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(12) Patent Application Publication (10) Pub. No.: US 2015/0023915 A1 MORRISON Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0023915 A1 MORRISON Et Al US 2015 0023915A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0023915 A1 MORRISON et al. (43) Pub. Date: Jan. 22, 2015 (54) TREATMENT FOR MELANOMA Publication Classification (71) Applicant: The Board of Regents of the University (51) Int. Cl. of Texas System, Austin, TX (US) A613 L/7048 (2006.01) A6II 45/06 (2006.01) (72) Inventors: Sean MORRISON, Dallas, TX (US); A638/20 (2006.01) Ugur ESKIOCAK, Dallas, TX (US) A638/2I (2006.01) A 6LX3/59 (2006.01) A 6LX39/395 (2006.01) (73) Assignee: The Board of Regents of the University (52) U.S. Cl. of Texas System, Austin, TX (US) CPC ........... A6 IK3I/7048 (2013.01); A61 K3I/519 (2013.01); A61 K39/3955 (2013.01); A61 K (21) Appl. No.: 14/280,376 38/2013 (2013.01); A61 K38/21 (2013.01); A61K 45/06 (2013.01) USPC ......... 424/85.4; 514/26: 424/130.1; 424/85.2 (22) Filed: May 16, 2014 (57) ABSTRACT Related U.S. Application Data The present invention relates to combination therapies for melanoma, and in particular, metastatic melanoma. Drugs for (60) Provisional application No. 61/847,797, filed on Jul. use in such therapies in include MEK inhibitors combination 18, 2013. with cardiac glycosides. Patent Application Publication Jan. 22, 2015 Sheet 1 of 8 US 2015/0023915 A1 §§§§ .338; fi383.388S (WI) uxof Patent Application Publication Jan. 22, 2015 Sheet 2 of 8 US 2015/0023915 A1 Patent Application Publication Jan. 22, 2015 Sheet 3 of 8 US 2015/0023915 A1 granyss,zizoyisºTuixofibra©SÅ?G ' C Patent Application Publication Jan. 22, 2015 Sheet 4 of 8 US 2015/0023915 A1 fittie, Patent Application Publication Jan. 22, 2015 Sheet 5 of 8 US 2015/0023915 A1 *·&·,?w.«,æø••• •?+a«.*-** tigiusska euised ixofit {}S{}{}{} ***** Patent Application Publication Jan. 22, 2015 Sheet 6 of 8 US 2015/0023915 A1 {iji Saka eused ixof Patent Application Publication Jan. 22, 2015 Sheet 7 of 8 US 2015/0023915 A1 Kes is es w \ tipiu seae eused upxoid·····················**?································· sy c w &: --- it:33 83.38:C Patent Application Publication Jan. 22, 2015 Sheet 8 of 8 US 2015/0023915 A1 s 3. s s &S 8 & & s s s US 2015/0023915 A1 Jan. 22, 2015 TREATMENT FOR MELANOMA intraarterial, Subcutaneous, oral or intra-tumoral administra 0001. The present application claims benefit of priority to tion, or may comprise local, regional or systemic administra U.S. Provisional Application Ser. No. 61/847,797, filed Jul. tion, or may comprise continuous infusion over a period of 18, 2013, the entire contents of which are hereby incorporated time. The subject may have failed one or more standard by reference. melanoma therapies. 0008. The MEK inhibitor may be administered before the BACKGROUND OF THE INVENTION cardiac glycoside therapy, at the same time as the cardiac glycoside therapy or after the cardiac glycoside therapy. The 0002 I. Technical Field MEK inhibitor may be administered more than once, and/or 0003. The present invention relates generally to the fields the cardiac glycoside may be administered more than once. of medicine and oncology genetics. More particularly, it The cardiac glycoside may be selected from digoxin, digi relates to the combined use of MEK inhibition and cardiac toxin, gitoxin, oleandrin, neriifolin, bufalin, marinobufage glycosides to treat melanoma, particularly metastatic mela nin, cinobufagenin, UNBS1450 and lanatoside C. The MEK Oa. inhibitor may be selected from trametinib, AS703026 (Pima 0004 II. Related Art sertib, MSC1936369B), AZD8330 (ARRY-424704), Selu 0005 Melanoma is a malignant tumor of melanocytes. metinib (AZD6244), PD-325901, GDC-0973 (XL518) and Melanocytes are cells that produce the dark pigment, mela CI-1040 (PD184352). The amount sufficient to inhibit said nin, which is responsible for the color of skin. They predomi melanoma may be less than the amount required for inhibi nantly occur in skin, but are also found in other parts of the tion by any single agent alone. The amount Sufficient to body, including the bowel, oral cavity and the eye. Melanin inhibit said melanoma may be less toxic than the amount also protects the deeper layers of the skin from the sun’s required for inhibition by any single agent alone. harmful ultraviolet (UV) rays. When people spend time in the 0009. The method may further comprising treating said Sunlight, the melanocytes make more melanin and cause the Subject with an additional agent, such as an immunomodula skin to tan. This also happens when skin is exposed to other tor (e.g., imiquimod, IL-2 or interferon), or a chemotherapeu forms of ultraviolet light (such as in a tanning booth). If the tic agent, Such as dacarbazine. The method may also further skin receives too much ultraviolet light, the melanocytes Suf comprise excising a melanoma lesion, where excising occurs fer genetic damage and can be transformed into cancerous prior to, after or concurrent with MEK inhibition/cardiac melanoma cells. glycoside treatment. The meloma may be BRAF wild-type or 0006 Because of the link to cumulative sun exposure, the BRAF mutated, such as where the BRAF mutation is V600E chance of getting melanoma increases with age, but many or V600K. The cardiac glycoside may be digitoxin or is young people also get melanoma. In fact, melanoma is one of digoxin. The immunomodulator may be an antibody against the most common cancers in young adults. Each year in the PD1 or CTLA4, such as Ipilimumab. U.S., more than 50,000 people young and old learn that 0010. It is contemplated that any method or composition they have melanoma. And, according to a WHO report, about described herein can be implemented with respect to any 48,000 melanoma related deaths occur worldwide each year. other method or composition described herein. The treatment includes surgical removal of the tumor, and if melanoma is found early while relatively small and thin, 0011. The use of the word “a” or “an when used in con complete removal gives a high cure rate. The chance of the junction with the term “comprising in the claims and/or the melanoma coming back or spreading depends on how deeply specification may mean “one but it is also consistent with it has invaded into the layers of the skin. Thus, the more the meaning of"one or more.” “at least one.” and “one or more progressed the lesion, the great the chancer for recurrence than one.” and/or metastasis. For melanomas that recur or spread, treat 0012. Other objects, features and advantages of the ments include chemo- plus immunotherapy or radiation present invention will become apparent from the following therapy, but the prognosis for Such patients, including those detailed description. It should be understood, however, that exhibiting metastatic disease (AJCC Stage III and IV) is poor, the detailed description and the specific examples, while indi with 5-year survival rates being less than 10%. As such, cating specific embodiments of the invention, are given by improved treatments for melanoma, particularly for advanced way of illustration only, since various changes and modifica metastatic disease, are urgently needed. tions within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed descrip SUMMARY OF THE INVENTION tion. 0007 Thus, in accordance with the present invention, BRIEF DESCRIPTION OF THE DRAWINGS there is provided a method of inhibiting melanoma in a Sub ject comprising administering to said subject (a) a MEK 0013 The following drawings form part of the present inhibitor, and (b) a cardiac glycoside, in an amount Sufficient specification and are included to further demonstrate certain to inhibit said melanoma. The Subject may be a human or a aspects of the present invention. The invention may be better non-human mammal. Inhibiting may comprise inhibiting the understood by reference to one or more of these drawings in growth of primary melanomas, inhibiting metastasis, inhib combination with the detailed description of specific embodi iting the growth of metastases, killing circulating melanoma ments presented herein. cells, inducing remission, extending remission, or inhibiting 0014 FIGS. 1A-C. Therapeutically achievable and safe recurrence. The melanoma may be AJCC stage III disease or levels of digitoxin are sufficient for anti-melanoma activity. AJCC stage IV disease. The subject may have previously FIG. 1A, ICso values of digitoxin for various melanomas and received a radiotherapy, a chemotherapy, an immunotherapy, human umbilical cord blood cells (hUCB). Melanomas that a molecularly targeted therapy or had surgical resection of a are sensitive to digitoxin at therapeutically achievable doses tumor. Administering may comprise topical, intravenous, are indicated in orange. FIG. 1B, Representative dose US 2015/0023915 A1 Jan. 22, 2015 response curves. FIG. 1C, Digitoxin concentrations mea vehicle only (200 ul 0.5% promethylcellulose, 0.2% Sured in the plasma of the mice 4 hours after 0.5 mg/kg Tween80 by gavage and 50% DMSO with osmotic pump). injection. Tumors were measured every 3-4 days with calipers. FIG. 6B, 0015 FIG. 2. Melanoma regression after treatment with a Average tumor weight (N=5) and standard deviation for each combination of MEK inhibitor (Trametinib, GSK1 120212) treatment. The statistical significance of differences between and digitoxin. The effect of digitoxin alone, or in combination mean values was assessed by the Student's t-test. FIG. 6C, with the MEK inhibitor, was tested in xenograft assays using Melanomas excised and photographed at the end of treat primary melanomas from patients. Melanoma cells were ment. FIG. 6D, Digoxin levels achieved in plasma of mice at injected Subcutaneously in the right flanks of immunocom the conclusion of therapy (21-days). promised NSG mice. When tumors became palpable, mice (0020 FIGS.
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