Compositions, systems, and methods for treating cancer, tumor treatment fields, and VEGF inhibitors

Abstract

Disclosed are compositions, systems, and methods for reducing the survival rate of cancer cells, treating cancer, and preventing an increase in the volume of tumors present in the body of a living being. The systems and methods include applying an alternating magnetic field in combination with the administration of at least one composition comprising at least one small molecule anti-angiogenic agent that specifically interacts with VEGF.

Description

Background Art

[0001] Tumor treating fields (TT fields) are alternating electric fields in the intermediate frequency range (e.g., 100 - 500 kHz) of low intensity (e.g., 1 - 3 V / cm) that target solid tumors by inhibiting mitosis. This non-invasive treatment targets solid tumors and is described, for example, in U.S. Patent Nos. 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,675, 10,188,851, and 10,441,776. TT fields are typically delivered through two pairs of transducer arrays that generate a magnetic field perpendicular to the tumor being treated, and the electrode arrays that make up each pair are placed on opposite sides of the body part being treated. Specifically, in the OPTUNE® system, one pair of electrodes is placed on the left and right (LR) of the tumor, and the other pair of electrodes is placed on the front and back (AP) of the tumor. TT fields are approved for the treatment of glioblastoma multiforme (GBM) and can be delivered, for example, via the OPTUNE® system (Novocure, Jersey, Channel Islands of Helius) that includes transducer arrays placed on the shaved head of the patient.

[0002] Each transducer array used for delivery of TT fields with the OPTUNE® device consists of a series of ceramic disk electrodes coupled to the patient's skin (such as the shaved head of the patient for GBM treatment) via a layer of conductive medical gel. The purpose of the medical gel is to conform to the body's contours and provide good electrical contact between the array and the skin, and thus the gel interface bridges the skin and reduces interference. The device is intended for the patient to wear continuously for 2 - 4 days for hygiene care and re-shaving (if necessary), after which a new array set is worn again. Therefore, the medical gel remains in substantial continuous contact with the area of the patient's skin for 2 - 4 days at a time. In addition, the array can be shifted several centimeters in either direction so that the skin heals between treatment sessions. Thus, the area of skin that was covered by the electrodes / gel for 2 - 4 days is exposed for 2 - 4 days when the replaced electrodes are shifted slightly, after which the device can be reapplied to the original area of the skin for the next 2 - 4 days.

[0003] Angiogenesis is the process of forming new blood vessels to increase the supply of nutrients and oxygen to parts of the body with insufficient blood supply. Angiogenesis is known to be one of the characteristic processes of cancer. In addition, vascular endothelial growth factor (VEGF) is known to play an important role in promoting angiogenesis.

[0004] As a result of investigating TTFields as a potential therapeutic improvement for osteosarcoma, Oh et al. (Technology in Cancer Research & Treatment (2020) doi:10.1177 / 1533033820947481) demonstrated that TTFields prevent angiogenesis in human tumor endothelial cells and downregulate the expression of VEGF and matrix metalloproteinase 2 (MMP2). In addition, Tang et al. (J Int Med Res (2012) 40(1):85-94) demonstrated that a decrease in VEGF expression was observed in melanoma cell lines and mouse tumor models in mice upon exposure to moderate alternating electric fields. Furthermore, Kim et al. (Oncotarget(2016) 7:65125-65136) demonstrated that TTFields inhibit the migration, invasion, and angiogenesis of glioblastoma cells and claimed that TTFields are a promising anti-invasive and anti-angiogenic treatment strategy for use in GBM patients.

Summary of the Invention

Problems to be Solved by the Invention

[0005] Despite the availability of tumor treatment field-based therapies, glioblastoma multiforme (GBM) remains the most common and aggressive primary malignant tumor of the adult central nervous system. The current standard treatment for recurrent GBM is bevacizumab (AVASTIN®, Genentech, Inc., San Francisco, CA), a humanized monoclonal antibody against vascular endothelial growth factor A (VEGF-A). New preclinical and clinical data suggest that anti-VEGF-A therapy may be effective in GBM (Shiyu et al., Biomedicine & Pharmacotherapy (2021) 141:111810). However, patients inevitably acquire resistance to bevacizumab, and overall survival rates are often not significantly improved.

[0006] Ansstas et al. (Case Rep Neurol (2016) 8:1-9) combined a "pulse dose" approach of bevacizumab administration with TTFields therapy. Recurrent GBM patients discontinued treatment with bevacizumab and were then treated with TTFields therapy alone. Subsequently, if symptoms appeared or evidence of progression was seen on radiographic images, bevacizumab was re-administered in a "pulse dose" regimen. The results of this study support the use of TTFields therapy combined with pulse dose bevacizumab as an option for patients with refractory GBM. Fallah et al. (J Clin Oncology (2020) 38(15_suppl):2537) showed that the combination of bevacizumab and TTFields is safe and feasible and has a clinical effect in recurrent GBM patients.

[0007] Davidi et al. (Journal of Radiation Oncology (2021) 111 (3):e47-e48), Gkika et al. (Cancers (Basel)(2022) 14(6):1568), and Davidi et al. (Cancers (Basel)(2022) 14(12):2959) investigated adding TTFields therapy to the treatment of hepatocellular carcinoma (HCC, a highly malignant liver cancer and one of the leading causes of cancer-related death worldwide) using sorafenib, a multi-kinase inhibitor and the main first-line treatment drug for advanced HCC. The combination therapy of TTFields / sorafenib showed an improvement in response rate compared to the conventional control group in patients with advanced HCC. Jo et al. (Int J Mol Sci(2018) 19(11):3684) studied the effect of sorafenib on the anti-tumor and anti-angiogenic activities of TTFields in glioblastoma cells and found that the combination therapy inhibited tumor cell motility, invasiveness, and angiogenesis.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0009] Before explaining at least one embodiment of the concept(s) of the present invention in detail by way of illustrative language and results, it should be understood that the application of the concept(s) of the present invention is not limited to the details of the configuration and arrangement of components described in the following explanation. The concept(s) of the present invention allows for other embodiments and can be practiced or implemented in various ways. Therefore, the language used herein is intended to give the broadest possible scope and meaning, and the embodiments are illustrative and not exhaustive. Also, it should be understood that the expressions and terms used herein are for explanatory purposes and should not be regarded as limiting.

[0010] Unless otherwise defined herein, scientific and technical terms used in connection with the presently disclosed inventive concept(s) shall have the meanings commonly understood by those of ordinary skill in the art, and further, unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. The foregoing techniques and procedures are generally carried out according to conventional methods well known in the art and are as described in various general and more specific references cited and described throughout this specification. The nomenclature, as well as the experimental procedures and techniques, used in connection with analytical chemistry, organic synthetic chemistry, medicinal chemistry, and pharmaceutical chemistry described herein are well known and commonly used in the art. Standard techniques are used for chemical synthesis and chemical analysis.

[0011] All patents, published patent applications, and non-patent publications described herein are indicative of the skill level of those of ordinary skill in the art to which the presently disclosed inventive concept(s) pertain. All patents, published patent applications, and non-patent publications referenced anywhere in this application are hereby expressly incorporated by reference in their entirety to the same extent as if each individual patent or publication was specifically and individually indicated to be incorporated by reference.

[0012] All compositions, assemblies, systems, kits, and / or methods disclosed herein can be made and executed without undue experimentation in light of the present disclosure. Although the compositions, assemblies, systems, kits, and methods of the inventive concept(s) are described with reference to specific embodiments, it will be apparent to those of ordinary skill in the art that changes can be made in the compositions and / or methods and in the steps or the order of the steps of the methods described herein without departing from the spirit, concept, and scope of the inventive concept(s). All such similar alternatives and modifications that are apparent to those of ordinary skill in the art are considered to be within the spirit, scope, and concept of the inventive concept(s) as defined by the appended claims.

[0013] The following terms used in accordance with this disclosure shall be understood to have the following meanings, unless otherwise specified.

[0014] The use of the terms "a" or "an" when used in combination with the term "comprising" in the claims and / or the specification may mean "one", but is also consistent with the meaning of "one or more", "at least one", "one or two or more". Thus, the terms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, the expression "compound" may refer to one or more compounds, two or more compounds, three or more compounds, four or more compounds, or a greater number of compounds. The term "plural" refers to "two or more".

[0015] The use of the term "at least one" is understood to include quantities greater than one, including but not limited to 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, etc. The term "at least one" may extend to 100 or more than 1000, depending on the term to which it is added, and the quantities 100 / 1000 are not considered limiting, and higher limits may also give satisfactory results. In addition, the use of the term "at least one of X, Y, Z" is understood to include only X, only Y, only Z, and any combination of X, Y, Z. The use of ordinal terms ("first", "second", "third", "fourth", etc.) is only for the purpose of distinguishing two or more items and does not mean an order or importance in which one item is superior to another, or an additional order, etc.

[0016] The use of the term "or" in a claim is used to mean an inclusive "and / or" unless explicitly indicated to refer to alternatives only or the alternatives are not mutually exclusive. For example, the condition "A or B" is satisfied by any of the following: A is true (or present) and B is false (or present), A is false (or present) and B is true (or present), or both A and B are true (or present).

[0017] As used herein, references to "one embodiment", "an embodiment", "some embodiments", "an example", "for example", or "an illustration" mean that a particular element, function, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. For example, the various places in the specification where the phrases "in some embodiments" or "in an example" appear do not necessarily all refer to the same embodiment. Further, all references to one or more embodiments or examples are to be construed as not limiting the claims.

[0018] Throughout this application, the term "about" is used to indicate that a value includes inherent variations of the error of the value, the method used to determine the value, or variations that exist between the subjects of study. For example, without limitation, when the term "about" is used, the specified value may vary plus or minus 20 percent, or 15 percent, or 12 percent, or 11 percent, or 10 percent, or 9 percent, or 8 percent, or 7 percent, or 6 percent, or 5 percent, or 4 percent, or 3 percent, or 2 percent, or 1 percent from the specified value as appropriate for the disclosed method and as understood by one of ordinary skill in the art.

[0019] As used herein in the specification and claims (if any), the terms "comprising" (and any form of "comprising", such as "comprise" or "comprises"), "having" (and any form of "having", such as "have" or "has"), "including" (and any form of "including", such as "includes" or "include"), or "containing" (and any form of "containing", such as "contains" or "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0020] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the items listed before that term. For example, "A, B, C, or combinations thereof" is intended to include at least one of the following: A, B, C, AB, AC, BC, or ABC. Also, if order is important in a particular context, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB may also be used. Continuing with this example, combinations containing repetitions of one or more items or terms, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are explicitly included. One of ordinary skill in the art will understand that, unless otherwise apparent from the context, there is usually no limit to the number of items or terms being combined.

[0021] As used herein, the term "substantially" means that the event or situation described below occurs completely, or occurs to a considerable extent or degree. For example, when associated with a particular event or situation, the term "substantially" means that the event or situation described later occurs at least 80% of the time, at least 85% of the time, at least 90% of the time, or at least 95% of the time. For example, the term "substantially adjacent" can mean that two items are 100% adjacent to each other, that two items are very close to each other but not 100% adjacent, or that a portion of one of the two items is not 100% adjacent to the other item but is very close to the other item.

[0022] The term "pharmaceutically acceptable" refers to compounds and compositions suitable for administration to humans and / or animals without excessive side effects such as toxicity, irritation, and / or allergic reactions commensurate with a reasonable benefit / risk ratio.

[0023] As used herein, the terms "patient" or "subject" include human and veterinary subjects. "Mammal" for therapeutic purposes refers to any animal classified as a mammal, including but not limited to humans, domestic animals, farm animals, non-human primates, and other animals with mammary tissue.

[0024] The term "treatment" refers to both therapeutic treatments and prophylactic measures. Persons in need of treatment include not only those who already suffer from a particular symptom / disease / infection, but also those who are at risk of developing a particular symptom / disease / infection (such as those in need of prophylactic measures), but are not limited thereto. The term "treating" refers to administering a drug / element / method to a patient for therapeutic and / or prophylactic purposes.

[0025] As used herein, the terms "therapeutic composition" or "pharmaceutical composition" refer to a drug that can be administered in vivo to provide a therapeutic and / or prophylactic effect.

[0026] Administering a therapeutically effective amount or a prophylactically effective amount is intended to provide a therapeutic benefit in the treatment, prevention, and / or management of a disease, symptom, and / or infection. A specific therapeutically effective amount can be readily determined by a general physician and can vary depending on factors known in the art such as the type of symptom / disease / infection, the patient's medical history and age, the stage of the symptom / disease / infection, and the co-administration of other drugs (but not limited thereto).

[0027] As used in accordance with the concepts of the present invention, the term "effective amount" refers to the amount of a biologically active molecule or its complex or derivative, or the amount of a treatment protocol (e.g., an alternating electric field), that is sufficient to exert a detectable therapeutic effect without undue side effects (such as toxicity, irritation, allergic reaction, etc., but not limited thereto) commensurate with a reasonable benefit / risk ratio. Therapeutic effects include, but are not limited to, preventing, inhibiting, or reducing the occurrence of at least one symptom, disease, and / or infection. The effective amount for a subject varies depending on the type of subject, the subject's physique and health condition, the nature and severity of the symptom / disease / infection to be treated, the administration method, the treatment period, the nature of combination therapy (if any), the specific formulation used, etc. Therefore, an exact effective amount cannot be specified in advance. However, the effective amount in a specific situation can be determined by one of ordinary skill in the art through routine experimentation based on the information provided herein.

[0028] As used herein, the term "combination therapy" is used interchangeably with the terms "combined therapy", "concurrent therapy", and "adjuvant therapy" and is understood to mean that a patient in need of treatment is treated or administered another drug for a symptom / disease / infection in combination with the treatment of the present disclosure. This combination therapy can be a sequential therapy where the patient is first treated with one treatment protocol / pharmaceutical composition and then with another treatment protocol / pharmaceutical composition, or the two treatment protocols / pharmaceutical compositions are administered simultaneously.

[0029] As used herein, the terms "administration" and "administering" include, but are not limited to, all routes of administration known in the art, including oral, topical, transdermal, parenteral, subcutaneous, intranasal, mucosal, intramuscular, intraperitoneal, intravitreal, and intravenous routes, and are understood to include both topical application and systemic application. In addition, the compositions (and / or methods of administration) of the present disclosure can be designed to provide delayed release, controlled release, or sustained release using formulation techniques well known in the art.

[0030] As used herein, the term "small molecule" refers to a natural or artificial compound having a defined structure that binds to a specific biological macromolecule and acts as an effector to change the activity or function of the target to which it binds. Small molecules typically have a molecular weight in the range of about 1 Da to about 1.5 kDa, and due to their small size, the molecules can diffuse through cell membranes and reach intracellular sites of action as needed. Small molecules are generally smaller than nucleic acids, proteins, enzymes, antibodies, polysaccharides, biologic agents, and other biotherapeutic agents having a size greater than 1.5 kDa.

[0031] Turning to the concepts of the present invention, a combination therapy for cancer is disclosed herein. The combination therapy includes using an alternating electric field (e.g., TT field) in combination with at least one small molecule anti-angiogenic agent that interacts with either vascular endothelial growth factor (e.g., VEGF, VEGF-A, VEGF-B, VEGF-C, VEGF-D) or a receptor for VEGF (e.g., VEGFR, VEGFR-1, VEGFR-2, VEGFR-3) and inhibits the interaction between VEGF and VEGFR to inhibit the VEGF signaling pathway. The combination of the alternating electric field (e.g., TT field) and the small molecule anti-angiogenic agent(s) provides a synergistic effect in the treatment of cancer.

[0032] Certain non-limiting embodiments of the present disclosure relate to a method of reducing the viability of cancer cells. The method includes: (1) administering to the cancer cells at least one composition, the at least one composition comprising at least one small molecule anti-angiogenic agent that specifically and physically interacts with VEGF or VEGFR, selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits signaling by VEGFR; and (2) applying an alternating electric field to the cancer cells for a period of time.

[0033] Certain additional non-limiting embodiments of the present disclosure relate to a method of treating cancer in a subject. The method includes: (1) administering to the subject at least one composition, the at least one composition comprising at least one small molecule anti-angiogenic agent that specifically and physically interacts with VEGF or VEGFR, selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits signaling by VEGFR; and (2) applying an alternating electric field to a target region of the subject.

[0034] Certain additional non-limiting embodiments of the present disclosure relate to a method of reducing the volume of a tumor present in a living body, the tumor comprising a plurality of cancer cells. The method comprises: (1) administering to a subject at least one composition, the at least one composition comprising at least one small molecule anti-angiogenic agent that specifically and physically interacts with VEGF or VEGFR, selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits signal transduction by VEGFR; and (2) applying an alternating electric field to a target region of the subject.

[0035] Certain additional non-limiting embodiments of the present disclosure relate to a method of preventing an increase in the volume of a tumor present in a living body, the tumor comprising a plurality of cancer cells. The method comprises: (1) administering to a subject at least one composition, the at least one composition comprising at least one small molecule anti-angiogenic agent that specifically and physically interacts with VEGF or VEGFR, selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits signal transduction by VEGFR; and (2) applying an alternating electric field to a target region of the subject.

[0036] The small molecule anti-angiogenic agents utilized in accordance with the present disclosure are defined as those that specifically and physically interact with VEGF or VEGFR, selectively inhibit the interaction between VEGF and VEGFR, and / or inhibit signal transduction by VEGFR. "Specifically and physically interact" means that there is an actual physical interaction between the small molecule anti-angiogenic agent and VEGF that inhibits / substantially prevents VEGF from interacting with VEGFR, or there is an actual physical interaction between the small molecule anti-angiogenic agent and VEGFR that inhibits / substantially prevents VEGFR from interacting with VEGF. This "specific interaction" occurs between the specific structure of the small molecule anti-angiogenic agent and VEGF or VEGFR, as opposed to a "non-specific interaction" that does not depend on the specific structure of the small molecule anti-angiogenic agent and VEGF / VEGFR. "Selectively inhibits the interaction" means that the small molecule anti-angiogenic agent has an IC 50Bind preferentially to VEGF and bind in a manner that inhibits its ability to interact with its VEGFR, as determined by the value, or the small molecule anti-angiogenic agent is IC 50 Means binding preferentially to VEGFR and binding in a manner that inhibits its ability to interact with VEGF, as determined by the value. However, the phrases "specifically and physically interact with VEGF or VEGFR" and "selectively inhibit the interaction between VEGF and VEGFR and / or inhibit signaling by VEGFR" are not meant to imply that the small molecule anti-angiogenic agent binds / interacts only with VEGF or VEGF alone. In fact, certain small molecule anti-angiogenic agents used in accordance with the present disclosure are multi-kinase inhibitors that may "specifically and physically interact" with other ligands or receptors and "selectively inhibit" the interaction between said ligand / receptor.

[0037] In certain (but not limited) ways, at least one composition has an inhibitory concentration of about less than 15 nmol / L (i.e., 15 nM), such as about less than 14 nM, about less than 13 nM, about less than 12 nM, about less than 11 nM, about less than 10 nM, about less than 9 nM, about less than 8 nM, about less than 7 nM, about less than 6 nM, about less than 5 nM, about less than 4 nM, about less than 3 nM, about less than 2 nM, about less than 1 nM, etc., but not limited thereto, the half-maximal inhibitory concentration (IC 50 ) that selectively inhibits the interaction between at least one VEGF / VEGFR ligand-receptor pair. In certain (but non-limiting) embodiments, at least one composition has a half-maximal inhibitory concentration (IC 50 ) of less than about 10 nmol / L (10 nM) that selectively inhibits the interaction between at least one VEGF / VEGFR ligand receptor pair.

[0038] Steps (1) and (2) of any of the methods of the present disclosure can be carried out simultaneously, in particular, substantially simultaneously, or can be carried out sequentially, in whole or in part. When the steps are carried out sequentially, in whole or in part, at least one composition comprising at least one small molecule anti-angiogenic agent can be administered before or after the application of the alternating electric field is initiated.

[0039] The methods of the present disclosure can be utilized to treat any type of cancer cell / cancer / tumor that responds to treatment with an alternating electric field (e.g., TT field) and / or a small molecule anti-angiogenic agent. Non-limiting examples of cancer cells / cancers / tumors that can be treated in accordance with the present disclosure include hepatocellular carcinoma, glioblastoma, pleural mesothelioma, differentiated thyroid cancer, advanced renal cell carcinoma, ovarian cancer, pancreatic cancer, lung cancer, breast cancer, etc., and any combination thereof.

[0040] Any type of conductive or non-conductive electrode(s) and / or transducer array(s) that are known in the art or contemplated herein for generating an alternating electric field can be utilized to generate an alternating electric field in accordance with the methods of the present disclosure. Non-limiting examples of electrodes and transducer arrays that can be utilized to generate an alternating electric field in accordance with the present disclosure include, but are not limited to, those that function as part of the TTFields systems described in U.S. Pat. Nos. 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,675, 10,188,851, 10,441,776, and 11,452,863, and those described in U.S. Patent Application Nos. 2018 / 0001078, 2018 / 0160933, 2019 / 0117956, 2019 / 0307781, and 2019 / 0308016.

[0041] An alternating electric field can be generated at any frequency in accordance with the present disclosure. For example (but not limited to), the alternating electric field can be 50 kHz, 75 kHz, 100 kHz, 125 kHz, 150 kHz, 175 kHz, 200 kHz, 225 kHz, 250 kHz, 275 kHz, 300 kHz, 325 kHz, 350 kHz, 375 kHz, 400 kHz, 425 kHz, 450 kHz, 475 kHz, 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, 800 kHz, 850 kHz, 900 kHz, 950 kHz, 1 MHz, 2 MHz, 3 MHz, 4 MHz, 5 MHz, 6 MHz, 7 MHz, 8 MHz, 9 MHz, 10 MHz, etc., as well as ranges formed from any of the above values (e.g., a range of about 50 kHz to about 10 MHz, a range of about 50 kHz to about 1 MHz, a range of about 50 kHz to about 500 kHz, a range of about 100 kHz to about 500 kHz, a range of about 150 kHz to about 300 kHz, etc.), and ranges formed by combining two integers between two of the above values (e.g., a range of about 122 kHz to about 313 kHz, a range of about 78 kHz to about 298 kHz, etc.).

[0042] In certain (but non-limiting) embodiments, the alternating electric field can be applied at two or more different frequencies. When two or more frequencies are present, each frequency is selected from any of the above values, or a range formed from any of the above values, or a range formed by combining two integers included between two of the above values.

[0043] An alternating electric field can have any electric field strength within a subject / cancer cell as long as it can function in accordance with the present disclosure. For example (but not limited to), the alternating electric field can be at least about 1 V / cm, about 1.5 V / cm, about 2 V / cm, about 2.5 V / cm, about 3 V / cm, about 3.5 V / cm, about 4 V / cm, about 4.5 V / cm, about 5 V / cm, about 5.5 V / cm, about 6 V / cm, about 6.5 V / cm, about 7 V / cm, about 7.5 V / cm, about 8 V / cm, about 9 V / cm, about 9.5 V / cm, about 10 V / cm, about 10.5 V / cm, about 11 V / cm, about 11.5 V / cm, about 12 V / cm, about 12.5 V / cm, about 13 V / cm, about 13.5 V / cm, about 14 V / cm, about 14.5 V / cm, about 15 V / cm, about 15.5 V / cm, about 16 V / cm, about 16.5 V / cm, about 17 V / cm, about 17.5 V / cm, about 18 V / cm, about 18.5 V / cm, about 19 V / cm, about 19.5 V / cm, about 20 V / cm, etc., as well as ranges formed from any of the above values (e.g., a range from about 1 V / cm to about 20 V / cm, a range from about 1 V / cm to about 10 V / cm, a range from about 1 V / cm to about 4 V / cm, etc.), and ranges formed by combining two integers between two of the above values (e.g., a range from about 1.1 V / cm to about 18.6 V / cm, a range from about 1.2 V / cm to about 9.8 V / cm, a range from about 1.3 V / cm to about 4.7 V / cm, etc.).

[0044] The alternating electric field may be applied in a single direction between a pair of arrays, or may be alternately applied in two directions / channels (e.g., front-back and left-right) between two pairs of arrays. For example, a particular TT field device (the OPTUNE® system, manufactured by Novocure Limited, St. Helier, Jersey) operates in two directions to increase the likelihood that dividing cells will be aligned with the electric field so that the electric field can exert the desired anti-mitotic effect. However, it is understood that the scope of the present invention includes the application of an alternating electric field in a single direction. As used herein, the term "alternating electric field" is understood to include application not only in a single direction / channel, but also in two directions / channels. Further, as used herein, the term "alternating electric field" is understood to include not only the application of a single alternating electric field, but also the application of a plurality of alternating electric fields continuously over a period of time.

[0045] The alternating electric field can be applied for any duration or cumulative time sufficient to achieve a decrease in the survival rate of cancer cells and / or a decrease in tumor volume (and / or prevention of an increase in tumor volume). The period during which the alternating electric field is applied includes both a continuous period and a cumulative period. That is, the period during which the alternating electric field is applied includes not only a single session (i.e., continuous application), but also multiple sessions with short breaks between sessions (i.e., continuous application over a cumulative period). For example, a subject may be permitted to take breaks during treatment with an alternating electric field device, and it is expected that the device will be placed on the body and left operating for at least about 60%, at least about 70%, or at least about 80% of the entire treatment period (e.g., 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, etc.).

[0046] For example, but not limited to, the alternating electric field may be applied for at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 21 days, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, etc., as well as ranges formed from any of the above values (e.g., for example, a range from about 1 hour to about 6 months, a range from about 24 hours to about 72 hours, etc.), and ranges formed by combining two integers between two of the above values (e.g., a range from about 14 hours to about 68 hours, etc.) over a continuous or cumulative period.

[0047] In certain (but non-limiting) embodiments, the time for which the alternating electric field is applied is at least about 24 hours.

[0048] Any small molecule anti-angiogenic agent that specifically interacts with either VEGF or VEGFR and / or specifically inhibits signal transduction by VEGFR, whether known in the art or otherwise contemplated herein, can be utilized in accordance with the present disclosure as long as the agent can act as an anti-angiogenic agent that reduces the formation of new blood vessels to cancer cells / tumors. This anti-angiogenic effect occurs by direct interaction of the molecule with VEGF or VEGFR, selectively inhibiting the interaction of VEGF with its respective VEGFR, thereby inhibiting VEGF signal transduction. Non-limiting examples of small molecule anti-angiogenic agents that can be utilized in accordance with the present disclosure include lenvatinib, axitinib, regorafenib, cabozantinib, anlotinib, pazopanib, albendazole, lucitanib, motesanib, aflibercept, ponatinib, cediranib, tivozanib, teratinib, apatinib, semaxanib, fruquintinib, lucitanib, anlotinib, taxifolin, sulfatinib, dovitinib, nintedanib, AZD2932, LY2874455, MGCD-265 analog, ZM306416, ZM323881, KRN633, YF-452, ODM-203, AEE788, BMS605541, MAZ51, Ki8751, SU5402, SU5408, SU5205, SU5214, SU6668, SU14813, XL092, XL184, BAW2881, BFH772, A-13958, SKLB1002, WAY-340935, ZD-4190, hVEGF-IN-1, R1530, VEGF-Grab, soluble vascular endothelial growth factor decoy receptor FP3, VEGF decoy receptor fusion protein, decoy receptor of VEGF, and combinations thereof.

[0049] Certain (but non-limiting) examples of small molecule drugs that can be utilized in accordance with the present disclosure are shown in Table 1 along with their IC 50 values. [Table 1]

[0050] On the one hand, the IC values of sorafenib against VEGFR-1, VEGFR-2, and VEGFR-3, which have been used so far, are 21 nM, 90 nM, and 16 nM, respectively. At least one small molecule anti-angiogenic agent of the present disclosure has an IC value of about 10 nM or less against one, two, or three of VEGFR-1, VEGFR-2, and VEGFR-3, and / or at least one small molecule anti-angiogenic agent of the present disclosure specifically binds (not merely preferentially binds) to only one of VEGF or VEGFR, as described in detail herein. For example, but not limited to, aflibercept is a soluble fusion protein of a part of the human extracellular domains of VEGFR-1 and VEGFR-2 and the Fc portion of human immunoglobulin (Ig), and thus, aflibercept binds only to VGEF-A / PIGF. 50 On the one hand, the IC values of sorafenib against VEGFR-1, VEGFR-2, and VEGFR-3, which have been used so far, are 21 nM, 90 nM, and 16 nM, respectively. At least one small molecule anti-angiogenic agent of the present disclosure has an IC value of about 10 nM or less against one, two, or three of VEGFR-1, VEGFR-2, and VEGFR-3, and / or at least one small molecule anti-angiogenic agent of the present disclosure specifically binds (not merely preferentially binds) to only one of VEGF or VEGFR, as described in detail herein. For example, but not limited to, aflibercept is a soluble fusion protein of a part of the human extracellular domains of VEGFR-1 and VEGFR-2 and the Fc portion of human immunoglobulin (Ig), and thus, aflibercept binds only to VGEF-A / PIGF. 50 On the one hand, the IC values of sorafenib against VEGFR-1, VEGFR-2, and VEGFR-3, which have been used so far, are 21 nM, 90 nM, and 16 nM, respectively. At least one small molecule anti-angiogenic agent of the present disclosure has an IC value of about 10 nM or less against one, two, or three of VEGFR-1, VEGFR-2, and VEGFR-3, and / or at least one small molecule anti-angiogenic agent of the present disclosure specifically binds (not merely preferentially binds) to only one of VEGF or VEGFR, as described in detail herein. For example, but not limited to, aflibercept is a soluble fusion protein of a part of the human extracellular domains of VEGFR-1 and VEGFR-2 and the Fc portion of human immunoglobulin (Ig), and thus, aflibercept binds only to VGEF-A / PIGF.

[0051] In certain (but non-limiting) embodiments, at least one small molecule anti-angiogenic agent specifically and physically interacts with one or more of VEGF-A, VEGF-B, VEGF-C, and / or VEGF-D to inhibit VEGF / VEGFR interaction and VEGFR signaling.

[0052] In certain (but non-limiting) embodiments, at least one small molecule anti-angiogenic agent specifically and physically interacts with one or more of VEGFR-1, VEGFR-2, and / or VEGFR-3 to inhibit VEGF / VEGFR interaction and VEGF signaling. In certain (but non-limiting) embodiments, at least one small molecule anti-angiogenic agent is a type I, type II, and / or type III VEGFR inhibitor. Type I VEGFR inhibitors, also known as ATP-competitive inhibitors, generate hydrophobic interactions with the adenine region, form one to three hydrogen bonds with residues around the active site of the receptor, and compete with the binding to the active "DFG-in" structure within the ATP-binding pocket. Non-limiting examples of type I VEGFR inhibitors that can be utilized in accordance with the present disclosure include pazopanib, axitinib, ponatinib, motesanib, etc., and any combination thereof. Type II VEGFR inhibitors are characterized by binding to the inactive "DFG-out" structure of the kinase and occupying the hydrophobic pocket adjacent to the ATP-binding site. Non-limiting examples of type II VEGFR inhibitors that can be utilized in accordance with the present disclosure include cabozantinib, lenvatinib, regorafenib, lucitanib, etc., and any combination thereof. Type III inhibitors, also known as covalent inhibitors, may exert pharmacological functions by irreversibly binding to cysteine at a specific site of the kinase. Non-limiting examples of type III VEGFR inhibitors include batatinib, etc.

[0053] A composition comprising a low molecular weight anti-angiogenic agent(s) can be provided in any formulation known in the art or contemplated herein. In certain (but non-limiting) embodiments, a composition containing at least one low molecular weight anti-angiogenic agent comprises one or more pharmaceutically acceptable carriers (thus, the composition is also referred to as a "pharmaceutical composition"). Non-limiting examples of suitable pharmaceutically acceptable carriers include water, saline, dextrose solution, fructose or mannitol, calcium carbonate, cellulose, ethanol, oils of animal, plant or synthetic origin, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, detergents, liposome carriers, sodium chloride, saline, buffer solutions such as phosphate buffered saline, and / or other substances that are physiologically acceptable and / or safe to use, diluents, excipients such as polyethylene glycol (PEG), or any combination thereof. For pharmaceutically acceptable carriers suitable for pharmaceutical formulations, see, for example, Remington: The Science and Practice of Pharmacy, 23rd ed ((2020).

[0054] In certain (but non-limiting) embodiments, a composition comprising a small molecule anti-angiogenic agent(s) may further contain one or more additional activating agents. Various active drug(s) used in combination with an alternating electric field or a small molecule anti-angiogenic agent are known in the art, and certain combination therapies are approved by the FDA or are currently in clinical trials. Non-limiting examples of therapeutic agents that can be used in combination with a small molecule anti-angiogenic agent(s) according to the present disclosure include, but are not limited to, anti-PD-1 therapeutic agents such as pembrolizumab, tislelizumab, nivolumab, and semaprimab; anti-PD-L1 therapeutic agents such as atezolizumab, avelumab, and durvalumab; chemotherapeutic agents such as paclitaxel, docetaxel, ifosfamide, etoposide (VP-16), gemcitabine, romustatin, nab-paclitaxel, temozolomide, and carboplatin; TKI inhibitors such as everolimus; mTOR inhibitors; Akt inhibitors; PI3K inhibitors; PARP inhibitors; FGF inhibitors; anti-LAB3 agents; anti-CTLA-4 therapeutic agents; aromatase inhibitors such as letrozole; monoclonal antibodies such as, but not limited to, denosumab and pembrolizumab; biological agents such as anti-VEGF antibodies or anti-VEGFR antibodies such as, but not limited to, VEGFR-2 antibodies such as ramucirumab and DC101; and any combination thereof.

[0055] In certain (but non-limiting) embodiments, the small molecule anti-angiogenic agent(s) present in the composition is bound to another substance. For example, but not limited to, the small molecule anti-angiogenic agent(s) can be bound to a particle or other substance for targeted delivery of the drug to a specific location in the body. In another specific (but non-limiting) embodiment, the composition may contain a small molecule anti-angiogenic agent(s) encapsulated in nanoparticles.

[0056] In addition, any composition of the present disclosure may contain other drugs that enable administration of the composition by a specific route of administration. For example, but not limited to, the composition may be formulated for administration by oral, topical, transdermal, parenteral, subcutaneous, intranasal, mucosal, intramuscular, intraperitoneal, intravitreal, and / or intravenous routes. Based on the route of administration, the composition may also contain, in addition to the activator, one or more additional components (e.g., small molecule anti-angiogenic agent(s) and / or additional therapeutic agent). Examples of additional secondary compounds that may be present include, but are not limited to, fillers, salts, buffers, preservatives, stabilizers, solubilizers, wetting agents, emulsifying agents, dispersing agents, and other substances well known in the art.

[0057] In certain (but non-limiting) embodiments, at least one composition comprising a small molecule anti-angiogenic agent(s) is administered orally to the cell / subject / tumor.

[0058] At least one composition comprising a small molecule anti-angiogenic agent(s) may be administered before or after the application of the alternating electric field is initiated. In certain (but non-limiting) embodiments, at least one composition comprising a small molecule anti-angiogenic agent(s) may be administered after the application of the alternating electric field is initiated. In particular (but not limited to), at least one composition comprising a small molecule anti-angiogenic agent(s) may be administered during (e.g., before the period during which the alternating electric field is applied has elapsed) and / or after the application of the alternating electric field has elapsed.

[0059] For example (but not limited to), at least one composition comprising a small molecule anti-angiogenic agent(s) can be administered after at least about 3 hours, about 6 hours, about 9 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, etc., as well as ranges formed from any of the above values (e.g., the range of about 24 hours to about 96 hours, etc.), and ranges formed by combining two integers between two of the above values (e.g., the range of about 14 hours to about 94 hours, etc.) after the application of the alternating electric field is initiated. In certain (but non-limiting) embodiments, at least one composition comprising a small molecule anti-angiogenic agent(s) is administered at least about 24 hours after the initiation of the application of the alternating electric field.

[0060] In other non-limiting examples, at least one composition comprising a small molecule anti-angiogenic agent(s) can be administered after the period during which the alternating electric field is applied has elapsed, and at least one composition comprising a small molecule anti-angiogenic agent(s) is administered within about 3 hours, about 6 hours, about 9 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, etc. after the period during which the alternating electric field is applied has elapsed.

[0061] In certain (but non-limiting) embodiments, at least one composition comprising a small molecule anti-angiogenic agent(s) is administered within about 96 hours after the period has elapsed.

[0062] A composition comprising a small molecule anti-angiogenic agent(s) can be administered to cancer cells / subjects at any concentration that provides a therapeutically effective concentration of the small molecule anti-angiogenic agent(s). In certain non-limiting embodiments, the application of an alternating electric field reduces the amount of small molecule anti-angiogenic agent(s) required to be therapeutically effective compared to the normal therapeutically effective amount administered in the absence of the alternating electric field. For example, but not limited to, the therapeutically effective concentration of the small molecule anti-angiogenic agent(s) can be at least about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more lower than the dosage of the small molecule anti-angiogenic agent(s) known to be therapeutically effective in the absence of the application of an alternating electric field. In certain (but non-limiting) embodiments, the therapeutically effective concentration of the small molecule anti-angiogenic agent(s) is at least about 50% lower compared to the dosage of the small molecule anti-angiogenic agent(s) known to be therapeutically effective in the absence of the alternating electric field.

[0063] The therapeutically effective concentration of the small molecule anti-angiogenic agent(s) utilized in accordance with the present disclosure can be, for example (but not limited to), about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 11 nM, about 12 nM, about 12.5 nM, about 13 nM, about 14 nM, about 15 nM, about 20 nM, about 25 nM, about 30 nM, about 35 nM, about 40 nM, about 45 nM, about 50 nM, about 55 nM, about 60 nM, about 65 nM, about 70 nM, about 75 nM, about 80 nM, about 85 nM, about 90 nM, about 95 nM, about 100 nM, about 110 nM, about 120 nM, about 130 nM, about 140 nM, about 150 nM, etc., as well as ranges formed from any of the above values (e.g., a range from about 12.5 nM to about 100 nM, etc.), and ranges formed by combining two integers between two of the above values (e.g., a range from about 17 nM to about 83 nM, etc.).

[0064] In certain (but non-limiting) embodiments, the therapeutically effective concentration of the small molecule anti-angiogenic agent(s) is from about 12.5 nM to about 100 nM.

[0065] In certain (but not limited to) embodiments, the method includes one or more additional steps. For example (but not limited thereto), the method may further include the step of (3) stopping the application of the alternating electric field (e.g., but not limited thereto) so that the cells / tissue can recover. Further, either of steps (1) and / or (2) may be repeated one or more times.

[0066] In certain (but not limited to) embodiments, the method includes co-treatment with two or more compositions. Thus, the method may include the additional step of (4) administering at least a second composition to the cancer cells / subject. In certain (but not limited to) embodiments, the at least second composition may contain one or more of any of the active substances disclosed herein or otherwise contemplated for use with a small molecule anti-angiogenic agent(s).

[0067] A variety of substances and therapies used in combination with small molecule anti-angiogenic agents(s) are known in the art, and certain combination therapies have been approved by the FDA or are currently in clinical trials. Non-limiting examples of therapeutic agents that can be used in combination with small molecule anti-angiogenic agents(s) in accordance with the present disclosure include anti-PD-1 therapeutic agents such as pembrolizumab, tislelizumab, nivolumab, and semaprimab (but not limited thereto); anti-PD-L1 therapeutic agents such as atezolizumab, avelumab, and durvalumab; chemotherapeutic agents such as paclitaxel, docetaxel, ifosfamide, etoposide (VP-16), gemcitabine, romustatin, nab-paclitaxel, temozolomide, and carboplatin (but not limited thereto); TKI inhibitors such as everolimus (but not limited thereto); mTOR inhibitors; Akt inhibitors; PI3K inhibitors; PARP inhibitors; FGF inhibitors; anti-LAB3 agents; anti-CTLA-4 therapeutic agents; aromatase inhibitors such as letrozole (but not limited thereto), monoclonal antibodies (but not limited thereto, such as denosumab and pembrolizumab); biological agents such as anti-VEGF or anti-VEGFR antibodies (but not limited thereto, such as anti-VEGFR-2 antibodies such as ramucirumab and DC101); and any combination thereof.

[0068] If present, step (4) may be carried out substantially simultaneously with the administration of the first composition in step (1) or sequentially in whole or in part, whereby the two separate compositions are administered simultaneously or sequentially in whole or in part. In addition, the two compositions administered in steps (1) and (4) may be administered by the same route (e.g., both orally), or the two compositions may be administered by different routes (e.g., one composition is administered orally and the other composition is administered intravenously).

[0069] If present, any additional administration step (4) can be carried out in the same manner(s) and time frame(s) as described above for the first composition, before or after the application of the alternating electric field is initiated, during the application of the alternating electric field, and / or after the application of the alternating electric field has elapsed.

[0070] That is, for example (but not limited to), the second composition can be administered after at least about 3 hours, about 6 hours, about 9 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, and similarly, a range formed from any of the above values (e.g., a range of about 24 hours to about 96 hours, etc.), and a range combining two integers included between two of the above values (e.g., a range of about 14 hours to about 94 hours, etc.) after the application of the alternating electric field is initiated. In certain (but non-limiting) embodiments, the second composition is administered at least about 24 hours after the application of the alternating electric field is initiated.

[0071] In other non-limiting examples, the second composition can be administered after the period during which the alternating electric field is applied has elapsed. In this case, the second composition is administered within about 3 hours, about 6 hours, about 9 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, etc. after the period during which the alternating electric field is applied has elapsed. In certain (but non-limiting) embodiments, the second composition is administered within about 96 hours after the period has elapsed.

[0072] In addition, for example (but not limited to), the second composition may be administered at least about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, etc., and ranges formed from any of the above values (e.g., the range of about 24 hours to about 96 hours, etc.), and ranges combining two integers between the above two values (e.g., the range of about 14 hours to about 94 hours, etc.) after the administration of the first substance. In certain (but non-limiting) embodiments, the second composition is administered at least about 12 hours after the administration of the first substance.

[0073] In certain (but non-limiting) embodiments, the method may further comprise the step of (5) subjecting the cell / subject to at least one additional therapy. Any therapy known in the art or contemplated for use in combination with alternating electric fields (e.g., TT fields) and / or small molecule anti-angiogenic agent therapy herein may be utilized in accordance with the methods of the present disclosure. Non-limiting examples of additional therapies that can be utilized include radiation therapy, photodynamic therapy, transarterial chemoembolization (TACE), or combinations thereof.

[0074] In certain (but non-limiting) embodiments, the method may further comprise (6) applying a second alternating electric field to the target region of the subject, wherein the alternating electric field is administered at a frequency different from the frequency of the alternating electric field of step (2). That is, the method of the present disclosure may include applying a first alternating electric field at a first frequency over a first period, and applying the first alternating electric field at the first frequency over the first period increases the permeability of the cell membrane of cancer cells. Then, at least one composition comprising at least one small molecule anti-angiogenic agent can be administered, and the increased permeability of the cell membrane allows the substance to pass through the cell membrane. Next, a second alternating electric field can be applied at a second frequency over a second period, the second frequency being different from the first frequency, and the second alternating electric field at the second frequency reduces the survival rate of cancer cells. The use of alternating electric fields at two different frequencies (which affect cell membrane permeability and cell survival rate) is described in detail in U.S. Patent Application No. 2020 / 0009376, the entire contents of which are hereby expressly incorporated by reference.

[0075] Steps (1) and (2) and any of steps (3), (4), (5), and (6) can be repeated one or more times. Each step can be repeated as many times as necessary. When step (2) is repeated, the transducer array can be placed at a position slightly different from the original placement of the subject, and by repositioning the array in this way, the treatment of the tumor / cancer can be further promoted. In addition, step (1) of administering the composition(s) / additional therapy(ies) and any of steps (4) and (5) (if present) can be repeated at various times and at various intervals to follow known and / or generally accepted dosages / treatment regimens of the composition / therapy.

[0076] The use of ordinal numbers for any step is for illustrative purposes only, and the method of the present disclosure may include one or more of any of steps (3), (4), (5), and (6) alone or in combination with each other. That is, the method of the present disclosure may perform step (3) when steps (4) or (5) are absent, perform step (4) when steps (3) or (5) are absent, perform step (5) when steps (3) and (4) are absent, and perform step (6) when (3), (4), and / or (5) are absent. In other words, the scope of the method disclosed herein includes performing steps (1)-(2) (repeating each step as necessary), performing steps (1)-(3) (repeating one or more of steps (1)-(3) as necessary), performing steps (1)-(2) and (4) (repeating one or more of steps (1)-(2) and (4) as necessary), performing steps (1)-(2) and (5) (repeating one or more of steps (1)-(2) and (5) as necessary), performing steps (1)-(4) (repeating one or more of steps (1)-(4) as necessary), performing steps (1)-(3) and (5) (repeating one or more of steps (1)-(3) and (5) as necessary), performing steps (1)-(2) and (4)-(5) (repeating one or more of steps (1)-(4) as necessary), and repeating one or more of steps (1)-(2) and (4)-(5) as necessary), performing step (6) alone in combination with steps (1)-(2), or in combination with one or more of steps (3)-(5), or performing all of steps (1)-(6) (further repeating one or more of steps (1)-(6) as necessary).

[0077] Although the above explicitly describes the use of a combination therapy of two substances, it is understood that the scope of the present disclosure also includes combination therapies of three or more compositions. Accordingly, the method can include one or more additional steps (similar to steps (1) and (4)) of administering an additional composition to the subject. The additional substances administered by this method can be selected from either substances disclosed herein or substances contemplated for use in combination with a small molecule anti-angiogenic agent (as disclosed above herein with respect to any step (4)). Further, the administration of the additional substances can be substantially simultaneous with the administration of the first and second compositions / substances, or completely or partially sequentially, in the same manner(s) and time frame(s) as described above for the first and second compositions / substances.

[0078] Certain non-limiting embodiments of the present disclosure relate to kits comprising a combination of any component of an alternating electric field (e.g., TT field) generating system (e.g., as disclosed in U.S. Pat. Nos. 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,675, 10,188,851, 10,441,776, and 11,452,863, and U.S. Patent Application Nos. 2018 / 0001078, 2018 / 0160933, 2019 / 0117956, 2019 / 0307781, and 2019 / 0308016, including one or more transducer arrays and / or one or more hydrogel compositions, but not limited thereto) and at least one of any composition comprising a small molecule anti-angiogenic agent(s) as disclosed herein or otherwise contemplated herein. The kit may optionally further contain one or more of any composition (such as one or more optional compositions comprising at least one additional activator) as disclosed herein or otherwise contemplated herein. The kit may optionally further include one or more devices (or one or more components of a device) used in one or more additional treatment steps.

[0079] In certain (but non-limiting) embodiments, the kit may further include instructions for performing any of the methods disclosed or contemplated herein. For example (but not limited to), the kit may include instructions for applying one or more components of an alternating electric field (e.g., TT field) generating device to a patient's skin, instructions for applying an alternating electric field to the patient, the timing and method of administering a composition comprising a small molecule anti-angiogenic agent(s), and optionally instructions regarding the method of administering one or more optional additional compositions, and / or instructions regarding when to activate and deactivate the alternating electric field in relation to the administration of the composition comprising a small molecule anti-angiogenic agent(s), and / or the administration of one or more optional compositions, and / or the treatment steps.

[0080] In addition to the components described in detail above, the kit may further contain other component(s) / reagent(s) for carrying out any of the specific methods described herein or otherwise contemplated. For example (but not limited to), the kit may contain (i) components for preparing the skin prior to discarding the hydrogel composition and / or transducer array on the skin (e.g., razor, cleansing composition, wipe / towel, etc.); (ii) components for removing the gel / transducer array(s); (iii) components for cleansing the skin after removing the gel / transducer array(s); and / or (iv) and / or (iv) other components used in the system (i.e., conductive material, non-conductive material, soothing gel or cream, bandage, etc.). Since the nature of these additional component(s) / reagent(s) depends on the specific treatment format and their identification is within the skill of those in the art, further description is considered unnecessary. Also, the components / reagents included in the kit may be in separate containers / compartments depending on the sterility, cross-reactivity, stability of the components / reagents, or various components / reagents may be combined in one or more containers / compartments.

[0081] The kit can be placed within any package that enables the components contained therein to function in accordance with the present disclosure. In certain non-limiting embodiments, the kit further includes a sealed package in which the components are placed. In certain (but non-limiting) embodiments, the sealed package is substantially impermeable to air and / or substantially impermeable to light.

[0082] In addition, the kit may further include a set of written instructions that describe how to use one or more of the components of the kit. Such kits can be used in any of the methods described herein or otherwise contemplated.

[0083] In certain non-limiting embodiments, the shelf life of the kit is at least about 6 months, such as (but not limited to) at least about 9 months, or at least about 12 months. Certain non-limiting embodiments of the present disclosure relate to a system comprising a combination of any component of an alternating electric field generating system (such as one or more transducer arrays and / or one or more hydrogel compositions disclosed in U.S. Patent Nos. 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,675, 10,188,851, 10,441,776, and 11,452,863, and U.S. Patent Application Nos. 2018 / 0001078, 2018 / 0160933, 2019 / 0117956, 2019 / 0307781, and 2019 / 0308016, but not limited thereto) disclosed or otherwise contemplated herein, and at least one of any composition comprising a small molecule anti-angiogenic agent(s) disclosed or otherwise contemplated herein. The system may optionally further comprise one or more of any composition disclosed or contemplated herein. The system may optionally further comprise one or more devices (or one or more components of a device) used in one or more additional treatment steps. Examples Examples are shown below. However, it should be understood that the present disclosure is not limited to the application to the specific experiments, results, and experimental procedures disclosed below herein. Rather, the examples are provided merely as one of various embodiments and are intended to be illustrative rather than exhaustive. Example 1

[0084] In the prior art referred to in the above Background section, although the TT field has been shown to have anti-angiogenic activity, in this example, it is shown that VEGF expression increases by TT field treatment and that new blood vessel formation actually increases.

[0085] MOSE-L-FFL was injected into mice (day 0), and an orthotopic ovarian cancer mouse model was created and confirmed by IVIS on day 15. From day 16, the mice were treated with a 200 kHz TT field (or heat control) for 10 days. As seen in Figure 1, an increase in blood vessels was observed in the ovaries filled with tumors in the mice treated with the TT field compared to the untreated control (heat-treated mice).

[0086] The mice in this in vivo ovarian cancer model were sacrificed on day 26, blood samples were collected, collected in designated serum tubes, centrifuged at 1000 g for 15 minutes, and stored at -20°C. The serum was incubated on a cytokine array membrane, and as shown in Figure 2, an increase in VEGF secreted after TT field treatment was observed compared to the heat-treated mice.

[0087] Next, LLC-2 was injected into mice (day 0), and by confirming on day 7, mice with rectal lung cancer were created. From day 7, the mice were treated with a 150 kHz TT field for 14 days. On day 21, the mice were sacrificed, blood samples were collected and collected in designated serum tubes, centrifuged at 1000 g for 15 minutes, and stored at -20°C. The serum was incubated on a cytokine array membrane, and as shown in Figure 3, an increase in secreted VEGF after the TT field was observed compared to the heat-treated mice.

[0088] Next, the mice in the same in vivo ovarian cancer model as Figures 1-2 were sacrificed on day 26, and tumor samples were collected for histological analysis of the tumor tissue. The tumor tissue was stained by immunohistochemical staining of CD31 (a marker for endothelial cells and blood vessels), and the images were quantified. CD31 staining was shown in brown (DAB staining). As shown in Figure 4, the microvessel density of the tumors treated with the TT field was significantly higher than that of the control tumors treated with heat. Thus, in contrast to current literature suggesting an anti-angiogenic effect for TT field therapy, in this example, application of the TT field actually has a pro-angiogenic effect, resulting in increased VEGF expression and formation of a new vascular system supplying the tumor, as demonstrated. Thus, administration of at least one small molecule anti-angiogenic agent abrogated the pro-angiogenic effect of TT field application in combination therapy. Example 2

[0089] Lenvatinib (prescribed as LENVIMA® and manufactured by Eisai Co., Ltd. in Nutley, New Jersey) is a multi-kinase inhibitor of VEGFR1-3. Clinically, it has been used for the treatment of differentiated thyroid cancer (DTC), advanced renal cell carcinoma (RCC), and hepatocellular carcinoma.

[0090] In this example, the combined effect of the TT field and lenvatinib was investigated to understand the influence of the tumor microenvironment and the changes that the extracellular matrix (ECM) undergoes after application of the TT field. The tumor microenvironment, particularly ECM components, has been shown to be an important part of tumor progression and clinical outcome (Henke et al. (2020) Front Mol Biosci. 6:160; Baghban et al. (2020) Cell Commun Signal, 18:59; Popova et al. (2022) Cancers, 14(1):238). Lenvatinib is a multi-kinase inhibitor that inhibits many pathways that have been observed to be upregulated upon TT field application. The pathways inhibited include the three major vascular endothelial growth factor receptors 1, 2, 3 (VEGFR-1, -2, -3), fibroblast growth factor receptors 1, 2, 3, 4 (FGFR-1, -2, -3, -4), platelet-derived growth factor receptor alpha (PDGFRα), c-Kit, and the RET proto-oncogene. Furthermore, these pathways are known to control ECM formation (Nelson et al. (1997) JVasc Surg, 26(1):104-12; Xu et al. (1996) J Cell Biol, 132(1-2):239-49; Vlodavsky et al. (1990) Cancer Metastasis Rev, 9(3):203-2).

[0091] In this example, the combination therapy of TT field and lenvatinib in an INOVITRO™ 3D model (manufactured by Novocure Ltd., Route, Switzerland) in which collagen and cancer cells were grown in a 3D structure was studied. In this example, the combination therapy of TT field and lenvatinib in an INOVIVO™ system (manufactured by Novocure Ltd., Route, Switzerland, see, for example, Davidi (2020) Neuro-Oncology, 22(Supplement 2):ii104) is also being studied.

[0092] Experiments were conducted to evaluate cell and tumor growth (cell number or 3D image capture INOVITRO™, tumor growth INOVIVO™ monitoring), apoptosis (INOVITRO™ - AnnexinV / PI staining and INOVIVO™ - Ki67 tissue staining), cytokine and chemokine secretion (tumor-derived lysates, and conditioned media and serum examined by ELISA, cytokine array, multiplex assay, or Luminex assay), collagen expression (by collagen staining and secretion), and tissue angiogenesis - neovascularization (by CD31 staining).

[0093] The cell lines used are either cancers commonly treated with lenvatinib (differentiated thyroid cancer (DTC), advanced renal cell carcinoma (RCC), hepatocellular carcinoma, etc.) and / or cancer cell lines commonly treated with TT field (glioblastoma or pleural mesothelioma, etc.).

[0094] In particular, the combined effect of TT field and lenvatinib was investigated in an ovarian cancer cell line (A2780). The effects of the combination therapy on cell number and apoptosis are shown in Figures 5 - 6. As described above, the combination of TT field and lenvatinib enhanced the effect more than either therapy alone. Therefore, the use of combination therapy including TT field and lenvatinib results in a synergistic effect. The combination therapy of TT field / lenvatinib is effective in reducing the survival rate of cancer cells, decreasing the tumor volume, and preventing tumor volume increase compared to the case of either treatment alone. In addition, when TT field is used in combination with lenvatinib, the amount of lenvatinib required to obtain a therapeutic effect is reduced, and when lenvatinib is combined with TT field, the therapeutic effective concentration of lenvatinib is reduced by at least about 50% compared to the dosage of lenvatinib known to have a therapeutic effect in the absence of an alternating electric field. Non-limiting exemplary embodiments of the concept(s) of the present invention

[0095] Exemplary Embodiment 1. A method for reducing the survival rate of cancer cells, comprising: (1) administering at least one composition to cancer cells, wherein the at least one composition specifically [physically] interacts with either vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling with an IC 50 less than about 10 nmol / L. The step includes at least one small molecule anti-angiogenic agent, and (2) applying an alternating electric field to the cancer cells for a certain period of time.

[0096] Exemplary Embodiment 2. The method according to Exemplary Embodiment 1, wherein the method is carried out in vitro or in vivo.

[0097] Exemplary Embodiment 3. The method according to Exemplary Embodiment 1, wherein the method is carried out in vivo.

[0098] Exemplary Embodiment 4. The method according to any one of Exemplary Embodiments 1 to 3, wherein the cancer cells are selected from the group consisting of hepatocellular carcinoma cells, glioblastoma cells, pleural mesothelioma cells, differentiated thyroid carcinoma cells, advanced renal cell carcinoma cells, ovarian cancer, pancreatic cancer, lung cancer cells, breast cancer cells, and combinations thereof.

[0099] Exemplary Embodiment 5. A method for treating cancer in a subject, comprising: (1) administering at least one composition to the subject, wherein the at least one composition specifically interacts with either vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling with an IC 50 less than about 10 nmol / L. The step includes at least one small molecule anti-angiogenic agent, and (2) applying an alternating electric field to the target region of the subject.

[0100] Exemplary Embodiment 6. A method for reducing the volume of a tumor and / or preventing an increase in the volume of a tumor, wherein the tumor is present in a living body and contains a plurality of cancer cells, comprising: (1) administering to a subject at least one composition, wherein the at least one composition specifically interacts with either vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling at an IC 50 less than about 10 nmol / L. The step includes at least one small molecule anti-angiogenic agent; and (2) applying an alternating electric field to a target region of the subject.

[0101] Exemplary Embodiment 7. The method according to Exemplary Embodiment 5 or 6, wherein the at least one composition is orally administered to the subject.

[0102] Exemplary Embodiment 8. The method according to any one of Exemplary Embodiments 5 to 7, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, glioblastoma, pleural mesothelioma, differentiated thyroid cancer, advanced renal cell carcinoma, ovarian cancer, pancreatic cancer, lung cancer, breast cancer, and combinations thereof.

[0103] Exemplary Embodiment 9. The method according to any one of Exemplary Embodiments 1 to 8, wherein the at least one small molecule anti-angiogenic agent specifically interacts with at least one of VEGF-A, VEGF-B, VEGF-C, or VEGF-D.

[0104] Exemplary Embodiment 10. The method according to any one of Exemplary Embodiments 1 to 9, wherein the at least one small molecule anti-angiogenic agent specifically interacts with at least one of VEGFR-1, VEGFR-2, or VEGFR-3.

[0105] Exemplary Embodiment 11. The method according to any one of Exemplary Embodiments 1 to 10, wherein at least one small molecule anti-angiogenic agent is lenvatinib, axitinib, regorafenib, cabozantinib, anlotinib, pazopanib, albendazole, lucitanib, motesanib, aflibercept, ponatinib, cediranib, thiazovivin, teratinib, apatinib, semaxanib, fruquintinib, lucitanib, anlotinib, taxifolin, sulfatinib, dovitinib, nintedanib, AZD2932, LY2874455, MGCD-265 analog, ZM306416, ZM323881, KRN633, YF-452, ODM-203, AEE788, BMS 605541, MAZ51, Ki 8751, SU 5402, SU 5408, SU5205, SU5214, SU 6668, SU 14813, XL 092, XL 184, BAW2881, BFH772, A-13958, SKLB1002, WAY-340935, ZD-4190, hVEGF-IN-1, R1530, VEGF-Grab, soluble vascular endothelial growth factor decoy receptor FP3, VEGF decoy receptor fusion protein, decoy receptor for VEGF, and combinations thereof.

[0106] Exemplary Embodiment 12. The method according to any one of Exemplary Embodiments 1 to 11, wherein at least one small molecule anti-angiogenic agent is a type I VEGFR inhibitor.

[0107] Exemplary Embodiment 13. The method according to Exemplary Embodiment 12, wherein the type I VEGFR inhibitor is selected from the group consisting of pazopanib, axitinib, ponatinib, motesanib, and combinations thereof.

[0108] Exemplary Embodiment 14. The method according to any one of Exemplary Embodiments 1 to 13, wherein at least one small molecule anti-angiogenic agent is a type II VEGFR inhibitor.

[0109] Exemplary Embodiment 15. The method according to Exemplary Embodiment 14, wherein the type II VEGFR inhibitor is selected from the group consisting of cabozantinib, lenvatinib, regorafenib, lucitanib, and combinations thereof.

[0110] Exemplary Embodiment 16. The method according to any one of Exemplary Embodiments 1 to 15, wherein at least one small molecule anti-angiogenic agent is a type III VEGFR inhibitor.

[0111] Exemplary Embodiment 17. A method for reducing the survival rate of cancer cells, and / or treating cancer in a subject, and / or reducing the volume of a tumor, and / or preventing an increase in the volume of a tumor, comprising: (1) administering at least one composition to cancer cells / a subject, wherein the at least one composition is a selective inhibitor of vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), and comprises at least one small molecule anti-angiogenic agent that specifically binds to VEGF or VEGFR alone and does not bind to other targets; and (2) applying an alternating electric field to the cancer cells / target region of the subject for a certain period of time.

[0112] Exemplary Embodiment 18. The method according to Exemplary Embodiment 17, wherein this method is carried out in vitro or ex vivo.

[0113] Exemplary Embodiment 19. The method according to Exemplary Embodiment 17, wherein this method is carried out in vivo.

[0114] Exemplary Embodiment 20. The method according to any one of Exemplary Embodiments 17 to 19, wherein the cancer / cancer cells are selected from the group consisting of hepatocellular carcinoma cells, glioblastoma cells, pleural mesothelioma cells, differentiated thyroid cancer cells, advanced renal cell carcinoma cells, ovarian cancer, pancreatic cancer, lung cancer cells, breast cancer cells, and combinations thereof.

[0115] Exemplary Embodiment 21. The method according to any one of Exemplary Embodiments 17 to 20, wherein at least one small molecule anti-angiogenic agent is aflibercept.

[0116] Exemplary Embodiment 22. A method for reducing the survival rate of cancer cells, comprising: (1) administering at least one composition to cancer cells, wherein the at least one composition comprises lenvatinib; and (2) applying an alternating electric field to the cancer cells for a certain period of time.

[0117] Exemplary Embodiment 23. The method according to Exemplary Embodiment 22, which is carried out in vitro or ex vivo.

[0118] Exemplary Embodiment 24. The method according to Exemplary Embodiment 22, which is carried out in vivo.

[0119] Exemplary Embodiment 25. The method according to any one of Exemplary Embodiments 22 to 24, wherein the cancer / cancer cells are selected from the group consisting of hepatocellular carcinoma cells, glioblastoma cells, pleural mesothelioma cells, differentiated thyroid carcinoma cells, advanced renal cell carcinoma cells, ovarian cancer, pancreatic cancer, lung cancer cells, breast cancer cells, and combinations thereof.

[0120] Exemplary Embodiment 26. A method for treating cancer in a subject, comprising: (1) administering at least one composition to the subject, wherein the at least one composition comprises lenvatinib; and (2) applying an alternating electric field to a target region of the subject.

[0121] Exemplary Embodiment 27. A method for reducing the volume of a tumor and / or preventing an increase in the volume of a tumor, wherein the tumor is present in vivo and comprises a plurality of cancer cells, comprising: (1) administering at least one composition to the subject, wherein the at least one composition comprises lenvatinib; and (2) applying an alternating electric field to a target region of the subject.

[0122] Exemplary Embodiment 28. The method according to Exemplary Embodiment 26 or 27, wherein the at least one composition is administered orally to the subject.

[0123] Exemplary Embodiment 29. A method according to any one of exemplary embodiments 26 to 28, wherein the composition containing lenvatinib is administered to cancer cells at a therapeutically effective concentration of lenvatinib.

[0124] Exemplary Embodiment 30. A method according to exemplary embodiment 29, wherein the therapeutically effective concentration of lenvatinib is at least about 50% reduced relative to the dosage of lenvatinib known to be therapeutically effective in the absence of an alternating current electric field.

[0125] Exemplary Embodiment 31. A method according to exemplary embodiment 29 or 30, wherein the therapeutically effective concentration of lenvatinib is from about 12.5 nM to about 100 nM.

[0126] Exemplary Embodiment 32. A method according to any one of exemplary embodiments 1 to 31, having at least one of the following: the alternating current electric field is applied at a frequency in the range of about 50 kHz to about 1 MHz, the alternating current electric field has an electric field strength of at least about 1 V / cm in at least a part of the cancer cells, and the period during which the alternating current electric field is applied is at least about 24 hours.

[0127] Exemplary Embodiment 33. A method according to any one of exemplary embodiments 1 to 32, wherein steps (1) and (2) are carried out substantially simultaneously.

[0128] Exemplary Embodiment 34. A method according to any one of exemplary embodiments 1 to 32, wherein steps (1) and (2) are carried out in whole or in part sequentially, and at least one composition is administered before the application of the alternating current electric field is initiated.

[0129] Exemplary Embodiment 35. A method according to any one of exemplary embodiments 1 to 33, wherein steps (1) and (2) are carried out in whole or in part sequentially, and at least one composition is administered after the application of the alternating current electric field is initiated.

[0130] Exemplary Embodiment 36. The method according to exemplary embodiment 35, wherein at least one composition is administered at least 24 hours after the application of the alternating electric field is started.

[0131] Exemplary Embodiment 37. The method according to exemplary embodiment 36, wherein at least one composition is administered before the period during which the alternating electric field is applied elapses.

[0132] Exemplary Embodiment 38. The method according to exemplary embodiment 36, wherein at least one composition is administered after a certain period has elapsed.

[0133] Exemplary Embodiment 39. The method according to exemplary embodiment 38, wherein at least one composition is administered within about 96 hours after the period has elapsed.

[0134] Exemplary Embodiment 40. The method according to any one of exemplary embodiments 1 to 39, wherein the time during which the alternating electric field is applied is in the range of about 24 hours to about 72 hours.

[0135] Exemplary Embodiment 41. The method according to any one of exemplary embodiments 1 to 40, wherein this method further includes a step of stopping the application of the alternating electric field.

[0136] Exemplary Embodiment 42. The method according to any one of exemplary embodiments 1 to 41, wherein at least one composition further includes a pharmaceutically acceptable carrier.

[0137] Exemplary Embodiment 43. The method according to any one of exemplary embodiments 1 to 42, wherein steps (1) and (2) are repeated one or more times.

[0138] Exemplary Embodiment 44. A method according to any one of exemplary embodiments 1 to 43, the method comprising applying a first alternating current electric field to the cancer cells / target region of a subject for a certain period of time, and applying a second alternating current electric field to the cancer cells / target region of the subject for a certain period of time, wherein the first alternating current electric field and the second alternating current electric field have different frequencies.

[0139] Exemplary Embodiment 45. A method according to exemplary embodiment 44, wherein the first frequency affects cell permeability and the second frequency affects cell viability.

[0140] Exemplary Embodiment 46. A method according to any one of exemplary embodiments 1 to 45, wherein at least one composition further comprises at least one additional therapeutic agent.

[0141] Exemplary Embodiment 47. A method according to any one of exemplary embodiments 1 to 46, the method further comprising administering a second composition to the cancer cells, the second composition comprising at least one additional therapeutic agent, and the first and second compositions being administered substantially simultaneously or sequentially in whole or in part.

[0142] Exemplary Embodiment 48. A method according to exemplary embodiment 46 or 47, wherein at least one additional therapeutic agent is selected from the group consisting of checkpoint immune inhibitors, anti-PD-1 therapeutic agents, chemotherapeutic agents, TKI inhibitors, mTOR inhibitors, Akt inhibitors, aromatase inhibitors, radiation therapeutic agents, biological agents, and combinations thereof.

[0143] Exemplary Embodiment 49. A method according to exemplary embodiment 48, wherein at least one additional therapeutic agent is selected from the group consisting of pembrolizumab, tislelizumab, paclitaxel, docetaxel, ifosfamide, etoposide (VP-16), gemcitabine, carboplatin, everolimus, letrozole, denosumab, and combinations thereof.

[0144] Exemplary Embodiment 50. A method according to any one of exemplary embodiments 1 to 49, further comprising the step of subjecting the cell / subject to at least one additional therapy.

[0145] Exemplary Embodiment 51. A method according to exemplary embodiment 50, wherein the at least one additional therapy is selected from the group consisting of radiation therapy, photodynamic therapy, transarterial chemoembolization (TACE), and combinations thereof.

[0146] Exemplary Embodiment 52. A composition for use in a method according to any one of exemplary embodiments 1 to 16 and 32 to 51 (when dependent on exemplary embodiments 1 to 16), wherein the composition specifically interacts with either vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling with an IC 50 of less than about 10 nmol / L, and comprises at least one small molecule anti-angiogenic agent.

[0147] Exemplary Embodiment 53. Use of a composition in a method according to any one of exemplary embodiments 1 to 16 and 32 to 51 (when dependent on exemplary embodiments 1 to 16), wherein the composition specifically interacts with either vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling with an IC 50 of less than about 10 nmol / L, and comprises at least one small molecule anti-angiogenic agent.

[0148] Exemplary Embodiment 54. A composition for use in a method according to any one of exemplary embodiments 17 to 21 and 32 to 51 (when dependent on exemplary embodiments 17 to 21), wherein the composition is a selective inhibitor of either vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), and comprises at least one small molecule anti-angiogenic agent that specifically and alone binds to VEGF or VEGFR and does not bind to other targets.

[0149] Use of a composition in the method according to any one of exemplary embodiments 55. Exemplary embodiments 17-21 and 32-51 (when dependent on exemplary embodiments 17-21), wherein the composition is a selective inhibitor of vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), and specifically binds to VEGF or VEGFR alone and does not bind to other targets, and comprises at least one small molecule anti-angiogenic agent.

[0150] Exemplary embodiment 56. A composition for use in the method according to any one of exemplary embodiments 22-31 and 32-51 (when dependent on exemplary embodiments 22'31), wherein the composition comprises lenvatinib.

[0151] Use of a composition in the method according to any one of exemplary embodiments 57. Exemplary embodiments 22-31 and 32-51 (when dependent on exemplary embodiments 22-31), wherein the composition comprises lenvatinib.

[0152] Exemplary embodiment 58. A kit comprising at least one pair of transducer arrays for generating an alternating electric field between them when the transducer arrays are applied to at least one cell and / or placed on a subject, and at least one composition according to any one of exemplary embodiments 52, 54, or 56.

[0153] The present invention describes the concept(s) of the present invention in conjunction with the specific experiments, results, and words shown below, but it is clear that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the present invention is intended to embrace all alternatives, modifications, and variations that fall within the spirit and broad scope of the present disclosure.

Claims

1. A kit comprising: at least one pair of transducer arrays for generating an alternating electric field therebetween when the transducer arrays are applied to at least one cell and / or disposed on a subject; Specifically interacts with either vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling with an IC of less than about 10 nmol / L ５０ A kit comprising at least one composition comprising at least one small molecule anti-angiogenic agent that inhibits at.

2. A kit comprising: at least one pair of transducer arrays for generating an alternating electric field therebetween when the transducer arrays are applied to at least one cell and / or disposed on a subject; and at least one composition comprising at least one small molecule anti-angiogenic agent that is a selective inhibitor of vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), specifically binds to VEGF or VEGFR alone and does not bind to other targets.

3. A kit comprising: at least one pair of transducer arrays for generating an alternating electric field therebetween when the transducer arrays are applied to at least one cell and / or disposed on a subject; and at least one composition comprising lenvatinib.

4. A composition for use in the method according to any one of claims 10 to 25 and 41 to 60, which specifically interacts with either vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling with an IC ５０ of less than about 10 nmol / L, comprising at least one small molecule anti-angiogenic agent.

5. Use of a composition in the method according to any one of Claims 10 - 25 and 41 - 60, wherein the composition specifically interacts with either vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling with an IC50 of less than about 10 nmol / L, the use comprising at least one small molecule anti-angiogenic agent.

6. A composition for use in the method according to any one of Claims 26 - 30 and 41 - 60, wherein the composition is a selective inhibitor of vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), and comprises at least one small molecule anti-angiogenic agent that specifically binds to VEGF or VEGFR alone and does not bind to other targets.

7. Use of a composition in the method according to any one of Claims 26 - 30 and 41 - 60, wherein the composition is a selective inhibitor of vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), and comprises at least one small molecule anti-angiogenic agent that specifically binds to VEGF or VEGFR alone and does not bind to other targets.

8. A composition for use in the method according to any one of claims 31 to 60, the composition comprising lenvatinib.

9. Use of a composition in the method according to any one of claims 31 to 60, the composition comprising lenvatinib.

10. A method for reducing the survival rate of cancer cells, the method comprising: (1) Administering at least one composition to cancer cells, wherein the at least one composition specifically interacts with either vascular endothelial growth factor (VEGF) or a VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling with an IC of less than about 10 nmol / L ５０ and comprises at least one small molecule anti-angiogenic agent that inhibits at, said step; (2) applying an alternating electric field to the cancer cells for a certain period of time.

11. The method according to claim 10, wherein the method is carried out in vitro / 91> or ex vivo.

12. The method according to claim 10, wherein the method is carried out in vivo.

13. The cancer cells are selected from the group consisting of hepatocellular carcinoma cells, glioblastoma cells, pleural mesothelioma cells, differentiated thyroid cancer cells, advanced renal cell carcinoma cells, ovarian cancer, pancreatic cancer, lung cancer cells, breast cancer cells, and combinations thereof. The method according to any one of claims 10 to 12.

14. A method for treating cancer in a subject, the method comprising: (1) administering to a subject at least one composition, wherein the at least one composition specifically interacts with either vascular endothelial growth factor (VEGF) or a VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling with an IC of less than about 10 nmol / L ５０ and comprises at least one small molecule anti-angiogenic agent that inhibits at least one of the foregoing steps; (2) applying an alternating electric field to the target region of the subject.

15. A method for reducing the volume of a tumor and / or preventing an increase in the volume of a tumor, the tumor existing in vivo and containing a plurality of cancer cells, the method comprising: (1) administering to a subject at least one composition, wherein the at least one composition specifically interacts with either vascular endothelial growth factor (VEGF) or a VEGF receptor (VEGFR), selectively inhibits the interaction between VEGF and VEGFR, and / or inhibits VEGFR signaling with an IC ５０ of less than about 10 nmol / L, comprising at least one small molecule anti-angiogenic agent, said step; (2) applying an alternating electric field to the target region of the subject.

16. The method according to claim 14 or 15, wherein the at least one composition is administered orally to the subject.

17. The cancer is selected from the group consisting of hepatocellular carcinoma, glioblastoma, pleural mesothelioma, differentiated thyroid cancer, advanced renal cell carcinoma, ovarian cancer, pancreatic cancer, lung cancer, breast cancer, and combinations thereof. The method according to any one of claims 14 to 16.

18. The method according to any one of claims 10 to 17, wherein the at least one small molecule anti-angiogenic agent specifically interacts with at least one of VEGFA, VEGFB, VEGFC, or VEGFD.

19. The method according to any one of claims 10 to 18, wherein the at least one small molecule anti-angiogenic agent specifically interacts with at least one of VEGFR-1, VEGFR-2, or VEGFR-3.

20. The at least one small molecule anti-angiogenic agent is selected from the group consisting of lenvatinib, axitinib, regorafenib, cabozantinib, anlotinib, pazopanib, albendazole, lucitanib, motesanib, aflibercept, ponatinib, cediranib, thiazovivin, teratinib, apatinib, semaxanib, fruquintinib, lucitanib, anlotinib, taxifolin, sulfatinib, dovitinib, nintedanib, AZD2932, LY2874455, MGCD-265 analog, ZM 306416, ZM 323881, KRN 633, YF-452, ODM-203, AEE 788, BMS 605541, MAZ51, Ki 8751, SU 5402, SU 5408, SU5205, SU5214, SU 6668, SU 14813, XL 092, XL 184, BAW2881, BFH772, A-13958, SKLB1002, WAY-340935, ZD-4190, hVEGF-IN-1, R1530, VEGFR-Grab, soluble vascular endothelial growth factor decoy receptor FP3, VEGFR decoy receptor fusion protein, decoy receptor for VEGFR, and combinations thereof, according to any one of claims 10 to 19.

21. The method according to any one of claims 10 to 20, wherein the at least one small molecule anti-angiogenic agent is a type I VEGFR inhibitor.

22. The method according to claim 21, wherein the type I VEGFR inhibitor is selected from the group consisting of pazopanib, axitinib, ponatinib, motesanib, and combinations thereof.

23. The method according to any one of claims 10 to 22, wherein the at least one small molecule anti-angiogenic agent is a type II VEGFR inhibitor.

24. The method according to claim 23, wherein the type II VEGFR inhibitor is selected from the group consisting of cabozantinib, lenvatinib, regorafenib, lucitanib, and combinations thereof.

25. The method according to any one of claims 10 to 24, wherein the at least one small molecule anti-angiogenic agent is a type III VEGFR inhibitor.

26. A method of reducing the survival rate of cancer cells and / or treating cancer in a subject and / or reducing the volume of a tumor and / or preventing an increase in the volume of a tumor, the method comprising: (1) Administering at least one composition to a cancer cell / subject, wherein the at least one composition is a selective inhibitor of vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR), and comprises at least one small molecule anti-angiogenic agent that specifically binds to VEGF or VEGFR alone and does not bind to other targets, said step; (2) Applying an alternating electric field to the cancer cells / target region of the subject for a certain period of time, a method comprising.

27. The method according to claim 26, wherein the method is carried out in vitro or ex vivo.

28. The method according to claim 26, wherein the method is carried out in vivo.

29. The cancer / cancer cells are selected from the group consisting of hepatocellular carcinoma cells, glioblastoma cells, pleural mesothelioma cells, differentiated thyroid carcinoma cells, advanced renal cell carcinoma cells, ovarian cancer, pancreatic cancer, lung cancer cells, breast cancer cells, and combinations thereof, according to any one of claims 26 to 28. Method.

30. The method according to any one of claims 26 to 29, wherein the at least one small molecule anti-angiogenic agent is aflibercept.

31. A method of reducing the survival rate of cancer cells, the method comprising: (1) Administering at least one composition to cancer cells, wherein the at least one composition comprises lenvatinib, said step; (2) Applying an alternating electric field to the cancer cells for a certain period of time, a method comprising.

32. The method according to claim 31, wherein the method is carried out in hydro or ex vivo.

33. The method according to claim 31, wherein the method is carried out in vivo.

34. The cancer / cancer cells are selected from the group consisting of hepatocellular carcinoma cells, glioblastoma cells, pleural mesothelioma cells, differentiated thyroid carcinoma cells, advanced renal cell carcinoma cells, ovarian cancer, pancreatic cancer, lung cancer cells, breast cancer cells, and combinations thereof, according to any one of claims 31 to 33. Method.

35. A method of treating cancer in a subject, the method comprising: (1) Administering at least one composition to the subject, wherein the at least one composition comprises lenvatinib, said step; (2) Applying an alternating electric field to the target region of the subject, a method comprising.

36. A method for reducing the volume of a tumor and / or preventing an increase in the volume of a tumor, wherein the tumor is present in a living body and contains a plurality of cancer cells, and the method comprises: (1) administering at least one composition to a subject, wherein the at least one composition contains lenvatinib, and the step; (2) applying an alternating electric field to a target region of the subject.

37. The method according to claim 35 or 36, wherein the at least one composition is orally administered to the subject.

38. The method according to any one of claims 35 to 37, wherein the composition containing lenvatinib is administered to cancer cells at a therapeutically effective concentration of lenvatinib.

39. The method according to claim 38, wherein the therapeutically effective concentration of lenvatinib is at least about 50% reduced compared to the dosage of lenvatinib known to be therapeutically effective in the absence of an alternating electric field.

40. The method according to claim 38 or 39, wherein the therapeutically effective concentration of lenvatinib is from about 12.5 nM to about 100 nM.

41. The method according to any one of claims 10 to 40, which is at least one of the following. The alternating electric field is applied at a frequency in the range of about 50 kHz to about 1 MHz The alternating electric field has an electric field strength of at least about 1 V / cm in at least a part of the cancer cells The time during which the alternating electric field is applied is at least about 24 hours

42. The method according to any one of claims 10 to 41, wherein steps (1) and (2) are carried out substantially simultaneously.

43. The method according to any one of claims 10 to 41, wherein steps (1) and (2) are carried out in whole or in part sequentially, and the at least one composition is administered before the application of the alternating electric field is started.

44. The method according to any one of claims 10 to 41, wherein steps (1) and (2) are carried out in whole or in part sequentially, and the at least one composition is administered after the application of the alternating electric field is started.

45. The method according to claim 44, wherein the at least one composition is administered at least 24 hours after the application of the alternating electric field is started.

46. The method according to claim 45, wherein the at least one composition is administered before the period during which the alternating electric field is applied elapses.

47. The method according to claim 45, wherein the at least one composition is administered after the passage of said period.

48. The method according to claim 47, wherein the at least one composition is administered within about 96 hours after the passage of said period.

49. The method according to any one of claims 10 to 48, wherein the time for which the alternating electric field is applied is in the range of about 24 hours to about 72 hours.

50. The method according to any one of claims 10 to 49, further comprising the step of terminating the application of the alternating electric field.

51. The method according to any one of claims 10 to 50, wherein the at least one composition further comprises a pharmaceutically acceptable carrier.

52. The method according to any one of claims 10 to 51, wherein steps (1) and (2) are repeated one or more times.

53. The method according to any one of claims 10 to 52, comprising applying a first alternating electric field to the cancer cells / target region of the subject for a certain period of time and applying a second alternating electric field to the cancer cells / target region of the subject for a certain period of time, wherein the first and second alternating electric fields have different frequencies.

54. The method according to claim 53, wherein the first frequency affects cell permeability and the second frequency affects cell viability.

55. The method according to any one of claims 10 to 54, wherein the at least one composition further comprises at least one additional therapeutic agent.

56. The method according to any one of claims 10 to 55, comprising further administering a second composition to the cancer cells, the second composition comprising at least one additional therapeutic agent, and the first and second compositions being administered substantially simultaneously or wholly or partially sequentially.

57. The at least one additional therapeutic agent is selected from the group consisting of checkpoint immune inhibitors, anti-PD-1 therapeutic agents, chemotherapeutic agents, TKI inhibitors, mTOR inhibitors, Akt inhibitors, aromatase inhibitors, radiotherapy agents, biological agents, and combinations thereof, according to claim 55 or 56.

58. The method of claim 57, wherein the at least one additional therapeutic agent is selected from the group consisting of pembrolizumab, tislelizumab, paclitaxel, docetaxel, ifosfamide, etoposide (VP-16), gemcitabine, carboplatin, everolimus, letrozole, denosumab, and combinations thereof.

59. The method according to any one of claims 10 to 58, further comprising the step of administering at least one additional therapy to the cell / subject.

60. The method of claim 59, wherein the at least one additional therapy is selected from the group consisting of radiotherapy, photodynamic therapy, transarterial chemoembolization (TACE), and combinations thereof.

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