Treatment of metastatic or invasive brain cancer

Abstract

Described is a method of preventing, reducing the risk of, or treating, brain metastases in a subject suffering from cancer. Described is also a method of preventing, reducing the risk of, or treating, invasive and / or metastatic brain cancer in a subject. Advantageously, the methods comprise administration of at least one blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class 1d anti-arrythmia drugs, such as from ranolazine, eleclazine, GS561587 and CPD 458967.

Description

[0001] TREATMENT OF METASTATIC OR INVASIVE BRAIN CANCER

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a method of preventing, reducing the risk of, or treating, brain metastases in a subject suffering from cancer.

[0004] BACKGROUND OF THE INVENTION

[0005] When cancer that began somewhere else in the body spreads to the brain and causes a brain tumour, it is called metastatic brain cancer (also called secondary brain tumours). The resulting tumours are called brain metastases. Currently available treatments and treatment options for metastatic brain cancer are set out in a reference by Johns Hopkins neurosurgeon Chetan Bettegowda, accessed on 11 October 2023 at internet address www.hopkinsmedicine.org / health / conditions-and-diseases / metastatic-brain-tumours.

[0006] Metastatic brain cancer is caused by cancer cells spreading (metastasizing) to the brain from a different part of the body. The most common types of cancer that can spread to the brain are cancers of the lung, breast, skin (melanoma), colon, kidney and thyroid gland. Lung, breast and colon are 3 of the 4 most common cancers in the US and Europe, prostate being the 4th. Metastatic brain tumours are five times more common than primary brain tumours (those that originate in the brain). Metastatic brain tumours can grow rapidly, crowding or destroying nearby brain tissue. Sometimes a patient may have multiple metastatic tumours in different areas of the brain.

[0007] A number of treatments are available for metastatic brain cancer, but these are invasive, often the cancer develops drug resistance, they are sometimes very expensive and often uncertain.

[0008] In addition to metastatic brain tumours, primary aggressive brain tumours originating from e.g., glioblastoma are also particularly difficult to treat, due to their aggressiveness and invasiveness, and are often resistant to standard-of-care treatment. The critical issue is that the brain is shielded from the remainder of the body by the blood-brain barrier (BBB) which only allows very few substances to pass. Consequently, many drugs that could treat brain metastases are not functional as the drug cannot access the location of the brain metastasis because of the blood-brain barrier. The fact that most standard-of-care treatment aims at killing cancer cells itself poses a difficulty in treatment because of the lack of certainty that all the cancer cells in a primary or secondary tumour have in fact been killed. If some have already escaped, they may form micro metastases elsewhere in the body, and which are impossible to locate because of their small size, and / or cancer stem cells may also escape the standard-of-care treatment and become active sometime later after treatment has finished.

[0009] Most standard-of-care treatments involve the use of molecules which cannot pass into brain due to the blood-brain barrier, and hence can be ineffective against invasive and metastatic tumour cells which have already passed into the brain. Moreover, the cancers develop drug resistance as a common feature of many of the drugs used to treat primary and secondary cancers.

[0010] Because of the need for a drug to cross the blood-brain barrier to be effective against secondary cancers in the brain, there are fewer treatment options than in the rest of the body. Many compounds are not able to cross the blood-brain barrier; especially large molecules and proteins commonly used in chemotherapy and immunotherapy treatments.

[0011] It has been found in a long-term study by Badwe et al. (Effect of Peritumoral Infiltration of Local An[a]esthetic Before Surgery on Survival in Early Breast Cancer, J Clin Oncol 2023;41 :3318-3328) that patients treated with lidocaine, a painkiller, before surgery for breast cancer have increased survival rates as compared with those who were not administered lidocaine. Lidocaine is a general-purpose sodium ion channel blocker. Breast cancer is one of the cancers known to metastasise to the brain.

[0012] It was recently found from analysis of 165 mixed cancer patients (breast, colon and prostate cancer patients) that cancer patients who had received treatment with the class Id drug ranolazine prior to cancer diagnosis had a significant 60% reduced risk of death compared to patients which 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). Additionally, patients who received ranolazine after the cancer diagnosis also had a significant 45% reduced risk of death following treatment.

[0013] The common features in relation to most standard treatments is that they attempt to kill the tumours rather than preventing them forming in the first place, or if formed preventing them from spreading further, and in that way reverse or stall the tumour aggressiveness. It would be preferable if a treatment was available which prevented the secondary metastatic tumours forming in the first place or prevented them from spreading further once formed. This is particularly necessary in relation to any secondary tumours which escape the initial tumour and, in the cancers listed above find a site in the brain where they can grow, often with long term fatal results to the patient.

[0014] Taken together with the difficulties of treating, in particular, brain cancers, metastatic and otherwise, as described above, there is an urgent need for better treatment options for these cancer types, which may improve the expected outcome for the patients.

[0015] SUMMARY OF THE INVENTION

[0016] The present invention relates to the treatment of cancer in a subject in the need thereof with one or more anti-arrythmia drugs that target the late / persistent current of VGSCs, in order to reduce the prevalence of metastases or reduce progression to metastatic cancer, in particular brain metastases and further to reduce the invasiveness of tumours in the brain.

[0017] An aspect of the present invention relates to a blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject.

[0018] Another aspect of the present invention relates to a blood-brain barrier permeable drug selected from Vaughan Williams Class Id anti-arrythmia drugs for use in preventing the occurrence of invasive and / or metastatic brain cancer in a subject.

[0019] Another aspect of the present invention relates to a prophylactic use of a Vaughan Williams Class Id anti-arrythmia drug for reducing the risk of brain metastasis in cancer patients, such as in particular lung cancer patients.

[0020] Another aspect of the present invention relates to a method for reducing the invasiveness of a brain tumour, comprising administration of an efficient amount of a Vaughan Williams Class Id anti-arrythmia drug.

[0021] Another aspect of the present invention relates to a method for reducing the risk for an invasive and / or metastatic brain cancer in a subject comprising administering a therapeutically effective amount of a Vaughan Williams Class Id anti-arrythmia drug to a subject not diagnosed with an invasive and / or metastatic brain cancer, thereby reducing the risk for an invasive and / or metastatic brain cancer in a subject. Another aspect of the present invention relates to a method for reducing cellular migration and / or reduce motile formation from a brain tumour in a subject comprising administering a therapeutically effective dose of a Vaughan Williams Class Id anti-arrythmia drug.

[0022] Another aspect of the present invention is a drug selected from ranolazine or eleclazine for use in treating an 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 dosage of 1-1000 mg per dose.

[0023] BRIEF DESCRIPTION OF THE FIGURES

[0024] Fig. 1. Illustration of pathway causing cancer cells to become invasive.

[0025] Fig. 2. Illustration of inhibition of VGSC via. TTX or through the Lido binding site.

[0026] Fig. 3. Illustration of the different stages of cancer development.

[0027] Fig. 4. Cancer mortality of control group versus ranolazine-treated group.

[0028] Fig. 5. Cancer progression of control group versus ranolazine-treated group.

[0029] Fig. 6. General metastasis progression control group versus ranolazine-treated group 5 years post-diagnosis.

[0030] Fig. 7. Brain metastasis progression control group versus ranolazine-treated group 5 years post-diagnosis.

[0031] DETAILED DISCLOSURE OF THE INVENTION

[0032] The present disclosure relates to the use of anti-arrhythmic drugs which target the voltage gated sodium channels, in a specific manner which reduces the late or persistent sodium current, in the treatment of cancers, in particular brain cancers, such as metastatic brain cancers (i.e., secondary brain tumours), or primary brain cancers, such as e.g., glioblastoma. The inventors have found an effective means of preventing the primary cancer metastasising to the brain and if it has already started to metastasise, inhibiting the secondary tumours from metastasising further and thereby not requiring any further treatment or making them easier to treat by conventional means because the tumours would be smaller and localized.

[0033] Accordingly, the present disclosure especially relates to a blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject.

[0034] Additionally, the present disclosure relates to a method of treatment of an invasive and / or metastatic brain cancer in a subject comprising administration of an effective amount of a blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs.

[0035] In embodiments, the treatment reduces the invasiveness of the cancer.

[0036] Class Id drugs

[0037] Miles Vaughan Williams classified anti-arrhythmic drugs by their mode of action. This classification has been recently updated by Lei et al. (Modernized Classification of Cardiac Antiarrhythmic Drugs, Circulation 2018;138: 1879-1896, DOI: 10.1161 / CIRCULATIONAHA.118.035455).

[0038] Lei et al., supra, describes the class Id drugs ("Class Id drugs") as follows; "Nav 1.5, Reduction in late Na+ current (INaL), affecting action potential (AP) recovery, refractoriness, repolarization reserve, and QT interval". Ranolazine is the only commercially available member of this class, and it is used for treating stable angina, ventricular tachycardia and as a potential new class of drugs for the management of tachyarrhythmias. Lei et al. describes the likely mode of action as a decrease in AP recovery time and a reduction in EAD-induced triggered activity.

[0039] Class Id drugs work by inhibiting the persistent or long current in the voltage gated sodium channel ("VGSC"), thereby inhibiting sodium from entering into the cell in quantity and causing protons to be expelled. The mechanism of action will be further explained below.

[0040] Djamgoz et al. In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis, Cancers 2019;ll:1675, DOI: 10.3390 / cancerslllll675') describes the function of the persistent sodium current in Voltage gated sodium channels in enabling cancers to metastasise. Is has been proposed that there are at least 8 different binding sites on the VGSC molecules, (See e.g., 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). Without being limited to theory, the Class Id drugs, such as ranolazine, are proposed to bind to the "lido" i.e., the binding site for lidocaine as illustrated in Fig. 2.

[0041] Interestingly, EP3132791B1 describes the use of persistent current sodium channel blockers for the inhibition of metastasis in cancer, with ranolazine being described as a drug suitable for this purpose and EP3579840B1 describes the use of certain other drugs including eleclazine for this general purpose.

[0042] However, none of these documents deal with the specific problem that standard-of-care treatments for certain common cancers as listed herein may not completely kill the cancer cells, and that they may escape from the primary tumour before during or after the standard- of-care treatment, in which case there is a high probability that the tumour will metastasise to the brain. Commonly standard-of-care drug treatments in these cases are generally ineffective because the drugs cannot cross the blood-brain barrier or are very unpleasant and potentially dangerous to healthy cells, such as e.g., radiation or proton beam therapies.

[0043] Surprisingly, it was found that compounds of the drug class Id as defined above, in particular ranolazine, when provided either before or with the standard care for specific types of cancers, improved the prognosis and life expectancy of cancer patients (See Examples 1-3).

[0044] Example 2, for example, shows that there is a beneficial effect of ranolazine treatment especially on brain metastasis, which could not be readily anticipated based on the overall reduction in metastases. Together with the data presented in Example 1, these results support that ranolazine, and other class Id drugs capable of crossing the blood-brain barrier, are an excellent choice for treating brain cancers, by inhibiting the invasiveness and metastatic potential of the brain tumours.

[0045] Especially the correlation between treatment with the drug ranolazine and the improved survival and reduced metastasis in brain metastases patients was surprising, since brain metastasis involve the presence of brain tumours, which are protected from most standard treatments by the blood-brain barrier. Accordingly, the finding that ranolazine is capable to penetrate the blood-brain barrier in an effective amount to achieve these effects is surprising.

[0046] Examples of other brain cancers is e.g., glioblastoma which is the most aggressive and invasive brain cancer. Glioblastomas develop from astrocytes in the brain or spinal cord where they grow quickly and invade and destroy healthy tissue. Glioblastomas are generally highly treatment resistant to conventional radiation- and chemotherapy, and reoccurrence after treatment is very common. Patient survival without treatment is about 6 months, which can be extended to around 15 months with the standard treatment protocol, however less than 5% of patients survive more than five years after first diagnosis.

[0047] Due to the severity of especially glioblastoma, efficient therapies which can either extend the median survival rate or reduce the invasiveness of the cancer are highly sought for.

[0048] Accordingly, the present disclosure also provides a drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in preventing the occurrence of invasive and / or metastatic brain cancer in a subject. The current disclosure therefore also provides a method for reducing the invasiveness of a brain tumour, comprising administration of an efficient amount of a Vaughan Williams Class Id anti-arrythmia drug.

[0049] While it is beneficial to initiate the treatment with a Vaughan Williams Class Id anti-arrythmia drug after the diagnosis of a metastatic cancer, it may also prove beneficial to initiate treatment at an earlier cancer stage.

[0050] Therefore, the present disclosure also provides a method for reducing the risk for an invasive and / or metastatic brain cancer in a subject comprising administering a therapeutically effective amount of a Vaughan Williams Class Id anti-arrythmia drug to a subject not diagnosed with an invasive and / or metastatic brain cancer, thereby reducing the risk for an invasive and / or metastatic brain cancer in a subject. In embodiments, the subject has been diagnosed with cancer.

[0051] Alternatively, subjects who has been exposed to known carcinogens may also benefit from early treatment with of a Vaughan Williams Class Id anti-arrythmia drug, since it is known to reduce the cancer progression. Accordingly, in some embodiments, the subject has been exposed to one or more carcinogens, such as an oncovirus, ionizing radiation, or other group 1 cancer carcinogens.

[0052] In further embodiments, the subject has 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

[0053] The Vaughan Williams Class Id anti-arrythmia drug is further suitable for prophylactic use, which entails reducing the risk of brain metastasis in cancer patients, such as in particular lung cancer patients. As is established in, e.g., Examples 1 and 2, ranolazine reduces the invasiveness of tumours, such as e.g., lung-, breast or prostate tumours and hinders the metastatic ability of same. Surprisingly, the amount of ranolazine which is able to pass the blood-brain barrier and ends up in the brain, is effective to inhibit the further development of metastatic tumours at an early stage. The presented data thereby supports that the amount of ranolazine that ends up in the brain is sufficiently high for treatment of brain cancers, such as metastatic brain cancers, glioblastoma, astrocytoma and neuroblastoma.

[0054] For example, ranolazine, or another suitable Vaughan Williams Class Id drug, can be prescribed to a subject prior to a cancer diagnosis. The subject may, for example, be at risk for developing a cancer, optionally because of a genetic predisposition. The subject may also already have an undiagnosed cancer, such as e.g., an undiagnosed glioblastoma. Due to the treatment with ranolazine, an undiagnosed cancer, e.g., glioblastoma, is inhibited in its invasiveness, or its development towards invasiveness inhibited or slowed down. The time to diagnosis is thereby extended, since the invasiveness of the tumour is effectively reduced at an earlier stage.

[0055] Alternatively, ranolazine, or another suitable Vaughan Williams Class Id drug, can be prescribed to a subject after an initial diagnosis, e.g., of a glioblastoma. The invasiveness of the glioblastoma can thereby be inhibited, or its development towards invasiveness inhibited or slowed down. The progression of the cancer can thereby be reduced and / or the patient's life span extended.

[0056] Overall, there is a long felt need for development of new treatment strategies that can improve the outcome for a patient diagnosed with metastatic brain tumours, in particular a patient diagnosed with a glioblastoma or other brain cancer such as e.g., an astrocytoma or neuroblastoma. What is surprising and has unexpectedly been found is that Class Id anti- arrhythmic drugs like ranolazine and eleclazine are capable of effectively crossing the bloodbrain barrier, thereby being present in the brain at serum concentrations that are sufficient to result in a preventive or otherwise therapeutic effect, although the brain concentrations can be lower than for the rest of the body. Thus, in embodiments, the invasive brain cancer is glioblastoma, neuroblastoma or astrocytoma.

[0057] As used herein the term "blood-brain barrier permeable" refers to a drug or compound which, when administered, can be actively or passively transported across the blood-brain barrier to an extent providing for a therapeutically effective amount of the drug is transported into the central nervous system, preferably into the brain. The Class Id drugs are generally capable of being administered orally, e.g. in pill form, but may alternatively be administered by injection or infusion, e.g. intravenously. By "therapeutically effective amount" or "therapeutically effective dose", it is intended an amount or dosage the drug, that when administered to a patient suffering from cancer brings about a positive therapeutic response with respect to treatment of the patient, such as, e.g., reduction of metastatic behaviour of the cancer, prevention of metastatic behaviour of the cancer, reduction of pain, or the like.

[0058] Standard-of-care

[0059] In cancer treatment there is a number of standard-of-care treatments that are used depending on the type of cancer and its stage, and are generally a combination of multiple treatments, such as radiation therapy combined with chemotherapy and / or immunotherapy.

[0060] Radiation therapy treats metastatic brain tumours by using X-rays and other forms of radiation (light energy) to destroy cancer cells or prevent a tumour from growing. These painless treatments involve passing beams of radiation through the brain, which can treat cancers in areas that are difficult to reach through surgery. Procedures may include any one or a combination of the following: i. External beam radiation therapy delivers radiation from a machine and through the body to reach metastatic tumours.

[0061] II. Whole-brain radiation targets the entire brain to hit multiple tumours or any metastatic disease that hides from an MRI scan. ill. Stereotactic radiosurgery (e.g., Cyberknife) directs a high dose of radiation targeted to the specific shape of the tumour, sparing surrounding healthy tissue from unnecessary radiation exposure. iv. Proton therapy uses protons (instead of X-rays) to treat metastatic brain tumours. Like stereotactic radiosurgery, proton therapy minimizes harm to healthy tissue surrounding a tumour. v. Brachytherapy is radioactive material implanted within a tumour to prevent further growth.

[0062] These procedures may be performed after surgery to prevent tumours from recurring at the surgical site and growing into other brain tissue. Studies are now looking at how to manage the long-term effects of treatment.

[0063] It was recently found that in an analysis of 253 breast cancer patients with brain metastases the use of an antiepileptic drug (AED), valproic acid, improves overall survival in breast cancer patients with brain metastases in the setting of whole brain radiotherapy. Median Overall Survival was 9 months for patients taking any AED (n = 101) versus 4 months for those not taking the anti-epilepsy drug (AED) (p = 0.0003) (Reddy et al., CNS Irradiation 2015;117(2) :308-314, DOI: 10.1016 / j.radonc.2015.10.009). The AED is targeting the central nervous system and therefore is designed to be able to cross the blood-brain barrier.

[0064] An alternative or supplementary treatment is e.g., metastatic brain tumour surgery. Surgery provides fast relief of "mass effect" — pressure inside the skull resulting from a growing metastatic tumour and swelling of the brain. The goal of surgery is to minimize the amount of space the tumour takes up by debulking, which means removing as much of the tumour as possible while maintaining neurological function. Surgery for metastatic brain cancer is used when there is a clear link between the symptoms and the tumour's location, the primary cancer is treatable and under control, and the tumour can be safely removed.

[0065] Another alternative or supplementary treatment is e.g., chemotherapy for metastatic brain tumours. Because traditional chemotherapy cannot cross the blood-brain barrier, newer treatments called targeted therapy are used as the primary type of chemotherapy for treating metastatic brain tumours. These drugs identify and attack cancer cells (the target) with minimal harm to normal cells while preventing the growth and spread of cancer cells. Targeted therapy can be administered after surgery or in conjunction with radiation therapy to destroy remaining cancer cells. Targeted therapies used to treat metastatic brain tumours include Trastuzumab for breast cancer that has spread to the brain and Erlotinib for the most common type of lung cancer (non-small cell lung cancer) that has spread to the brain.

[0066] Additional treatment options for metastatic brain tumours that have developed over the last few decades is e.g., immunotherapy for metastatic brain tumours. Cancer immunotherapy has developed drugs, vaccines and other therapies that trigger the immune system's natural abilities to fight cancer. Many immunotherapy drugs for metastatic brain tumours act as "checkpoint inhibitors". Normally, tumour cells can evade attack by activating certain proteins (called checkpoint proteins) that disarm the immune system. Checkpoint inhibitors prevent tumour cells from exploiting this process. Immunotherapy drugs to treat metastatic brain tumours include atezolizumab, ipilimumab, pembrolizumab and nivolumab.

[0067] The common features in relation to all of these treatments is that they attempt to kill the tumours rather than preventing them forming in the first place, or if formed preventing them from spreading further. This often results in drug resistance and failure of therapy or relapse.

[0068] If metastatic cancers enter the brain, only a limited option for treatment exists, both because of the need for the drug to pass the blood-brain barrier and because of side effects in relation to the central nervous system if the drug does pass the blood-brain barrier. Voltage gated sodium channels (VGSCs) and their Mode of Operation

[0069] As used herein, "voltage-gated sodium channels" or "VGSCs" refer to a class of integral membrane proteins which form ion channels. They conduct sodium ions (Na+) through a cell's plasma membrane into cells. In humans, there are nine different VGSC alpha subunit or "Nav" proteins (Navi. I to Navi.9), which are encoded by nine genes (SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SCN10A, and SCN11A, respectively). As used herein, unless contradicted by context, the term may refer to any and all known VGSCs.

[0070] Without being limited to theory, Figure 1 sets out a pathway causing cancer cells to become invasive. It starts under hypoxic conditions with the development of aberrant Nav channels forming. The Nav channels exists in several splice variants, which expression differs with tissue and developmental stage.

[0071] For the purpose of the present disclosure, the term "splice variants" are variants of the VGSCs which occur due to alternative splicing of the gene or RNA encoding the particular VGSC, leading to different sequence variants of the same gene being expressed. Splice variants are also commonly referred to as isoforms. For example, the human Navi.5 is proposed to have at least six isoforms, resulting from alternative splicing, listed under the uniport.org identifier Q14524, where the isoform designated Q14524-4, comprises substitution of residues 206-211 from "TTEFVD" to "VSENIK", which leads to the channel exhibiting the persistent sodium current. As is also evident from the uniport.org identifier Q14524, the substitution of residues 206-211 is also seen in other splice variants, such as e.g., the isoform designated in Q14524-5, Navi.5a or Exl8del, which is only found expressed in neuroblastoma, but which comprises the 206-211 substitution and deletion of residues 1077-1130.

[0072] Those that are believed to be responsible for the invasiveness of the cancer can be a splice variant which is a neo-natal form. The Nav channel which is predominant has been identified in a number of cancers and has, where tested, been found to include a neo-natal splice variant (designated as "nNav..."), as shown in Table 1.

[0073] Table 1

[0074] Accordingly, in the present disclosure, it is preferable that the VGSC targeted by the class Id drug includes one or more Nav channel splice variants resulting in late sodium currents such as e.g., the neonatal form of Navi.5, also designated nNavl.5. In embodiments, the target is selected from one or more of Navi.5, Navi.6 and Navi.7. In additional embodiments, the target is one or more splice variants of Navi.5, Navi.6 and / or Navi.7. It is preferable that the splice variants targeted are expressed in the invasive and / or metastatic cancer. Preferably, the splice variant targeted is a splice variant expressed in metastatic brain cancer, or invasive primary brain cancer such as e.g., glioblastoma or neuroblastoma. It is commonly recognised that expression of VGSCs in cancer cells are at least in part responsible for driving the invasiveness and motile generation of several cancers. Accordingly, in some embodiments, the cancer that is treated is a tumorigenic cancer, and the treatment reduces motile cell formation in the tumour and / or tumour cell migration from the tumour. In some aspects, the present disclosure therefore also provides a method for reducing cellular migration and / or reduce motile formation from a brain tumour in a subject comprising administering a therapeutically effective dose of a Vaughan Williams Class Id anti-arrythmia drug.

[0075] Figure 2 illustrates inhibition of invasiveness by VGSC blockage. According to the illustrated mechanism, blockage of VGSC leads to reduced invasiveness of tumour cells. Various agents have been assessed to block or inactivate VGSC:

[0076] • Completely - usually toxic like TTX, CN2

[0077] • Partially - Many side effects, Lidocaine, Procaine, Tricyclic, AED, Valproate, Mexiletine

[0078] • Selective - Targeted treatment, low side effects (inhibits aberrant function) - Ranolazine or Eleclazine

[0079] • Silencing - Silencing RIMA

[0080] 11 animal and 9 clinical data studies with different blocking or inactivation mechanisms show that treating the VGSC will reduce metastasis and / or improve survival and / or lower the tumour burden.

[0081] In embodiments, the administration of the drug improves the life expectancy of the subject.

[0082] As shown in Figure 2, various agents have been proposed to block the VGSC current. It can be blocked completely, but such agents are toxic, like TTX. It can also be partially blocked with agents like lidocaine, but these are non-selective, have side effects and cannot be administered for long term use.

[0083] Then there are the selective late current blockers which are the Class Id drugs of the invention. Because these selectively block only or largely the aberrant function of the VGSC, they are safe to use as chronic treatments so that if any invasive tumour cells have escaped into the brain, the class Id drugs can be administered for life and will inhibit the invasive cells in the brain growing into life endangering metastatic tumours. Accordingly, in some embodiments, the treatment provided herein reduces the invasiveness of said cancer without killing the tumour cells. In additional embodiments, the treatment provided herein reduces the invasiveness of said cancer without substantially affecting proliferation of the cancer cells.

[0084] Silencing the RNA is a technology in development.

[0085] As is shown in Figure 3, as a result of the long or persistent current of the VGSC remaining open, sodium can flood into the cell, expelling protons to maintain the electrical balance within the tumour cells. This acidification of the space between the cells allows cysteine cathepsins B and S to eat away at the extra cellular matrix allowing invasive tumour cells compete with aberrant VGSCs to invade surrounding tissue and ultimately escape into the lymph system or bloodstream to create distant metastases. Although many will be destroyed by the body's natural defence mechanisms, some may escape and invade new organs and in particular to the brain, leading in time to metastatic brain tumours.

[0086] Where standard-of-care treatment is given to the primary tumours, the primary care method may not be able to kill those cells which are already invasive and which have found their way into the brain, as a Stage 3 cancer. In addition, because primary care is usually designed to kill cancer cells, it damages the environment, and some cancer cells may escape into the bloodstream where it is possible that some may escape the body's natural defence mechanism and lodge in the brain as a metastatic cancer.

[0087] What is surprising is that Class Id drugs, is that they only block the long or persistent VGSC current as aberrant function, and will selectively inhibit invasiveness of tumours and because these drugs can cross the blood-brain barrier in sufficient concentrations, with low side effects, and can be given as a long term drug to inhibit brain metastasis in those tumours which are susceptible to brain tumours and for which no other effective long term prophylactic treatment currently exists.

[0088] Cancer known to lead to metastatic brain cancer are e.g., lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer and thyroid cancer. Accordingly, it is preferable that the persistent VGSC current blockers disclosed herein are used in the treatment of one or more of these cancers. Further, it is also preferred that the persistent VGSC current blockers as disclosed herein are used in the treatment of primary brain cancers, in particular aggressive and / or invasive brain cancers, such as e.g., glioblastoma or neuroblastoma. In embodiments, ranolazine is used in the treatment of metastatic brain cancer or invasive brain cancer. In embodiments, eleclazine is used in the treatment of metastatic brain cancer or invasive brain cancer. In embodiments, GS561587 is used in the treatment of metastatic brain cancer or invasive brain cancer. In embodiments, CPD 458967 is used in the treatment of metastatic brain cancer or invasive brain cancer. In embodiments, the invasive brain cancer is glioblastoma or neuroblastoma, such as glioblastoma.

[0089] Method of treatment

[0090] Adjuvant treatment is considered as a supplement to the standard-of-care treatment. As such the adjuvant treatment may be provided before or during the standard-of-care treatment. As described herein, a patient diagnosed with a primary cancer in a metastatic state may benefit from being started on e.g., ranolazine treatment immediately following diagnosis of metastatic cancer. Accordingly, when a patient is diagnosed with a primary cancer known to metastasize to the brain, such as e.g., lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer and thyroid cancer, it may be beneficial to initiate the administration of the adjuvant treatment immediately, or soon after diagnosis, to hinder the further metastasis and invasiveness of potentially unrecognised brain metastases. Accordingly, in some instances treatment with the Vaughan Williams Class Id anti-arrythmia drug may be initiated before the standard-of-care treatment. In other instances, the drug is provided together with a standard-of-care treatment for the cancer. In additional instances, the drug is provided after diagnosis of the cancer, such as 1 month, 3 months, 6 months, 12 months or such as 24 months after diagnosis of the cancer. In additional instances, the administration of the drug is initiated at least 1 month before the initiation of the standard- of-care treatment, such as at least 2 months, 3 months, 4 months, 5 months or such as at least 6 months before initiation of the standard-of-care treatment.

[0091] In embodiments, the subject is diagnosed with a cancer selected from the group consisting of lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer and thyroid cancer. In further embodiments, the subject is diagnosed with metastatic brain cancer. In further embodiments, the subject is diagnosed with a brain cancer at a non-invasive and / or non-metastatic stage.

[0092] The criteria for a suitable adjuvant treatment therefore may include at least the following factors a) The treatment should be active to inhibit metastasis both within and outside the brain; b) The drug should be able to pass the blood-brain barrier; c) The drug should not affect the primary "standard-of-care" treatment; d) The drug should not show long term rejection by tumours; e) The drug should have limited side effects, especially to the central nervous system and therefore should show low or minimal activity towards Navi.1-1.4 and 1.8 and 1.9.

[0093] In embodiments, the standard-of-care treatment comprises administration of at least one chemotherapeutic and / or immunotherapeutic. In additional embodiments, the standard-of- care treatment comprises surgery and / or radiotherapy. In further embodiments, the standard-of-care treatment comprises a combination of any two of surgery, radiotherapy, administration a chemotherapeutic and administration of an immunotherapeutic. Accordingly, in embodiments, the drug is provided for administration in combination with at least one further substance.

[0094] In embodiments, the at least one further substance is selected from the group consisting of minoxidil, aprikalim, bimakalim, cromakalim, diazoxide, emakalim, levcromakahm, mazokalim, naminidil, nicorandil, pinacidil, pilmakalim, sarakalim, tolfenamic acid, lupirtine, retigabine, riluzole, NS1619, NS11021, benzo imidazolone 1-EBIO, rottierin, retigabine, or a combination comprising any two or more thereof.

[0095] For instance, it may be beneficial to combine a Class Id drug with one or more further compounds which affects the permeability of the blood-brain barrier, such that a higher effective dose of the Class Id drug is achieved in the brain. For example, minoxidil can potentiate the effect of a Class Id drug, e.g., ranolazine, by increasing the blood-brain barrier permeability, thereby leading to a more potent effect of the drug on brain cancers. In some embodiments, the further compound potentiates the effect of the Class Id drug by increasing the blood-brain barrier permeability. In some embodiments, the further compound is minoxidil. In some embodiments the Class Id drug is ranolazine and the further compound is minoxidil.

[0096] In additional embodiments, the at least one further substance is selected from a KATP opener, a Kca opener and a Kv opener.

[0097] In additional embodiments, the at least one further substance is selected from the group consisting of amiloride and digoxin, or a combination thereof

[0098] In additional embodiments, the at least one further substance is an epithelial sodium channel (ENaC) blocker.

[0099] In additional embodiments, the at least one further substance comprises is selected from the group consisting of AG1478, gefitinib, erlotinib, afatinib, osimertinib, and dacomitinib, or a combination comprising any two or more thereof

[0100] By "reducing the invasiveness of a cancer", it is intended a significant reduction of the invasiveness of the cancer cells under predetermined conditions, e.g., normoxic or hypoxic conditions. Examples of assays suitable to determine invasiveness are provided elsewhere and are well known to the skilled person. A significant reduction of invasiveness includes, e.g., a reduction by at least about 10 percent, 20 percent or more, such as by at least 30 percent, 40 percent, 50 percent, 60 percent, 70 percent or 80 percent as compared to a control. While the treatment suggestions provided herein reduces invasiveness and metastatic properties of the cancer, it may be preferable that the treatment does not affect the proliferation of the tumour. The proliferation stage often refers to the stage where the cancer increases in the number of cancer cells to form a primary tumour of increasing size, typically with a smooth and well-defined surface.

[0101] The proposed treatment is to use a class Id Vaughan Williams anti arrythmia drug (as the classification has been modified by Lei) as an adjuvant treatment to the standards of care given to patients whose cancers are prone to metastasise into the brain (typically lung, breast, skin (melanoma), colon, kidney and thyroid gland), a pharmaceutically applicable dose of such a drug, provided the same can pass the blood-brain barrier, such treatment typically to be started at or about the time of the diagnosis of cancer (but can be started later) and to be continued for the life of the patient.

[0102] Drugs particularly suitable for this application include e.g.,

[0103] 1. Ranolazine

[0104] 2. Eleclazine (GS6615)

[0105] 3. GS561587 and

[0106] 4. CPD 458967

[0107] The anti-metastatic properties of ranolazine are described in EP3132791B1 which is incorporated herein by reference. Currently prescribed dosages and side effects of ranolazine are described at e.g. internet address www.mayoclinic.org / drugs-supplements / ranolazine- oral-route / side-effects / drg-

[0108] 20069114?p=l#:~:text=Descriptions,or%20lipid%2Dlowering%20 medicines (accessed on 11 October 2023 and 11 October 2024). A typical starter dose would be 500 mg, followed by a twice daily dose of 375-500 mg.

[0109] The anti-metastatic properties of eleclazine are described in EP 3579840B1, which is incorporated herein by reference. Typical doses would be a starter dose of 60mg followed by a daily dose once a day of 3-6mg.

[0110] The properties of ranolazine, eleclazine, GS561597 and CPD 458967 are all described in In embodiments, the drug is administered at a therapeutically effective dose, optionally at a dosage level corresponding to the range 1 pmol to 10 pmol. In particular embodiments, the drug is administered in a dosage level in the range of 1 pmol to 10 pmol.

[0111] Further, the drug may be administered at a dosage from about 1 mg to about 2000 mg, optionally at a dosage from about 1 mg to about 1000 mg and wherein the subject is an adult human patient, such as an adult human patient having a weight in the range of about 50 to about 150 kg.

[0112] As such, the drug may be administered twice daily, once daily, once every two days, once every 3 days, once every 5 days, once every week, once every two weeks, or once monthly, such as once daily.

[0113] In some instances, the drug is administered twice daily at a dose of 100-1000 mg pr. dose to an adult human patient, such as 1000 mg twice daily. As such a suitable dose regimen, may entail administering a starter dose of 375 mg twice daily for a first period and then increase the dose to 500 mg twice daily for a second period. If a patient still experiences symptoms, the dose may be increased further to 750-1000 mg twice daily. As such, the first period may be 2-4 weeks. The second period may be 1 week to several months. Another treatment regimen may entail that the drug is administered twice daily at a dose of 1-10 mg pr. dose to an adult human patient, such as 3-6 mg pr. dose. As such a suitable dose regimen, may entail administering a starter dose of 3 mg for a first period and then increase the dose to 6 mg for a second period. If a patient still experiences symptoms, the dose may be increased further to 10-20 mg. In embodiments, the use comprises administration of a one-time initial boost dose of the drug of from about 5 mg to about 1000 mg, such as 10-100 mg. In some embodiments, the drug is administered over 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 more. Further, the use may entail administration of the drug at a one-time initial boost dose of from about 5 mg to about 100 mg followed by administration of a dosage from about 1 mg to about 20 mg once daily for a period of at least 4 weeks, such as a daily dosage of 3 mg or 6 mg for 6 or 8 weeks.

[0114] It is preferable that the drugs used in the treatment regimen as described herein are drugs which are capable of inhibiting the persistent sodium current in VGSCs, while also being able to cross the blood-brain barrier. Additionally, it is also favourable that the drugs are specific towards Navi.5, Navi.6 and / or Navi.7, with only low or no interaction with other Nav channels, such as e.g., Navi.1-1.4, 1.8 and 1.9. According to Zablocki et al., supra, both ranolazine and eleclazine have properties which inhibit the persistent or long sodium VGSC, pass the blood-brain barrier to some extent and have low interactions with Nav channels other than Navi.5, 1.6 and 1.7 which appear to be the channels primarily associated with metastatic cancers (see Djamgoz et al., supra).

[0115] As can be seen from Zablocki et al., supra, the inhibition of the long sodium current in the VGSC seems to be a property of the class Id Vaughan Williams classification, that most are small molecules which will pass the blood-brain barrier to a sufficient concentration to be effective but they each need to be tested for metabolic side effects, and for a low propensity to interact with Nav 1.1-1.4 and 1.8 and 1.9, otherwise there will be side effects in the central nervous system which make the compound unsuitable for long term usage.

[0116] The current resulting from the VGCS is usually split into two phases, a transient phase lasting for a few milliseconds, followed by the long or persistent phase which is indicated by an impaired inactivation of the channel leading of a current, often lasting up to seconds. This is usually seen in electrophysiological current traces measuring the action potential of cells, where the VGSC traces are observed to have a fast transient sodium current (downward spike), followed by, under normal circumstances, a complete return of the current to the baseline often after 5-10 ms. However, the persistent current as seen from the improper inactivation of the VGSCs is seen by the current not returning to the baseline after 5-10 ms, but rather the current maintains as a persistent current that lasts for 100 ms or more, reflecting the long-lasting increase in a small fraction of sodium current.

[0117] A property of the class Id Vaughan Williams classification drugs is that they effectively block the persistent sodium current, by this it is meant that the drug at least reduces the persistent part of the VGSC current without completely blocking the transient part.

[0118] As such, reducing the persistent current should be understood as a reduction of at least 50%, such as at least 60%, 70%, 80%, or 90%, such as of at least 95%, in the area-under-the- curve in the time after the transient current, i.e., 10ms after stimulation, such as for instances in an 20-200 ms time frame. On the other hand, the drug should not completely block the transient part of the current, with this it is intended that the drug should still allow for a substantial transient current, i.e., in the 0-10 ms timeframe after stimulation, such as e.g., at least 10% of the transient current, preferably more than 50% of the transient current, such as 10%-100% of the transient current.

[0119] In view of Zablocki et al., supra, eleclazine, GS561587 and CPD 458967 have the necessary properties to be effective inhibitors of metastasis without undesirable side effects, and ranolazine also has this effect. It is preferable that the treatment comprises administration of one or more of ranolazine, eleclazine, GS561587 and CPD 458967. In embodiments, the drug is selected from the group consisting of ranolazine, eleclazine, GS561587 and CPD 458967. In additional embodiments, the Vaughan Williams Class Id anti-arrythmia drug is ranolazine or eleclazine.

[0120] The time from diagnosis to treatment initiation varies from country to country, and can be from a few days to several months, depending on the complexity of the selected standard-of- care treatment, the overall waiting time in the specific healthcare system, and the complexity of the cancer. For instance, glioblastoma patients may have to wait for several weeks to months from diagnosis to surgery, which may lead to additional invasion of the brain by the tumour and worsening of the patient in the time from diagnosis to surgery.

[0121] As used herein, the term "standard-of-care" or "standard-of-care treatment" refers to the treatment that is generally accepted by medical experts as a proper treatment for a certain type of disease and that is widely used by health care professionals.

[0122] Due to this waiting time, several patients show a progression in the disease state, especially for more aggressive cancer types, resulting a worsening in the prognosis of the patient.

[0123] Accordingly, it is imperative that the treatment is initiated as soon as possible.

[0124] The treatment as provided by the present disclosure enables early treatment without the need for elaborate and lengthy diagnostic procedures before treatment initiation, since it generally relates to a tablet which may be taken orally once or twice daily without requiring complex interventions, which may suffer from delays due to lack of hospital capacity for e.g., surgery or radiation treatment. As such the treatment provided herein can reduce the consequences of extending the time from first diagnosis to complex intervention since it inhibits the progression of the cancer, compared to the progression in the absence of the herein provided treatment.

[0125] For this reason the treatments proposed herein using the Vaughan Williams Class Id anti- arrythmia drugs for the treatment are especially beneficial, since the treatment can be initiated immediately after diagnosis, without having to wait for more complex treatment paradigms to be initiated. Particular benefits includes that the dosages and treatment regimens for these types of drugs, such as e.g., ranolazine are well known, and only presents modest side effects compared to radiation therapy or chemotherapy. While the ability of the Vaughan Williams Class Id anti-arrythmia drugs to inhibit metastasis and invasiveness of some cancers, the ability of some of these compounds to cross the blood-brain barrier opens up for several new uses of these drugs in treatment of brain specific cancers, as described herein.

[0126] Therefore, when a patient is diagnosed with a cancer that is known to form brain metastases, it may be beneficial to administer one or more of the Vaughan Williams Class Id anti- arrythmia drugs, in particular ranolazine, eleclazine, GS561587 or CPD 458967, even before brain metastases are identified, in order to reduce the invasiveness and further metastasis of unidentified brain metastases. In some embodiments, the drug is ranolazine, eleclazine, GS561587 or CPD 458967.

[0127] As used herein, "treating" or "treatment" of a brain cancer includes, but is not limited to, reducing metastatic behaviour of a brain cancer, preventing metastatic behaviour of a brain cancer, reducing pain sensation, reducing the invasiveness of a brain cancer, preventing invasiveness of a brain cancer, reducing the overall aggressiveness of the brain cancer, or any combination thereof. So, in separate and specific embodiments, a method of treatment according to the disclosure may (i) reduce metastatic behaviour of the brain cancer, (ii) prevent metastatic behaviour of the brain cancer, (iii) reduce pain sensation in a patient suffering from the brain cancer, (iv) reduce the invasiveness of the brain cancer, or (v) prevent invasiveness of the brain cancer, or may comprise a combination of two or more of (i) to (v).

[0128] By "reducing metastatic behaviour" of cancer, it is intended a reduction of any behaviour associated with the movement of detached cancer cells through the circulation (blood or lymph) to accumulate and / or create secondary tumours in other organs or locally invade surrounding tissues. Typically, the patient is in Stage 2, 3 or 4, such as in stage 3 or 4. Reducing metastatic behaviour may, for example, include one or more of (i) reducing transcription, translation and / or expression of particular splice variants such as the neonatal and / or adult VGSCs (e.g., Navi.5) in cancer cells as compared to a control; (ii) reducing cancer cell invasiveness; (iii) reduce peak VGSC current density in cancer cells; (iv) reduce the proportion of cancer cells demonstrating VGSC currents; (v) reducing cancer cell motility (e.g., reduced lateral motility), (vi) reducing cancer cell migration (e.g., transverse migration), and (vii) reducing the persistent part of the VGSC current without eliminating the transient part. The VGSC may, for example, be Navi.5, such as the neonatal variant denoted nNavl.5. "Motility" reflects the ability of the tumour cells to initially move to and through the basement membrane into the surrounding tissue; "invasiveness" of the cells reflects the ability of tumour cells which have entered the surrounding tissue to move through that tissue towards the circulation system; and "migration" reflects the ability of the tumour cells to migrate from that tissue into the circulatory system via the walls thereof. By "preventing metastatic behaviour" of cancer, it is intended to refer prophylactic treatment of a cancer patient at risk for, but not yet diagnosed with, a metastatic disease, so as to prevent or reduce the risk for a metastatic behaviour of the cancer as described above. Typically, the patient is in Phase 1, 2 or 3. Preventing metastatic behaviour may, for example, include preventing or reducing the expression of a VGSC, e.g., one or more of Nav(s) in adult and / or neonatal form, such as nNavl.5. The terms "phase" and "stage" is herein used interchangeably.

[0129] By "reducing the overall aggressiveness of a cancer", it is intended a reduction of any behaviour associated with the progression of cancer, in quantitative or qualitative terms. In some embodiments, reducing the aggressiveness of a cancer refers to the reversal of a cancer in any one of Phase 3, 4 or 5 to a lower-number phase, including, but not limited to, from Phase 3 to Phase 2 or lower, from Phase 4 to Phase 3 or lower, and from Phase 5 to Phase 4 or lower. In some embodiments, reducing the aggressiveness of a cancer refers to the reversal of a cancer or tumour in a malignant state to a cancer or tumour in a benign state. In some embodiments, by "reducing the overall aggressiveness of a cancer", it is intended a reduction of a cancer to non-metastatic but not necessarily non-invasive state. By "reducing the invasiveness of a cancer", it is intended a significant reduction of the invasiveness of the cancer cells under predetermined conditions, e.g., normoxic or hypoxic conditions.

[0130] Commonly cancers are divided into five different stages. In stage 0 abnormal cells are present but have not spread to nearby tissue. In stage 1-3 cancer is present and the higher the number, the larger the tumour and the more it has spread into nearby tissues. Normally stage 3 is where the cancer is characterized as invasive cancer, which have often spread to the local tissue (invasion), but where the cancer has not yet spread to, or is not identified in distal parts of the body. Stage 4 is the final stage where the cancer has metastasized to distal parts of the body. Normally the stage is determined as a part of the diagnosis, and is often determined by a combination of several analyses, including but not limited to blood tests, blood counts, cytogenetic analyses, immunophenotyping, liquid biopsies, biomarker analysis, CT scans, X-ray scans, MRI, PET scans, ultrasound and the like.

[0131] As is also disclosed herein, it has previously been found that e.g., ranolazine can reduce the invasiveness and metastatic ability of certain cancers. The realization that compounds such as Ranolazine can enter the brain in a therapeutically relevant amount by crossing the bloodbrain barrier is a remarkable step forward for the treatment of advanced cancers with brain metastases, since it allows for a treatment which effectively inhibits the further development of the cancer. As used herein the term "metastatic brain cancer" refer to a cancer which has spread from the peripheral system, such as from lung or prostate into the central nervous system, in particular into the brain and established one or more tumours in the CNS, preferably in the brain.

[0132] In embodiments, the treatment as disclosed herein is provided to stage 3 cancer patients. In other embodiments, the treatment as disclosed herein is provided to stage 4 cancer patients. In additional embodiments, the treatment as disclosed herein is provided to stage 4 cancer patients diagnosed with brain metastases. In additional embodiments, the treatment as disclosed herein is provided to stage 4 cancer patients not diagnosed with brain metastases.

[0133] In some cases, the treatment can be provided in stage 1 or 2 cancer patients diagnosed with a cancer known for being aggressive or invasive, such as e.g., lung cancer, colorectal cancer, breast cancer, pancreatic cancer or prostate cancer. In some embodiments, 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.

[0134] In other cases, where brain metastases or primary brain tumours are identified, it may also be beneficial to initiate the treatment with one or more of the Vaughan Williams Class Id anti-arrythmia drugs, in particular ranolazine, eleclazine, GS561587 or CPD 458967, immediately after diagnosis, in order to reduce the invasiveness of the tumours. As such the administration of the Vaughan Williams Class Id anti-arrythmia drugs, in particular ranolazine, eleclazine, GS561587 or CPD 458967, can be said to place the tumours in a stasis, where the ability of the tumour to invade surrounding tissues and become metastatic is reduced or abolished.

[0135] Suitable patients include mammalian patients, such as humans, monkeys, rabbits, dogs, cats, cows, horses, pigs, mice and rats, suffering from cancer. Preferably, the patient is a human patient, such as an adult human patient. Typically, such an adult human patient may have a weight in the range of about 50 to about 150 kg, such as about 60 to about 100 kg, such as about 70 kg. The terms "subject" and "patient" is herein used interchangeably.

[0136] In some embodiments, the patient is suffering from a VGSC-expressing cancer. A VGSC- expressing cancer may, for example, be identified by immunohistochemical or analysis of a cancer cell-containing sample (such as a tumour biopsy or blood sample) obtained from the patient, using detectable monoclonal or polyclonal antibodies specific for one or more VGSCs to detect the expression of a VGSC on the cancer cells. The VGSC-expressing cancer may particularly comprise VGSCs comprising splice-variants of Navi.5, Navi.6 and / or Navi.7, optionally a neonatal splice variant such as nNavl.5. In some embodiments, the patient / subject treated according to the present disclosure has been diagnosed with angina, such as chronic angina. For example, the patient may have been diagnosed with an International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code for angina. In some embodiments, the patient / subject treated according to the present disclosure has not been diagnosed with angina, such as chronic angina.

[0137] In some embodiments, the patient / subject treated according to the present disclosure has not earlier been prescribed a Class Id drug, e.g., has not earlier been prescribed ranolazine.

[0138] In some embodiments, the patient / subject treated according to the present disclosure has earlier been prescribed a Class Id drug, e.g., has earlier been prescribed ranolazine.

[0139] Typically, the drugs as referred to herein are formulated as a pharmaceutical composition, for administration by any suitable route to a subject, including, but not limited to, oral, buccal, sublabial, sublingual, rectal, intravenous, subcutaneous, intradermal, intramuscular, transdermal and intranasal administration and / or direct administration to a tumour, such as a primary tumour.

[0140] Accordingly, the drugs as mentioned herein can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the tumour or cancer to be treated. Sustained-release systems may also be used, particularly so as to release the substance(s) over a prolonged period of time. Delivery can also be performed by local (e.g., intra-tumoral) or systemic administration of a composition, such as a pharmaceutical composition, comprising the selected Vaughan Williams Class Id anti- arrythmia drug.

[0141] As such, the drug may be administered in any suitable manner known to the skilled person. It is however preferred that the drug is administered in a form which allows for the drug to effectively be distributed to the brain, without having to provide the drug via intraspinal or intrathecal injection.

[0142] Accordingly, in some embodiments, the drug is for enteral, such as oral, administration. In other embodiments, the drug is for parenteral administration, such as intravenous (i.v.) injection or infusion. In further embodiments, the drug is provided for administration in combination with at least one further substance. EXAMPLES

[0143] EXAMPLE 1 - Mortality of Patients Diagnosed with Cancer After Prior Ranolazine Treatment

[0144] The aim of the present study was to examine the overall progression-free survival among patients with a diagnosis for angina pectoris and receiving ranolazine which develop select cancers of interest after initiation of ranolazine.

[0145] Methods

[0146] For the present study, patient data was retrieved from the TriNetX electronic health records (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), containing healthcare information from more than 110 million patients, and subsequently analysed.

[0147] The main objective of the study was to examine the overall and progression free survival among patients with a ranolazine prescription that develop select cancers of interest (triple negative breast cancer, castration-resistant prostate cancer, BCR (biochemical recurrence) prostate cancer, glioblastoma, colon cancer, lung cancer, pancreatic cancer) after initiation of ranolazine.

[0148] Firstly, all patients with at least one prescription for ranolazine was identified. After applying selection criteria detailed in below, all eligible patients were classified into the overall ranolazine cohort. The date of the first ranolazine prescription was defined as the index date for the overall cohort. A 6-month period prior to the index date (ending on index date-1) was defined as the pre-index period. For survival outcomes, the patients were followed up through the end of the follow-up or death.

[0149] Those among the overall cohort who subsequently developed any of the cancers of interest (with no prior cancer diagnoses during baseline) were identified. The overall survival and progression free survival outcomes were examined in the both the overall ranolazine cohort and the cohort of angina patients who developed cancer.

[0150] The inclusion criteria for the patients included present study were:

[0151] 1. Patients with evidence of prescription for ranolazine during the selection window

[0152] 2. Patients >18 years old on the index ranolazine prescription 3. Patients with the select cancer of interest (first diagnosis of cancer after the first ranolazine prescription will be termed as the index cancer diagnosis)

[0153] The exclusion criteria for the patients included present study were:

[0154] 4. Patients with prior use of ranolazine during the 6 months before first ranolazine prescription

[0155] 5. Patients with any prior diagnosis of any cancer or chemotherapy during the 6 months prior to the index cancer diagnosis

[0156] 6. Patients with New York Heart Association (NYHA) Class IV heart failure during the 4 weeks prior to the index cancer diagnosis

[0157] 7. Patients with known left ventricular ejection fraction (EF) < 45% during the 4 weeks prior to the index cancer diagnosis

[0158] 8. Patients with evidence of lidocaine administered for local anaesthesia during the 4 weeks prior to the index cancer diagnosis

[0159] The study was concluded after a five year follow up period, where the cancer progression and overall mortality was evaluated across all the indicated cancers (N = 65,000).

[0160] Results

[0161] In the present study, cancer progression and cancer mortality five years after diagnosis of cancer was evaluated, comparing cancer patients prescribed ranolazine to a matched control cohort of cancer patients not prescribed ranolazine.

[0162] When looking at the large cancer cohort from the cancers indicated above there was a 42% reduction in overall mortality in the ranolazine patient group compared to the control group (see Fig. 4). (p-value <0.0001, n = 65.000), across all cancer types.

[0163] Accordingly, the present study supports that treatment with ranolazine significantly improves the prognostic outcome for the patients, towards a reduced mortality of the patients who received ranolazine. EXAMPLE 2 - Metastases in Lung Cancer Patients Following Ranolazine Administration

[0164] Methods

[0165] For the present study, patient data was retrieved from the TriNetX electronic health records (EHR) database and subsequently analysed, as described in Example 1.

[0166] The main objective of the study was to examine the overall and progression free survival among patients with receiving ranolazine following diagnosis with selected cancers of interest (triple negative breast cancer, castration-resistant prostate cancer, BCR prostate cancer, glioblastoma, colon cancer, lung cancer, pancreatic cancer).

[0167] Firstly, all patients with at least one prescription for ranolazine was identified. After applying selection criteria detailed in below, all eligible patients were classified into the overall ranolazine cohort. The date of the initial cancer diagnosis was defined as the index date for the overall cohort. A 6-month period prior to the index date (ending on index date-1) was defined as the pre-index period.

[0168] In the present study, the included patients were diagnosed with a cancer of interest (breast-, lung-, colon-, prostate- and pancreatic cancer) up to 2 years prior to their first ranolazine prescription (N = 5,400).

[0169] Inclusion criteria

[0170] 1. Patients with evidence of prescription for ranolazine during the selection window

[0171] 2. Patients >18 years old on or before the first ranolazine prescription

[0172] 3. Patients with the select cancer of interest during the 24 months prior to the first ranolazine prescription (first diagnosis of cancer during this period will be defined as index cancer diagnosis).

[0173] Exclusion criteria

[0174] 4. Patients with any prior diagnosis of any cancer diagnosis or chemotherapy during the 24 months prior to the index cancer diagnosis

[0175] 5. Patients with prior use of ranolazine during the 6 months before first ranolazine prescription

[0176] 6. Patients with New York Heart Association (NYHA) Class IV heart failure during the 4 weeks prior to the index cancer diagnosis 7. Patients with known left ventricular ejection fraction (EF) < 45% during the 4 weeks prior to the index cancer diagnosis

[0177] 8. Patients with evidence of lidocaine administered for local anaesthesia during the 4 weeks prior to the index cancer diagnosis

[0178] The study was concluded after a five year follow up period, where the cancer progression was evaluated across all the indicated cancers (N = 5400), while the progression to metastatic cancer and metastatic brain cancer was evaluated for a lung cancer subcohort (N = 200).

[0179] Results

[0180] The effects of ranolazine treatment after an initial cancer diagnosis was evaluated in a cohort of 5,400 patients, with different cancer types, while the progression into metastatic cancer and metastatic brain cancer was evaluated for a subcohort of lung cancer patients (N = 200).

[0181] Firstly, it was evaluated if there was a change in cancer progression in the cohort of patients containing breast-, lung, colon-, prostate and pancreatic cancer patients, who had been diagnosed with cancer before onset of first ranolazine treatment.

[0182] As can be seen from Fig. 5, the cohort of cancer patients prescribed ranolazine after being diagnosed with cancer had a 37% reduced cancer progression in general compared to control arm. (p-value <0.0001, n = 5.400).

[0183] The cohort was split into a subcohort for lung patients (N = 200) to analyse general metastasis or brain metastasis five years after diagnosis of lung cancer, comparing patients prescribed ranolazine after the cancer diagnosis to a control cohort of lung cancer patients who had not been prescribed ranolazine.

[0184] It was found that lung cancer patients prescribed ranolazine after being diagnosed with lung cancer had a 29,6% reduced risk of developing metastasis in general within 5-years after being diagnosed as compared to control arm. (p-value = 0,0304, n=200). The results are also shown in Fig. 6, showing that about 33% of the patients developed metastasis, while only about 24% of the ranolazine treated patients developed metastases.

[0185] Additionally, with respect to brain metastasis, as is also shown in Fig. 7, it was observed that lung cancer patients who started taking ranolazine after cancer diagnose had a 45,3% reduced risk of developing brain metastasis in general within 5-years after being diagnosed compared to control arm. (p-value = 0,0979, n = 200), where about 12% of the patients in the control group developed brain metastases, while only about 6.5% of the patients developed brain metastases within the 5-year period.

[0186] EXAMPLE 3 - Prevention of Invasiveness in Glioblastoma Patients Following Ranolazine Treatment

[0187] Methods

[0188] For the present study, patient data is retrieved from the TriNetX electronic health records (EHR) database.

[0189] The main objective of the study is to examine the overall and progression free survival among patients with a diagnosis for angina pectoris and receiving ranolazine following diagnosis with glioblastoma.

[0190] Firstly, all patients with at least one prescription for ranolazine was identified. After applying selection criteria detailed in below, all eligible patients were classified into the overall ranolazine cohort. The date of the first ranolazine prescription is defined as the index date for the overall cohort. A 12-month, 24-month, 36-month, 48-month or 60-month period prior to the index date (ending on index date-1) is defined as the pre-index period.

[0191] In the present study, the included patients are diagnosed with glioblastoma up to 2 years prior to their first ranolazine prescription.

[0192] Inclusion criteria

[0193] 1. Patients with evidence of angina diagnosis during the selection window.

[0194] 2. Patients with evidence of prescription for ranolazine during the selection window on or after the first angina diagnosis

[0195] 3. Patients >18 years old on or before the first ranolazine prescription

[0196] 4. Patients with glioblastoma during the 12 months prior to the first ranolazine prescription (first diagnosis of cancer during this period will be defined as index cancer diagnosis)

[0197] Exclusion criteria

[0198] 1. Patients with any prior diagnosis of any cancer diagnosis or chemotherapy during the 12 months prior to the index cancer diagnosis 2. Patients with prior use of ranolazine during the 6 months before first ranolazine prescription

[0199] 3. Patients with New York Heart Association (NYHA) Class IV heart failure during the 4 weeks prior to the index cancer diagnosis

[0200] 4. Patients with known left ventricular ejection fraction (EF) < 45% during the 4 weeks prior to the index cancer diagnosis

[0201] 5. Patients with evidence of lidocaine administered for local anaesthesia during the 4 weeks prior to the index cancer diagnosis

[0202] Results

[0203] In the present ongoing study, the invasiveness of glioblastomas and long-term survival of glioblastoma patients are evaluated, comparing patients prescribed ranolazine prior to being diagnosed with glioblastoma and continued after diagnosis with a control matched cohort not prescribed ranolazine prior or subsequent to glioblastoma diagnosis.

[0204] The main goal of the study is to evaluate whether ranolazine treatment initiated after a glioblastoma diagnosis can reduce or prevent invasiveness of the cancer, the long-term survival of the glioblastoma patients, or both, as compared to the control group.

[0205] The outcome is the identification of an increased long-term survival of glioblastoma patients treated with ranolazine as compared to the control group.

[0206] Another outcome is the identification of a reduced invasiveness of the glioblastoma in patients who had undergone treatment with ranolazine as compared to the control group.

[0207] SPECIFIC EMBODIMENTS

[0208] 1. A drug selected from the class of Vaughan Williams Class Id anti-arrythmia drugs (as modified by Lei) to effectively block the persistent sodium current while allowing the transient sodium current to pass, and which can pass the blood-brain barrier and which interacts with

[0209] 1 or more of Nav 1.5, 1.6 and 1.7.

[0210] 2. A drug which is a class Id Vaughan Williams anti-arrythmia drug capable of reducing the late Na+current (INaL) of voltage-gated sodium channel (Nav) 1.5, 1.6, or 1.7, or any combination of two or more thereof, for use in a method of preventing, reducing the risk of, or treating, brain metastases in a subject suffering from cancer. 3. The drug for the use of item 2, which drug is capable of passing the blood-brain- barrier, optionally capable of passing the blood-brain-barrier in an effective amount to prevent, reduce the risk of, or treat, brain metastases.

[0211] 4. The drug for the use of any one of items 2 and 3, wherein the cancer is a cancer prone to metastasising to the brain.

[0212] 5. The drug for the use of item 4, wherein the cancer is selected from lung cancer, breast cancer, skin cancer (melanoma), colon cancer, kidney cancer and thyroid cancer.

[0213] 6. The drug for the use of any one of items 2 to 5, wherein the subject is diagnosed with the cancer.

[0214] 7. The drug for the use of any one of items 2 to 6, wherein the subject is selected for, optionally undergoing, a standard-of-care treatment for the cancer.

[0215] 8. The drug for the use of any one of items 2 to 7, wherein the standard-of-care treatment comprises administration of at least one chemotherapeutic or immunotherapeutic drug which cannot pass the blood-brain-barrier, optionally cannot pass the blood-brain- barrier in an effective amount to prevent, reduce the risk of, or treat, brain metastases.

[0216] 9. The drug for the use of any one of items 2 to 7, wherein the standard-of-care treatment comprises at least one of surgery and radiotherapy.

[0217] 10. The drug for the use of any one of items 2 to 9, wherein the use is in a method of preventing brain metastases, optionally wherein the subject has not been diagnosed with a brain metastasis.

[0218] 11. The drug for the use of any one of items 2 to 9, wherein the use is in a method of reducing the risk of brain metastases, optionally wherein the subject has not been diagnosed with a brain metastasis.

[0219] 12. The drug for the use of any one of items 2 to 9, wherein the use is in a method of treating brain metastases, optionally wherein the subject has been diagnosed with at least one brain metastasis.

[0220] 13. The drug for the use of any one of items 2 to 12, which drug is ranolazine. 14. The drug for the use of any one of items 2 to 12, which drug is eleclazine (GS6615).

[0221] 15. The drug for the use of any one of items 2 to 12, which drug is GS561587.

[0222] 16. The drug for the use of any one of items 2 to 12, which drug is CPD 458967.

[0223] 17. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is ranolazine, eleclazine GS561587, or CPD 458967, b) the drug is administered orally once or twice daily at a dosage of 1-1000 mg pr. dose, and c) the subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer.

[0224] 18. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is ranolazine, b) the drug is administered orally twice daily at a dosage of 100-1000 mg pr. dose, and c) the subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer.

[0225] 19. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is eleclazine, b) the drug is administered orally daily at a dosage of 1-20 mg pr. dose, c) the subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer.

[0226] 20. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is GS561587, b) the drug is administered orally daily at a dosage of 1-100 mg pr. dose, c) the subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer. 21. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is CPD 458967, b) the drug is administered orally daily at a dosage of 1-100 mg pr. dose, c) the subject is an adult human patient diagnosed with cancer, such as glioblastoma or lung cancer.

[0227] 22. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, 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.

[0228] 23. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, 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 subject is an adult human patient diagnosed with lung cancer.

[0229] 24. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, 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 subject is an adult human patient diagnosed with glioblastoma.

[0230] 25. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is ranolazine, b) the drug is administered orally twice daily at a dosage of 100-1000 mg pr. dose, and c) the subject is an adult human patient diagnosed with lung cancer. 26. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is ranolazine, b) the drug is administered orally twice daily at a dosage of 100-1000 mg pr. dose, and c) the subject is an adult human patient diagnosed with metastatic brain cancer.

[0231] 27. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is ranolazine, b) the drug is administered orally twice daily at a dosage of 100-1000 mg pr. dose, and c) the subject is an adult human patient diagnosed with glioblastoma.

[0232] 28. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is eleclazine GS561587, or CPD 458967, b) the drug is administered orally once daily at a dosage of 1-100 mg, and c) the subject is an adult human patient diagnosed with lung cancer.

[0233] 29. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is eleclazine GS561587, or CPD 458967, b) the drug is administered orally once daily at a dosage of 1-100 mg, and c) the subject is an adult human patient diagnosed with glioblastoma.

[0234] 30. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject, wherein a) the drug is eleclazine GS561587, or CPD 458967, b) the drug is administered orally once daily at a dosage of 1-100 mg, and c) the subject is an adult human patient diagnosed with metastatic brain cancer.

Claims

CLAIMS1. A blood-brain barrier permeable drug selected from the group consisting of Vaughan Williams Class Id anti-arrythmia drugs for use in treating an invasive and / or metastatic brain cancer in a subject.

2. The blood-brain barrier permeable drug for use according to claim 1, wherein the treatment reduces the invasiveness of the cancer.

3. A blood-brain barrier permeable drug selected from Vaughan Williams Class Id anti- arrythmia drugs for use in preventing the occurrence of invasive and / or metastatic brain cancer in a subject.

4. The blood-brain barrier permeable drug for use according to any one of claims 1-3, wherein the drug is selected from the group consisting of ranolazine, eleclazine, GS561587 and CPD 458967.

5. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the invasive brain cancer is glioblastoma, neuroblastoma or astrocytoma.

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

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

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

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

10. The blood-brain barrier permeable drug for use according to any one of claims 1-8, wherein the drug is provided together with a standard-of-care treatment for the cancer.

11. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the standard-of-care treatment comprises administration of at least one chemotherapeutic and / or immunotherapeutic.

12. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the standard-of-care treatment comprises surgery and / or radiotherapy.

13. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the administration of the drug improves the life expectancy of the subject.

14. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the administration of the drug is initiated at least 1 month before the initiation of the standard-of-care treatment, such as at least 2 months, 3 months, 4 months, 5 months or such as at least 6 months before initiation of the standard-of-care treatment.

15. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the cancer is a tumorigenic cancer, and the treatment reduces motile cell formation in the tumour and / or tumour cell migration from the tumour.

16. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the treatment reduces the invasiveness of said cancer without killing the tumour cells.

17. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the treatment reduces the invasiveness of said cancer without substantially affecting proliferation of the cancer cells.

18. The blood-brain barrier permeable drug 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. The blood-brain barrier permeable drug 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. The blood-brain barrier permeable drug for use according to any one of claims 1-18, wherein the subject (i) has not been diagnosed with angina, (ii) has not been prescribedranolazine, or (Hi) has not been diagnosed with angina and has not been prescribed ranolazine prior to any cancer diagnosis.

21. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the drug is administered at a therapeutically effective dose.

22. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the drug is administered at a dosage level in the range of 1 pmol to 10 pmol.

23. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the drug is administered at a dosage from about 1 mg to about 2000 mg, optionally at a dosage from about 1 mg to about 1000 mg and wherein the subject is an adult human patient, such as an adult human patient having a weight in the range of about 50 to about 150 kg.

24. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the drug is administered twice daily, once daily, once every two days, once every 3 days, once every 5 days, once every week, once every two weeks, or once monthly, such as once daily.

25. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the drug is administered twice daily at a dose of 500-1000 mg pr. dose to an adult human patient, such as 750 mg twice daily.

26. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the drug is administered over 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 more.

27. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the use comprises administration of a one-time initial boost dose of the drug of from about 10 mg to about 100 mg.

28. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the use comprises administration of the drug at a one-time initial boost dose of from about 10 mg to about 100 mg followed by administration of a dosage from about 1 mg to about 20 mg once daily for a period of at least 4 weeks, such as a daily dosage of 3 mg or 6 mg for 6 or 8 weeks.

29. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the drug is for oral administration.

30. The blood-brain barrier permeable drug for use according to any one of the preceding claims, wherein the drug is for parenteral administration, such as intravenous (i.v.) injection or infusion.

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

32. The blood-brain barrier permeable drug for use according to claim 30, wherein the at least one further substance is selected from the group consisting of minoxidil, aprikalim, bimakalim, cromakalim, diazoxide, emakalim, levcromakalim, mazokalim, naminidil, nicorandil, pinacidil, pilmakalim, sarakalim, tolfenamic acid, lupirtine, retigabine, riluzole, NS1619, NS11021, benzo imidazolone 1-EBIO, rottierin, retigabine, or a combination comprising any two or more thereof.

33. The blood-brain barrier permeable drug for use according to claim 31 or 32, wherein the at least one further substance is selected from a KATP opener, a KCaopener and a Kv opener.

34. The blood-brain barrier permeable drug for use according to any one of claims 31-33, wherein the at least one further substance is selected from the group consisting of amiloride and digoxin, or a combination thereof.

35. The blood-brain barrier permeable drug 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. The blood-brain barrier permeable drug for use according to any one of claims 31-35, wherein the at least one further substance comprises is selected from the group consisting of AG1478, gefitinib, erlotinib, afatinib, osimertinib, and dacomitinib, or a combination comprising any two or more thereof.

37. A prophylactic use of a Vaughan Williams Class Id anti-arrythmia drug for reducing the risk of brain metastasis in cancer patients, such as in particular lung cancer patients.

38. A method for reducing the invasiveness of a brain tumour, comprising administration of an efficient amount of a Vaughan Williams Class Id anti-arrythmia drug.

39. A method for reducing the risk for an invasive and / or metastatic brain cancer in a subject comprising administering a therapeutically effective amount of a Vaughan Williams Class Id anti-arrythmia drug to a subject not diagnosed with an invasive and / or metastatic brain cancer, thereby reducing the risk for an invasive and / or metastatic brain cancer in a subject.

40. The method according to claim 39, wherein the Vaughan Williams Class Id anti- arrythmia drug is ranolazine or eleclazine.

41. The method according to 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 according to claim 39 or 40, wherein the subject (i) has not been diagnosed with angina, (ii) has not been prescribed ranolazine, or (iii) has not been 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 according to 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 at 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 an oncovirus, ionizing radiation, or other group 1 cancer carcinogens.

46. A method for reducing cellular migration and / or reduce motile formation from a brain tumour in a subject comprising administering a therapeutically effective dose of a Vaughan Williams Class Id anti-arrythmia drug.

47. The method according to claim 46, wherein the drug is ranolazine, eleclazine,GS561587 or CPD 458967.

48. A drug selected from ranolazine or eleclazine for use in treating an 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 dosage of 1-1000 mg per dose.

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