Treatment of metastatic or invasive brain cancer

Abstract

A method of preventing, reducing the risk, or treating brain metastasis in a subject having cancer is described. Also described is a method of preventing, reducing the risk, or treating invasive and / or metastatic brain cancer in a subject. Advantageously, the method comprises administering at least one blood-brain barrier permeable drug selected from a Vaughan Williams Class 1 d antiarrhythmic drug, for example selected from ranolazine, eleclazine, GS561587, and CPD 458967.

Description

Invention Field

[0001] This invention relates to a method for preventing, reducing the risk of, or treating brain metastases in subjects with cancer. Background of the Invention When cancer that originates in another part of the body spreads to the brain and causes a brain tumor, it is called metastatic brain cancer (also known as secondary brain tumor). The resulting tumor is called a brain metastasis. For information on currently available treatments and options for metastatic brain cancer, see the references of Johns Hopkins University neurosurgeon Chetan Bettegowda, accessed October 11, 2023, at www.hopkinsmedicine.org / health / conditions-and-diseases / metastatic-brain-tumours.

[0003] Metastatic brain cancer is caused by cancer cells spreading (metastasizing) from different parts of the body to the brain. The most common types of cancer that can spread to the brain are lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer, and thyroid cancer. Lung cancer, breast cancer, and colon cancer are three of the four most common cancers in the United States and Europe, with prostate cancer being the fourth. Metastatic brain tumors are five times more common than primary brain tumors (those that originate in the brain). Metastatic brain tumors can grow rapidly, compressing or destroying nearby brain tissue. Sometimes a patient may have multiple metastatic tumors in different areas of the brain.

[0004] There are many treatment options available for metastatic brain cancer, but these methods are invasive, cancer often develops resistance, they are sometimes very expensive, and often uncertain.

[0005] Besides metastatic brain tumors, primary invasive brain tumors originating from sources such as glioblastoma are particularly difficult to treat due to their aggressive and invasive nature, and often their resistance to standard treatments. The key problem is that the brain is separated from the rest of the body by the blood-brain barrier (BBB), which allows only a very small amount of substances to pass through. Therefore, many drugs that can treat brain metastases are ineffective because they cannot reach the site of the metastasis due to the blood-brain barrier.

[0006] The fact that most standard treatments aim to kill the cancer cells themselves presents a challenge because it is impossible to determine whether all cancer cells in the primary or secondary tumor have actually been killed. If some cancer cells have escaped, they may form micrometastases elsewhere in the body and are impossible to locate due to their small size, and / or cancer stem cells may also escape standard treatment and become active at some point after treatment ends.

[0007] Most standard treatments involve using molecules that cannot cross the blood-brain barrier to enter the brain, and therefore may be ineffective against invasive and metastatic tumor cells that have already entered the brain. Furthermore, the development of drug resistance is a common feature of many drugs used to treat primary and secondary cancers.

[0008] Because drugs need to cross the blood-brain barrier to effectively combat secondary cancers in the brain, treatment options are fewer than in other parts of the body. Many compounds cannot cross the blood-brain barrier; especially large molecules and proteins commonly used in chemotherapy and immunotherapy.

[0009] Badwe and others ( Effect of Peritumoral Infiltration of Local An[a]esthetic Before Surgery on Survival in Early Breast Cancer A long-term study (J Clin Oncol 2023;41:3318-3328) found that patients who received lidocaine (a pain reliever) before breast cancer surgery had improved survival rates compared to those who did not receive lidocaine. Lidocaine is a universal sodium channel blocker. Breast cancer is one of the cancers known to metastasize to the brain.

[0010] A recent analysis of 165 patients with mixed cancers (breast cancer, colon cancer, and prostate cancer) found that cancer patients who received class 1D ranolazine treatment before their cancer diagnosis had a significantly lower risk of death by 60% compared to those who never received ranolazine (Fairhurst et al.). Sodium channel-inhibiting drugs and cancer-specific survival: a population-based study of electronic primary care data (BMJ Open 2023;13:e064376. doi:10.1136 / bmjopen-2022-064376). Furthermore, patients who received ranolazine after cancer diagnosis also had a significantly reduced risk of death after treatment (45%).

[0011] A common feature associated with most standard treatments is that they attempt to kill the tumor rather than first preventing its formation, or if it has already formed, preventing its further spread, and thus reversing or delaying the tumor's invasiveness.

[0012] It would be preferable to have a treatment that could first prevent the formation of secondary metastatic tumors, or, once formed, prevent their further spread. This is especially important for any secondary tumor that escapes the initial tumor and (in the cancers listed above) finds a site in the brain where it can grow, as these cancers often have long-term, fatal consequences for patients.

[0013] As stated above, given the difficulty of treating, especially brain cancer (metastatic and others), there is an urgent need for better treatment options for these cancer types to improve patient outcomes. Invention Summary

[0014] This invention relates to the use of one or more antiarrhythmic drugs that target late / continuous VGSC currents to treat cancer in subjects in need of treatment to reduce the incidence of metastasis or reduce the progression to metastatic cancer, particularly brain metastases, and further reduce the invasiveness of intracranial tumors.

[0015] One aspect of the present invention relates to a blood-brain barrier-penetrating drug selected from the Vaughan Williams Class 1d antiarrhythmic drug group for the treatment of invasive and / or metastatic brain cancer in a subject.

[0016] Another aspect of the invention relates to a blood-brain barrier-penetrating drug selected from Vaughan Williams Class 1d antiarrhythmic drugs for the prevention of invasive and / or metastatic brain cancer in subjects.

[0017] Another aspect of the invention relates to the preventive use of Vaughan Williams Class 1d antiarrhythmic drugs for reducing the risk of brain metastases in cancer patients, particularly lung cancer patients.

[0018] Another aspect of the invention relates to a method for reducing the invasiveness of brain tumors, comprising administering an effective amount of Vaughan Williams Class 1d antiarrhythmic drug.

[0019] Another aspect of the invention relates to a method for reducing the risk of invasive and / or metastatic brain cancer in a subject, comprising administering a therapeutically effective amount of Vaughan Williams Class 1d antiarrhythmic drug to a subject who has not been diagnosed with invasive and / or metastatic brain cancer, thereby reducing the risk of invasive and / or metastatic brain cancer in the subject.

[0020] Another aspect of the invention relates to a method for reducing cell migration and / or reducing motility formation in a subject's brain tumor, comprising administering a therapeutically effective dose of a Vaughan Williams Class 1d antiarrhythmic drug.

[0021] Another aspect of the invention is a drug selected from ranolazine or eleclazine for treating invasive and / or metastatic brain cancer in a subject, wherein the subject is an adult human patient diagnosed with metastatic brain cancer, glioblastoma or lung cancer, and the drug is administered orally once or twice daily at a dose of 1-1000 mg per dose. Brief description of the attached diagram Figure 1 A schematic diagram illustrating the pathways that cause cancer cells to become aggressive.

[0023] Figure 2 A schematic diagram of VGSC inhibition via TTX or through the Lido binding site.

[0024] Figure 3 A diagram illustrating different stages of cancer development.

[0025] Figure 4 Cancer mortality rates in the control group and the ranolazine treatment group.

[0026] Figure 5 Cancer progression in the control group and the ranolazine treatment group.

[0027] Figure 6 General metastatic progression in the control group and the ranolazine treatment group 5 years after diagnosis.

[0028] Figure 7 Brain metastasis progression in the control group and the ranolazine treatment group 5 years after diagnosis.

[0029] Detailed disclosure of the invention This invention relates to the use of antiarrhythmic drugs that target voltage-gated sodium channels in a specific manner to reduce late or persistent sodium currents, for the treatment of cancers, particularly brain cancers such as metastatic brain cancers (i.e., secondary brain tumors) or primary brain cancers such as glioblastoma. The inventors have discovered an effective method to prevent primary cancer from metastasizing to the brain, and if metastasis has already begun, to inhibit further metastasis of secondary tumors, thereby eliminating the need for any further treatment, or making them more easily treatable by conventional methods due to their smaller size and localized nature.

[0030] Therefore, the present invention specifically relates to a blood-brain barrier-penetrating drug selected from the Vaughan Williams Class 1d antiarrhythmic drug group for the treatment of subjects with invasive and / or metastatic brain cancer.

[0031] Furthermore, the present invention relates to a method for treating invasive and / or metastatic brain cancer in a subject, comprising administering an effective amount of a drug selected from the Vaughan Williams Class 1d antiarrhythmic drug group that can penetrate the blood-brain barrier.

[0032] In the implementation plan, the treatment reduces the invasiveness of the cancer.

[0033] Class 1d drugs Miles Vaughan Williams classified antiarrhythmic drugs according to their modes of action. This classification was recently updated by Lei et al. (Modernized Classification of Cardiac Antiarrhythmic Drugs, Circulation 2018;138:1879-1896, DOI: 10.1161 / CIRCULATIONAHA.118.035455).

[0034] Lei et al. (ibid.) described Class 1D drugs as follows: “Nav 1.5, reducing late Na+ current (INaL), affecting action potential (AP) recovery, refractory period, repolarization reserve, and QT interval.” Ranolazine is the only commercially available member of this class of drugs, used to treat stable angina, ventricular tachycardia, and as a potential new class of drugs for the treatment of tachyarrhythmias. Lei et al. described a possible mode of action as reducing AP recovery time and reducing EAD-induced triggering activity.

[0035] Class 1d drugs exert their effects by inhibiting persistent or long-term currents in voltage-gated sodium channels (“VGSCs”), thereby suppressing the massive influx of sodium into cells and the resulting proton expulsion. Their mechanism of action will be explained further below.

[0036] Djamgoz et al. In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis, Cancers 2019;11: 1675, DOI: 10.3390 / cancers11111675 This describes the function of continuous sodium current in voltage-gated sodium channels in enabling cancer metastasis.

[0037] At least eight distinct binding sites have been proposed on the VGSC molecule (see, for example, Stevens et al., “Neurotoxins and their binding areas on voltage-gated sodium channels”, Front. Pharmacol., 09 November 2011, Sec. Pharmacology of Ion Channels and Channelopathies, volume 2 - 2011). Not limited by theory, Class 1 drugs, such as ranolazine, are thought to bind to the “lido” binding site, i.e., lidocaine. Figure 2 As shown.

[0038] Interestingly, EP3132791B1 describes the use of a continuous current sodium channel blocker to inhibit cancer metastasis, in which ranolazine is described as a drug suitable for this purpose, and EP3579840B1 describes the use of certain other drugs (including eleclazine) for this general purpose.

[0039] However, none of these studies address the specific problem that standard treatments for certain common cancers (such as those listed in this article) may fail to completely kill cancer cells, and these cells may escape from the primary tumor before, during, or after standard treatment, in which case the likelihood of tumor metastasis to the brain is high. In these cases, conventional standard drug treatments are often ineffective because the drugs cannot cross the blood-brain barrier, or are very unsuitable for healthy cells and potentially dangerous, such as radiation therapy or proton beam therapy.

[0040] Surprisingly, class 1d drug compounds as defined above, particularly ranolazine, have been found to improve the prognosis and life expectancy of cancer patients when administered before or with standard treatment for certain types of cancer (see Examples 1-3).

[0041] For example, Example 2 demonstrates the beneficial effects of ranolazine treatment, particularly for brain metastases, which would be difficult to predict based solely on an overall reduction in metastases. Combined with the data presented in Example 1, these results support ranolazine and other Class 1D drugs capable of crossing the blood-brain barrier as an excellent option for treating brain cancer by inhibiting the invasiveness and metastatic potential of brain tumors.

[0042] The correlation between ranolazine treatment and improved survival and reduced metastasis in patients with brain metastases is particularly surprising, as brain metastases involve the presence of brain tumors that are protected by the blood-brain barrier and are not affected by most standard treatments. Therefore, it is surprising to find that ranolazine can penetrate the blood-brain barrier in effective amounts to achieve these effects.

[0043] Other examples of brain cancer include glioblastoma, which is the most aggressive and invasive type of brain cancer. Glioblastoma develops from astrocytes in the brain or spinal cord, where they grow rapidly and invade and destroy healthy tissue. Glioblastoma is often highly resistant to conventional radiotherapy and chemotherapy, and recurrence after treatment is very common. The survival time for patients without treatment is approximately 6 months, which can be extended to approximately 15 months with standard treatment regimens; however, less than 5% of patients survive more than five years after initial diagnosis.

[0044] Given the severity of glioblastoma, in particular, there is an urgent need for effective therapies that can prolong median survival or reduce cancer invasiveness.

[0045] Therefore, the present invention also provides a medicine selected from Vaughan Williams Class 1d antiarrhythmic drugs for the prevention of invasive and / or metastatic brain cancer in a subject. Therefore, the present invention also provides a method for reducing the invasiveness of brain tumors, comprising administering an effective amount of a Vaughan Williams Class 1d antiarrhythmic drug.

[0046] While it is beneficial to start treatment with Vaughan Williams Class 1d antiarrhythmic drugs after a diagnosis of metastatic cancer, it may also prove beneficial to start treatment at an earlier stage of cancer.

[0047] Therefore, the present invention also provides a method for reducing the risk of invasive and / or metastatic brain cancer in a subject, comprising administering a therapeutically effective amount of Vaughan Williams Class 1d antiarrhythmic drug to a subject who has not been diagnosed with invasive and / or metastatic brain cancer, thereby reducing the risk of the subject developing invasive and / or metastatic brain cancer. In an embodiment, the subject has been diagnosed with cancer.

[0048] Alternatively, subjects exposed to known carcinogens may also benefit from early treatment with Vaughan Williams Class 1d antiarrhythmic drugs, as they are known to reduce cancer progression. Therefore, in some implementations, subjects have been exposed to one or more carcinogens, such as tumor viruses, ionizing radiation, or other Class 1 cancer carcinogens.

[0049] In a further implementation plan, the subjects have been diagnosed with lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer, thyroid cancer, or brain cancer at a non-invasive and / or non-metastatic stage.

[0050] Vaughan Williams Class 1d antiarrhythmic drugs are further explored for preventative use, which is necessary to reduce the risk of brain metastases in cancer patients, particularly those with lung cancer.

[0051] As described in Examples 1 and 2, ranolazine reduces the invasiveness of tumors (e.g., lung tumors, breast tumors, or prostate tumors) and inhibits their metastatic potential. Surprisingly, the amount of ranolazine that can cross the blood-brain barrier and ultimately enter the brain is sufficient to inhibit the further development of metastatic tumors at an early stage. Therefore, the presented data support that the amount of ranolazine entering the brain is sufficiently high for treating brain cancers such as metastatic brain cancer, glioblastoma, astrocytoma, and neuroblastoma.

[0052] For example, ranolazine or other suitable Vaughan Williams Class 1 medications can be prescribed to subjects before a cancer diagnosis. Subjects may be at risk of developing cancer, optionally due to a genetic predisposition. Subjects may also already have undiagnosed cancer, such as undiagnosed glioblastoma. Due to ranolazine treatment, the invasiveness of undiagnosed cancer (e.g., glioblastoma) is suppressed, or its development towards invasiveness is inhibited or slowed. The time to diagnosis is thus extended because the tumor's invasiveness is effectively reduced at an earlier stage.

[0053] Alternatively, ranolazine or other suitable Vaughan Williams Class 1 medications can be prescribed to the subject after initial diagnosis (e.g., after a diagnosis of glioblastoma). The invasiveness of glioblastoma can thus be suppressed, or its progression towards invasiveness can be inhibited or slowed. Cancer progression can thus be reduced and / or the patient's lifespan can be prolonged.

[0054] Overall, there has long been a need to develop new treatment strategies that can improve the prognosis of patients diagnosed with metastatic brain tumors, particularly those diagnosed with glioblastoma or other brain cancers such as astrocytoma or neuroblastoma. Surprisingly and unexpectedly, Class 1 antiarrhythmic drugs such as ranolazine and eleclazine can effectively cross the blood-brain barrier, thus presenting in the brain at serum concentrations sufficient to produce preventative or other therapeutic effects, although the concentrations in the brain may be lower than in other parts of the body. Therefore, in this implementation, the invasive brain cancer is glioblastoma, neuroblastoma, or astrocytoma.

[0055] As used herein, the term "blood-brain barrier permeability" refers to the extent to which a drug or compound, when administered, can cross the blood-brain barrier via active or passive transport to deliver a therapeutically effective amount of the drug to the central nervous system, preferably the brain. Class 1D drugs are typically administered orally, for example in pill form, but may also be administered by injection or infusion, such as intravenous injection.

[0056] "Therapeutic effective dose" or "therapeutic effective amount" refers to a certain amount or dose of drug that, when administered to a cancer patient, produces a positive therapeutic response, such as reducing cancer metastasis, preventing cancer metastasis, or alleviating pain.

[0057] Standard treatment In cancer treatment, there are many standard treatment methods, which are used according to the type and stage of cancer, and are often a combination of multiple treatment methods, such as radiotherapy combined with chemotherapy and / or immunotherapy.

[0058] Radiation therapy treats metastatic brain tumors by using X-rays and other forms of radiation (light energy) to destroy cancer cells or stop tumor growth. These painless treatments involve passing beams of radiation through the brain, which can treat cancers in areas difficult to reach through surgery. Procedures may include any one or a combination of the following: i. External beam radiotherapy delivers radiation from a machine and travels through the body to reach metastatic tumors.

[0059] ii. Whole-brain radiation therapy targets the entire brain to hit multiple tumors or any metastatic disease hidden in MRI scans.

[0060] iii. Stereotactic radiosurgery (e.g., Cyberknife) directs high doses of radiation to the specific shape of the tumor, protecting surrounding healthy tissue from unnecessary radiation exposure.

[0061] iv. Proton therapy uses protons (instead of X-rays) to treat metastatic brain tumors. Similar to stereotactic radiosurgery, proton therapy minimizes damage to healthy tissue surrounding the tumor.

[0062] v. Brachytherapy involves implanting radioactive material into the tumor to stop its further growth.

[0063] These procedures can be performed after surgery to prevent tumor recurrence at the surgical site and growth into other brain tissues. Research is currently underway on how to manage the long-term effects of the treatment.

[0064] A recent study found that in an analysis of 253 breast cancer patients with brain metastases, the use of the antiepileptic drug (AED) valproic acid in the context of whole-brain radiotherapy improved overall survival in patients with breast cancer brain metastases. The median overall survival was 9 months (n = 101) in patients who received any AED, compared to 4 months in patients who did not receive an AED (p = 0.0003) (Reddy et al., CNS Irradiation 2015;117(2):308-314, DOI: 10.1016 / j.radonc.2015.10.009). AEDs target the central nervous system and are therefore designed to cross the blood-brain barrier.

[0065] An alternative or complementary treatment is, for example, surgery for metastatic brain tumors. Surgery rapidly relieves the "mass effect"—the intracranial pressure caused by the growth of metastatic tumors and cerebral edema. The goal of surgery is to minimize the amount of space occupied by the tumor through debulking, which means removing as much of the tumor as possible while preserving neurological function. Surgery for metastatic brain cancer is suitable when there is a clear link between symptoms and tumor location, the primary cancer is treatable and under control, and the tumor can be safely removed.

[0066] Another alternative or complementary treatment is chemotherapy, for example, for metastatic brain tumors. Because traditional chemotherapy cannot cross the blood-brain barrier, a new type of treatment called targeted therapy is used as the primary type of chemotherapy for metastatic brain tumors. These drugs identify and attack cancer cells (targets) with minimal damage to normal cells, while simultaneously inhibiting the growth and spread of cancer cells. Targeted therapy can be administered after surgery or in combination with radiation therapy to destroy any remaining cancer cells. Targeted therapies used to treat metastatic brain tumors include trastuzumab for breast cancer that has spread to the brain and erlotinib for the most common type of lung cancer that has spread to the brain (non-small cell lung cancer).

[0067] Another treatment option for metastatic brain tumors that has developed over the past few decades is immunotherapy, such as for metastatic brain tumors. Cancer immunotherapy has developed drugs, vaccines, and other therapies that trigger the immune system's natural anti-cancer capabilities. Many immunotherapeutic drugs used for metastatic brain tumors function as "checkpoint inhibitors." Normally, tumor cells can evade attack by activating certain proteins that disarm the immune system (called checkpoint proteins). Checkpoint inhibitors prevent tumor cells from utilizing this process. Immunotherapy drugs used to treat metastatic brain tumors include atezolizumab, ipilimumab, pembrolizumab, and nivolumab.

[0068] A common characteristic of all these treatments is that they attempt to kill the tumor rather than first preventing its formation, or, if it has already formed, preventing its further spread. This often leads to drug resistance, treatment failure, or relapse.

[0069] If metastatic cancer reaches the brain, there are only limited treatment options, both because drugs need to cross the blood-brain barrier and because if they do cross the blood-brain barrier, they can have side effects on the central nervous system.

[0070] Voltage-gated sodium channels (VGSCs) and their mode of operation As used herein, “voltage-gated sodium channels” or “VGSCs” refer to a class of integrated membrane proteins that form ion channels. They translocate sodium ions (Na+) into the cell across the cell membrane. In humans, there are nine distinct VGSC α subunits, or “Nav” proteins (Nav1.1 to Nav1.9), encoded by nine genes (SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SCN10A, and SCN11A, respectively). As used herein, unless the context contradicts, the term may refer to any and all known VGSCs.

[0071] Unrestricted by theory Figure 1This paper elucidates the pathway that leads to the invasiveness of cancer cells. It begins with the development of abnormal Nav channels under hypoxic conditions. Several splicing variants of Nav channels exist, and their expression varies depending on the tissue and developmental stage.

[0072] For the purposes of this invention, the term "splicing variant" refers to a variant of a VGSC resulting from alternative splicing of a gene or RNA encoding a specific VGSC, leading to the expression of different sequence variants of the same gene. Splicing variants are also commonly referred to as isotypes. For example, human Nav1.5 is believed to have at least six isotypes generated by alternative splicing, listed under identifier Q14524 on uniport.org, wherein the isotype designated Q14524-4 contains a substitution of residues 206-211 from "TTEFVD" to "VSENIK", which results in the channel exhibiting a sustained sodium current. As can also be seen from identifier Q14524 on uniport.org, the substitution of residues 206-211 is also found in other splicing variants, such as the isotype designated Q14524-5, Nav1.5a, or Ex18del, which is expressed only in neuroblastoma but contains the 206-211 substitution and the deletion of residues 1077-1130.

[0073] Factors considered responsible for cancer aggressiveness may be neonatal splice variants. The dominant Nav channel has been identified in a variety of cancers and tested to contain a neonatal splice variant (designated "nNav…"), as shown in Table 1.

[0074] Table 1 .

[0075] Therefore, in this invention, the VGSCs preferably targeted by the class 1d drug comprise one or more splice variants of the Nav channel that cause late sodium currents, such as a neonatal form of Nav1.5, also designated as nNav1.5. In embodiments, the target is selected from one or more of Nav1.5, Nav1.6, and Nav1.7. In other embodiments, the target is one or more splice variants of Nav1.5, Nav1.6, and / or Nav1.7. Preferably, the targeted splice variant is expressed in invasive and / or metastatic cancers. Preferably, the targeted splice variant is a splice variant expressed in metastatic brain cancer or invasive primary brain cancer (e.g., glioblastoma or neuroblastoma).

[0076] It is generally accepted that VGSC expression in cancer cells is at least partially responsible for driving the invasiveness and motility of several cancers. Therefore, in some embodiments, the cancer being treated is a tumorigenic cancer, and the treatment reduces the formation of motile cells in the tumor and / or the migration of tumor cells from the tumor. In some aspects, the present invention therefore also provides a method for reducing cell migration and / or reducing motility in a subject's brain tumor, comprising administering a therapeutically effective dose of a Vaughan Williams Class 1d antiarrhythmic drug.

[0077] Figure 2 This demonstrates the inhibition of invasiveness through VGSC blockade. According to the described mechanism, VGSC blockade leads to a reduction in tumor cell invasiveness. Various drugs have been evaluated for blocking or inactivating VGSC: Complete blockade – usually toxic, such as TTX, CN2 Partial blockade – many side effects, lidocaine, procaine, tricyclic antidepressants, aEDs, valproate, mexiletine • Selective blockade – targeted therapy, low side effects (inhibits abnormal function) – ranolazine or eleclazine • Silence – Silencing RNA.

[0078] Eleven animal studies and nine clinical data studies using different blocking or inactivation mechanisms showed that treatment of VGSC reduces metastasis and / or improves survival and / or reduces tumor burden.

[0079] In the implementation plan, administration of the drug improved the life expectancy of the subjects.

[0080] like Figure 2 As shown, various drugs have been proposed for blocking VGSC currents. Complete blocking is possible, but these drugs are toxic, such as TTX. Partial blocking is also possible with drugs such as lidocaine, but these are non-selective, have side effects, and cannot be used for long-term purposes.

[0081] Then there are selective late-current blocking agents, namely the Class 1 drugs of this invention. Because these drugs selectively or primarily block the abnormal function of the VGSC, they can be safely used for long-term treatment. Therefore, if any aggressive tumor cells have escaped into the brain, the Class 1 drugs can be administered for life and will inhibit the growth of aggressive cells in the brain into life-threatening metastatic tumors. Thus, in some embodiments, the treatment provided herein reduces the invasiveness of the cancer without killing tumor cells. In other embodiments, the treatment provided herein reduces the invasiveness of the cancer without significantly affecting the proliferation of cancer cells.

[0082] Silencing RNA is a technology under development.

[0083] like Figure 3 As shown, due to the prolonged or continuous current of the VGSC, sodium can flood into the cell and expel protons to maintain the electrical balance within the tumor cell. This acidification of the intercellular space allows cysteine ​​cathepsins B and S to erode the extracellular matrix, enabling invasive tumor cells to compete with abnormal VGSCs to invade surrounding tissues and eventually escape into the lymphatic system or bloodstream, leading to distant metastases. Although many are eliminated by the body's natural defense mechanisms, some may escape and invade new organs, particularly the brain, ultimately resulting in metastatic brain tumors.

[0084] When primary tumors are treated with standard therapy, primary treatments may not kill cells that have become aggressive and found a way to enter the brain—stage 3 cancer. Furthermore, because primary treatments are typically designed to kill cancer cells, they disrupt the environment, and some cancer cells may escape into the bloodstream. It is possible that some of these escape the body's natural defenses and settle in the brain as metastatic cancer.

[0085] Surprisingly, Class 1d drugs block only long-term or continuous VGSC currents as abnormal functions and selectively inhibit tumor invasiveness. Because these drugs can cross the blood-brain barrier at sufficient concentrations, they have few side effects and can be given as long-term medications to inhibit brain metastases in tumors that are prone to becoming brain tumors, for which there are currently no other effective long-term preventive treatments.

[0086] Cancers known to cause metastatic brain cancer include, for example, lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer, and thyroid cancer. Therefore, the continuous VGSC current blocking agents disclosed herein are preferred for treating one or more of these cancers. Further, the continuous VGSC current blocking agents disclosed herein are also preferred for treating primary brain cancer, particularly invasive and / or aggressive brain cancer, such as glioblastoma or neuroblastoma. In embodiments, ranolazine is used to treat metastatic or aggressive brain cancer. In embodiments, eleclazine is used to treat metastatic or aggressive brain cancer. In embodiments, GS561587 is used to treat metastatic or aggressive brain cancer. In embodiments, CPD 458967 is used to treat metastatic or aggressive brain cancer. In embodiments, the aggressive brain cancer is glioblastoma or neuroblastoma, such as glioblastoma.

[0087] Treatment Adjuvant therapy is considered complementary to standard treatment. Therefore, adjuvant therapy can be provided before or during standard treatment. As described in this article, patients diagnosed with primary cancer in a metastatic state may benefit from starting treatment such as ranolazine immediately after the diagnosis of metastatic cancer. Therefore, when a patient is diagnosed with a primary cancer known to metastasize to the brain, such as lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer, and thyroid cancer, it may be beneficial to begin adjuvant therapy immediately or soon after diagnosis to prevent further metastasis and invasiveness of potentially unidentified brain metastases. Therefore, in some cases, treatment with Vaughan Williams Class 1 antiarrhythmic drugs can be initiated before standard treatment. In other cases, the drug is provided along with standard cancer treatment. In still other cases, the drug is provided after cancer diagnosis, such as 1 month, 3 months, 6 months, 12 months, or as in 24 months after diagnosis. In yet another case, drug administration is initiated at least 1 month before the start of standard treatment, such as at least 2 months, 3 months, 4 months, 5 months, or as in 6 months before the start of standard treatment.

[0088] In one implementation scheme, the subject was diagnosed with a cancer selected from lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer, and thyroid cancer. In a further implementation scheme, the subject was diagnosed with metastatic brain cancer. In a further implementation scheme, the subject was diagnosed with brain cancer at a non-invasive and / or non-metastatic stage.

[0089] The criteria for appropriate adjuvant therapy can therefore include at least the following factors: a. The treatment should be active in inhibiting both intracerebral and extracerebral metastasis; b. The drug should be able to cross the blood-brain barrier; c. Medications should not interfere with primary "standard care" treatments; d. The medication should not cause long-term rejection by the tumor; e. The drug should have limited side effects, especially on the central nervous system, and therefore should exhibit low or minimal activity for Nav1.1-1.4 and 1.8 and 1.9.

[0090] In one implementation, standard treatment includes administration of at least one chemotherapy drug and / or immunotherapy drug. In another implementation, standard treatment includes surgery and / or radiation therapy. In a further implementation, standard treatment includes any combination of surgery, radiation therapy, administration of chemotherapy drugs, and administration of immunotherapy drugs.

[0091] Therefore, in the embodiments, the drug is provided for administration in combination with at least one further substance.

[0092] In the implementation scheme, the at least one further substance is selected from minoxidil, apracarin, bismacarin, cromakalim, diazoxide, immacarin, levcromakahm, mazocarin, naminidil, nicoridil, pinacidil, pilmakalim, saracarin, tofenamic acid, lupirtine, retigabine, riluzole, NS1619, NS11021, benzimidazole 1-EBIO, carmalazine, retigabine, or a combination of any two or more of these substances.

[0093] For example, combining a Class 1 drug with one or more further compounds that affect blood-brain barrier permeability may be beneficial, thus enabling a higher effective dose of the Class 1 drug in the brain. For instance, minoxidil can enhance the effect of a Class 1 drug (e.g., ranolazine) by increasing blood-brain barrier permeability, thereby producing a stronger drug effect against brain cancer. In some embodiments, the further compound enhances the effect of the Class 1 drug by increasing blood-brain barrier permeability. In some embodiments, the further compound is minoxidil. In some embodiments, the Class 1 drug is ranolazine and the further compound is minoxidil.

[0094] In another embodiment, the at least one further substance is selected from K. ATP Opening agent, K Ca Opening agents and Kv opening agents.

[0095] In another embodiment, the at least one further substance is selected from amiloride and digoxin, or a combination thereof.

[0096] In another embodiment, the at least one further substance is an epithelial sodium channel (ENaC) blocker.

[0097] In another embodiment, the at least one further substance is selected from AG1478, gefitinib, erlotinib, afatinib, osimertinib, and dacomitinib, or a combination of any two or more of them.

[0098] "Reducing cancer invasiveness" means significantly reducing the invasiveness of cancer cells under predetermined conditions (e.g., normoxic or hypoxic conditions). Examples of suitable assays for determining invasiveness are provided elsewhere and are well known to those skilled in the art. A significant reduction in invasiveness includes, for example, a reduction of at least about 10%, 20%, or more, such as at least 30%, 40%, 50%, 60%, 70%, or 80%, compared to a control.

[0099] While the treatment recommendations presented herein reduce the invasiveness and metastatic properties of cancer, it may be preferable that the treatments do not affect tumor proliferation. The proliferative phase often refers to the stage in which cancer cells increase in number to form a primary tumor that grows in size, typically with a smooth and well-defined surface.

[0100] The proposed treatment is the use of class 1d Vaughan Williams antiarrhythmic drugs (as modified by Lei) as adjunctive therapy for patients whose cancer is prone to metastasize to the brain (usually the lungs, breast, skin (melanoma), colon, kidneys, and thyroid), as standard treatment, administered at a pharmaceutically appropriate dose, provided that the drug can cross the blood-brain barrier. This treatment is typically initiated at or around the time of cancer diagnosis (but may be started later) and continues for the patient's entire life.

[0101] Drugs particularly suitable for this application include, for example: 1. Ranolazine 2. Eleclazine (GS6615) 3. GS561587 and 4. CPD 458967.

[0102] The anti-metastatic properties of ranolazine are described in EP3132791B1, which is incorporated herein by reference. Dosage and side effects of currently prescribed ranolazine are described, for example, at www.mayoclinic.org / drugs-supplements / ranolazine-oral-route / side-effects / drg-20069114 p=1#:~:text=Descriptions,or%20lipid%2Dlowering%20medicines (accessed on October 11, 2023 and October 11, 2024). The typical starting dose is 500 mg, followed by twice-daily doses of 375-500 mg.

[0103] The anti-metastatic properties of eleclazine are described in EP 3579840B1, which is incorporated herein by reference. The typical dose is an initial dose of 60 mg, followed by 3-6 mg once daily.

[0104] The properties of ranolazine, eleclazine, GS561597, and CPD 458967 are all described in Zablocki et al. ( Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties, J Med Chem 2016, 59, 9005-9017, DOI: 10.1021 / acs.jmedchem.6b00939 ).

[0105] In the embodiments, the drug is administered at a therapeutically effective dose, optionally at a dose level corresponding to the range of 1 μmol to 10 μmol. In a particular embodiment, the drug is administered at a dose level in the range of 1 μmol to 10 μmol.

[0106] Furthermore, the drug may be administered at a dose of about 1 mg to about 2000 mg, optionally at a dose of about 1 mg to about 1000 mg, wherein the subject is an adult human patient, such as an adult human patient weighing in the range of about 50 to about 150 kg.

[0107] Therefore, the medication can be administered twice daily, once daily, once every two days, once every three days, once every five days, once weekly, once every two weeks, or once monthly, such as once daily.

[0108] In some cases, the drug is administered to adult patients twice daily at a dose of 100-1000 mg, for example, 1000 mg twice daily. Therefore, a suitable dosing regimen might require a starting dose of 375 mg twice daily for the first cycle, followed by increasing the dose to 500 mg twice daily for the second cycle. If the patient continues to experience symptoms, the dose may be further increased to 750-1000 mg twice daily. Thus, the first cycle could be 2-4 weeks. The second cycle could be from 1 week to several months. Another treatment regimen might require the drug to be administered to adult patients twice daily at a dose of 1-10 mg, for example, 3-6 mg per dose. Therefore, a suitable dosing regimen might require a starting dose of 3 mg for the first cycle, followed by increasing the dose to 6 mg for the second cycle. If the patient continues to experience symptoms, the dose may be further increased to 10-20 mg. In embodiments, the use includes administering the drug in a single initial booster dose of about 5 mg to about 1000 mg, for example, 10-100 mg. In some embodiments, the drug is administered for a period of at least 4 weeks, such as at least 8 weeks, at least 12 weeks, at least 24 weeks, at least 48 weeks, or longer. Furthermore, the intended use may require administration of the drug in a single initial booster dose of about 5 mg to about 100 mg, followed by once-daily administration of about 1 mg to about 20 mg for a period of at least 4 weeks, such as a daily dose of 3 mg or 6 mg for 6 or 8 weeks.

[0109] Preferably, the drugs used in the treatment regimens described herein are those capable of inhibiting sustained sodium currents in the VGSC and also capable of crossing the blood-brain barrier. Furthermore, drugs that are specific to Nav1.5, Nav1.6, and / or Nav1.7 and have only low or no interaction with other Nav channels (e.g., Nav1.1-1.4, 1.8, and 1.9) are also preferred.

[0110] According to Zablocki et al. (ibid.), both ranolazine and eleclazine have the properties of inhibiting sustained or long-term sodium VGSCs, crossing the blood-brain barrier to some extent, and having low interaction with Nav channels other than Nav1.5, 1.6, and 1.7, which appear to be the channels primarily associated with metastatic cancer (see Djamgoz et al., ibid.).

[0111] As can be seen from Zablocki et al. (ibid.), the inhibition of long-term sodium currents in VGSCs appears to be a characteristic of the Class 1d Vaughan Williams classification, most of which are small molecules that will cross the blood-brain barrier effectively at sufficient concentrations. However, each of these requires testing for metabolic side effects, as well as testing for low propensity to interact with Nav 1.1-1.4 and 1.8 and 1.9, otherwise side effects in the central nervous system will occur, making the compounds unsuitable for long-term use.

[0112] The current generated by VGSC typically occurs in two phases: a transient phase lasting several milliseconds, followed by a long-duration or persistent phase characterized by impaired channel inactivation leading to a sustained current that often lasts for several seconds. This is commonly observed in electrophysiological current trajectories measuring cellular action potentials, where the VGSC trajectory exhibits a rapid transient sodium current (downward spike), which, under normal conditions, usually returns to baseline completely after 5–10 ms. However, persistent currents caused by inappropriate VGSC inactivation are characterized by the current not returning to baseline after 5–10 ms, but rather remaining as a persistent current for 100 ms or longer, reflecting a long-term increase in a small portion of the sodium current.

[0113] One characteristic of Class 1d Vaughan Williams class drugs is that they effectively block the continuous sodium current, meaning that the drug at least reduces the continuous portion of the VGSC current without completely blocking the transient portion.

[0114] Therefore, reducing the sustained current should be understood as a reduction of at least 50% in the area under the curve (AUC) within the timeframe of 20-200 ms after the transient current (i.e., 10 ms after stimulation), for example, at least 60%, 70%, 80%, or 90%, for example, at least 95%. On the other hand, the drug should not completely block the transient portion of the current, meaning that the drug should still allow a significant transient current, i.e., at least 10% of the transient current within the 0-10 ms timeframe after stimulation, preferably more than 50%, for example, 10%-100% of the transient current.

[0115] Referring to Zablocki et al. (ibid.), eleclazine, GS561587, and CPD 458967 possess the necessary properties to act as effective inhibitors of metastasis without producing adverse side effects, and ranolazine also has this effect.

[0116] Preferably, the treatment comprises administration of one or more of ranolazine, eleclazine, GS561587, and CPD 458967. In one embodiment, the drug is selected from ranolazine, eleclazine, GS561587, and CPD 458967. In another embodiment, the Vaughan Williams Class 1d antiarrhythmic drug is ranolazine or eleclazine.

[0117] The time from diagnosis to the start of treatment varies by country and can range from days to months, depending on the complexity of the chosen standard treatment, the overall wait time of a particular healthcare system, and the complexity of the cancer. For example, patients with glioblastoma may have to wait weeks to months from diagnosis to surgery, which could lead to additional invasion of the tumor into the brain and deterioration of the patient during the period from diagnosis to surgery.

[0118] As used in this article, the term "standard-of-care treatment" refers to treatment that is generally recognized by medical experts as appropriate for a particular type of disease and is widely used by healthcare professionals.

[0119] Because of this waiting time, some patients experience disease progression, especially for more aggressive types of cancer, leading to a worse prognosis.

[0120] Therefore, it is imperative to begin treatment as soon as possible.

[0121] The treatment provided by this invention enables early treatment without the need for complex and lengthy diagnostic procedures prior to the initiation of treatment, as it typically involves a tablet that can be taken orally once or twice daily without complex interventions that may be delayed due to insufficient hospital capacity, such as surgery or radiation therapy. Therefore, the treatment provided herein can reduce the consequences of prolonged time from initial diagnosis to complex interventions because it inhibits cancer progression compared to the absence of the treatment provided herein.

[0122] For this reason, the treatment proposed in this article using Vaughan Williams Class 1d antiarrhythmic drugs is particularly beneficial because treatment can be initiated immediately after diagnosis, without waiting for a more complex treatment modality. Particular benefits include the well-known dosage and treatment regimens of these types of drugs (e.g., ranolazine) and the minimal side effects compared to radiotherapy or chemotherapy. While the ability of Vaughan Williams Class 1d antiarrhythmic drugs to inhibit the metastasis and invasiveness of some cancers is known, the ability of some of these compounds to cross the blood-brain barrier opens the door to several new uses for these drugs in the treatment of brain-specific cancers, as described in this article.

[0123] Therefore, when a patient is diagnosed with cancer known to form brain metastases, administration of one or more Vaughan Williams Class 1 antiarrhythmic drugs, particularly ranolazine, eleclazine, GS561587, or CPD 458967, may be beneficial, even before brain metastases are identified, to reduce the invasiveness of unidentified brain metastases and further metastasis. In some implementations, the drug is ranolazine, eleclazine, GS561587, or CPD 458967.

[0124] As used herein, “treating” or “treatment” for brain cancer includes, but is not limited to, reducing the metastatic behavior of brain cancer, preventing the metastatic behavior of brain cancer, reducing pain, reducing the invasiveness of brain cancer, preventing the invasiveness of brain cancer, reducing the overall invasiveness of brain cancer, or any combination thereof. Therefore, in individual and specific embodiments, the treatment method according to the invention may (i) reduce the metastatic behavior of brain cancer, (ii) prevent the metastatic behavior of brain cancer, (iii) alleviate pain in patients with brain cancer, (iv) reduce the invasiveness of brain cancer, or (v) prevent the invasiveness of brain cancer, or may include a combination of two or more of (i) to (v).

[0125] "Reducing metastatic behavior of cancer" means reducing any behavior associated with the movement of detached cancer cells through the circulation (blood or lymphatic system) to accumulate in other organs and / or form secondary tumors or locally invade surrounding tissues. Typically, the patient is in stage 2, 3, or 4, e.g., stage 3 or 4. Reducing metastatic behavior may include, for example, one or more of the following: (i) reducing the transcription, translation, and / or expression of specific splice variants (such as neonatal and / or adult VGSCs (e.g., Nav1.5)) in cancer cells compared to a control; (ii) reducing cancer cell invasiveness; (iii) reducing peak VGSC current density in cancer cells; (iv) reducing the proportion of cancer cells exhibiting VGSC currents; (v) reducing cancer cell motility (e.g., reducing lateral motility); (vi) reducing cancer cell migration (e.g., lateral migration); and (vii) reducing the persistent portion of VGSC currents without eliminating the transient portion. A VGSC may be, for example, Nav1.5, e.g., a neonatal variant of nNav1.5. "Mobility" reflects the ability of tumor cells to initially move and enter the surrounding tissues through the basement membrane; "invasiveness" reflects the ability of tumor cells that have entered the surrounding tissues to move through that tissue into the circulatory system; and "migration" reflects the ability of tumor cells to migrate from that tissue through its wall into the circulatory system.

[0126] "Preventive measures against metastatic cancer" refers to preventive treatment of cancer patients at risk of metastatic disease but not yet diagnosed with metastatic disease, in order to prevent or reduce the risk of metastatic behavior. Typically, patients are in stage 1, 2, or 3. Preventive measures against metastasis may include, for example, preventing or reducing the expression of VGSCs, such as one or more adult and / or neonatal forms of Nav(s), such as nNav1.5. The terms "phase" and "stage" are used interchangeably herein.

[0127] "Reducing the overall invasiveness of cancer" means reducing any behavior associated with cancer progression, either quantitatively or qualitatively. In some embodiments, reducing cancer invasiveness means reversing cancer from stage 3, 4, or 5 to a lower stage, including but not limited to, from stage 3 to stage 2 or lower, from stage 4 to stage 3 or lower, and from stage 5 to stage 4 or lower. In some embodiments, reducing cancer invasiveness means reversing a malignant cancer or tumor to a benign cancer or tumor. In some embodiments, "reducing the overall invasiveness of cancer" means reducing cancer to a non-metastatic, but not necessarily non-invasive, state. "Reducing cancer invasiveness" means significantly reducing the invasiveness of cancer cells under predetermined conditions (e.g., normoxic or hypoxic conditions).

[0128] Cancer is typically classified into five distinct stages. In stage 0, abnormal cells are present but have not yet spread to nearby tissues. In stages 1-3, cancer is present, with higher stages indicating larger tumors and greater spread to nearby tissues. Stage 3 is usually the stage where cancer is characterized as invasive, having typically spread to local tissues (invasion), but not yet to distant sites of the body or yet to be identified. Stage 4 is the final stage, where cancer has metastasized to distant sites of the body. Stage is usually determined as part of a diagnosis and is often determined by a combination of analyses, including but not limited to blood tests, blood cell counts, cytogenetic analysis, immunophenotyping, liquid biopsy, biomarker analysis, CT scans, X-ray scans, MRI, PET scans, and ultrasound.

[0129] As also disclosed in this article, it has been previously found that ranolazine, for example, can reduce the invasiveness and metastatic potential of certain cancers. The recognition that compounds such as ranolazine can cross the blood-brain barrier to reach the brain in therapeutically relevant amounts represents a significant advance for treating advanced cancers with brain metastases, as it allows for a treatment that effectively inhibits further cancer progression.

[0130] As used herein, the term “metastatic brain cancer” refers to cancer that has spread from the peripheral system (e.g., from the lungs or prostate) to the central nervous system, particularly the brain, and has established one or more tumors in the CNS (preferably in the brain).

[0131] In one embodiment, the treatment disclosed herein is provided to a patient with stage 3 cancer. In another embodiment, the treatment disclosed herein is provided to a patient with stage 4 cancer. In yet another embodiment, the treatment disclosed herein is provided to a patient with stage 4 cancer diagnosed with brain metastases. In yet another embodiment, the treatment disclosed herein is provided to a patient with stage 4 cancer who has not been diagnosed with brain metastases.

[0132] In some cases, treatment can be provided to patients diagnosed with stage 1 or 2 cancer known to be invasive or aggressive, such as lung cancer, colorectal cancer, breast cancer, pancreatic cancer, or prostate cancer. In some implementations, the subjects are adults diagnosed with triple-negative breast cancer, castration-resistant prostate cancer, BCR prostate cancer, glioblastoma, colon cancer, lung cancer, or pancreatic cancer.

[0133] In other cases, when brain metastases or primary brain tumors are identified, it may be beneficial to begin treatment immediately after diagnosis with one or more Vaughan Williams Class 1 antiarrhythmic drugs, particularly ranolazine, eleclazine, GS561587, or CPD 458967, to reduce tumor invasiveness. Therefore, it can be said that administration of Vaughan Williams Class 1 antiarrhythmic drugs, particularly ranolazine, eleclazine, GS561587, or CPD 458967, renders the tumor in a state of arrest, where its ability to invade surrounding tissues and become metastatic is reduced or eliminated.

[0134] Suitable patients include mammalian patients with cancer, such as humans, monkeys, rabbits, dogs, cats, cattle, horses, pigs, mice, and rats. Preferably, patients are human patients, such as adult human patients. Typically, such adult human patients can weigh between about 50 and 150 kg, for example, about 60 to 100 kg, for example, about 70 kg. The terms "subject" and "patient" are used interchangeably herein.

[0135] In some implementations, the patient has VGSC-expressing cancer. VGSC-expressing cancer can be identified, for example, by immunohistochemistry or analysis of a sample containing cancer cells obtained from the patient (such as a tumor biopsy or blood sample), using detectable monoclonal or polyclonal antibodies specific to one or more VGSCs to detect the expression of VGSCs on the cancer cells. VGSC-expressing cancer may particularly contain VGSCs comprising splice variants of Nav1.5, Nav1.6, and / or Nav1.7, optionally neosplice variants such as nNav1.5.

[0136] In some embodiments, the patient / subject being treated according to the present invention has been diagnosed with angina, such as chronic angina. For example, the patient may have been diagnosed with an angina diagnosis code in the International Classification of Diseases, Tenth Revision, Clinical Revision (ICD-10-CM). In some embodiments, the patient / subject being treated according to the present invention has not been diagnosed with angina, such as chronic angina.

[0137] In some implementations, the patients / subjects treated according to the present invention have not previously been prescribed Class 1 drugs, such as ranolazine.

[0138] In some implementations, the patients / subjects treated according to the present invention have previously been prescribed a Class 1 drug, such as ranolazine.

[0139] Typically, the drugs mentioned herein are formulated into pharmaceutical compositions for administration to a subject via any suitable route, including but not limited to oral, buccal, sublipal, sublingual, rectal, intravenous, subcutaneous, intradermal, intramuscular, transdermal, and intranasal administration and / or direct administration to tumors, such as primary tumors.

[0140] Therefore, the drugs mentioned herein can be administered in various ways as needed for local or systemic treatment and depending on the tumor or cancer to be treated. Sustained-release systems can also be used, particularly for releasing the substance over an extended period of time. Delivery can also be achieved by local (e.g., intratumoral) or systemic administration of a composition comprising a selected Vaughan Williams Class 1d antiarrhythmic drug (e.g., a pharmaceutical composition).

[0141] Therefore, the drug can be administered in any suitable manner known to those skilled in the art. However, it is preferred that the drug be administered in a form that allows for effective distribution to the brain, rather than being delivered via intraspinal or intrathecal injection.

[0142] Therefore, in some embodiments, the drug is administered enterically (e.g., orally). In other embodiments, the drug is administered parenterally, such as by intravenous (iv) injection or infusion. In a further embodiment, the drug is provided for administration in combination with at least one further substance. Example

[0143] Example 1 – Mortality rate in patients diagnosed with cancer after prior ranolazine treatment The aim of this study was to examine the overall progression-free survival of patients diagnosed with angina and treated with ranolazine who developed a selected cancer of interest after starting ranolazine treatment.

[0144] method For this study, data was collected from the TriNetX Electronic Health Record (EHR) database (Palchuk MB et al.). A global federated real-world data and analytics platform for research JAMIA Open.2023 May 13;6(2):ooad035. doi: 10.1093 / jamiaopen / ooad035) retrieves patient data, which contains healthcare information from more than 110 million patients and is subsequently analyzed.

[0145] The primary objective of this study was to examine the overall survival and progression-free survival of patients prescribed ranolazine who developed selected cancers of interest (triple-negative breast cancer, castration-resistant prostate cancer, BCR (biochemical relapse) prostate cancer, glioblastoma, colon cancer, lung cancer, and pancreatic cancer) after starting ranolazine treatment.

[0146] First, all patients with at least one ranolazine prescription were identified. After applying the selection criteria detailed below, all eligible patients were categorized into the overall ranolazine cohort. The date of the first ranolazine prescription was defined as the index date of the overall cohort. The six-month period prior to the index date (up to the index date - 1) was defined as the pre-index period. For survival outcomes, patients were followed up until the end of follow-up or death.

[0147] Patients in the overall cohort who subsequently developed any cancer of interest (without a prior cancer diagnosis during baseline) were then identified. Overall survival and progression-free survival outcomes were examined in both the overall ranolazine cohort and the cohort of patients with angina who developed cancer.

[0148] The inclusion criteria for patients included in this study were: 1. Patients with evidence of ranolazine prescription during the selection window period. 2. Patients ≥18 years of age when taking ranolazine prescriptions. 3. Patients with selected cancers of interest (the first cancer diagnosis after the first prescription of ranolazine will be referred to as the index cancer diagnosis).

[0149] The exclusion criteria for patients included in this study were: 4. Patients who previously used ranolazine within 6 months prior to their first ranolazine prescription. 5. Patients who have had any previous cancer diagnosis or chemotherapy within 6 months prior to their initial cancer diagnosis. 6. Patients with New York Heart Association (NYHA) class IV heart failure within 4 weeks prior to their index cancer diagnosis. 7. Patients with a known left ventricular ejection fraction (EF) ≤ 45% within 4 weeks prior to the indexing of cancer diagnosis. 8. Patients with evidence of local anesthesia with lidocaine during the 4 weeks prior to the diagnosis of cancer.

[0150] The study ended after a five-year follow-up period, assessing cancer progression and overall mortality for all specified cancers (N=65,000).

[0151] result In this study, cancer progression and cancer mortality were assessed five years after cancer diagnosis, and a matched control cohort of cancer patients who were prescribed ranolazine was compared with a cohort of cancer patients who were not prescribed ranolazine.

[0152] When examining large cancer cohorts of the aforementioned cancers, the overall mortality rate was reduced by 42% in the ranolazine patient group compared to the control group (see [link to data]). Figure 4 (p-value < 0.0001, n = 65,000), covering all cancer types.

[0153] Therefore, this study supports the claim that ranolazine treatment significantly improves patient outcomes and reduces mortality in patients receiving ranolazine.

[0154] Example 2 – Metastasis in Lung Cancer Patients After Ranolazine Administration method For this study, patient data were retrieved from the TriNetX Electronic Health Record (EHR) database and subsequently analyzed, as described in Example 1.

[0155] The primary objective of this study was to examine the overall survival and progression-free survival of patients who received ranolazine after being diagnosed with selected cancers of interest (triple-negative breast cancer, castration-resistant prostate cancer, BCR prostate cancer, glioblastoma, colon cancer, lung cancer, and pancreatic cancer).

[0156] First, all patients with at least one ranolazine prescription were identified. After applying the selection criteria detailed below, all eligible patients were categorized into the overall ranolazine cohort. The date of the initial cancer diagnosis was defined as the index date of the overall cohort. The period of 6 months prior to the index date (up to the index date - 1) was defined as the pre-index period.

[0157] In this study, patients included had been diagnosed with cancer of interest (breast cancer, lung cancer, colon cancer, prostate cancer, and pancreatic cancer) up to 2 years prior to their first ranolazine prescription (N=5,400).

[0158] Inclusion criteria 1. Patients with evidence of ranolazine prescription during the selection window period. 2. Patients ≥18 years of age at or before the first prescription of ranolazine. 3. Patients who have selected cancers of interest within 24 months prior to their first ranolazine prescription (the first cancer diagnosis during this period will be defined as an index cancer diagnosis).

[0159] Exclusion criteria 4. Patients with any prior diagnosis of cancer or chemotherapy within the 24 months preceding the indexed cancer diagnosis. 5. Patients who previously used ranolazine within 6 months prior to their first ranolazine prescription. 6. Patients with New York Heart Association (NYHA) class IV heart failure within 4 weeks prior to their index cancer diagnosis. 7. Patients with a known left ventricular ejection fraction (EF) ≤45% within 4 weeks prior to the indexing of cancer diagnosis. 8. Patients with evidence of local anesthesia with lidocaine during the 4 weeks prior to the diagnosis of cancer.

[0160] The study ended after a five-year follow-up period, assessing cancer progression in all designated cancers (N=5400), while assessing progression to metastatic cancer and metastatic brain cancer in the lung cancer subcohort (N=200).

[0161] result In a cohort of 5,400 patients with different cancer types, the efficacy of ranolazine treatment after initial cancer diagnosis was evaluated, while in a subcohort of lung cancer patients (N=200), progression to metastatic cancer and metastatic brain cancer were assessed.

[0162] First, the study assessed whether changes in cancer progression occurred in a cohort of patients with breast cancer, lung cancer, colon cancer, prostate cancer, and pancreatic cancer who had been diagnosed with cancer prior to the initiation of their first ranolazine treatment.

[0163] like Figure 5 As shown, compared with the control group, the overall cancer progression rate was reduced by 37% in the cohort of cancer patients who were prescribed ranolazine after being diagnosed with cancer (p < 0.0001, n = 5,400).

[0164] The cohort was split into a subcohort of lung cancer patients (N=200) to analyze general metastasis or brain metastasis five years after lung cancer diagnosis, and to compare patients who were prescribed ranolazine after cancer diagnosis with a control cohort of lung cancer patients who were not prescribed ranolazine.

[0165] Compared with the control group, lung cancer patients who received ranolazine prescriptions after a lung cancer diagnosis had a 29.6% lower risk of developing general metastases within 5 years of diagnosis (p=0.0304, n=200). Results were also shown in... Figure 6 The study showed that approximately 33% of patients developed metastases, compared to only about 24% of patients treated with ranolazine.

[0166] In addition, regarding brain metastasis, such as Figure 7 It was also observed that, compared with the control group, lung cancer patients who started taking ranolazine after cancer diagnosis had a 45.3% lower overall risk of developing brain metastases within 5 years of diagnosis (p=0.0979, n=200), with approximately 12% of patients in the control group developing brain metastases, while only approximately 6.5% of patients developed brain metastases within the 5-year period.

[0167] Example 3 – Prevention of invasiveness in glioblastoma patients after ranolazine treatment method For this study, patient data were retrieved from the TriNetX Electronic Health Record (EHR) database.

[0168] The primary objective of this study was to examine the overall survival and progression-free survival of patients diagnosed with angina pectoris and treated with ranolazine after being diagnosed with glioblastoma.

[0169] First, all patients with at least one ranolazine prescription were identified. After applying the selection criteria detailed below, all eligible patients were categorized into the overall ranolazine cohort. The date of the first ranolazine prescription was defined as the index date of the overall cohort. The periods of 12, 24, 36, 48, or 60 months prior to the index date (up to the index date - 1) were defined as the pre-index period.

[0170] In this study, patients included were diagnosed with glioblastoma up to 2 years prior to their first rhanozine prescription.

[0171] Inclusion criteria 1. Patients with evidence of a diagnosis of angina during the selection window period.

[0172] 2. Patients with evidence of ranolazine prescription at or after the initial diagnosis of angina during the selection window period. 3. Patients ≥18 years of age at or before the first prescription of ranolazine. 4. Patients who developed glioblastoma within 12 months prior to their first rhinolophine prescription (the first cancer diagnosis during this period will be defined as an index cancer diagnosis).

[0173] Exclusion criteria 1. Patients with any prior diagnosis of cancer or chemotherapy within the 12 months preceding the indexed cancer diagnosis. 2. Patients who previously used ranolazine within 6 months prior to their first ranolazine prescription. 3. Patients with New York Heart Association (NYHA) class IV heart failure within 4 weeks prior to their index cancer diagnosis. 4. Patients with a known left ventricular ejection fraction (EF) ≤45% within 4 weeks prior to the indexing cancer diagnosis. 5. Patients with evidence of local anesthesia with lidocaine during the 4 weeks prior to the diagnosis of cancer.

[0174] result The current ongoing study assesses the invasiveness of glioblastoma and the long-term survival of patients with glioblastoma by comparing patients who were prescribed ranolazine before their diagnosis and continued to use it after diagnosis with a matched control cohort who were not prescribed ranolazine before or after their glioblastoma diagnosis.

[0175] The primary objective of the study was to evaluate whether, compared to a control group, ranolazine treatment initiated after a glioblastoma diagnosis could reduce or prevent the aggressiveness of the cancer, improve long-term survival in glioblastoma patients, or both.

[0176] The results showed that patients with glioblastoma treated with ranolazine had increased long-term survival compared to the control group.

[0177] Another result was the identification of reduced glioblastoma invasiveness in patients treated with ranolazine compared to the control group. Detailed Implementation Plan

[0178] 1. A drug selected from the Vaughan Williams Class 1d antiarrhythmic drug class (as modified by Lei) to effectively block continuous sodium currents while allowing transient sodium currents to pass through, and which is capable of crossing the blood-brain barrier and interacts with one or more of Nav 1.5, 1.6 and 1.7.

[0179] 2. A drug that can reduce voltage-gated sodium channels (Nav) 1.5, 1.6, or 1.7, or any combination of two or more thereof, in late-stage Na+. + The Class 1d Vaughan Williams antiarrhythmic drug, INaL, is used in subjects with cancer to prevent brain metastases, reduce the risk of brain metastases, or treat brain metastases.

[0180] 3. The drug for the purpose described in paragraph 2, wherein the drug is capable of crossing the blood-brain barrier, and optionally is capable of crossing the blood-brain barrier in an effective amount to prevent brain metastasis, reduce the risk of brain metastasis, or treat brain metastasis.

[0181] 4. A drug for the purpose described in either paragraph 2 or 3, wherein the cancer is a cancer that is prone to metastasize to the brain.

[0182] 5. The drug for the purpose described in paragraph 4, wherein the cancer is selected from lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer, and thyroid cancer.

[0183] 6. A drug for any of the uses described in any of items 2 to 5, wherein the subject is diagnosed with the cancer described.

[0184] 7. The drug for any of the uses described in any of items 2 to 6, wherein the subject is selected to receive standard care treatment for the cancer, and optionally is receiving standard care treatment for the cancer.

[0185] 8. A drug for any of the uses described in any of items 2 to 7, wherein the standard care treatment includes administration of at least one chemotherapy drug or immunotherapy drug that cannot cross the blood-brain barrier, optionally not in an effective amount to prevent brain metastasis, reduce the risk of brain metastasis, or treat brain metastasis.

[0186] 9. The drug for any of the uses described in any of items 2 to 7, wherein the standard care treatment includes at least one of surgery and radiation therapy.

[0187] 10. A drug for use according to any one of items 2 to 9, wherein said use is in a method of preventing brain metastases, optionally wherein said subject has not been diagnosed with brain metastases.

[0188] 11. A drug for use according to any one of items 2 to 9, wherein said use is in a method of reducing the risk of brain metastases, optionally wherein said subject has not been diagnosed with brain metastases.

[0189] 12. The drug for use according to any one of items 2 to 9, wherein said use is in a method of treating brain metastases, optionally wherein said subject has been diagnosed with at least one brain metastasis.

[0190] 13. A drug for use according to any one of items 2 to 12, wherein the drug is ranolazine.

[0191] 14. A medicine for any of the uses described in any of items 2 to 12, wherein the medicine is eleclazine (GS6615).

[0192] 15. A drug for use according to any one of items 2 to 12, wherein the drug is GS561587.

[0193] 16. A drug for use according to any one of items 2 to 12, wherein the drug is CPD 458967.

[0194] 17. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug is ranolazine, eleclazine GS561587, or CPD 458967. b) The drug is administered orally once or twice daily at a dose of 1-1000 mg per dose, and c) The subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer.

[0195] 18. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug is ranolazine. b) The drug is administered orally twice daily at a dose of 100-1000 mg per dose, and c) The subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer.

[0196] 19. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug in question is eleclazine. b) The drug is administered orally daily at a dose of 1-20 mg per dose. c) The subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer.

[0197] 20. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug in question is GS561587. b) The drug is administered orally daily at a dose of 1-100 mg per dose. c) The subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer.

[0198] 21. A drug capable of penetrating the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug in question is CPD 458967. b) The drug is administered orally daily at a dose of 1-100 mg per dose. c) The subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer.

[0199] 22. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug is ranolazine, eleclazine GS561587, or CPD 458967. b) The drug is administered intravenously at a daily dose of 1-2000 mg pr., and c) The subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer.

[0200] 23. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug is ranolazine, eleclazine GS561587, or CPD 458967. b) The drug is administered intravenously or orally at a daily dose of 1-2000 mg, and c) The subjects were adult human patients diagnosed with lung cancer.

[0201] 24. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug is ranolazine, eleclazine GS561587, or CPD 458967. b) The drug is administered intravenously or orally at a daily dose of 1-2000 mg, and c) The subjects were adult human patients diagnosed with glioblastoma.

[0202] 25. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug is ranolazine. b) The drug is administered orally twice daily at a dose of 100-1000 mg per dose, and c) The subjects were adult human patients diagnosed with lung cancer.

[0203] 26. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug is ranolazine. b) The drug is administered orally twice daily at a dose of 100-1000 mg per dose, and c) The subjects were adult human patients diagnosed with metastatic brain cancer.

[0204] 27. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug is ranolazine. b) The drug is administered orally twice daily at a dose of 100-1000 mg per dose, and c) The subjects were adult human patients diagnosed with glioblastoma.

[0205] 28. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug in question is either eleclazine GS561587 or CPD 458967. b) The drug is administered orally once daily at a dose of 1-100 mg, and c) The subjects were adult human patients diagnosed with lung cancer.

[0206] 29. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug in question is eleclazine GS561587 or CPD 458967. b) The drug is administered orally once daily at a dose of 1-100 mg, and c) The subjects were adult human patients diagnosed with glioblastoma.

[0207] 30. A drug capable of crossing the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects, wherein... a) The drug in question is eleclazine GS561587 or CPD 458967. b) The drug is administered orally once daily at a dose of 1-100 mg, and c) The subjects were adult human patients diagnosed with metastatic brain cancer.

Claims

1. A drug that can cross the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the treatment of invasive and / or metastatic brain cancer in subjects.

2. A medicament capable of penetrating the blood-brain barrier for use according to claim 1, wherein the treatment reduces the invasiveness of the cancer.

3. A drug that can cross the blood-brain barrier, selected from Vaughan Williams Class 1d antiarrhythmic drugs, for the prevention of invasive and / or metastatic brain cancer in subjects.

4. A blood-brain barrier-penetrating medicament for use according to any one of claims 1-3, wherein the medicament is selected from ranolazine, eleclazine, GS561587 and CPD 458967.

5. A medicament capable of penetrating the blood-brain barrier for use according to any one of the preceding claims, wherein the invasive brain cancer is glioblastoma, neuroblastoma, or astrocytoma.

6. A blood-brain barrier-penetrating medicament for use according to any one of claims 1-5, wherein the subject is diagnosed with a cancer selected from lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer, and thyroid cancer.

7. A blood-brain barrier-penetrating medicament for use according to any one of claims 1-4 or 6, wherein the subject is diagnosed with metastatic brain cancer.

8. A blood-brain barrier-penetrating medicament for use according to any one of claims 1-4 or 6, wherein the subject is diagnosed with brain cancer in a non-invasive and / or non-metastatic stage.

9. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the medicament is provided prior to standard care treatment.

10. A blood-brain barrier-penetrating medicament for use according to any one of claims 1-8, wherein the medicament is provided together with standard care treatment for said cancer.

11. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the standard care treatment includes administration of at least one chemotherapy and / or immunotherapy.

12. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the standard care treatment includes surgery and / or radiation therapy.

13. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein administration of the medicament improves the life expectancy of the subject.

14. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein administration of the medicament is initiated at least one month prior to the commencement of standard care treatment, for example, at least two, three, four, five months, or, for example, at least six months prior to the commencement of standard care treatment.

15. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the cancer is a tumorigenic cancer, and the treatment reduces the formation of motile cells in the tumor and / or the migration of tumor cells from the tumor.

16. A medicament capable of penetrating the blood-brain barrier for use according to any one of the preceding claims, wherein the treatment reduces the invasiveness of the cancer without killing tumor cells.

17. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the treatment reduces the invasiveness of the cancer without substantially affecting the proliferation of cancer cells.

18. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the subject is an adult human diagnosed with triple-negative breast cancer, castration-resistant prostate cancer, BCR prostate cancer, glioblastoma, colon cancer, lung cancer, or pancreatic cancer.

19. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the subject (i) has been diagnosed with angina, (ii) has been prescribed ranolazine prior to any cancer diagnosis, or (iii) has been diagnosed with angina and has been prescribed ranolazine prior to any cancer diagnosis.

20. A blood-brain barrier-penetrating medicament for use according to any one of claims 1-18, wherein the subject (i) is not diagnosed with angina, (ii) is not prescribed ranolazine, or (iii) is not diagnosed with angina and has not been prescribed ranolazine prior to any cancer diagnosis.

21. A medicament capable of penetrating the blood-brain barrier for use according to any one of the preceding claims, wherein the medicament is administered at a therapeutically effective dose.

22. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the medicament is administered at a dose level in the range of 1 μmol to 10 μmol.

23. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the medicament is administered at a dose of about 1 mg to about 2000 mg, optionally at a dose of about 1 mg to about 1000 mg, and wherein the subject is an adult human patient, such as an adult human patient weighing in the range of about 50 to about 150 kg.

24. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the medicament is administered twice daily, once daily, once every two days, once every three days, once every five days, once weekly, once every two weeks, or once monthly, for example, once daily.

25. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the medicament is administered twice daily to an adult human patient at a dose of 500-1000 mg, for example, 750 mg twice daily.

26. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the medicament is administered for a period of at least 4 weeks, such as at least 8 weeks, such as at least 12 weeks, such as at least 24 weeks, such as at least 48 weeks, or longer.

27. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein said use comprises administering a single initial booster dose of about 10 mg to about 100 mg of said medicament.

28. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the use comprises administration of the medicament in a single initial booster dose of about 10 mg to about 100 mg, followed by administration once daily at a dose of about 1 mg to about 20 mg for a period of at least 4 weeks, for example, a daily dose of 3 mg or 6 mg for 6 or 8 weeks.

29. A medicament capable of penetrating the blood-brain barrier for use according to any one of the preceding claims, wherein the medicament is for oral administration.

30. A blood-brain barrier-penetrating medicament for use according to any one of the preceding claims, wherein the medicament is intended for parenteral administration, such as intravenous (iv) injection or infusion.

31. A medicament capable of penetrating the blood-brain barrier for use according to any one of the preceding claims, wherein the medicament is provided for administration in combination with at least one further substance.

32. A blood-brain barrier-penetrating medicament for use according to claim 30, wherein the at least one further substance is selected from minoxidil, alpracalin, bismacalin, cromakalim, diazoxide, imacalin, levocalocarin, mazocarin, naminidil, nicordil, pinacidil, pilmakalim, salakalim, tofenamic acid, lupirtine, retigabine, riluzole, NS1619, NS11021, benzimidazole 1-EBIO, carmalazine, retigabine, or a combination of any two or more thereof.

33. A medicament capable of penetrating the blood-brain barrier for use according to claim 31 or 32, wherein the at least one further substance is selected from K. ATP Opening agent, K Ca Opening agents and Kv opening agents.

34. A medicament capable of penetrating the blood-brain barrier for use according to any one of claims 31-33, wherein the at least one further substance is selected from amiloride and digoxin, or a combination thereof.

35. A medicament capable of penetrating the blood-brain barrier for use according to any one of claims 31-34, wherein the at least one further substance is an epithelial sodium channel (ENaC) blocker.

36. A blood-brain barrier-penetrating medicament for use according to any one of claims 31-35, wherein the at least one further substance comprises a combination of AG1478, gefitinib, erlotinib, afatinib, osimertinib, and dacomitinib, or a combination of any two or more thereof.

37. Vaughan Williams Class 1d antiarrhythmic drugs are used for preventative purposes to reduce the risk of brain metastases in cancer patients, particularly lung cancer patients.

38. A method for reducing the invasiveness of brain tumors, comprising administering an effective amount of Vaughan Williams Class 1d antiarrhythmic drug.

39. A method for reducing the risk of invasive and / or metastatic brain cancer in a subject, comprising administering a therapeutically effective amount of Vaughan Williams Class 1d antiarrhythmic drug to a subject who has not been diagnosed with invasive and / or metastatic brain cancer, thereby reducing the risk of invasive and / or metastatic brain cancer in the subject.

40. The method of claim 39, wherein the Vaughan Williams Class 1d antiarrhythmic drug is ranolazine or eleclazine.

41. The method of claim 39 or 40, wherein the subject (i) has been diagnosed with angina, (ii) has been prescribed ranolazine prior to any cancer diagnosis, or (iii) has been diagnosed with angina and has been prescribed ranolazine prior to any cancer diagnosis.

42. The method of claim 39 or 40, wherein the subject (i) is not diagnosed with angina, (ii) is not prescribed ranolazine, or (iii) is not diagnosed with angina and has not been prescribed ranolazine prior to any cancer diagnosis.

43. The method according to any one of claims 39 to 42, wherein the subject has been diagnosed with cancer.

44. The method of claim 43, wherein the subject has been diagnosed with lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer, thyroid cancer, or brain cancer in a non-invasive and / or non-metastatic stage, optionally wherein the brain cancer is glioblastoma.

45. The method according to any one of claims 39 to 44, wherein the subject has been exposed to one or more carcinogens, such as tumor viruses, ionizing radiation or other Class 1 carcinogens.

46. ​​A method for reducing cell migration and / or reducing motor formation in a subject's brain tumor, comprising administering a therapeutically effective dose of a Vaughan Williams Class 1d antiarrhythmic drug.

47. The method of claim 46, wherein the drug is ranolazine, eleclazine, GS561587 or CPD458967.

48. A drug selected from ranolazine or eleclazine for treating invasive and / or metastatic brain cancer in a subject, wherein the subject is an adult human patient diagnosed with metastatic brain cancer, glioblastoma, or lung cancer, and the drug is administered orally once or twice daily at a dose of 1-1000 mg per dose.

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