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(12) Patent Application Publication (10) Pub. No.: US 2013/0184218 A1 Paul Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0184218 A1 Paul Et Al US 2013 O184218A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0184218 A1 Paul et al. (43) Pub. Date: Jul.18, 2013 (54) TARGETEDOSMOTIC LYSIS OF CANCER (52) U.S. Cl. CELLS CPC ............. A6 IK3I/7048 (2013.01); A61K 45/06 (2013.01); A61N I/36 (2013.01) (76) Inventors: Dennis J. Paul, New Orleans, LA (US); USPC ............ 514/17.4: 514/26: 514/279; 514/450; Harry J. Gould, New Orleans, LA (US) 514/171; 514/216:514/729; 514/460, 514/366; 514/521: 514/511; 514/456; 607/116 (21) Appl. No.: 13/552,909 (57) ABSTRACT A targeted osmotic lysis (TOL) of tumor cells that over express Voltage-gated sodium channels (VGSCs) has been (22) Filed: Jul.19, 2012 developed that uses a combined therapy of a drug that blocks Sodium, potassium-adenosine triphosphatase (Na', K"-AT Related U.S. Application Data Pase) that is then followed by an activation of VGSCs, for example, by electrical or pharmacological stimulation. Acti (60) Provisional application No. 61/510,258, filed on Jul. vation of VGSCs conducts sodium into the cancer cells in 21, 2011. much greater amounts than non-cancer cells. Water follows this sodium gradient into the cancer cells, causing Swelling and lysis. Because non-cancerous cells do not over-express Publication Classification VGSCs, less sodium and less water will enter the cells, and the non-cancerous cells will not lyse. This method is appli (51) Int. Cl. cable to all cells that over-express VGSCs, including, but not A6 IK3I/7048 (2006.01) limited to, highly invasive breast cancer, prostate cancer, A6 IN L/36 (2006.01) Small cell lung cancer, non-small cell lung carcinoma, lym A6 IK 45/06 (2006.01) phoma, mesothelioma, neuroblastoma, and cervical cancer. Patent Application Publication Jul.18, 2013 Sheet 1 of 2 US 2013/O184218-A1 140 120 100 8 O 6 O 4 O 2 O Control Ouabain Veratridine Ouabain (100nM) (30nM) VeratridineH Fig. 1 Patent Application Publication Jul.18, 2013 Sheet 2 of 2 US 2013/O184218-A1 500 -o- saline-No stim I G. Saline-Stim o CD ---V-- Ouabain-No Stim O E 01 - ... v. - Ouabain-stim s O ---" 300 ?o-y- / - y - V - O... " 1. V i 200 ass' 4.---v---y-...-v- y --v 1 1. 9 2.2 -- -...-V-V--W- -V/ - 100 6-V O 5 10 15 2O Days Post-treatment Fig. 2 US 2013/0184218 A1 Jul. 18, 2013 TARGETEDOSMOTICLYSIS OF CANCER 170,000 U.S. women diagnosed with invasive breast cancer CELLS are Successfully treated with traditional mastectomy, lumpec tomy, chemotherapy and/or radiation. Of the 207,000 people 0001. The benefit of the filing date of provisional U.S. contracting breast cancer each year, 40% of the cancers are application Ser. No. 61/510,258, filed Jul. 21, 2011, is considered to be “highly invasive’, and over-express VGSCs claimed under 35 U.S.C. S 119(e) in the United States and is (10). claimed under applicable treaties and conventions in all coun 0006. The family of sodium channels named “voltage tries. gated Sodium channels' was so designated due to the sensi TECHNICAL FIELD tivity to Small changes (>40 mV.) in the Voltage gradient across the cellular membrane. They have also been shown to 0002 This invention pertains to a method to target cancer be activated by many forms of stimulation mechanical dis cells that over-express Voltage-gated sodium channels (VG turbances in the membrane, ultrasound (29), magnetic fields SCs or “sodium channels') and to cause osmotic lysis of these (29), and several drugs. There are nine members of the VGSC cancer cells by initially inhibiting the Sodium, potassium family, with variants of many of the isoforms. They are des adenosine triphosphatase (Na', K"-ATPase or “sodium ignated Na1.X., where X represents 1-9. Subtypes are desig pump'), and then stimulating the VGSCs to cause sodium and nated with a letter a, b, etc. water to enter the cancer cells. 0007 Na', K"-ATPase is a ubiquitous transmembrane protein in animal cells, and functions to maintain an ion BACKGROUND ART imbalance across the cell membrane where more charged ions are located outside of the cell, largely sodium ions, than 0003 Chemotherapy and radiotherapy of metastatic can inside. This produces an electrochemical gradient that is in cer, because of toxicity to both normal and abnormal tissues, homeostatic balance. When ionic imbalance shifts in the pres present the clinician with the difficult challenge of trying to ence of a change in Voltage an action potential is generated kill the neoplastic disease before killing the patient; a balance causing a transient osmotic shift toward an intracellular between treatment and rescue. All traditional cancer treat hypertonic state. The restoration of the sodium imbalance is ments are associated with toxicity, an increase in morbidity, an essential function performed by Na', K"-ATPase. When and a reduction in quality of life that may extend far beyond Na', K"-ATPase does not function properly, water follows the period of treatment. A major focus of current anti-neo sodium into the cell to restore osmotic balance thereby plastic treatments is targeting treatment to the cancer cells, for increasing cell volume. In normal cells this shift in cell vol example, targeting proteins expressed or over-expressed by umeistolerated due to membrane compliance. Blocking Na", cancer cells, but not by normal tissue. K"-ATPase function can lead to a loss of cellular excitability 0004. Many invasive cancer cell types over-express volt and an increase in cellular volume. Many inhibitors are age-gated Sodium channels (VGSCs; or “sodium channels’) known, including the cardiac glycosides. The isozymes vary by more than 1000-fold greater than normal cells (1, 2, 7). in their sensitivity to each of the cardiac glycoside drugs. Cancer cells that over-express VGSCs are epithelial carcino More than 30 drugs have been shown to inhibit sodium pump mas that include, but are not limited to, highly invasive breast activity. These include ouabain, digitalis and its active ingre cancer (4, 10, 13,27), prostate cancer (2,6,7,8, 18, 19, 20, 21, dients digoxin and digitoxin. 22, 26), Small cell lung cancer (3, 23), non-small cell lung 0008 U.S. Patent Application Publication No. 2007/ carcinoma (28), lymphoma (9), neuroblastoma (25), and cer 0105790 discloses the use of cardiac glycosides (e.g., ouabain vical cancer (5). Mesothelioma which is not classified as an and proscillaridin) either alone or in combination with other epithelial cancer is also known to over-express VGSCs (12). standard cancer therapeutic agents to treat pancreatic cancers When these sodium channels are activated, Na" is conducted by causing cell apoptosis. into the cells. In these cancers, the degree of metastasis is directly related to an increased expression of VGSCs (1,7; see 0009 U.S. Patent Application Publication No. 2009/ also U.S. Pat. No. 7,393,657). Physiologically, these cancer 0018088 discloses the use of cardiac glycosides, including cells share certain cellular properties with normal excitable digoxin and ouabain, to induce cell apoptosis as a treatment cells such as neurons and cardiac myocytes (for example, the for cancer. conduction of action potentials). U.S. Pat. No. 7,393,657 discloses the use of inhibitors of VGSCs as a treatment for DISCLOSURE OF INVENTION cancer, including breast cancer. 0010 We have discovered that, in cancer cells that express 0005 Of the 1.6 million people contracting epithelial cell excess VGSCs, if the Na". K-ATPase (sodium pump) is cancer each year in the U.S., 40% are considered to be “highly blocked, and thenVGSCs are activated, the cells will lyse and invasive' and over-express VGSCs (10). These patients diag die. The activation of the VGSCs causes Na' to be conducted nosed with malignant/metastatic carcinomas are treated cur into the cells, but due to the inhibition of the sodium pumps, rently with major and often disfiguring Surgical procedures, the Na" cannot be pumped back out of the cell. Because water chemotherapy and/or radiation. More than 400,000 people flows into the cell based on a Na" gradient, water flowing into die from epithelial cell carcinoma each year in the United the cell causes the cells that over-express Na channels (i.e., States and an estimated 10 times that world-wide. In addition, allow more Na" into the cells) to swell and burst when mem another 1,200,000 U.S. patients diagnosed with invasive can brane compliance is exceeded. Because a lesser amount of cer are Successfully treated with traditional Surgery, chemo Na" enters normal cells that do not over-express VGSCs, therapy and/or radiation. Breast cell carcinoma is an example normal tissue does not swell or lyse. We have called this of a highly invasive cancer. More than 40,000 people die from two-stage treatment “Targeted Osmotic Lysis” (TOL), and breast cell carcinoma each year in the United States and have shown that this treatment is effective in treating highly 465,000 world-wide. Greater than 90% of these deaths are invasive cancer cells. In addition, we have shown that some due to metastasis of the primary tumor. In addition, another highly invasive cancer cells over-express Na', K"-ATPase US 2013/0184218 A1 Jul. 18, 2013 (the sodium pump) to compensate for the increase in Na carcinomas are expected to over-express VGSCs, including influx through the over-expressed VGSCs (unpublished; Data but not limited, to gliomas, neuromas, hepatic cancer, ovarian not shown). For example, MCF-7 breast cancer cells over cancer, bladder cancer, pancreatic cancer, thyroid cancer, express Na', K"-ATPase by 8- to 10-fold, whereas MDA splenic cancer, stomach cancer, cervical cancer, skin cancers, MB-231 breast cancer cells over-express Na', K"-ATPase by testicular cancer, renal cancer, and oral cancers.
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