFR inhibitors or combinations thereof. In some embodiments, the formulation further includes a pharmaceutically acceptable carrier or diluent. For example, a pharmaceutical composition is disclosed, which includes an FGF inhibitor or FGFR inhibitor and a pharmaceutically acceptable carrier. For example, a pharmaceutical composition is disclosed, which includes pemitinib or AZD4547 and a pharmaceutically acceptable carrier. A pharmaceutical composition is also disclosed, which includes an FGF inhibitor or FGFR inhibitor and a pharmaceutically acceptable diluent.

[0054] In some aspects, in any of the disclosed methods, a FGF inhibitor or a FGFR inhibitor can be administered with a pharmaceutically acceptable carrier and / or diluent.

[0055] For example, the compositions described herein may include a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" refers to a material or carrier, as is well known to those skilled in the art, which is selected to minimize any degradation of the active ingredient and minimize any side effects of the subject. Examples of carriers include dimyristoylphosphatidylcholine (DMPC), phosphate buffered saline or multivesicular liposomes. For example, PG:PC: cholesterol: peptide or PC: peptide can be used as a carrier of the present invention. Other suitable pharmaceutically acceptable carriers and preparations thereof are described in Remington: The Science and Practice of Pharmacy (19th Edition) by AR Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of pharmaceutically acceptable salt is used in the preparation to make the preparation isotonic. Other examples of pharmaceutically acceptable carriers include, but are not limited to, saline, Ringer's solution and glucose solution. The pH of the solution may be from about 5 to about 8, or from about 7 to about 7.5. Other carriers include sustained release formulations, such as semipermeable matrices of solid hydrophobic polymers containing the composition, which are in the form of shaped articles, such as films, stents (implanted into blood vessels during angioplasty), liposomes, or microparticles. It will be apparent to those skilled in the art that certain carriers may be more preferred, depending, for example, on the route of administration and the concentration of the composition to be administered. The most typical of these are standard carriers for human administration, including solutions such as sterile water, saline, and buffered solutions having a physiological pH.

[0056] The pharmaceutical composition may also include carriers, thickeners, diluents, buffers, preservatives, etc., as long as the expected activity of the polypeptide, peptide, nucleic acid, and carrier of the present invention is not impaired. The pharmaceutical composition may also include one or more active ingredients (in addition to the composition of the present invention), such as antimicrobial agents, anti-inflammatory agents, anesthetics, etc. In the methods described herein, the disclosed compositions may be delivered to cells by a variety of mechanisms. The pharmaceutical composition may be administered in a variety of ways, depending on whether local or systemic treatment is desired, and the area to be treated.

[0057] 1. Delivery of the composition

[0058] Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and injectable organic esters (e.g. ethyl oleate). Aqueous carriers include water, alcohol / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral carriers include sodium chloride solution, Ringer's dextrose, glucose and sodium chloride, lactated Ringer's solution or fixed oils. Intravenous carriers include liquid and nutritional supplements, electrolyte supplements (e.g., supplements based on Ringer's dextrose), etc. Preservatives and other additives may also be present, such as antibacterial agents, antioxidants, chelating agents, and inert gases, etc.

[0059] Formulations for optical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0060] Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or adhesives may be desirable. Some compositions may be administered in the form of pharmaceutically acceptable acid or base addition salts, which are formed by reacting with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid and phosphoric acid) and organic acids (e.g., formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid and fumaric acid), or by reacting with inorganic bases (e.g., sodium hydroxide, ammonium hydroxide, potassium hydroxide) and organic bases (e.g., monoalkyl, dialkyl, trialkyl and arylamines and substituted ethanolamines).

[0061] E. Treatment methods

[0062] Disclosed is a method for treating a subject in need, comprising: applying an alternating electric field to a target site of a subject in need at a certain frequency for a period of time; and administering one or more FGF inhibitors or FGFR inhibitors to the subject in need. Also disclosed is a method for treating a subject in need, comprising: applying an alternating electric field to a target site of a subject in need at a certain frequency for a period of time; and administering a composition including one or more FGF inhibitors or FGFR inhibitors to the subject in need.

[0063] In some aspects, the subject in need has cancer. In some aspects, the subject in need has mesothelioma, ovarian cancer, or lung cancer. In some aspects, the subject in need has brain cancer, pancreatic cancer, breast cancer, or colon cancer.

[0064] In some aspects, the target site comprises one or more cancer cells. In some aspects, the target site comprises one or more mesothelioma cells, ovarian cancer cells, lung cancer cells, brain cancer cells, pancreatic cancer cells, breast cancer cells, or colon cancer cells.

[0065] In some respects, before, after or simultaneously using one or more FGF inhibitors or FGFR inhibitors, apply alternating electric field.In some respects, the step of applying alternating electric field starts at least one hour before FGF inhibitor or FGFR inhibitor.In some respects, the step of applying alternating electric field starts at least 30 minutes before FGF inhibitor or FGFR inhibitor.In some respects, applying alternating electric field simultaneously can refer to applying in 5,10,15,20,25,30,35,40,45,50,55 or 60 minutes before or after using FGF inhibitor or FGFR inhibitor.In some respects, alternating electric field can be applied, and use FGF inhibitor or FGFR inhibitor, at least 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 or 24 hours. In some aspects, applying the alternating electric field while administering the one or more FGF inhibitors or FGFR inhibitors includes applying the alternating electric field during a time when the one or more FGF inhibitors or FGFR inhibitors are active at a particular state in the subject.

[0066] In some aspects, one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

[0067] In some aspects, the frequency of the alternating electric field is between 50kHz and 1MHz. In some aspects, the frequency of the alternating electric field is 150kHz or 200kHz. In some aspects, the alternating electric field can be any range described herein.

[0068] In some aspects, the alternating electric field has a field strength between 0.1 V / cm RMS and 10 V / cm RMS. In some aspects, the alternating electric field has a field strength between 0.5 V / cm RMS and 4 V / cm RMS. In some aspects, the alternating electric field has a field strength of 0.9 V / cm RMS. In some aspects, the alternating electric field has any field strength described herein.

[0069] In some aspects, the disclosed methods of treatment may also include administering a cancer therapeutic agent. In some aspects, the cancer therapeutic agent is a known cancer therapeutic agent except an FGF or FGFR inhibitor. For example, cancer therapy may be, but is not limited to, chemotherapy, radiotherapy, immunotherapy, or hormone therapy.

[0070] In some aspects, before, after or while using a cancer therapeutic agent, an alternating electric field is applied. In some aspects, before, after or while using a cancer therapeutic agent, an FGF or FGFR inhibitor is applied. In some aspects, one or more FGF or FGFR inhibitors and cancer therapeutic agents are used simultaneously, and an alternating electric field is applied before or after the FGF or FGFR inhibitor and the cancer therapeutic agent.

[0071] In some aspects, the steps of the disclosed method must be performed in the order of the listed steps. For example, a method for treating a subject in need is disclosed, comprising first applying an alternating electric field at a certain frequency to a target site of a subject in need for a period of time; then administering one or more FGF inhibitors or FGFR inhibitors or a composition comprising one or more FGF inhibitors or FGFR inhibitors to the subject in need.

[0072] Alternatively, the steps of the disclosed method can be performed in a different order than the listed steps. For example, a method for treating a subject in need is disclosed, comprising first administering one or more FGF inhibitors or FGFR inhibitors or compositions comprising one or more FGF inhibitors or FGFR inhibitors to a subject in need, and then applying an alternating electric field to the target site of the subject in need for a period of time at a certain frequency. In some aspects, first administering one or more FGF inhibitors or FGFR inhibitors or compositions comprising one or more FGF inhibitors or FGFR inhibitors can increase the sensitivity of cells in the subject to the alternating electric field.

[0073] In some aspects, the steps of the disclosed methods can be performed in any order.

[0074] F. Methods of affecting cells

[0075] In some aspects, affecting a cancer cell can refer to increasing the sensitivity of the cell to an alternating electric field, increasing cytotoxicity in the cell, or enhancing or maintaining sensitivity to an alternating electric field.

[0076] Disclosed is a method for increasing the sensitivity of cells to an alternating electric field, comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cells, thereby increasing the sensitivity of the cells to the alternating electric field.

[0077] Disclosed is a method for increasing cytotoxicity in a cell, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby increasing the cytotoxicity in the cell.

[0078] Disclosed is a method for maintaining or enhancing the sensitivity of a cell to an alternating electric field, comprising: applying an alternating electric field to a cell at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby maintaining or enhancing the sensitivity of the cell to the alternating electric field. In some aspects, maintaining or enhancing the sensitivity of a cell to an alternating electric field is the same as reducing the resistance of the cell to the alternating electric field. Therefore, also disclosed is a method for reducing the resistance of a cell to an alternating electric field, comprising: applying an alternating electric field to a cell at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby reducing the resistance of the cell to the alternating electric field.

[0079] Disclosed is a method for maintaining or enhancing the sensitivity of cells to an alternating electric field, comprising: applying an alternating electric field to a target site of a subject in need at a certain frequency for a period of time; and administering one or more FGF inhibitors or FGFR inhibitors to the subject in need, thereby maintaining or enhancing the sensitivity of cells to the alternating electric field. Therefore, also disclosed is a method for reducing the resistance of cells in a cell to an alternating electric field, comprising: applying an alternating electric field to a target site of a subject in need at a certain frequency for a period of time; and administering one or more FGF inhibitors or FGFR inhibitors to the subject in need, thereby reducing the resistance of cells in a cell to an alternating electric field.

[0080] In some aspects of the method of maintaining or enhancing sensitivity or the method of reducing resistance, a step of detecting increased FGF expression in the subject or cell is performed after the step of applying the alternating electric field and before the step of contacting or administering the FGF or FGFR inhibitor.

[0081] In some aspects, the methods disclosed herein may further include the step of applying an alternating electric field to the cells at a certain frequency for a period of time, which step may be performed after the first round of alternating electric field plus FGF inhibitor or FGFR inhibitor has been applied or applied to the subject or cell. For example, disclosed herein is a method for maintaining or enhancing the sensitivity of cells to alternating electric fields, comprising: applying an alternating electric field to a target site of a subject in need at a certain frequency for a period of time; and administering one or more FGF inhibitors or FGFR inhibitors to a subject in need, thereby maintaining or enhancing the sensitivity of cells to the alternating electric field, and also including applying an alternating electric field to the target site of a subject in need for a period of time at a certain frequency after the sensitivity of the cell to the alternating electric field has been maintained or enhanced.

[0082] In some respects, contact or use step is performed when the response of cell or experimenter to alternating electric field has been reduced.In some respects, contact or use step is performed after applying alternating electric field for 3,4,5,6,7,8,9 or 10 days.In some respects, before cell is contacted with FGF or FGF inhibitor, or before experimenter is used FGF or FGF inhibitor, determine the increase of detecting FGF expression.In some respects, detect FGF expression and carry out to obtain baseline reading before applying alternating electric field, then detect again after applying alternating electric field for at least 1,2,3,4,5,6 or 7 days or at least 1,2,3 or 4 weeks.In some respects, can determine whether experimenter has reduced to the response of alternating electric field by analyzing FGF downstream signal.For example, can measure and determine whether experimenter has reduced to the response of alternating electric field by determining the existence of FGF in serum, determining the existence of pAkt in biopsy and / or determining that tumor shrinkage (or tumor growth) lacks response.

[0083] In some aspects, the disclosed method can be directly implemented to a subject. For example, the method can be directly implemented to a subject in need, wherein the subject is a living subject. In some aspects, the disclosed method can be implemented to a sample obtained from a subject. In some aspects, the disclosed method can be implemented in vitro in a subject, and therefore, the cell can be in vitro. In some aspects, the disclosed method can be implemented in vivo in a subject, and therefore, the cell can be in vivo in a subject. In some aspects, the cell (in vitro or in vivo) can be a mesothelioma cell, an ovarian cancer cell, a lung cancer cell, a brain cancer cell, a pancreatic cancer cell, a breast cancer cell, or a colon cancer cell. In some aspects, the cell can be from a cell line, including but not limited to cell lines A2780 or H1299.

[0084] In some aspects, the steps of the disclosed methods must be implemented in the order of the listed steps. For example, a method of treating a subject in need is disclosed, comprising first applying an alternating electric field at a certain frequency to a target site of a subject in need for a period of time; then administering one or more FGF inhibitors or FGFR inhibitors or a composition comprising one or more FGF inhibitors or FGFR inhibitors to the subject in need.

[0085] Alternatively, the steps of the disclosed method can be implemented in an order different from the listed steps. For example, a method for treating a subject in need is disclosed, comprising first administering one or more FGF inhibitors or FGFR inhibitors or compositions comprising one or more FGF inhibitors or FGFR inhibitors to a subject in need, and then applying an alternating electric field to the target site of the subject in need for a period of time at a certain frequency. In some aspects, first administering one or more FGF inhibitors or FGFR inhibitors or compositions comprising one or more FGF inhibitors or FGFR inhibitors can increase the sensitivity of cells in the subject to the alternating electric field.

[0086] In some aspects, the steps of the disclosed methods can be performed in any order.

[0087] G. Kit

[0088] The above materials and other materials can be packaged together in any suitable combination as a kit that can be used to implement or assist in implementing the disclosed methods. It is useful if the kit components in a given kit are designed and suitable for use together in the disclosed methods. For example, a kit including one or more FGF or FGFR inhibitors and one or more materials for delivering alternating electric fields is disclosed, such as the Optune system. The materials for delivering alternating electric fields may include a signal generator and a pair of electrodes. In some embodiments, the materials for delivering alternating electric fields may include a signal generator (e.g., an AC signal generator), a pair or more pairs of electrode arrays (wherein each electrode array includes two or more electrodes), or a controller. In some aspects, the materials for delivering alternating electric fields may include the Optune system or one or more components thereof.

[0089] In some aspects, a material for delivering an alternating electric field may include a system comprising Figure 1 One or more elements of the system shown. Figure 1 is a block diagram of an exemplary material system for delivering an alternating electric field. The system includes an AC signal generator 20, which is designed to generate a first AC output and a second AC output, for example, with a frequency between 50kHz and 500kHz. When the system is used to apply an alternating electric field to a human body, the first AC output is applied to a first pair of electrodes 10L and 10R located on the left and right sides of a cancer cell; the second AC output is applied to a second pair of electrodes 10A and 10P located in front of and behind the cancer cell. The AC signal generator 20 can also be used to apply the first AC output to a dish (or a dedicated Inovitro TM The second AC output is applied to the electrodes on the left and right walls of the dish (or a dedicated Inovitro TMThe AC signal generator 20 may be used to generate an alternating electric field on the front and rear walls of the in vitro culture dish. In either case, the voltage generated by the AC signal generator 20 should be sufficient to induce an electric field of at least 1 V / cm in at least a portion of the cancer cells. In some embodiments, the voltage generated by the AC signal generator 20 should be sufficient to induce an electric field of 1 V / cm to 10 V / cm in at least a portion of the cancer cells.

[0090] In some embodiments, (a) a first AC output is applied to the L / R electrodes for a 1 second sub-interval; (b) a second AC output is applied to the A / P electrodes for a 1 second sub-interval; and the two-step sequence (a) and (b) is repeated during treatment. The AC signal generator 20 can be configured to generate the first AC output and the second AC output such that the first AC output and the second AC output have an amplitude and / or frequency that depends on the state of at least one control input.

[0091] The controller 30 continuously sends a control signal to at least one control input during each 1 second subinterval. Figure 1 The controller 30 and the AC signal generator 20 are depicted as two different blocks, but the two blocks can be integrated into a single hardware device. The structural details of the controller 30 and the nature of the control signal will depend on the design of the AC signal generator 20. In one example, the design of the AC signal generator 20 is similar to the AC signal generator described in U.S. Pat. No. 9,910,453, which is incorporated herein by reference in its entirety. This particular AC signal generator has two output channels (i.e., a first channel for L / R and a second channel for A / P).

[0092] In some embodiments, a kit is disclosed, which includes one or more FGF and FGFR inhibitors, materials for delivering alternating electric fields, and additional therapeutic agents. For example, a kit is disclosed, which includes one or more of aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, ritonavir, sertraline, one or more FGF and FGFR inhibitors, and one or more materials for delivering alternating electric fields (e.g., Optune system). In some aspects, the kit may also include temozolomide.

[0093] Example

[0094] A. Example 1

[0095] 1. Overview

[0096] The FGF / FGFR signaling pathway plays a role in the development and progression of different cancers. The FGF signaling pathway regulates many cellular processes, such as cell proliferation, apoptosis, angiogenesis, migration, invasion, and metastasis. FGF / FGFR can be regulated by Notch, N-CAM, miRNA, synthetic compounds, antibodies, and natural substances. FGF / FGFR displays its physiological functions by regulating its downstream targets (e.g., Ras, PI3K / AKT, ERK, NF-kB, VEGF). Therefore, targeting FGF / FGFR can be an effective method for treating cancer patients.

[0097] FGF / FGFR exerts its physiological functions by regulating major downstream signaling pathways, such as RAS / MAPK and PI3K / AKT / mTOR, which can be blocked by chemical inhibitors, antibodies, receptor decoys, and natural drugs of FGF / FGFR. Therefore, targeting FGF / FGFR can be an effective approach to treat different cancers (e.g., patients with female reproductive system cancers). Secreted FGF binds to one of four transmembrane receptors (FGFR1, FGFR2, FGFR3, and FGFR4) with an intracellular tyrosine kinase domain in a 2:2:2 HSPG-FGF-FGF receptor ratio. Ligand binding specificity is determined by the differential expression patterns of FGF, FGF receptor, and glycosaminoglycan structures, different receptor binding abilities, the requirement for specific cofactors (e.g., Klotho family proteins), and alternative splicing of FGF receptors that results in two different versions of the extracellular Ig-like domain III (b or c). After HSPG ligands bind to FGF receptors, the receptors homodimerize, leading to the activation of the kinase domain in the receptor cytoplasm, and the recruitment and docking of adapter proteins (such as FRS2, GRB2, Shb and Shc). These adapter proteins then activate multiple downstream signaling pathways, including the Ras-MAPK pathway, the Jak-STAT pathway, the PI 3-kinase-Akt pathway, the PLC pathway, the p38 and JNK MAPK pathways. Through these signaling pathways, FGF promotes basic cellular processes such as survival, proliferation, differentiation and movement. Therefore, targeting FGF can help treat cancer alone or in combination with other known cancer treatments (such as TTField) to treat cancer.

[0098] It has been found that targeting FGF / FGFR can enhance the anti-tumor effect of tumor therapeutic fields.

[0099] 2. Materials and Methods

[0100] i. Cell culture model

[0101] Human cell lines A2780 (ovarian cancer) and H1299 (non-small cell lung cancer) were obtained from the American Tissue Culture Collection (ATCC). Cells were grown in medium supplemented with 10% (v / v) fetal bovine serum (FBS) and streptomycin (50 μg / ml) in a 37°C humidified incubator supplied with 5% CO2. Medium and supplements were purchased from Biological Industries (Beit Haemek).

[0102] ii. Mouse Model

[0103] The ovarian tumor mouse model was established. MOSE-L-ffl cancer 5000 / 5μl cells were injected into 12-week-old female mice.

[0104] iii. In vitro

[0105] a. Inovitro system

[0106] TTFields (1.7 V / cm RMS) were applied to A2780 cells at 200 kHz and to H1229 cells at 150 kHz using the inovitro™ system.

[0107] b. Cell counting

[0108] Cytotoxicity was determined by cell counting using a Macsquant (Miltenyi Biotec) flow cytometer and expressed as the percentage of cells relative to control.

[0109] iv. In vivo

[0110] Mice were treated with TTField for 10 days using the in vivo system (Novocure, Haifa, Israel). Mice were sacrificed, blood samples were drawn and collected in designated serum tubes, centrifuged at 1000 g for 15 min, and stored at -20°C.

[0111] v. Cytokine Array Kit Analysis and Quantification

[0112] A cytokine array kit (ARY005B from R&D Systems for human samples and ARY028 for mouse samples) was used to simultaneously detect 105 cytokines in each human cell line. Conditioned medium (CM) / mouse serum samples were collected according to the manufacturer's instructions. The array membrane was incubated in blocking buffer for 1 hour at room temperature (all reagents were provided by the array kit). The samples were incubated on the membrane at 4°C on a shaker overnight before mixing with the reconstituted detection antibody cocktail. All following steps were performed at room temperature, and all washing procedures included three washes in 1× wash buffer for 10 minutes each. After incubation with the detection antibody, the membrane was washed and incubated with streptavidin-conjugated horseradish peroxidase (1:2000) on a shaker for 30 minutes. Unbound reagents were removed by washing, and the membrane was incubated in a chemiluminescent detection reagent for 1 minute. To assess changes after TTField treatment relative to the control group, the pixel density of the spots was measured using R&D Systems quantitation software (quick spots), and the results were analyzed as follows: [(protein pixel density in TTField-treated samples); (protein pixel density in control samples)].

[0113] 3. Results

[0114] Figure 2 An example showing the cytotoxic effect after 3 days of TTField treatment at the optimal cytotoxic frequency. To characterize the secreted cytokine profile after TTField application, a series of in vitro experiments were performed in which cells were treated at their cytotoxic frequency for 72 hours and cytokine array analysis was used to assess changes in secreted protein expression. After 3 days, cell counts in A2780 and H1299 cells were significantly reduced.

[0115] After TTField treatment of A2780 (200 kHz) and H1299 (150 kHz) cell lines for 3 days at the optimal cytotoxic frequency, the expression of FGF family growth factors was upregulated, especially basic FGF, FGF-7, and FGF-19 (see Figure 3A and Figure 3B ).

[0116] FIG. 4 shows that FGF-21 expression is upregulated after TTField application in an ovarian cancer mouse model.

[0117] Based on these results, one could inhibit / block FGF / FGFR signaling to enhance or maintain the effectiveness of TTFields while reducing the negative effects of FGF / FGFR signaling.

[0118] B. Example 2

[0119] 1. Background

[0120] Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis despite standard treatment with radiotherapy and temozolomide according to the Stupp protocol. Recently, a new therapy called tumor treating fields (TTFields) has been approved for clinical treatment, both as a monotherapy for recurrent GBM and in combination with adjuvant chemotherapy followed by radiotherapy. Furthermore, TTFields have been shown to act in an additive or synergistic manner with radiation, and preliminary clinical studies have shown that this combination is well tolerated, allowing the development of the randomized Trident trial. However, even with the addition of TTFields, GBM remains a fatal disease that is resistant to treatment. One of the reasons for GBM resistance is the presence of cancer stem cells (GSCs). This cell reservoir is responsible for the resistance of tumor cells to treatment and the subsequent proliferation of tumor-initiating cells that favor tumor regeneration. Hypoxia favors their maintenance. Studying the mechanisms of GSC resistance to TTFields is a major question that needs to be addressed.

[0121] FGFR1 has been shown to control the radioresistance of glioblastoma and glioblastoma stem cells (Gouaze-Andersson et al., Cancer Res. 2016; Gouaze-Andersson et al., Oncotarget 2018) and its inhibitory effect with FGFR inhibitors leads to glioblastoma radiosensitization (Ader et al., Eur. J. Cancer 2014). In addition, clinical data show that GBM patients with high levels of FGFR1 have shorter progression time and shorter overall survival after radiotherapy (Ducassou et al., Eur J Cancer 2013), and GBM patients expressing five gene markers (including α6-integrin, ZEB1 / YAP1, FGFR1 and FOXM1) in tumors have significantly shorter overall survival (Kowalski-Chauvel et al., Cancers 2019 11 (3)). These data show that targeting FGFR1 can increase the efficacy of glioblastoma treatment. In this study, the mechanisms of GBM stem cell resistance to TTField, specifically the FGFR1 pathway, were examined.

[0122] 2. Research Design and Methods

[0123] This study focused on the involvement of FGFR1 in controlling sensitivity to electric fields. This study was performed on several glioblastoma stem cells (GSCs), well characterized both in vitro and in vivo, obtained from the Claudius Regaud Institute's STEMRI clinical trial (NCT01872221). The inventors wish to thank the Claudius Regaud Institute for providing the glioblastoma stem cells used for these experiments.

[0124] Figure 5 It was shown that TTField treatment induced different levels of cytotoxic effects, which could distinguish 3 groups of GSCs, such as sensitive, intermediate and resistant to TTField. Figure 6 We show that TTFields in GSCs increase the expression of FGFR1 RNA. The expression of FGFR1 is increased in both TTF-sensitive and -resistant GSCs.

[0125] Figure 7 Shown are the expression levels of FGFR1 in resistant (SRC2) and sensitive (SRC1) cells in response to TTFields, and its inhibition using the FGFR1 inhibitor pemigatinib.

[0126] Figure 8 showed that FGFR1 inhibitors could sensitize all glioblastoma cell lines to TTFields, including cells that were previously resistant to TTFields. The mechanism of radiation-induced cell death could be a consequence of DNA damage leading to apoptosis, as TTFields are known to also generate DNA damage and reduce DNA repair mechanisms. Radiosensitivity was reduced after the addition of FGFR inhibitors. The increased sensitivity to TTFields when concomitantly treated with FGFR inhibition suggests a synergistic consequence of increased secretion of FGF family members in serum and conditioned medium after TTField application, thus explaining the reduced sensitivity of cells to TTFields.

[0127] These results distinguish GSCs that are sensitive or resistant to TTFields and suggest that FGFR1 inhibition can increase the sensitivity of glioblastoma cells to TTFields.

[0128] Illustrative Embodiments

[0129] An example of the many embodiments described herein is a method of treating a subject in need thereof, comprising: applying an alternating electric field to a target site in the subject in need thereof at a certain frequency for a period of time; and administering one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to the subject in need thereof.

[0130] In one example of many embodiments described herein, the subject is alive.

[0131] In one example of many embodiments described herein, the subject has mesothelioma, ovarian cancer, or lung cancer.

[0132] In one example of the many embodiments described herein, the target site includes one or more cancer cells.

[0133] In one example of the many embodiments described herein, an alternating electric field is applied before, after, or simultaneously with administration of one or more FGF or FGFR inhibitors.

[0134] In one example of the many embodiments described herein, one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

[0135] An example of the many embodiments described herein is a method of increasing the sensitivity of cells to an alternating electric field, comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting the cells with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, thereby increasing the sensitivity of the cells to the alternating electric field.

[0136] An example of many embodiments described herein is a method of increasing the sensitivity of a cell to an alternating electric field, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting the cell with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, thereby increasing the sensitivity of the cell to the alternating electric field, wherein the cell is in a subject.

[0137] An example of the many embodiments described herein is a method of increasing the sensitivity of cells to an alternating electric field, comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting the cells with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, thereby increasing the sensitivity of the cells to the alternating electric field, wherein the method is performed on the cells in vitro.

[0138] An example of many embodiments described herein is a method of increasing cytotoxicity in a cell, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting the cell with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, thereby increasing the cytotoxicity in the cell.

[0139] An example of many embodiments described herein is a method of increasing cytotoxicity in a cell, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors with the cell, thereby increasing the cytotoxicity in the cell, wherein the cell is in a subject.

[0140] An example of many embodiments described herein is a method of increasing cytotoxicity in a cell, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting the cell with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, thereby increasing the cytotoxicity in the cell, wherein the method is performed on the cell in vitro.

[0141] In one example of the many embodiments described herein, the FGF inhibitor inhibits or reduces FGF expression.

[0142] In one example of the many embodiments described herein, the FGF inhibitor blocks the upregulation of FGF expression in response to an alternating electric field.

[0143] In one example of the many embodiments described herein, the FGF inhibitor prevents FGF from interacting or binding with one or more FGF receptors (FGFRs).

[0144] In one example of the many embodiments described herein, the FGFR inhibitor prevents FGFR from interacting or binding with one or more FGFs.

[0145] In one example of the many embodiments described herein, the FGFR inhibitor blocks one or more FGF receptors (FGFR).

[0146] In one example of the many embodiments described herein, the FGF is FGF-21, FGF-19, FGF-7, basic FGF.

[0147] In one example of the many embodiments described herein, the FGFR is FGFR1, FGFR2, FGFR3, or FGFR4.

[0148] In one example of the many embodiments described herein, the FGFR inhibitor can be one or more inhibitors in Table 1.

[0149] In one example of many embodiments described herein, the cancer cell is an ovarian cancer or a lung cancer cell.

[0150] In one example of many embodiments described herein, the frequency of the alternating electric field is between 50 kHz and 1 MHz.

[0151] In one example of many embodiments described herein, the frequency of the alternating electric field is 150 kHz or 250 kHz.

[0152] In one example of many embodiments described herein, the alternating electric field has a field strength between 0.5 V / cm RMS and 4 V / cmRMS.

[0153] In one example of many embodiments described herein, the alternating electric field has a field strength of 0.9 V / cm RMS.

[0154] In one example of the many embodiments described herein, the method further comprises administering a cancer therapeutic agent.

[0155] An example of many embodiments described herein is a method of maintaining sensitivity of cells to an alternating electric field, comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cells, thereby maintaining sensitivity of the cells to the alternating electric field.

[0156] An example of many embodiments described herein is a method of maintaining sensitivity of a cell to an alternating electric field, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby maintaining sensitivity of the cell to the alternating electric field, wherein the cell is in a subject.

[0157] An example of the many embodiments described herein is a method for maintaining the sensitivity of cells to an alternating electric field, comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cells, thereby maintaining the sensitivity of the cells to the alternating electric field, wherein the method is performed on the cells in vitro.

[0158] An example of the many embodiments described herein is a method of maintaining sensitivity of a subject to an alternating electric field, the method comprising applying an alternating electric field to a target site of a subject in need thereof at a certain frequency for a period of time; and administering one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to the subject in need thereof, thereby maintaining the sensitivity of the cells to the alternating electric field.

[0159] An example of the many embodiments described herein is a method for maintaining the sensitivity of cells to an alternating electric field, the method comprising applying an alternating electric field to a target site of a subject in need thereof at a certain frequency for a period of time; and administering one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to the subject in need thereof, thereby maintaining the sensitivity of the cells to the alternating electric field.

[0160] In one example of the many embodiments described herein, described herein is a method for maintaining sensitivity of a subject to an alternating electric field, the method comprising applying an alternating electric field to a target site of a subject in need thereof at a certain frequency for a period of time; and administering one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to the subject in need thereof, thereby maintaining sensitivity of the subject or cells to the alternating electric field, wherein the subject is alive.

[0161] In one example of many embodiments described herein, the method further includes, after applying the alternating electric field and before administering one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to the subject in need thereof, detecting an increase in FGF expression in the subject or cell.

[0162] In one example of many embodiments described herein, contacting is performed when the response of the cell to the alternating electric field has decreased.

[0163] In one example of many embodiments described herein, contacting with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors is performed 3, 4, 5, 6, 7, 8, 9 or 10 days after applying the alternating electric field.

[0164] In one example of many embodiments described herein, contacting is performed when the subject's response to the alternating electric field has decreased.

[0165] In one example of the many embodiments described herein, the contacting is performed 3, 4, 5, 6, 7, 8, 9, or 10 days after performing step a).

[0166] In one example of the many embodiments described herein, an alternating electric field is applied before, after, or simultaneously with administration of one or more FGF or FGFR inhibitors.

[0167] In one example of the many embodiments described herein, one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

[0168] In one example of the many embodiments described herein, the FGF inhibitor inhibits or reduces FGF expression.

[0169] In one example of the many embodiments described herein, the FGF inhibitor blocks the upregulation of FGF expression in response to an alternating electric field.

[0170] In one example of the many embodiments described herein, the FGF inhibitor prevents FGF from interacting or binding with one or more FGF receptors (FGFRs).

[0171] In one example of the many embodiments described herein, the FGFR inhibitor prevents FGFR from interacting or binding with one or more FGFs.

[0172] In one example of the many embodiments described herein, the FGFR inhibitor blocks one or more FGF receptors (FGFR).

[0173] In one example of the many embodiments described herein, the FGF is FGF-21, FGF-19, FGF-7, or basic FGF.

[0174] In one example of the many embodiments described herein, the FGFR is FGFR1, FGFR2, FGFR3, or FGFR4.

[0175] In one example of the many embodiments described herein, the FGFR inhibitor can be one or more inhibitors in Table 1.

[0176] In one example of many embodiments described herein, the frequency of the alternating electric field is between 50 kHz and 1 MHz.

[0177] In one example of many embodiments described herein, the frequency of the alternating electric field is 150 kHz or 250 kHz.

[0178] In one example of many embodiments described herein, the alternating electric field has a field strength between 0.5 V / cm RMS and 4 V / cmRMS.

[0179] In one example of many embodiments described herein, the alternating electric field has a field strength of 0.9 V / cm RMS.

[0180] In one example of the many embodiments described herein, the method further comprises administering a cancer therapeutic agent.

[0181] An example of the many embodiments described herein is a method for using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor to treat a subject in need thereof, the method comprising applying an alternating electric field at a certain frequency to a target site in a subject in need thereof for a period of time; and administering the fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor to the subject in need thereof.

[0182] One example of the many embodiments described herein is a method of using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor to increase the sensitivity of a cell to an alternating electric field, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors with the cell, thereby increasing the sensitivity of the cell to the alternating electric field.

[0183] One example of the many embodiments described herein is a method of using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor to increase the sensitivity of a cell to an alternating electric field, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors with the cell, thereby increasing the sensitivity of the cell to the alternating electric field, wherein the cell is in a subject.

[0184] One example of the many embodiments described herein is a method of using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor to increase the sensitivity of a cell to an alternating electric field, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors with the cell, thereby increasing the sensitivity of the cell to the alternating electric field, wherein the method is performed on the cell in vitro.

[0185] One example of the many embodiments described herein is a method of using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor to increase cytotoxicity in a cell, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors with the cell, thereby increasing the cytotoxicity in the cell.

[0186] An example of many embodiments described herein is a method of using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor to increase cytotoxicity in a cell, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors with the cell, thereby increasing the cytotoxicity in the cell, wherein the cell is in a subject.

[0187] One example of the many embodiments described herein is a method of using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor to increase cytotoxicity in a cell, comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors with the cell, thereby increasing the cytotoxicity in the cell, wherein the method is performed on the cell in vitro.

[0188] In one example of many embodiments described herein, the subject is alive.

[0189] In one example of many embodiments described herein, the subject has mesothelioma, ovarian cancer, or lung cancer.

[0190] In one example of the many embodiments described herein, the target site includes one or more cancer cells.

[0191] In one example of the many embodiments described herein, an alternating electric field is applied before, after, or simultaneously with administration of one or more FGF or FGFR inhibitors.

[0192] In one example of the many embodiments described herein, one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

[0193] In one example of the many embodiments described herein, the FGF inhibitor inhibits or reduces FGF expression.

[0194] In one example of the many embodiments described herein, the FGF inhibitor blocks the upregulation of FGF expression in response to an alternating electric field.

[0195] In one example of the many embodiments described herein, the FGF inhibitor prevents FGF from interacting or binding with one or more FGF receptors (FGFRs).

[0196] In one example of the many embodiments described herein, the FGFR inhibitor prevents FGFR from interacting or binding with one or more FGFs.

[0197] In one example of the many embodiments described herein, the FGFR inhibitor blocks one or more FGF receptors (FGFR).

[0198] In one example of the many embodiments described herein, the FGF is FGF-21, FGF-19, FGF-7, basic FGF.

[0199] In one example of the many embodiments described herein, the FGFR is FGFR1, FGFR2, FGFR3, or FGFR4.

[0200] In one example of the many embodiments described herein, the FGFR inhibitor can be one or more inhibitors in Table 1.

[0201] In one example of many embodiments described herein, the cancer cell is an ovarian cancer or a lung cancer cell.

[0202] In one example of many embodiments described herein, the frequency of the alternating electric field is between 50 kHz and 1 MHz.

[0203] In one example of many embodiments described herein, the frequency of the alternating electric field is 150 kHz or 250 kHz.

[0204] In one example of many embodiments described herein, the alternating electric field has a field strength between 0.5 V / cm RMS and 4 V / cmRMS.

[0205] In one example of many embodiments described herein, the alternating electric field has a field strength of 0.9 V / cm RMS.

[0206] In one example of the many embodiments described herein, the method further comprises administering a cancer therapeutic agent.

[0207] One example of the many embodiments described herein is a method in which a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor is used to maintain the sensitivity of a cell to an alternating electric field, the method comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby maintaining the sensitivity of the cell to the alternating electric field.

[0208] An example of the many embodiments described herein is a method in which a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor is used to maintain the sensitivity of a cell to an alternating electric field, the method comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby maintaining the sensitivity of the cell to the alternating electric field, wherein the cell is in a subject.

[0209] One example of the many embodiments described herein is a method in which a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor is used to maintain the sensitivity of a cell to an alternating electric field, the method comprising: applying an alternating electric field to the cell at a certain frequency for a period of time; and contacting one or more FGF inhibitors or FGFR inhibitors with the cell, thereby maintaining the sensitivity of the cell to the alternating electric field, wherein the method is performed on the cell in vitro.

[0210] One example of the many embodiments described herein is a method in which a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor is used to maintain sensitivity of a subject to an alternating electric field, wherein an alternating electric field is applied to a target site of a subject in need thereof at a certain frequency for a period of time; and one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors are administered to the subject in need thereof, thereby maintaining sensitivity of the cells to the alternating electric field.

[0211] An example of the many embodiments described herein is a method in which a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor is used to maintain the sensitivity of a cell to an alternating electric field, the method comprising applying an alternating electric field to a target site of a subject in need thereof at a certain frequency for a period of time; and administering one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to the subject in need thereof, thereby maintaining the sensitivity of the cell to the alternating electric field.

[0212] An example of the many embodiments described herein is a method in which a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor is used to maintain sensitivity of a subject to an alternating electric field, wherein an alternating electric field is applied to a target site of a subject in need thereof at a certain frequency for a period of time; and one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors are administered to a subject in need thereof, thereby maintaining sensitivity of the subject or cells to the alternating electric field, wherein the subject is alive.

[0213] In one example of many embodiments described herein, the method further includes, after applying the alternating electric field and before administering one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to the subject in need thereof, detecting an increase in FGF expression in the subject or cell.

[0214] In one example of many embodiments described herein, contacting is performed when the response of the cell to the alternating electric field has decreased.

[0215] In one example of many embodiments described herein, contacting with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors is performed 3, 4, 5, 6, 7, 8, 9 or 10 days after applying the alternating electric field.

[0216] In one example of many embodiments described herein, contacting is performed when the subject's response to the alternating electric field has decreased.

[0217] In one example of the many embodiments described herein, the contacting is performed 3, 4, 5, 6, 7, 8, 9, or 10 days after performing step a).

[0218] In one example of the many embodiments described herein, an alternating electric field is applied before, after, or simultaneously with administration of one or more FGF or FGFR inhibitors.

[0219] In one example of the many embodiments described herein, one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

[0220] In one example of the many embodiments described herein, the FGF inhibitor inhibits or reduces FGF expression.

[0221] In one example of the many embodiments described herein, the FGF inhibitor blocks the upregulation of FGF expression in response to an alternating electric field.

[0222] In one example of the many embodiments described herein, the FGF inhibitor prevents FGF from interacting or binding with one or more FGF receptors (FGFRs).

[0223] In one example of the many embodiments described herein, the FGFR inhibitor prevents FGFR from interacting or binding with one or more FGFs.

[0224] In one example of the many embodiments described herein, the FGFR inhibitor blocks one or more FGF receptors (FGFR).

[0225] In one example of the many embodiments described herein, the FGF is FGF-21, FGF-19, FGF-7, or basic FGF.

[0226] In one example of the many embodiments described herein, the FGFR is FGFR1, FGFR2, FGFR3, or FGFR4.

[0227] In one example of the many embodiments described herein, the FGFR inhibitor can be one or more inhibitors in Table 1.

[0228] In one example of many embodiments described herein, the frequency of the alternating electric field is between 50 kHz and 1 MHz.

[0229] In one example of many embodiments described herein, the frequency of the alternating electric field is 150 kHz or 250 kHz.

[0230] In one example of many embodiments described herein, the alternating electric field has a field strength between 0.5 V / cm RMS and 4 V / cmRMS.

[0231] In one example of many embodiments described herein, the alternating electric field has a field strength of 0.9 V / cm RMS.

[0232] In one example of the many embodiments described herein, the method further comprises administering a cancer therapeutic agent.

[0233] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors for treating a subject in need thereof.

[0234] In one example of the many embodiments described herein, an alternating electric field is applied to a target site in a subject in need thereof at a certain frequency for a period of time.

[0235] In one example of many embodiments described herein, the subject has mesothelioma, ovarian cancer, or lung cancer.

[0236] In one example of the many embodiments described herein, the target site includes one or more cancer cells.

[0237] In one example of the many embodiments described herein, an alternating electric field is applied before, after, or simultaneously with administration of one or more FGF or FGFR inhibitors.

[0238] In one example of the many embodiments described herein, one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

[0239] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to increase the sensitivity of cells to the alternating electric field.

[0240] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to increase the sensitivity of a cell to the alternating electric field, wherein the cell is in a subject.

[0241] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to increase the sensitivity of cells to the alternating electric field, wherein the method is performed on the cells in vitro.

[0242] One example of the many embodiments described herein is the use of alternating electric fields in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to increase cytotoxicity in cells.

[0243] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to increase cytotoxicity in a cell, wherein the cell is in a subject.

[0244] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to increase cytotoxicity in cells, wherein the method is performed on the cells in vitro.

[0245] In one example of many embodiments described herein, an alternating electric field is applied to the cells at a certain frequency for a period of time.

[0246] In one example of the many embodiments described herein, one or more FGF inhibitors or FGFR inhibitors are contacted with a cell.

[0247] In one example of the many embodiments described herein, an alternating electric field is applied before, after, or simultaneously with administration of one or more FGF or FGFR inhibitors.

[0248] In one example of the many embodiments described herein, in the aforementioned embodiments, one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

[0249] In one example of the many embodiments described herein, the cell is in vitro.

[0250] In one example of many embodiments described herein, the cell is in a subject.

[0251] In one example of many embodiments described herein, the cancer cell is an ovarian cancer or a lung cancer cell.

[0252] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to maintain cell sensitivity to the alternating electric field.

[0253] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to maintain sensitivity of a cell to an alternating electric field, wherein the cell is in a subject.

[0254] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to maintain sensitivity of cells to the alternating electric field, wherein the method is performed on the cells in vitro.

[0255] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to maintain sensitivity of a subject to the alternating electric field.

[0256] One example of the many embodiments described herein is the use of an alternating electric field in combination with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to maintain sensitivity of a subject to an alternating electric field, wherein the cell is within the subject.

[0257] One example of the many embodiments described herein is the combination of alternating electric fields and one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors for maintaining sensitivity of a subject to alternating electric fields, wherein the method is performed on cells in vitro.

[0258] In one example of the many embodiments described herein, FGF expression is detected in a subject or cell.

[0259] In one example of many embodiments described herein, prior to administration of one or more FGF inhibitors or FGFR inhibitors, the response of the cell or subject to an alternating electric field is reduced.

[0260] In one example of the many embodiments described herein, administration of the one or more FGF inhibitors or FGFR inhibitors occurs 3, 4, 5, 6, 7, 8, 9, or 10 days after application of the alternating electric field.

[0261] In one example of the many embodiments described herein, an alternating electric field is applied before, after, or simultaneously with administration of one or more FGF or FGFR inhibitors.

[0262] In one example of the many embodiments described herein, one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

[0263] In one example of the many embodiments described herein, the FGF inhibitor inhibits or reduces FGF expression.

[0264] In one example of the many embodiments described herein, the FGF inhibitor blocks the upregulation of FGF expression in response to an alternating electric field.

[0265] In one example of the many embodiments described herein, the FGF inhibitor prevents FGF from interacting or binding with one or more FGF receptors (FGFRs).

[0266] In one example of the many embodiments described herein, the FGFR inhibitor prevents FGFR from interacting or binding with one or more FGFs.

[0267] In one example of the many embodiments described herein, the FGFR inhibitor blocks one or more FGF receptors (FGFR).

[0268] In one example of the many embodiments described herein, the FGF is FGF-21, FGF-19, FGF-7, or basic FGF.

[0269] In one example of the many embodiments described herein, the FGFR is FGFR1, FGFR2, FGFR3, or FGFR4.

[0270] In one example of the many embodiments described herein, the FGFR inhibitor can be one or more inhibitors in Table 1.

[0271] In one example of many embodiments described herein, the frequency of the alternating electric field is between 50 kHz and 1 MHz.

[0272] In one example of many embodiments described herein, the frequency of the alternating electric field is 150 kHz or 250 kHz.

[0273] In one example of many embodiments described herein, the alternating electric field has a field strength between 0.5 V / cm RMS and 4 V / cmRMS.

[0274] In one example of many embodiments described herein, the alternating electric field has a field strength of 0.9 V / cm RMS.

[0275] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the methods and compositions described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use in a method for treating a subject in need thereof, the method comprising: applying an alternating electric field at a frequency and for a period of time to a target site of a subject in need thereof; And administering a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor to the subject in need thereof.

2. A method for increasing the sensitivity of cells to an alternating electric field using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor, the method comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting the cells with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to increase the sensitivity of the cells to the alternating electric field.

3. A method for increasing the sensitivity of cells to an alternating electric field using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor, the method comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting the cell with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to increase the sensitivity of the cell to the alternating electric field, wherein the cell is located in the subject.

4. A factor receptor (FGFR) inhibitor for use in a method for increasing the sensitivity of a cell to an alternating electric field, the method comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting the cells with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to increase the sensitivity of the cells to the alternating electric field, wherein the method is performed on the cells in vitro.

5. A method for increasing cytotoxicity in a cell using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor, the method comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting the cell with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, thereby increasing cytotoxicity in the cell.

6. A method for increasing cytotoxicity in a cell using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor, the method comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors with the cell, thereby increasing cytotoxicity in the cell, wherein the cell is in a subject.

7. A method for increasing cytotoxicity in a cell using a fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor, the method comprising: applying an alternating electric field to the cells at a certain frequency for a period of time; and contacting the cell with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, thereby increasing cytotoxicity in the cell, wherein the method is performed on the cell in vitro.

8. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the subject is alive.

9. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the subject suffers from mesothelioma, ovarian cancer or lung cancer.

10. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the target site comprises one or more cancer cells.

11. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the alternating electric field is applied before, after or simultaneously with the administration of the one or more FGF or FGFR inhibitors.

12. An FGF inhibitor or FGFR inhibitor according to any of the preceding claims, wherein the one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

13. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the FGF inhibitor inhibits or reduces FGF expression.

14. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the FGF inhibitor blocks upregulation of FGF expression in response to an alternating electric field.

15. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the FGF inhibitor prevents FGF from interacting or binding with one or more FGF receptors (FGFRs).

16. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the FGFR inhibitor prevents FGFR from interacting or binding with one or more FGFs.

17. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the FGFR inhibitor blocks one or more FGF receptors (FGFR).

18. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the FGF is FGF-21, FGF-19, FGF-7, basic FGF.

19. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the FGFR is FGFR1, FGFR2, FGFR3 or FGFR4.

20. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the FGFR inhibitor may be one or more inhibitors in Table 1.

21. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the cancer cell is an ovarian cancer or lung cancer cell.

22. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the frequency of the alternating electric field is between 50 kHz and 1 MHz.

23. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the frequency of the alternating electric field is 150 kHz or 250 kHz.

24. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the field strength of the alternating electric field is between 0.5 V / cm RMS and 4 V / cm RMS.

25. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the field strength of the alternating electric field is 0.9 V / cm RMS.

26. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the method further comprises administering a cancer therapeutic agent.

27. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the fibroblast growth factor (FGF) inhibitor or fibroblast growth factor receptor (FGFR) inhibitor is used in a method for maintaining the sensitivity of a cell to an alternating electric field, the method comprising: Apply an alternating electric field to the cells at a certain frequency for a period of time; and contacting the cells with one or more FGF inhibitors or FGFR inhibitors to maintain the sensitivity of the cells to the alternating electric field.

28. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the fibroblast growth factor (FGF) inhibitor or fibroblast growth factor receptor (FGFR) inhibitor is used in a method for maintaining the sensitivity of a cell to an alternating electric field, the method comprising: Apply an alternating electric field to the cells at a certain frequency for a period of time; and contacting the cell with one or more FGF inhibitors or FGFR inhibitors to maintain sensitivity of the cell to the alternating electric field, wherein the cell is in a subject.

29. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the fibroblast growth factor (FGF) inhibitor or fibroblast growth factor receptor (FGFR) inhibitor is used in a method for maintaining the sensitivity of a cell to an alternating electric field, the method comprising: Apply an alternating electric field to the cells at a certain frequency for a period of time; and contacting the cells with one or more FGF inhibitors or FGFR inhibitors to maintain the sensitivity of the cells to the alternating electric field, wherein the method is performed on the cells in vitro.

30. A fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor, used in a method for maintaining a subject's sensitivity to an alternating electric field, wherein an alternating electric field is applied to a target site of a subject in need at a certain frequency for a period of time; and one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors are administered to the subject in need, thereby maintaining the sensitivity of the cells to the alternating electric field.

31. A fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor, a method for maintaining the sensitivity of cells to an alternating electric field, comprising applying an alternating electric field to a target site of a subject in need thereof at a certain frequency for a period of time; and administering one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to the subject in need thereof, thereby maintaining the sensitivity of the cells to the alternating electric field.

32. A fibroblast growth factor (FGF) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor, for use in a method for maintaining a subject's sensitivity to an alternating electric field, wherein an alternating electric field is applied to a target site of a subject in need thereof at a certain frequency for a period of time; and one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors are administered to the subject in need thereof, thereby maintaining the sensitivity of the subject or cells to the alternating electric field, wherein the subject is alive.

33. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the method further comprises: After applying the alternating electric field, and prior to administering one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to said subject in need thereof, an increase in FGF expression in said subject or cell is detected.

34. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the contacting is performed when the response of the cell to the alternating electric field has decreased.

35. An FGF inhibitor or FGFR inhibitor according to any of the preceding claims, wherein the contacting with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors is performed 3, 4, 5, 6, 7, 8, 9 or 10 days after applying the alternating electric field.

36. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the contacting is performed when the subject's response to the alternating electric field has decreased.

37. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the contacting is performed 3, 4, 5, 6, 7, 8, 9 or 10 days after step a).

38. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the alternating electric field is applied before, after or simultaneously with the administration of the one or more FGF or FGFR inhibitors.

39. The FGF inhibitor or FGFR inhibitor of any of the preceding claims, wherein the one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

40. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the FGF inhibitor inhibits or reduces FGF expression.

41. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the FGF inhibitor blocks upregulation of FGF expression in response to an alternating electric field.

42. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the FGF inhibitor prevents FGF from interacting or binding with one or more FGF receptors (FGFRs).

43. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the FGFR inhibitor prevents FGFR from interacting or binding with one or more FGFs.

44. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the FGFR inhibitor blocks one or more FGF receptors (FGFR).

45. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the FGF is FGF-21, FGF-19, FGF-7, or basic FGF.

46. ​​The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the FGFR is FGFR1, FGFR2, FGFR3 or FGFR4.

47. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the FGFR inhibitor may be one or more inhibitors in Table 1.

48. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the frequency of the alternating electric field is between 50 kHz and 1 MHz.

49. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the frequency of the alternating electric field is 150 kHz or 250 kHz.

50. The FGF inhibitor or FGFR inhibitor according to any one of the preceding claims, wherein the field strength of the alternating electric field is between 0.5 V / cm RMS and 4 V / cm RMS.

51. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the field strength of the alternating electric field is 0.9 V / cm RMS.

52. The FGF inhibitor or FGFR inhibitor of any one of the preceding claims, wherein the method further comprises administering a cancer therapeutic agent.

53. A method of treating a subject in need thereof, comprising: a) applying an alternating electric field to a target site of the subject in need thereof at a certain frequency for a period of time; as well as b) administering one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors to said subject in need thereof.

54. The method of any one of the preceding claims, wherein the subject has mesothelioma, ovarian cancer, or lung cancer.

55. The method of any of the preceding claims, wherein the target site comprises one or more cancer cells.

56. The method of any of the preceding claims, wherein the alternating electric field is applied before, after, or simultaneously with administration of the one or more FGF or FGFR inhibitors.

57. The method of any of the preceding claims, wherein the one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., during surgery or biopsy, guided by computed tomography), or via inhalation.

58. A method for increasing the sensitivity of a cell to an alternating electric field, comprising: a) applying an alternating electric field to the cells at a certain frequency for a period of time; as well as b) contacting the cells with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, Thereby increasing the sensitivity of cells to alternating electric fields.

59. A method of increasing cytotoxicity in a cell, comprising: a) applying an alternating electric field to the cells at a certain frequency for a period of time; as well as b) contacting the cells with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, Thereby increasing cytotoxicity in cells.

60. The method of any one of claims 58 to 59, wherein the cell is in vitro.

61. The method of any one of claims 58 to 69, wherein the cell is located within the subject.

62. The method of any one of the preceding claims, wherein the FGF inhibitor inhibits or reduces FGF expression.

63. The method of any of the preceding claims, wherein the FGF inhibitor blocks upregulation of FGF expression in response to an alternating electric field.

64. The method of any of the preceding claims, wherein the FGF inhibitor prevents FGF from interacting or binding with one or more FGF receptors (FGFRs).

65. The method of any one of the preceding claims, wherein the FGFR inhibitor prevents FGFR from interacting or binding with one or more FGFs.

66. The method of any one of the preceding claims, wherein the FGFR inhibitor blocks one or more FGF receptors (FGFR).

67. A method according to any of the preceding claims, wherein the FGF is FGF-21, FGF-19, FGF-7, basic FGF.

68. The method of any of the preceding claims, wherein the FGFR is FGFR1, FGFR2, FGFR3, or FGFR4.

69. The method according to any one of the preceding claims, wherein the FGFR inhibitor may be one or more inhibitors in Table 1.

70. The method of any one of claims 586 to 60, wherein the cancer cells are ovarian cancer or lung cancer cells.

71. A method according to any one of the preceding claims, wherein: The frequency of the alternating electric field is between 50 kHz and 1 MHz.

72. A method according to any preceding claim, wherein the frequency of the alternating electric field is 150 kHz or 250 kHz.

73. The method according to any of the preceding claims, wherein the alternating electric field has a field strength between 0.5 V / cm RMS and 4 V / cm RMS.

74. A method according to any of the preceding claims, wherein the field strength of the alternating electric field is 0.9 V / cmRMS.

75. The method of any of the preceding claims, further comprising administering a cancer therapeutic agent.

76. A method for maintaining the sensitivity of a cell to an alternating electric field, comprising: a) applying an alternating electric field to the cells at a certain frequency for a period of time; as well as b) contacting the cells with one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, Thereby maintaining the sensitivity of the cells to the alternating electric field.

77. A method for maintaining the sensitivity of a subject to an alternating electric field: a. applying an alternating electric field to a target site of the subject in need thereof at a certain frequency for a period of time; and b. administering to said subject in need thereof one or more fibroblast growth factor (FGF) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors, Thereby maintaining the sensitivity of the cells to the alternating electric field.

78. The method of any one of claims 76 or 77, wherein the method further comprises, after step a) and before step b), detecting an increase in FGF expression in the subject or cell.

79. The method of any one of claims 76 to 78, wherein the contacting in step b) is performed when the response of the cell to the alternating electric field is reduced.

80. The method of any one of claims 276 to 70, wherein the contacting in step b) is performed 3, 4, 5, 6, 7, 8, 9 or 10 days after step a).

81. The method of any one of claims 76 to 80, wherein the contacting in step b) is performed at a time when the subject's response to the alternating electric field is reduced.

82. The method of claim 81, wherein the contacting in step b) is performed 3, 4, 5, 6, 7, 8, 9 or 10 days after step a).

83. The method of any one of claims 76 to 82, wherein the alternating electric field is applied before, after, or simultaneously with administration of the one or more FGF or FGFR inhibitors.

84. The method of any one of claims 76 to 83, wherein the one or more FGF or FGFR inhibitors are administered intratumorally, intracranialy, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non-targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumoral injection (e.g., guided by computed tomography, during surgery or biopsy), or via inhalation.

85. The method of any one of claims 76 to 84, wherein the FGF inhibitor inhibits or reduces FGF expression.

86. The method of any one of claims 76 to 85, wherein the FGF inhibitor blocks upregulation of FGF expression in response to an alternating electric field.

87. The method of any one of claims 76 to 86, wherein the FGF inhibitor prevents FGF from interacting or binding with one or more FGF receptors (FGFRs).

88. The method of any one of claims 76 to 87, wherein the FGFR inhibitor prevents FGFR from interacting or binding with one or more FGFs.

89. The method of any one of claims 76 to 88, wherein the FGFR inhibitor blocks one or more FGF receptors (FGFR).

90. The method of any one of claims 76 to 89, wherein the FGF is FGF-21, FGF-19, FGF-7, basic FGF.

91. The method of any one of claims 76 to 90, wherein the FGFR is FGFR1, FGFR2, FGFR3 or FGFR4.

92. The method of any one of claims 76 to 91, wherein the FGFR inhibitor may be one or more inhibitors of Table 1.

93. A method according to any one of claims 76 to 92, wherein the frequency of the alternating electric field is between 50 kHz and 1 MHz.

94. The method of any one of claims 76 to 93, wherein the frequency of the alternating electric field is 150 kHz or 250 kHz.

95. The method of any one of claims 76 to 94, wherein the alternating electric field has a field strength between 0.5 V / cm RMS and 4 V / cm RMS.

96. The method of any one of claims 76 to 95, wherein the alternating electric field has a field strength of 0.9 V / cm RMS.

97. The method of any one of claims 76 to 96, further comprising administering a cancer therapeutic agent.

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