WO2014138802A1 - Canrenoate compositions for treating cancer - Google Patents

Canrenoate compositions for treating cancer Download PDF

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Publication number
WO2014138802A1
WO2014138802A1 PCT/AU2014/000262 AU2014000262W WO2014138802A1 WO 2014138802 A1 WO2014138802 A1 WO 2014138802A1 AU 2014000262 W AU2014000262 W AU 2014000262W WO 2014138802 A1 WO2014138802 A1 WO 2014138802A1
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Prior art keywords
canrenoate
cancer
individual
composition
cesium
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PCT/AU2014/000262
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French (fr)
Inventor
Andrew J.S. COATS
Stefan Anker
Jochen Springer
Original Assignee
Coats Andrew J S
Stefan Anker
Jochen Springer
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Application filed by Coats Andrew J S, Stefan Anker, Jochen Springer filed Critical Coats Andrew J S
Publication of WO2014138802A1 publication Critical patent/WO2014138802A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta

Definitions

  • the present invention relates to canrenoate compositions and uses thereof, including uses of the canrenoate compositions for treating cancer.
  • Cancer is the second most common cause of death in the United Stales, exceeded only by heart disease. In the United States, cancer accounts for 1 of every 4 deaths. With population growth and aging of the population, the number of new cancer patients is expected to double to 2.6 million people by 2050.
  • liver cancer is the sixth most common cancer worldwide and the third most common cause of cancer-related death.
  • the most common form of liver cancer is hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • systemic chemotherapies or supportive therapies are the mainstay treatment options.
  • most chemotherapeutic agents show limited effectiveness and have not been able to improve patient survival. See ,e.g. Ma YT. Palmer DH. Impact of restricting access to high-cost medications for hepatocellular carcinoma.
  • Potassium canrenoate is an aldosterone antagonist, which is a diuretic drug that antagonizes the action of aldosterone at mineralcortocoid receptors. Aldosterone antagonists are often used with other drugs for the management of chronic heart failure. Potassium canrenoate is not approved in the United States, but is used clinically in Europe and other countries as a diuretic. [00061 The disclosure of all publications, patents, patent applications, and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.
  • the present invention relates to canrenoate compositions and uses thereof, including uses of the canrenoate compositions for treating cancer.
  • Vf is an ion of an alkali metal (Group 1) selected from the group consisting of Li + (lithium), Na ⁇ (sodium), Rb ⁇ (rubidium), and Cs " (cesium).
  • Alkali metal Group 1 selected from the group consisting of Li + (lithium), Na ⁇ (sodium), Rb ⁇ (rubidium), and Cs " (cesium).
  • the present disclosure provides, in some embodiments, a pharmaceutical composition comprising cesium canrenoate.
  • the present disclosure provides, in some embodiments, a method of treating cancer in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the present disclosure provides, in some embodiments, a method of prolonging survival of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the present disclosure provides, in some embodiments, a method of preventing body weight loss of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • a method of improving quality of life in an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the present disclosure provides, in some embodiments, a method of preventing and/or treating loss of lean body mass in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the present disclosure provides, in some embodiments, a method of preventing and/or treating muscle wasting in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the canrenoate is a pharmaceutically acceptable salt of canrenoate.
  • the canrenoate is selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the canrenoate is cesium canrenoate.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • the cancer is selected from the group consisting of liver cancer, lung cancer, ovarian cancer, pancreatic cancer, melanoma, and brain cancer.
  • the cancer is selected from the group consisting of gastric cancer, pancreatic cancer, lung, esophageal, colorectal, head and neck cancer, and hematological malignancies.
  • the cancer is liver cancer.
  • the cancer is an early stage cancer.
  • the cancer is a late stage cancer.
  • the composition is administered orally.
  • the amount of canrenoate in the composition is about 10 to about 200 mg daily. In some embodiments, the composition is administered daily or twice daily.
  • kits comprising a pharmaceutical composition comprising a canrenoate and instruction for using the pharmaceutical composition for treating cancer.
  • Figure 1 is a diagram of the design study involving the Yoshida Hepatoma Model for cancer cachexia.
  • Figure 2 is a graph showing the percent survival of rat populations that were administered various dosages of cesium canrenoate (Cs-can). Comparison to placebo (plac) was also provided. The ample size in the population is indicated by “n.” “FIR” refers to hazard ratio. “CI” refers to confidence interval. “95% CF * is 95% confidence interval, “p” refers to p-value.
  • Figure 3 is a graph showing the percent survival of rat populations that were administered with various dosages of cesium canrenoate (Cs-can). The sample size in the population is indicated by “n.” “HR” refers to hazard ratio. “CI” refers to confidence interval. “95% CI” is 95% confidence interval, “p” refers to p-value.
  • Cs-can cesium canrenoate
  • Figure 4 is a graph showing the change in body weight (in grams ("g")) of rat populations that were administered with cesium canrenoate. Comparison to placebo (P) was also provided.
  • the asterisk (*) indicates p ⁇ 0.()5.
  • the two asterisks (**) indicate p ⁇ 0.01 vs placebo.
  • Figure 5 is a graph showing the change in lean body mass (in grams (“g")) of rat populations that were administered with various dosages of cesium canrenoate.
  • Figure 6 is a graph showing the change in fat mass (in grams ("g")) of rat populations that were administered with cesium canrenoate. Comparison to placebo (P) was also provided. The two asterisks (**) indicate p ⁇ 0.01 versus placebo. The three asterisks (***) indicate pO.001 vs placebo.
  • Figure 7A is a graph showing the weight of white adipose tissue (WAT) (in grams ("g")) of rat populations that were administered with various dosages of the cesium canrenoate at the endpoint of the study.
  • Figure 7B is a graph showing the weight of brown adipose tissue ( BA T) (in grams ("g")) of rat populations that were administered with various dosages of the cesium canrenoate at the endpoint of the study.
  • WAT white adipose tissue
  • BA T brown adipose tissue
  • P placebo
  • S sham
  • the three asterisks (***) indicate p ⁇ 0.001 vs placebo.
  • Figure 8A is a graph showing the change in tumor volume (in mL) of rat populations that were administered with dosages of the cesium canrenoate. Comparison to placebo (P) was also provided.
  • Figure 8B is a graph showing the change in total cells in a tumor of rat populations that were administered with various dosages of cesium canrenoate. Comparison to placebo (P) was also provided.
  • the asterisk (*) indicates p ⁇ 0.05 vs placebo.
  • Figure 9 is a graph showing effect of cesium canrenoate or doxorubicin on tumor growth, as assessed by BrdU incorporation and XTT assay with various tumor cells, namely, Kelly (neuroblastoma), Hela-93 (cervix carcinoma), and B16V (melanoma).
  • the present invention provides use of canrenoate compositions for achieving beneficial results in individuals having cancer, such as treating cancer, prolonging survival, preventing body weight loss, improving quality of life, and/or treating muscle wasting.
  • pharmaceutical compositions comprising canrenoates (such as cesium canrenoate).
  • the present invention is based on the surprising finding that canrenoate, specifically cesium canrenoate, significantly improved survival in animals having cancer in an experiment in which an animal was inoculated with hepatocellular carcinoma cells in a well-established animal model of hepatoma.
  • Other advantageous effects of the compositions were observed on preventing body weight loss, preserving lean body mass, and preserving fat mass in the animals.
  • these effects were observed in animals not developing cachexia or before the animals develop cachexia, suggesting mat at least some of the effect of cesium canrenoate that we observed may be independent and/or in addition to its effect on treating cancer cachexia.
  • the present invention in one aspect provides methods of treating cancer, prolonging survival, preventing body weight loss, preventing and/or treating muscle wasting, or improving quality of life in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • compositions comprising cesium canrenoate.
  • kits, unit dosages, medicines, and articles of manufacture that are useful for methods described herein.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, delay or slowing the progression of the disease, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • treatment is a reduction of pathological consequence of cancer. The methods of the invention contemplate any one or more of these aspects of treatment.
  • the term "individual” refers to a mammal and includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is a human.
  • an "at risk” individual is an individual who is at risk of developing cancer.
  • An individual “at risk” may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein.
  • At risk denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of cancer. An individual having one or more of these risk factors has a higher probability of developing cancer than an individual without these risk factor(s).
  • Adjuvant setting refers to a clinical setting in which an individual has had a history of cancer, and generally (but not necessarily) been responsive to therapy, which includes, but is not limited to, surgery (e.g. , surgery resection), radiotherapy, and chemotherapy. Ilowever, because of their history of cancer, these individuals are considered at risk of development of the disease.
  • Treatment or administration in the "adjuvant setting” refers to a subsequent mode of treatment.
  • the degree of risk e.g., when an individual in the adjuvant setting is considered as "high risk” or "low risk) depends upon several factors, most usually the extent of disease when first treated.
  • Neoadjuvant setting refers to a clinical setting in which the method is carried out before the primary/definitive therapy.
  • delaying the development of a disease means to defer, hinder, slow, retard, stabilize, and/or postpone development: of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a method that "delays" development of a disease is a method that reduces probability of disease development in a given time frame and/or reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
  • administration of one treatment modality in addition to another treatment modality such as administration of a nanoparticle composition described herein in addition to administration of the other agent to the same individual.
  • administration of a nanoparticle composition described herein in addition to administration of the other agent to the same individual.
  • "in conjunction with” refers to administration of one treatment modality before, during, or after delivery of the other treatment modality to the individual. Such combinations are considered to be part of a single treatment regimen or regime.
  • the term "effective amount” used herein refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease such as ameliorate, palliate, lessen, and/or delay one or more of its symptoms.
  • the term "simultaneous administration,” as used herein, means that a first therapy and second therapy in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes.
  • the first and second therapies may be contained in the same composition (e.g. , a composition comprising both a first and second therapy) or in separate compositions (e.g. , a first therapy in one composition and a second therapy is contained in another composition).
  • the term "sequential administration” means that the first therapy and second therapy in a combination therapy are administered with a time separation of more than about 1 5 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the first therapy or the second therapy may be administered first.
  • the first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.
  • the term “concurrent administration” means that the administration of the first therapy and that of a second therapy in a combination therapy overlap with each other.
  • pharmaceutically acceptable or “pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxieological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • Progression free survival indicates the length of time during and after treatment that the cancer does not grow. Progression-free survival includes the amount of time individuals have experienced a complete response or a partial response, as well as the amount of time individuals have experienced stable disease. In some embodiments, an individual has a capacity to accept more courses of chemotherapy during progression free survival.
  • salt means a salt which is acceptable for administration to a subject, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, lithium, sodium, potassium, rubidium, cesium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.
  • salt thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like.
  • the salt is a pharmaceutically acceptable salt, although this is not required for salts of intemiediate compounds that arc not intended for administration to the subject.
  • salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.
  • solvent refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
  • the solvent can be an organic compound, an inorganic compound, or a mixture of both.
  • Some examples of solvents include, but are not limited to, methanol, ⁇ ', ⁇ '-dimethylformamide, tetrahvdrofuran, dimemylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.
  • ''in conjunction with refers to administration of one treatment modality in addition to another treatment modality.
  • in conjunction with refers to administration of one treatment modality before, during or after administration of the other treatment modality to the individual .
  • Reference to "about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X” includes description of "X.”
  • the present application in one aspect provides methods of treating cancer.
  • a method of treating cancer in an individual having cancer comprising administering to the individual an effective amount of a composition comprising a canrenoate.
  • the composition comprises a
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of treating cancer in an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • a method of prolonging survival of an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of prolonging survival of an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • the method prolongs the survival of the individual by at least any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 18, or 24 months.
  • a method of prolonging progression- free survival in an individual with cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium cam-enoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of prolonging progression-free survival in an individual with cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • a method of alleviating one or more symptoms associated with cancer in an individual comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of alleviating one or more symptoms associated with cancer in an individual comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • a method of preventing body weight loss of an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of preventing body weight loss of an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • the body weight loss of the individual is no more than about 10% (for example no more than about any of 10%, 9%, 8%, 7%, 6%, or 5%) of the total body weight.
  • the body weight loss is evaluated over a time period of about 1 month to 2 years (for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12. 13, 14, 15, 16, 17, 18, 19 , 20 . 21, 22, 23, or 24 months).
  • a method o f treating muscle wasting ill an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate. sodium canrenoate. and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of treating muscle wasting in an individual having cancer comprising administering
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • the muscle wasting of the individual i s no more than about 10% (for example no more than about any of 10%, 9%, 8%>, 7%, 6%, or 5%) of the total body weight. In some etnbodiments, the muscle wasting is evaluated over a time period of about 1 month to 2 years
  • the method leads to a reduction of muscle wasting, i.e., a slow-down of muscle loss in the individual. In some embodiments, the method leads to a reversal of muscle wasting, i.e., an increase in muscle weight in the individual.
  • a method of preventing loss of lean body mass in an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • a method of treating loss of lean body mass in an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of preventing loss of lean body mass in an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about
  • the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. In some embodiments, the loss of lean body mass of the individual is no more than about 10% (for example no more than about any of 10%, 9%>,
  • the loss of lean body mass is evaluated over a time period of about 1 month to 2 years (for example, about 1 , 2, 3,
  • a method of preventing (or delaying) development of cancer cachexia in an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of preventing (or delaying) development of cancer cachexia in an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 0 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia, and the methods described herein can be used to improve one or more symptoms of cancer cachexia in an individual having cancer, the methods comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of improving one or more symptoms of cancer cachexia in an individual having cancer comprising administering (such as orally administering) to the individual an e ffective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia. Symptoms of cachexia include but not l imited to, loss of weight, muscle atrophy, fatigue, weakness, and loss of appetite.
  • a method of improving quality of life of an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium cam'enoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of improving quality of life of an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • Improvement of quality of life can be assessed, for example, by food intake, locomotive activity, and improvement in fatigue or dyspnea or global patient assessment scores, in short physical performance battery scores, in standard clinical assessment of functional performance, muscle strength, gait speed, leg strength and hand grip strength, 6-minute corridor walk test, stair climbing power, ability to tolerate courses of chemotherapy and other tests or instruments or questionnaires assessing patient quality of life.
  • a method of increasing food intake of an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of improving food intake in an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • a method of increasing locomotive activity of an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate. and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of improving locomotive activity of an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • a method of improvi ng fatigue or dyspnea an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of improving fatigue or dyspnea in an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • a method of preventing loss of body fat in an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. in some embodiments, the composition comprises cesium canrenoate.
  • a method of preventing loss of body fat in an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate composition in the composition is about 1 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • the loss of body fat of the individual is no more than about 10% (for example no more than about any of 10%, 9%, 8%, 7%, 6%. or 5%) of the total body fat.
  • the loss of body fat is evaluated over a time period of about 1 month to 2 years (for example, about 1 , 2. 3. 4. 5, 6. 7, 8, 9, 10. 11, 12, 13. 14, 15, 16. 17, 18, 19 5 20 , 21 , 22, 23, or 24 months).
  • Adipose tissue appears as two types: white adipose tissue and brown adipose tissue.
  • White adipose tissue cells contain a single large fat droplet, which forces the nucleus to be squeezed into a thin rim at the periphery. They have receptors for insulin, growth hormones, norepinephrine and glucocorticoids.
  • White adipose tissue is used as a store of energy.
  • White adipose tissue also acts as a thermal insulator, helping to maintain body temperature.
  • Brown adipose tissue cells contain numerous smaller droplets and a higher number of (iron containing) mitochondria, which gives a brown color to the cell. Brown fat also contains more capillaries than white fat, since it has a greater need for oxygen than most tissues. The methods provided herein are useful for preventing loss of both white adipose tissue and brown adipose tissue in an individual having cancer.
  • cardioprotective effects in an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate).
  • a method of preventing wasting of a heart muscle in an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate).
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of providing cardioprotective effects in an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate composition in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • canrenoate such as cesium canrenoate
  • a method of preventing wasting of a heart muscle in an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate composition in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • Cardioprotective effects include one or more of the following: preventing and treating atrial fibrillation and ventricular fibrillation, improving arrhythmias, improving diastolic function of a heart, and preventing and treating fibrosis of a heart.
  • the methods described herein are therefore useful for any one or more of these cardioprotective effects.
  • a method of preventing sudden death and/or cardiovascular death in an individual having cancer comprising administering to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate).
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of preventing sudden death and/or cardiovascular death in an individual having cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate composition in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • the methods described herein may be useful for any one or more of the following: 1 ) preventing loss of skeletal muscle associated with cancer; 2) treating fatigue associated with cancer; 3) treating muscle weakness associated with cancer; 4) strengthening skeletal muscle in an individual having cancer; 5 ) treatment of muscle wasting associated with cancer; 6) treating dyspnea associated with muscle changes in cancer; and 7) improving fatigue resistance of muscle in cancer.
  • Skeletal muscle includes, but is not limited to, gastrocnemius muscle, tibialis muscle, soleus muscle, and extensor digitorum longus (EDL) muscle, quadriceps, hamstrings, postural muscles, hand muscles, triceps, biceps, masseter and other jaw muscles, and intercostal and other respiratory muscles.
  • EDL extensor digitorum longus
  • the individual has been diagnosed with or is suspected of having cancer. In some embodiments, the individual exhibits one or more symptoms associated with cancer. In some embodiments, the individual has a low tumor burden. In some embodiments, the individual is a human. In some embodiments, the individual is at least about any of 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the individual is no more than about any of 35, 30, 20, 15, 10, 5, or 1 year old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the individual has a single lesion at presentation. In some embodiments, the individual has multiple lesions at presentation. In some embodiments, the individual has been previously treated for cancer. In some embodiments, the individual has not previously been treated for cancer.
  • cancers described herein can be of any stage.
  • cancers can be evaluated according to Overall Stage Grouping, outlined as follows:
  • the cancer is surgically treatable. In some embodiments, the cancer is not surgically treatable.
  • the cancer is an early stage cancer, such as Stage 0, Stage I, or Stage II. In some embodiments, the cancer is a late stage cancer, such as Stage III or Stage IV. In some embodiments, the cancer is Stage 111 A. In some embodiments, the cancer is Stage IIIB or Stage IV. In some embodiments, the cancer is Stage IV.
  • the cancer is early stage cancer, non-metastatic cancer, primary cancer, advanced cancer, locally advanced cancer, metastatic cancer, cancer in remission, or recurrent cancer.
  • the cancer is localized resectable, localized unresectable, or unresectable.
  • the cancer is a progressive cancer.
  • the cancer is substantially refractory to hormone therapy.
  • the cancer is HER2 positive.
  • the cancer is HER2 negative.
  • the cancer is estrogen receptor and/or progesterone receptor positive.
  • the cancer is estrogen receptor and/or progesterone receptor negative.
  • the methods can be practiced in a neoadjuvant setting, i.e., the method may be carried out before the primary/definitive therapy.
  • the method is a first line therapy.
  • the method is a second line therapy.
  • the cancer is a solid tumor.
  • the cancer is adenocarcinoma.
  • the cancer is sarcoma.
  • the cancer is any one of the following: biliary cancer
  • breast cancer e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast
  • brain cancer e.g., glioblastoma, meningioma; glioma, e.g., astrocytoma, oligodendroglioma; meduUoblastoma
  • cervical cancer e.g., cervical adenocarcinoma
  • colorectal cancer e.g., colon cancer, rectal cancer, colorectal adenocarcinoma
  • gastric cancer gastric cancer
  • stomach adenocarcinoma e.g., stomach adenocarcinoma
  • GIST gastrointestinal stromal tumor
  • squamous cell carcinoma e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC)), kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g... bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC). adenocarcmoma of the lung), leuketma (e.g., acute lymphoblastic leukemia
  • OSCC oral squamous cell carcinoma
  • kidney cancer e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma
  • liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
  • lung cancer e.g.. bronch
  • lymphoma e.g., Hodgkin lymphoma (IIL), non-Hodgkin lymphoma (NHL), follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL)), multiple myeloma (MM), myelodysplasia syndrome (MDS), myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential lymphoma (e.g., Hodgkin lymphoma (IIL), non-Hodgkin lymphoma (NHL), follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL)), multiple myeloma (MM), myelodysplasia syndrome (MDS), myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential
  • F,T thrombocythemia
  • AMM agnogenic myeloid metaplasia
  • PMF chronic myelocytic leukemia
  • CML chronic neutrophilic leukemia
  • CRL chronic neutrophilic leukemia
  • HES hypereosinophilic syndrome
  • neuroblastoma neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)), prostate cancer (e.g., prostate adenocarcinoma), skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA
  • melanoma basal cell carcinoma (BCC)
  • soft tissue sarcoma e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, rhabdomyosarcoma, myxosarcoma.
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, meduUoblastoma, colorectal cancer, head and neck cancer, lung cancer (e.g., small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)), leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogeneous leukemia (CML), chronic lymphocytic leukemia (CLL)), lymphoma (e.g., Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL)), multiple myeloma (MM), chronic myeloproliferative disorder (primary myelofibrosis, polycythemia vera, essential thrombocvtemia), osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, basal cell carcinoma (BCC)) and chondrosarcoma.
  • lung cancer e.g., small
  • the cancer is a cancer that is difficult to treat.
  • cancers that are difficult to treat include, but are not limited to, brain cancer (such as glioblastoma), liver cancer, lung cancer, ovarian cancer, pancreatic cancer, and skin cancer (such as melanoma).
  • brain cancer such as glioblastoma
  • liver cancer such as glioblastoma
  • lung cancer ovarian cancer
  • pancreatic cancer such as melanoma
  • skin cancer such as melanoma
  • the cancer is a cancer that is or is known to be associated with cachexia.
  • cancers that are associated with cachexia include, but are not limited to, gastric cancer, pancreatic cancer, lung, esophageal, colorectal, head and neck cancer, and hematological malignancies.
  • the cancer is liver cancer, such as hepatocarcinoma
  • the liver cancer (such as HCC) is early stage, non-metastatic, primary, advanced, locally advanced, metastatic, liver cancer (such as HCC) in remission, or recurrent liver cancer (such as recurrent HCC).
  • the liver cancer (such as HCC) is localized resectable (i.e., tumors that are confined to a portion of the liver that allows for complete surgical removal), localized unresectable (i.e., the localized tumors may be unresectable because crucial blood vessel structures are involved or because the liver is impaired), or unresectable (i.e., the tumors involve all lobes of the liver and/or has spread to involve other organs (e.g., lung, lymph nodes, bone).
  • organs e.g., lung, lymph nodes, bone
  • the liver cancer (such as HOC) is, according to TNM classifications, a stage 1 tumor (single tumor without vascular invasion), a stage II tumor (single tumor widt vascular invasion, or multiple tumors, none greater than 5 cm), a stage III tumor (multiple tumors, any greater than 5 cm, or tumors involving major branch of portal or hepatic veins), a stage IV tumor (tumors with direct invasion of adjacent organs other than the gallbladder, or perforation of visceral peritoneum), l tumor (regional lymph node metastasis), or Ml tumor (distant metastasis).
  • a stage 1 tumor single tumor without vascular invasion
  • a stage II tumor single tumor widt vascular invasion, or multiple tumors, none greater than 5 cm
  • a stage III tumor multiple tumors, any greater than 5 cm, or tumors involving major branch of portal or hepatic veins
  • a stage IV tumor tumors with direct invasion of adjacent organs other than the gallblad
  • the liver cancer (such as HCC) is, according to AJCC (American Joint Commission on Cancer) staging criteria, stage Tl, T2, T3, or T4 HCC.
  • the liver cancer is any one of liver cell carcinomas, fibrolamellar variants of HCC, and mixed hepatocellular cholangiocarcinomas.
  • the individual is of Asian ancestry. In some embodiments, the individual is HBsAg positive. In some embodiments, the individual is HBsAg negative. In some embodiments, the individual has underlying liver cirrhosis. In some embodiments, the individual does not have the underlying liver cirrhosis. In some of embodiments, the individual is genetically or otherwise predisposed (e.g., having a risk factor) to developing liver cancer (such as HCC).
  • HCC liver cancer
  • liver cancer include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease (e.g., hepatitis B or hepatitis C viral infection, liver cirrhosis), genetic (e.g., hereditary) considerations, and environmental exposure.
  • precursor disease e.g., hepatitis B or hepatitis C viral infection, liver cirrhosis
  • genetic e.g., hereditary
  • environmental exposure e.g., the individuals at risk for liver cancer (such as HCC) include, e.g., those having relatives who have experienced liver cancer (such as HCC), and those whose risk is determined by analysis of genetic or biochemical markers.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • liver cancer such as HCC
  • administering such as orally administering
  • an effective amount of a composition comprising canrenoate such as cesium canrenoate
  • the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • a method of prolonging survival of an individual having liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutical ly acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of prolonging survival of an individual having liver cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • the method prolongs the survival of the individual by at least any of 1, 2, 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, 18, or 24 months.
  • a method of preventing body weight loss of an individual having liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • a method of preventing (or delaying) development of cancer cachexia in an individual having liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • a method of preventing loss of lean body mass in an individual having liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • a method of preventing loss of body fat in an individual having liver cancer such as
  • HCC HCC
  • administering comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • a method of alleviating one or more symptoms associated with liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of alleviating one or more symptoms associated with liver cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • a method of prolonging progression- free survival in an individual with liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of prolonging progression-free survival in an individual with liver cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual lias no symptom of cancer cachexia.
  • the individual has one or more symptoms of cancer cachexia.
  • a method of treating muscle wasting in an individual having liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • me composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of treating muscle wasting in an individual having liver cancer (such as HCC).
  • the method comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the method leads to a reduction of muscle wasting, i.e., a slow-down of muscle loss.
  • the method leads to a reversal of muscle wasting, i.e., an increase in muscle weight.
  • a method of improving quality of life in an individual having liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of improving quality of life in an individual having liver cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • a method of increasing food intake of an individual having liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate. and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of increasing food intake of an individual having liver cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is ahout 10 mg to about 200 rag (such as about 20 to about 50 mg. for example) per day.
  • the individual has no symptom of cancer cachexia.
  • a method of increasing locomotive activity of an individual having liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of increasing locomotive activity of an individual having liver cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg lo about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • a method of improving fatigue and dyspnea in an individual having liver cancer comprising administering to the individual an effective amount of a composition comprising canrenoate.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • a method of improving fatigue and dyspnea in an individual having liver cancer comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day.
  • the individual has no symptom of cancer cachexia.
  • the individual being treated is no more than about 18 years old.
  • a method of treating a cancer in an individual having pediatric cancer comprising administering to the individual an effective amount of a composition comprising canrenoate, wherein the individual is no more than about 18 years old.
  • a method of promoting growth in an individual having a cancer wherein the individual is no more than about 18 years old.
  • a method of preventing loss of growth in an individual having cancer wherein the individual is no more than about 1 8 years old.
  • a method of treating muscle wasting in an indi vidual having cancer wherein the individual is no more than about 18 years old.
  • a method of prolonging survival of an individual having cancer wherein the individual is no more than about 18 years old.
  • a method of improving quality of life in an individual having cancer wherein the individual is no more man about 18 years old.
  • the individual is no more than about any of 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2. or 1 year old.
  • the individual is about 9 to about 15 years old.
  • the individual is about 5 to about 9 years old.
  • the individual is about 1 to about 5 years old.
  • the individual is no more than about 1 year old, such as about 6 months old to about 1 year old, less than about 6 months old, or less than about 3 months old.
  • the composition comprises a pharmaceutically acceptable salt of canrenoate.
  • the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
  • the composition comprises cesium canrenoate.
  • the individual no more than about 18 years old for the methods described herein has a solid tumor.
  • the solid tumor is sarcoma.
  • the solid tumor is carcinoma (such as adenocarcinoma).
  • the solid tumor is a neuroendocrine tumor.
  • the solid tumor is a cancer of the connectt ⁇ 'e tissue.
  • the solid tumor is a cancer arising from mesenchymal cells (e.g., skeletal muscle progenitor cells).
  • the solid tumor is a soft tissue tumor (such as soft tissue sarcoma).
  • the solid tumor is selected from the group consisting of neuroblastoma, rhabdomyosarcoma, osteosarcoma, retinoblastoma, CNS tumor, Wilm's tumor, and E wing's sarcoma.
  • the solid tumor is an abdominal tumor, a soft tissue tumor, a bone tumor, or an eye tumor.
  • the solid tumor is a brain tumor.
  • the solid tumor is melanoma.
  • the solid tumor is a soft tissue sarcoma, such as rhabdomyosarcoma.
  • the solid tumor is neuroblastoma.
  • the solid tumor is osteosarcoma.
  • the solid tumor is retinoblastoma.
  • the solid tumor is a heritable retinoblasmoma.
  • the individual no more than about 18 years old for the methods described herein has a central nervous system (CNS) tumor, such as an astrocytoma, a brain stem glioma, an ependymoma, a germ cell tumor, or a medulloblastoma. Childhood central nervous system tumors do not typically spread outside the brain and spinal cord.
  • the CNS tumor is a recurrent CNS tumor.
  • the individual no more than 18 years old for the methods described herein has Wilms' tumor (also known as nephroblastoma).
  • the individual has Stage I Wilms' tumor.
  • the mdividual has Stage II Wilms' tumor.
  • the individual has Stage III Wilms' tumor.
  • the mdividual has Stage IV Wilms' tumor.
  • the individual has Stage V Wilms' tumor.
  • the individual has recurrent Wilms' tumor.
  • the individual no more than 18 years old for the metiiods described herein has soft tissue sarcoma. In some embodiments, the individual has Stage 1 soft tissue sarcoma. In some embodiments, the individual has Stage II soft tissue sarcoma. In some embodiments, the individual has Stage III soft tissue sarcoma. In some embodiments, the individual has Stage IV soft tissue sarcoma. In some embodiments, the individual has recurrent soft tissue sarcoma.
  • the individual no more than about 18 years old for the methods described herein has Ewing's sarcoma. In some embodiments, the individual has localized Ewing's sarcoma. In some embodiments, the individual has metastatic Ewing's sarcoma. In some embodiments, the individual has Stage 1 Ewing's sarcoma. In some embodiments, the individual lias Stage 2 Ewing's sarcoma. In some embodiments, the individual has Stage 3 Ewmg's sarcoma. In some embodiments, the individual has Stage 4 Ewmg's sarcoma. In some embodiments, the individual has recurrent Ewing's sarcoma.
  • the individual no more than about 18 years old for the methods described herein has hepatoblastoma.
  • the individual no more than about 18 years old for the methods described herein has a haematological disease, such as leukemia (for example acute leukemia).
  • a haematological disease such as leukemia (for example acute leukemia).
  • compositions comprising a pharmaceutically acceptable salt of canrenoate or canrenoic acid:
  • Ivf is an ion of an alkali metal (Group 1), such as Li 1 (lithium), Na * (sodium), K f (potassium), Rb + (rubidium), and Cs + (cesium).
  • canrenoate or “a canrenoate composition” comprises a pharmaceutically acceptable salt of canrenoate and/or canrenoic acid.
  • a pharmaceutically acceptable salt of canrenoate is provided.
  • cesium canrenoate is provided.
  • the present disclosure also provides such compositions which are useful for the methods disclosed herein.
  • the present disclosure in one aspect, provides a compound of the formula:
  • M is an ion of an alkali metal (Group 1) selected from the group consisting of Li 4 (lithium), Na + (sodium), Rb + (rubidium), and Cs ' (cesium), in some embodiments, JVT is Li + (lithium).
  • M 1 is Na 1 (sodium).
  • M 1 is Rb 1 (rubidium).
  • M ⁇ is Cs + (cesium).
  • the systemic (IUPAC) name for cesium canrenoate is cesium 3- 7-hydroxy 0J3 ⁇ limethyl-3-oxo-2,8.9,l l J2,14,15,16- octahydro-1 /-/-cyclopenta[a
  • Caesium canrenoate has the chemical formula: C22II29O CS. The molecular weight is 490.37.
  • the pharmaceutical salts of canrenoate can be obtained commercially or through synthesis with procedures known in the art.
  • pharmaceutical salts of canrenoate can be synthesized from camenoic acid.
  • potassium canrenoate can be obtained commercially.
  • Canrenoic acid can be synthesized from potassium canrenoate, such as with adjustment of the pli of the reaction solution.
  • Reaction of camenoic acid with an electrolyte having an alkali metal (Group 1) would yield a pharmaceutical salt of canrenoate.
  • the electrolyte contains Li + (lithium), Na ⁇ (sodium), Rb + (rubidium), or Cs " (cesium).
  • CsOH cesium hydroxide
  • CsOH cesium hydroxide
  • the present disclosure provides, in some embodiments, a compound having the characteristics of a compound prepared by reaction of canrenoic acid and a cesium electrolyte (such as cesium hydroxide).
  • a cesium electrolyte such as cesium hydroxide.
  • the resulting compound has properties that are the same or similar to a compound prepared by the process.
  • the properties that can be measured and compared are molecular weight, ⁇ -NMR spectrum, IR spectrum, and melting point.
  • composition comprising a compound formula:
  • the composition is a pharmaceutical composition.
  • the composition further comprises other salt forms of canrenoate, such as lithium canrenoate, sodium canrenoate, potassium canrenoate, or rubidium canrenoate.
  • the composition further comprises potassium canrenoate.
  • the composition comprises at least 50. 60, 70, 80, 90, 91. 92, 93, 94, 95, 96, 97, 98, or 99% w/w of cesium canrenoate, where the percentage w/w is calculated by using the weight of cesium canrenoate and the total weight of canrenoate with the other salt form.
  • the composition comprises both cesium canrenoate and potassium canrenoate, wherein the weight ratio of the cesium canrenoate and the potassium canrenoate in the composition is more than about any of 2: 1 , 5:1 ,10:1 , 20:1 , 30: 1 , 40: 1, 50:1, 60:1 , 70: 1 , 80: 1 , 90: 1 , or 100: 1.
  • compositions described herein are present in pharmaceutical compositions.
  • the pharmaceutical compositions may further comprise one or more pharmaceutically acceptable carrier (or excipients).
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents.
  • the pharmaceutical composition is sterile.
  • unit dosage forms comprising a pharmaceutical composition described herein. These unit dosage forms can be stored in a suitable packaging in single or multiple unit dosages and may also be further sterilized and sealed. Unit dosage forms can be provided, for example, in the form of tablets, capsules, vials, and any other forms described herein.
  • a composition (such as a pharmaceutical composition, for example a unit dosage) comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition (such as pharmaceutical composition) is included in any of the following ranges: about 5 to about 10 mg, about 10 to about 20 mg, about 20 to about 30 mg, about 30 to about 40 mg, about 40 to abotit 50 mg, about 50 to about 60 mg, about 60 to about 70 mg, about 70 to about 80 mg, about 80 to about 90 mg, about 90 to about 100 mg, about 100 to about 1 10 mg, about 1 10 to about 120 mg, about 120 to about 130 mg, about 130 to about 140 mg, about 140 to about 150 mg, about 150 to about 160 mg.
  • canrenoate such as cesium canrenoate
  • the amount of canrenoate in the composition is included in any of the following ranges: about 5 to about 10 mg, about 10 to about 20 mg, about 20 to about 30 mg, about 30 to about 40 mg, about 40 to abotit 50 mg, about
  • the amount of canrenoate in the composition is about 20 to about 160 mg, including for example about 50 to about 150 mg, 80 to about 150 mg, about 90 to about 140 mg, about 100 to about 120 mg.
  • the composition is suitable for oral administration.
  • the composition is a pharmaceutically acceptable salt of canrenoate.
  • the composition is cesium canrenoate.
  • the composition is provided in a slow release form.
  • compositions, formulations, and unit dosages described herein in suitable packaging for use in the methods of treatment, methods of administration, and dosage regimens described herein.
  • suitable packaging for compositions described herein are known in the art, and include, for example, vial (such as sealed vials), vessels (such as sealed vessels), ampules, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. These articles of manufacture may further be sterilized and/or sealed.
  • the dosage of the compositions described herein administered to an individual may vary with the particular composition, the method of administration, and the particular stage of cancer.
  • the amount should be sufficient to produce a desirable response, such as a therapeutic or prophylactic response against cancer.
  • the amount of the composition is a therapeutically effective amount.
  • that amount of the composition is a prophvlactically effective amount.
  • the amount of total canrenoate in the composition is below the level that induces a toxicological effect (i.e., an effect above a clinically acceptable level of toxicity) or is at a level where a potential side effect can be controlled or tolerated when the composition is administered to the individual.
  • the amount of canrenoate (such as cesium canrenoate) in the composition is included in any of the following ranges: about 0.5 to about 5 mg, about 5 to about 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 1 50 to about 1 75 mg, about 1 75 to about 200 mg.
  • the amount of canrenoate in the composition is included in any of the following ranges: about 5 to about 10 mg, about 10 to about 20 mg, about 20 to about 30 mg, about 30 to about 40 mg, about 40 to about 50 mg, about 50 to about 60 mg, about 60 to about 70 mg, about 70 to about 80 mg, about 80 to about 90 mg, about 90 to about 100 mg, about 100 to about 110 mg, about 1 10 to about 120 mg, about 120 to about 1 30 mg, about 1 0 to about 140 mg, about 140 to about 1 50 mg, about 150 to about 160 mg.
  • the amount of canrenoate (such as cesium canrenoate) in the composition is about 20 to about 160 mg. including for example about 50 to about 150 mg, 80 to about 150 mg, about 90 to about 140 mg, about 100 to about 120 mg.
  • the amount of canrenoate (such as cesium canrenoate) in the composition includes at least about any of 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg. In some embodiments, the amount of canrenoate (such as cesium canrenoate) in the composition includes less than about any of 35 mg/kg, 30 mg/kg, 25 mg/kg, 20 mg/kg, 1 5 mg/kg, 1 0 mg/kg, 5 mg/kg, 2.5 mg kg, 2 mg/kg, 1 mg''kg, 0.5 mg/kg, or 0.1 mg/kg.
  • Exemplary dosing frequencies include, but are not limited to, weekly without break; weekly, three out of four weeks; once every three weeks; once every two weeks; weekly, two out of three weeks.
  • the composition is administered about once e er)' 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks.
  • the composition is administered at least about any of 1 x, 2x, 3x, 4x, 5x, 6x, or 7x (i.e. , daily) a week.
  • the intervals between each administration are less than about any of 6 months, 3 months, I month, 20 days, 15, days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days.
  • the intervals belvveen each administration are more than about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, there is no break in the dosing schedule. In some embodiments, the interval between each administration is no more than about a week. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered at least once (such as at least any of 2x, 3x, or 4x) daily.
  • the administration of the composition can be extended over an extended period of time, such as from about a month up to about seven years or life-long.
  • the composition is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 18, 24, 30, 36, 48, 60, 72, or 84 months or life-long.
  • the composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week.
  • compositions described herein can be administered to an individual (such as human) via various routes, including, for example, intravenous, intra-arterial, intraperitoneal, intraportal, intrapulmonary, oral, inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, intraocular, intrathecal, transmucosal, and transdermal.
  • sustained continuous release formulation of the composition may be used.
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic e ffect is maintained.
  • treatment may cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
  • compositions described herein may be formulated as solutions, emulsions, suspensions, dispersions, or inclusion complexes such as cyclodextrins in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • Pharmaceutical compositions of the embodiments may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • compositions may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP). sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or tale. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • the oral formulations may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di- glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaeeutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose,
  • non-aqueous vehicles e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • compositions may be provided in sterile aqueous solutions or suspensions, buff ered to an appropriate pH and isotonicity or in parenteral ly acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Formulations suitable for parenteral including intravenous administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose or an appropriate fraction thereof, of an active ingredient.
  • the methods of the embodiments comprise administering an effective amount of at least one compound of the embodiments; optionally the compound may be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful for treating a cancer afflicting the subject.
  • the additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the embodiments or may be included with a compound of the embodiments in a single pharmaceutical composition.
  • the additional active ingredients may be administered simultaneously with, prior to. or after administration of a compound of the embodiments.
  • the additional therapeutic agent is selected from the group consisting of progestins, corticosteroids, metoclopramide, cannabinoids, thalidomide, melatonin, clenbuterol, anabolic steroids, omega 3 fatty acids, NSAlDs, beta-blocking agents, 5H T-modulating agents.
  • kits, medicines, compositions, and unit dosage forms for use in any of the methods described herein.
  • Kits provided herein include one or more containers comprising any one of the compositions described herein and/or other agent(s), and in some embodiments, further comprise instructions for use in accordance with any of the methods described herein.
  • the kit may further comprise a description of selection of individual suitable for treatment.
  • Instructions supplied in the kits of the invention are typically written instructions on a label or package insert, (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • the kit comprises a) a composition comprising canrenoate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and b) instructions for administering the composition for treatment of cancer (such as liver cancer).
  • cancer such as liver cancer
  • kits of the invention are in suitable packaging.
  • suitable packaging include, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed N ylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information.
  • the present application thus also provides articles of manufacture, which include vials (such as sealed vials), bottles, jars, flexible packaging, and the like.
  • the instructions relating to the use of the compositions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • the containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of canrenoate as disclosed herein to provide effective treatment of an individual for an extended period, such as any of a week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the pharmaceutical compositions and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
  • the present disclosure provides, in some embodiments, a composition compri ing canrenoate for treating cancer in an individual having cancer.
  • a composition comprising canrenoate for preventing body weight loss of an individual having cancer is also provided.
  • the present disclosure provides, in some embodiments, a composition comprising canrenoate for the manufacture of a medicament for treating cancer in an individual having cancer.
  • a composition comprising canrenoate for the manufacture of a medicament for preventing body weight loss of an individual having cancer is provided.
  • FIG. 2 shows the percent survival of rats that were admini stered with cesium canrenoate (Cs-can) at dosages of 0.2, 1, 2.5, or 10 mg/kg/day.
  • One control group received a placebo (plac).
  • Figure 3 further shows the percent survival of rats that were administered with cesium canrenoate at dosages of 0.2, 1 , 10, or 20 mg kg/day.
  • 1 mg/kg/day of cesium canrenoate had the best effect on survival among all dosages tested.
  • cesium canrenoate was significantly superior to placebo.
  • Figure 4 shows the change of body weight (in grams) in rats administered with cesium canrenoate (Cs-can) at dosage of 0.2, 1, 10, or 20 mg/kg/day. As shown in Figure 4, rats receiving 0.2, 1 or 10 mg/kg/day of cesium canrenoate had less body weight loss than those in the placebo group.
  • Cs-can cesium canrenoate
  • lean mass was determined at the end of the study.
  • the sham lean body mass was 48.6 ⁇ 1.5 grams.
  • Figure 5 shows the change in lean body mass (in grams) of rats that were administered with cesium canrenoate at dosages of 0.2, 1 . 10, or 20 mg/kg/day. As shown in
  • Figure 6 shows the change in fat mass (in grams) of rats administered with cesium canrenoate at dosages of 0.2, 1, 10, or 20 mg/kg/day. As shown in Figure 6, rats receiving cesium canrenoate at 0.2, 1, 10, or 20 mg/kg/day or higher had less fat mass loss than those in the placebo group.
  • Figure 7A shows the weight of white adipose tissue (WAT) (in grams) of rats administered with cesium canrenoate al dosages of 0.2, 1 . 10, or 20 mg/kg/day.
  • WAT white adipose tissue
  • FIG 7B shows the weight of brown adipose tissue (BAT) (in grams) of rats administered with cesium canrenoate at dosages of 0.2, 1 , 10, or 20 mg/kg/day.
  • BAT brown adipose tissue
  • Cesium canrenoate at dosages of 0.2, I, 10, or 20 mg/kg/day protect BAT mass and thus treated rats retained better control of thermogenesis.
  • Figure 8A shows the tumor volume (in ml) of rats administered with cesium canrenoate at dosages of 0.2, 1 , 10, or 20 mg/kg/day.
  • Figure 8B shows the total number of cells in a tumor of rats administered with cesium canrenoate at dosages of 0.2, 1, 10, or 20 mg/kg/day. As shown in Figures 8A and 8B, rats receiving cesium canrenoate did not have any signi [leant effects on tumor growth compared to those in the placebo group.

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Abstract

The present invention relates to canrenoate compositions and uses thereof, including uses of the canrenoate compositions for treating cancer. The canrenoate compositions can also be used for treating cachexia, preventing body weight loss in subjects, preventing loss of lean body mass, preventing loss of adipose tissue in subjects, improving quality of life in subjects, and prolonging survival in cancer patients.

Description

CANRENOATE COMPOSITIONS FOR TREATING CANCER
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the priority benefit of U.S. Provisional Patent Application Serial No. 61/786,238, filed March 14, 2013, which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] The present invention relates to canrenoate compositions and uses thereof, including uses of the canrenoate compositions for treating cancer.
BACKGROUND
[0003] Cancer is the second most common cause of death in the United Stales, exceeded only by heart disease. In the United States, cancer accounts for 1 of every 4 deaths. With population growth and aging of the population, the number of new cancer patients is expected to double to 2.6 million people by 2050.
[0004] Liver cancer is the sixth most common cancer worldwide and the third most common cause of cancer-related death. The most common form of liver cancer is hepatocellular carcinoma (HCC). HCC is often diagnosed late in the course of clinical manifestation. As a result, only 10-15% of patients are candidates for curative surgery. For the majority of HCC patients, systemic chemotherapies or supportive therapies are the mainstay treatment options. Nevertheless, most chemotherapeutic agents show limited effectiveness and have not been able to improve patient survival. See ,e.g. Ma YT. Palmer DH. Impact of restricting access to high-cost medications for hepatocellular carcinoma. [Review] Expert Review of Pharmacoeconomics & Outcomes Research. 12(4):465-73, 2012 Aug.
[0005] Potassium canrenoate is an aldosterone antagonist, which is a diuretic drug that antagonizes the action of aldosterone at mineralcortocoid receptors. Aldosterone antagonists are often used with other drugs for the management of chronic heart failure. Potassium canrenoate is not approved in the United States, but is used clinically in Europe and other countries as a diuretic. [00061 The disclosure of all publications, patents, patent applications, and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.
BRIEF SUMMARY OF THE INVENTION
[0007] The present invention relates to canrenoate compositions and uses thereof, including uses of the canrenoate compositions for treating cancer.
[0008] The present disclosure provides, in some embodiments, a compound of the formula:
Figure imgf000003_0001
wherein Vf is an ion of an alkali metal (Group 1) selected from the group consisting of Li+ (lithium), Na÷ (sodium), Rb÷ (rubidium), and Cs" (cesium).
[0009] The present disclosure provides, in some embodiments, a compound of the formula:
Figure imgf000003_0002
[0010] The present disclosure provides, in some embodiments, a pharmaceutical composition comprising cesium canrenoate.
[0011] The present disclosure provides, in some embodiments, a method of treating cancer in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
[0012] The present disclosure provides, in some embodiments, a method of prolonging survival of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
[00131 The present disclosure provides, in some embodiments, a method of preventing body weight loss of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. [001 1 The present disclosure provides, in some embodiments, a method of improving quality of life in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
[0015] The present disclosure provides, in some embodiments, a method of preventing and/or treating loss of lean body mass in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
[0016] The present disclosure provides, in some embodiments, a method of preventing and/or treating muscle wasting in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
[0017] In some embodiments, the canrenoate is a pharmaceutically acceptable salt of canrenoate. in some embodiments, the canrenoate is selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the canrenoate is cesium canrenoate. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. In some embodiments, the cancer is selected from the group consisting of liver cancer, lung cancer, ovarian cancer, pancreatic cancer, melanoma, and brain cancer. In some embodiments, the cancer is selected from the group consisting of gastric cancer, pancreatic cancer, lung, esophageal, colorectal, head and neck cancer, and hematological malignancies. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is an early stage cancer. In some embodiments, the cancer is a late stage cancer. In some embodiments, the composition is administered orally. In some embodiments, the amount of canrenoate in the composition is about 10 to about 200 mg daily. In some embodiments, the composition is administered daily or twice daily.
[0018] The present disclosure provides, in some embodiments, a kit comprising a pharmaceutical composition comprising a canrenoate and instruction for using the pharmaceutical composition for treating cancer.
[001 ] Additional embodiments, features, and advantages of the invention wi ll be apparent from the following detailed description and through practice of the invention.
[0020] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference, in their entirety. BRIEF DESCRIPTION OP THE FIGURES
[0021] Figure 1 is a diagram of the design study involving the Yoshida Hepatoma Model for cancer cachexia.
[0022] Figure 2 is a graph showing the percent survival of rat populations that were administered various dosages of cesium canrenoate (Cs-can). Comparison to placebo (plac) was also provided. The ample size in the population is indicated by "n." "FIR" refers to hazard ratio. "CI" refers to confidence interval. "95% CF* is 95% confidence interval, "p" refers to p-value.
[0023] Figure 3 is a graph showing the percent survival of rat populations that were administered with various dosages of cesium canrenoate (Cs-can). The sample size in the population is indicated by "n." "HR" refers to hazard ratio. "CI" refers to confidence interval. "95% CI" is 95% confidence interval, "p" refers to p-value.
[0024] Figure 4 is a graph showing the change in body weight (in grams ("g")) of rat populations that were administered with cesium canrenoate. Comparison to placebo (P) was also provided. The asterisk (*) indicates p<0.()5. The two asterisks (**) indicate p<0.01 vs placebo.
[0025] Figure 5 is a graph showing the change in lean body mass (in grams ("g")) of rat populations that were administered with various dosages of cesium canrenoate.
Comparison to placebo (P) was also provided.
100261 Figure 6 is a graph showing the change in fat mass (in grams ("g")) of rat populations that were administered with cesium canrenoate. Comparison to placebo (P) was also provided. The two asterisks (**) indicate p<0.01 versus placebo. The three asterisks (***) indicate pO.001 vs placebo.
[0027] Figure 7A is a graph showing the weight of white adipose tissue (WAT) (in grams ("g")) of rat populations that were administered with various dosages of the cesium canrenoate at the endpoint of the study. Figure 7B is a graph showing the weight of brown adipose tissue ( BA T) (in grams ("g")) of rat populations that were administered with various dosages of the cesium canrenoate at the endpoint of the study. Comparison to placebo (P) and sham (S) was also provided. The three asterisks (***) indicate p<0.001 vs placebo.
[0028] Figure 8A is a graph showing the change in tumor volume (in mL) of rat populations that were administered with dosages of the cesium canrenoate. Comparison to placebo (P) was also provided. Figure 8B is a graph showing the change in total cells in a tumor of rat populations that were administered with various dosages of cesium canrenoate. Comparison to placebo (P) was also provided. The asterisk (*) indicates p<0.05 vs placebo.
[0029] Figure 9 is a graph showing effect of cesium canrenoate or doxorubicin on tumor growth, as assessed by BrdU incorporation and XTT assay with various tumor cells, namely, Kelly (neuroblastoma), Hela-93 (cervix carcinoma), and B16V (melanoma).
DETAILED DESCRIPTION OF THE INVENTION
[0030] The present invention provides use of canrenoate compositions for achieving beneficial results in individuals having cancer, such as treating cancer, prolonging survival, preventing body weight loss, improving quality of life, and/or treating muscle wasting. Also provided are pharmaceutical compositions comprising canrenoates (such as cesium canrenoate).
[0031 j The present invention is based on the surprising finding that canrenoate, specifically cesium canrenoate, significantly improved survival in animals having cancer in an experiment in which an animal was inoculated with hepatocellular carcinoma cells in a well-established animal model of hepatoma. Other advantageous effects of the compositions were observed on preventing body weight loss, preserving lean body mass, and preserving fat mass in the animals. Moreover, these effects were observed in animals not developing cachexia or before the animals develop cachexia, suggesting mat at least some of the effect of cesium canrenoate that we observed may be independent and/or in addition to its effect on treating cancer cachexia.
100321 Thus, the present invention in one aspect provides methods of treating cancer, prolonging survival, preventing body weight loss, preventing and/or treating muscle wasting, or improving quality of life in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
[00331 In another aspect, there are provided pharmaceutical compositions comprising cesium canrenoate.
[0034] Also provided are kits, unit dosages, medicines, and articles of manufacture that are useful for methods described herein.
Definitions
[0035] The following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings. [00361 As used herein, "treatment"' or "treating" is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, delay or slowing the progression of the disease, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival. Also encompassed by "treatment" is a reduction of pathological consequence of cancer. The methods of the invention contemplate any one or more of these aspects of treatment.
[0037] The term "individual" refers to a mammal and includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is a human.
[0038] As used herein, an "at risk" individual is an individual who is at risk of developing cancer. An individual "at risk" may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein. "At risk" denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of cancer. An individual having one or more of these risk factors has a higher probability of developing cancer than an individual without these risk factor(s).
[0039] "Adjuvant setting" refers to a clinical setting in which an individual has had a history of cancer, and generally (but not necessarily) been responsive to therapy, which includes, but is not limited to, surgery (e.g. , surgery resection), radiotherapy, and chemotherapy. Ilowever, because of their history of cancer, these individuals are considered at risk of development of the disease. Treatment or administration in the "adjuvant setting" refers to a subsequent mode of treatment. The degree of risk (e.g., when an individual in the adjuvant setting is considered as "high risk" or "low risk") depends upon several factors, most usually the extent of disease when first treated.
[0040] "Neoadjuvant setting" refers to a clinical setting in which the method is carried out before the primary/definitive therapy.
[0041] As used herein, "delaying" the development of a disease means to defer, hinder, slow, retard, stabilize, and/or postpone development: of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. A method that "delays" development of a disease is a method that reduces probability of disease development in a given time frame and/or reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
[0042] As used herein, by "combination therapy" is meant that a first agent be administered in conjunction with another agent. "In conjunction with" refers to
administration of one treatment modality in addition to another treatment modality, such as administration of a nanoparticle composition described herein in addition to administration of the other agent to the same individual. As such, "in conjunction with" refers to administration of one treatment modality before, during, or after delivery of the other treatment modality to the individual. Such combinations are considered to be part of a single treatment regimen or regime.
[0043] The term "effective amount" used herein refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease such as ameliorate, palliate, lessen, and/or delay one or more of its symptoms.
[0044] The term "simultaneous administration," as used herein, means that a first therapy and second therapy in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes. When the first and second therapies are administered simultaneously, the first and second therapies may be contained in the same composition (e.g. , a composition comprising both a first and second therapy) or in separate compositions (e.g. , a first therapy in one composition and a second therapy is contained in another composition).
[0045] As used herein, the term "sequential administration" means that the first therapy and second therapy in a combination therapy are administered with a time separation of more than about 1 5 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the first therapy or the second therapy may be administered first. The first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.
[0046] As used herein, the term "concurrent administration" means that the administration of the first therapy and that of a second therapy in a combination therapy overlap with each other.
[0047] As used herein, by "pharmaceutically acceptable" or "pharmacologically compatible" is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxieological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
[0048] "Progression free survival" (PFS) indicates the length of time during and after treatment that the cancer does not grow. Progression-free survival includes the amount of time individuals have experienced a complete response or a partial response, as well as the amount of time individuals have experienced stable disease. In some embodiments, an individual has a capacity to accept more courses of chemotherapy during progression free survival.
[0049] The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a subject, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from
pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, lithium, sodium, potassium, rubidium, cesium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.
[0050] The term "salt thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intemiediate compounds that arc not intended for administration to the subject. By way of example, salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.
[0051] "Solvate" refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, Λ',Λ'-dimethylformamide, tetrahvdrofuran, dimemylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.
[0052] It will be appreciated that the term "or a salt or solvate thereof is intended to include all permutations of salts and solvates, such as a solvate of a pharmaceutically acceptable salt of a subject compound.
[0053] As used herein, ''in conjunction with" refers to administration of one treatment modality in addition to another treatment modality. As such, "in conjunction with" refers to administration of one treatment modality before, during or after administration of the other treatment modality to the individual .
[0054] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly indicates otherwise.
[0055] Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X."
[0056] It is understood that aspects and variations of the invention described herein include "consisting" and/or "consisting essentially of aspects and variations.
Methods of the present invention
[0057] The present application in one aspect provides methods of treating cancer. In some embodiments, there is provided a method of treating cancer in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising a canrenoate. In some embodiments, the composition comprises a
pharmaceutically acceptable salt of canrenoate. n some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of treating cancer in an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. [00581 In some embodiments, there is provided a method of prolonging survival of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of prolonging survival of an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. In some embodiments, the method prolongs the survival of the individual by at least any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 18, or 24 months.
[0059] In some embodiments, there is provided a method of prolonging progression- free survival in an individual with cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium cam-enoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of prolonging progression-free survival in an individual with cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia.
[0060] In some embodiments, there is provided a method of alleviating one or more symptoms associated with cancer in an individual, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of alleviating one or more symptoms associated with cancer in an individual, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia.
[0061 ] In some embodiments, there is provided a method of preventing body weight loss of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of preventing body weight loss of an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. In some embodiments, the body weight loss of the individual is no more than about 10% (for example no more than about any of 10%, 9%, 8%, 7%, 6%, or 5%) of the total body weight. In some embodiments, the body weight loss is evaluated over a time period of about 1 month to 2 years (for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12. 13, 14, 15, 16, 17, 18, 19 , 20 . 21, 22, 23, or 24 months).
[0062] In some embodiments, there is provided a method o f treating muscle wasting ill an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate. sodium canrenoate. and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of treating muscle wasting in an individual having cancer, comprising administering
(such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. In some embodiments, the muscle wasting of the individual i s no more than about 10% (for example no more than about any of 10%, 9%, 8%>, 7%, 6%, or 5%) of the total body weight. In some etnbodiments, the muscle wasting is evaluated over a time period of about 1 month to 2 years
(for example, about 1 , 2, 3, 4, 5, 6, 7, 8. 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 , 20 , 21. 22,
23, or 24 months). In some embodiments, the method leads to a reduction of muscle wasting, i.e., a slow-down of muscle loss in the individual. In some embodiments, the method leads to a reversal of muscle wasting, i.e., an increase in muscle weight in the individual.
[0063] In some embodiments, there is provided a method of preventing loss of lean body mass in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, there is provided a method of treating loss of lean body mass in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of preventing loss of lean body mass in an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about
200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. In some embodiments, the loss of lean body mass of the individual is no more than about 10% (for example no more than about any of 10%, 9%>,
8%, 7%, 6%, or 5%) of the total lean body mass. In some embodiments, the loss of lean body mass is evaluated over a time period of about 1 month to 2 years (for example, about 1 , 2, 3,
4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13. 14, 15, 16. 17, 18, 19 , 20 , 21, 22, 23, or 24 months). [006 1 In some embodiments, there is provided a method of preventing (or delaying) development of cancer cachexia in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of preventing (or delaying) development of cancer cachexia in an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 0 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia.
[0065] In some embodiments, the individual has one or more symptoms of cancer cachexia, and the methods described herein can be used to improve one or more symptoms of cancer cachexia in an individual having cancer, the methods comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of improving one or more symptoms of cancer cachexia in an individual having cancer, comprising administering (such as orally administering) to the individual an e ffective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. Symptoms of cachexia include but not l imited to, loss of weight, muscle atrophy, fatigue, weakness, and loss of appetite.
[0066] In some embodiments, there is provided a method of improving quality of life of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium cam'enoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of improving quality of life of an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. Improvement of quality of life can be assessed, for example, by food intake, locomotive activity, and improvement in fatigue or dyspnea or global patient assessment scores, in short physical performance battery scores, in standard clinical assessment of functional performance, muscle strength, gait speed, leg strength and hand grip strength, 6-minute corridor walk test, stair climbing power, ability to tolerate courses of chemotherapy and other tests or instruments or questionnaires assessing patient quality of life.
[0067] In some embodiments, there is provided a method of increasing food intake of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of improving food intake in an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia.
[0068] In some embodiments, there is provided a method of increasing locomotive activity of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate. and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of improving locomotive activity of an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia.
[0069] In some embodiments, there is provided a method of improvi ng fatigue or dyspnea an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of improving fatigue or dyspnea in an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia.
100701 In some embodiments, there is provided a method of preventing loss of body fat in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodi ment s, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. in some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of preventing loss of body fat in an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate composition in the composition is about 1 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. In some embodiments, the loss of body fat of the individual is no more than about 10% (for example no more than about any of 10%, 9%, 8%, 7%, 6%. or 5%) of the total body fat. In some embodiments, the loss of body fat is evaluated over a time period of about 1 month to 2 years (for example, about 1 , 2. 3. 4. 5, 6. 7, 8, 9, 10. 11, 12, 13. 14, 15, 16. 17, 18, 19 5 20 , 21 , 22, 23, or 24 months).
[0071] Adipose tissue appears as two types: white adipose tissue and brown adipose tissue. White adipose tissue cells contain a single large fat droplet, which forces the nucleus to be squeezed into a thin rim at the periphery. They have receptors for insulin, growth hormones, norepinephrine and glucocorticoids. White adipose tissue is used as a store of energy. White adipose tissue also acts as a thermal insulator, helping to maintain body temperature. Brown adipose tissue cells contain numerous smaller droplets and a higher number of (iron containing) mitochondria, which gives a brown color to the cell. Brown fat also contains more capillaries than white fat, since it has a greater need for oxygen than most tissues. The methods provided herein are useful for preventing loss of both white adipose tissue and brown adipose tissue in an individual having cancer.
[0072] In some embodiments, there is provided a method of providing
cardioprotective effects in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate). In some embodiments, there is provided a method of preventing wasting of a heart muscle in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate). In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of providing cardioprotective effects in an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate composition in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, there is provided a method of preventing wasting of a heart muscle in an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate composition in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. Cardioprotective effects include one or more of the following: preventing and treating atrial fibrillation and ventricular fibrillation, improving arrhythmias, improving diastolic function of a heart, and preventing and treating fibrosis of a heart. The methods described herein are therefore useful for any one or more of these cardioprotective effects.
[0073] In some embodiments, there is provided a method of preventing sudden death and/or cardiovascular death in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate). In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of preventing sudden death and/or cardiovascular death in an individual having cancer, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate composition in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia.
[0074] The methods described herein may be useful for any one or more of the following: 1 ) preventing loss of skeletal muscle associated with cancer; 2) treating fatigue associated with cancer; 3) treating muscle weakness associated with cancer; 4) strengthening skeletal muscle in an individual having cancer; 5 ) treatment of muscle wasting associated with cancer; 6) treating dyspnea associated with muscle changes in cancer; and 7) improving fatigue resistance of muscle in cancer. Skeletal muscle includes, but is not limited to, gastrocnemius muscle, tibialis muscle, soleus muscle, and extensor digitorum longus (EDL) muscle, quadriceps, hamstrings, postural muscles, hand muscles, triceps, biceps, masseter and other jaw muscles, and intercostal and other respiratory muscles. The present application encompasses any of these methods.
[0075] In some embodiments, the individual has been diagnosed with or is suspected of having cancer. In some embodiments, the individual exhibits one or more symptoms associated with cancer. In some embodiments, the individual has a low tumor burden. In some embodiments, the individual is a human. In some embodiments, the individual is at least about any of 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the individual is no more than about any of 35, 30, 20, 15, 10, 5, or 1 year old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the individual has a single lesion at presentation. In some embodiments, the individual has multiple lesions at presentation. In some embodiments, the individual has been previously treated for cancer. In some embodiments, the individual has not previously been treated for cancer.
[0076] The cancer described herein can be of any stage. In general, cancers can be evaluated according to Overall Stage Grouping, outlined as follows:
Figure imgf000019_0001
[0077] In some embodiments, the cancer is surgically treatable. In some embodiments, the cancer is not surgically treatable.
[0078] In some embodiments, the cancer is an early stage cancer, such as Stage 0, Stage I, or Stage II. In some embodiments, the cancer is a late stage cancer, such as Stage III or Stage IV. In some embodiments, the cancer is Stage 111 A. In some embodiments, the cancer is Stage IIIB or Stage IV. In some embodiments, the cancer is Stage IV.
1007 1 hi some embodiments, the cancer is early stage cancer, non-metastatic cancer, primary cancer, advanced cancer, locally advanced cancer, metastatic cancer, cancer in remission, or recurrent cancer. In some embodiments, the cancer is localized resectable, localized unresectable, or unresectable. In some embodiments, the cancer is a progressive cancer. In some embodiments, the cancer is substantially refractory to hormone therapy. In some embodiments, the cancer is HER2 positive. In some embodiments, the cancer is HER2 negative. In some embodiments, the cancer is estrogen receptor and/or progesterone receptor positive. In some embodiments, the cancer is estrogen receptor and/or progesterone receptor negative.
[0080] The methods provided herein can be practiced in an adjuvant setting.
Alternatively, the methods can be practiced in a neoadjuvant setting, i.e., the method may be carried out before the primary/definitive therapy. In some embodiments, the method is a first line therapy. In some embodiments, the method is a second line therapy.
[0081 ] The methods described herein can be useful for treating and providing beneficial effects to individuals having a cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is adenocarcinoma. In some embodiments, the cancer is sarcoma.
[0082] In some embodiments, the cancer is any one of the following: biliary cancer
(e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., glioblastoma, meningioma; glioma, e.g., astrocytoma, oligodendroglioma; meduUoblastoma), cervical cancer (e.g., cervical adenocarcinoma), colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), esophageal cancer, gastric cancer
(e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer
(e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC)), kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g.. bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC). adenocarcmoma of the lung), leuketma (e.g., acute lymphoblastic leukemia
(ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (( M L), chronic lymphocytic leukemia (CLL)). lymphoma (e.g., Hodgkin lymphoma (IIL), non-Hodgkin lymphoma (NHL), follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL)), multiple myeloma (MM), myelodysplasia syndrome (MDS), myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential
thrombocythemia (F,T), agnogenic myeloid metaplasia (AMM) a.k.a. primary myelofibrosis
(PMF), chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)), prostate cancer (e.g., prostate adenocarcinoma), skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA). melanoma, basal cell carcinoma (BCC)) and soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, rhabdomyosarcoma, myxosarcoma).
[0083] In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, meduUoblastoma, colorectal cancer, head and neck cancer, lung cancer (e.g., small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)), leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogeneous leukemia (CML), chronic lymphocytic leukemia (CLL)), lymphoma (e.g., Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL)), multiple myeloma (MM), chronic myeloproliferative disorder (primary myelofibrosis, polycythemia vera, essential thrombocvtemia), osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, basal cell carcinoma (BCC)) and chondrosarcoma.
1008 1 hi some embodiments, the cancer is a cancer that is difficult to treat.
Examples of cancers that are difficult to treat include, but are not limited to, brain cancer (such as glioblastoma), liver cancer, lung cancer, ovarian cancer, pancreatic cancer, and skin cancer (such as melanoma).
[0085] In some embodiments, the cancer is a cancer that is or is known to be associated with cachexia. Examples of cancers that are associated with cachexia include, but are not limited to, gastric cancer, pancreatic cancer, lung, esophageal, colorectal, head and neck cancer, and hematological malignancies.
[0086] In some embodiments, the cancer is liver cancer, such as hepatocarcinoma
("HCC"), hepatoblastoma, cholangiocarcinoma, angiosarcoma, hem angiosarcoma, or lymphoma of the liver. In some embodiments, the liver cancer (such as HCC) is early stage, non-metastatic, primary, advanced, locally advanced, metastatic, liver cancer (such as HCC) in remission, or recurrent liver cancer (such as recurrent HCC). In some embodiments, the liver cancer (such as HCC) is localized resectable (i.e., tumors that are confined to a portion of the liver that allows for complete surgical removal), localized unresectable (i.e., the localized tumors may be unresectable because crucial blood vessel structures are involved or because the liver is impaired), or unresectable (i.e., the tumors involve all lobes of the liver and/or has spread to involve other organs (e.g., lung, lymph nodes, bone). In some embodiments, the liver cancer (such as HOC) is, according to TNM classifications, a stage 1 tumor (single tumor without vascular invasion), a stage II tumor (single tumor widt vascular invasion, or multiple tumors, none greater than 5 cm), a stage III tumor (multiple tumors, any greater than 5 cm, or tumors involving major branch of portal or hepatic veins), a stage IV tumor (tumors with direct invasion of adjacent organs other than the gallbladder, or perforation of visceral peritoneum), l tumor (regional lymph node metastasis), or Ml tumor (distant metastasis). In some embodiments, the liver cancer (such as HCC) is, according to AJCC (American Joint Commission on Cancer) staging criteria, stage Tl, T2, T3, or T4 HCC. In some embodiments, the liver cancer is any one of liver cell carcinomas, fibrolamellar variants of HCC, and mixed hepatocellular cholangiocarcinomas.
[0087] In some embodiments, the individual is of Asian ancestry. In some embodiments, the individual is HBsAg positive. In some embodiments, the individual is HBsAg negative. In some embodiments, the individual has underlying liver cirrhosis. In some embodiments, the individual does not have the underlying liver cirrhosis. In some of embodiments, the individual is genetically or otherwise predisposed (e.g., having a risk factor) to developing liver cancer (such as HCC). These risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease (e.g., hepatitis B or hepatitis C viral infection, liver cirrhosis), genetic (e.g., hereditary) considerations, and environmental exposure. In some embodiments, the individuals at risk for liver cancer (such as HCC) include, e.g., those having relatives who have experienced liver cancer (such as HCC), and those whose risk is determined by analysis of genetic or biochemical markers.
[0088] Thus, for example, in some embodiments, there is provided a method of treating liver cancer (such as HCC) in an individual having liver cancer (such as HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of treating liver cancer (such as HCC) in an individual having liver cancer (such as HCC), comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. Γη some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia.
[0089] In some embodiments, there is provided a method of prolonging survival of an individual having liver cancer (such as HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutical ly acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of prolonging survival of an individual having liver cancer (such as HCC), comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. In some embodiments, the method prolongs the survival of the individual by at least any of 1, 2, 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, 18, or 24 months.
[0090] In some embodiments, there is provided a method of preventing body weight loss of an individual having liver cancer (such as HCC). comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, there is provided a method of preventing (or delaying) development of cancer cachexia in an individual having liver cancer (such as HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, there is provided a method of preventing loss of lean body mass in an individual having liver cancer (such as HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, there is provided a method of preventing loss of body fat in an individual having liver cancer (such as
HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia.
[0091] In some embodiments, there is provided a method of alleviating one or more symptoms associated with liver cancer (such as HCC) in an individual, comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of alleviating one or more symptoms associated with liver cancer (such as HCC) in an individual, comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia.
[0092] In some embodiments, there is provided a method of prolonging progression- free survival in an individual with liver cancer (such as HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of prolonging progression-free survival in an individual with liver cancer (such as HCC), comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual lias no symptom of cancer cachexia. In some embodiments, the individual has one or more symptoms of cancer cachexia. [00931 In some embodiments, there is provided a method of treating muscle wasting in an individual having liver cancer (such as HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, me composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of treating muscle wasting in an individual having liver cancer (such as HCC). comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia. In some embodiments, the method leads to a reduction of muscle wasting, i.e., a slow-down of muscle loss. In some embodiments, the method leads to a reversal of muscle wasting, i.e., an increase in muscle weight.
[0094] In some embodiments, there is provided a method of improving quality of life in an individual having liver cancer (such as HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. in some embodiments, there is provided a method of improving quality of life in an individual having liver cancer (such as HCC), comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia.
[0095] In some embodiments, there is provided a method of increasing food intake of an individual having liver cancer (such as HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate. and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of increasing food intake of an individual having liver cancer (such as HCC), comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is ahout 10 mg to about 200 rag (such as about 20 to about 50 mg. for example) per day. In some embodiments, the individual has no symptom of cancer cachexia.
[0096] In some embodiments, there is provided a method of increasing locomotive activity of an individual having liver cancer (such as HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of increasing locomotive activity of an individual having liver cancer (such as HCC), comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg lo about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia.
|0097| In some embodiments, there is provided a method of improving fatigue and dyspnea in an individual having liver cancer (such as HCC), comprising administering to the individual an effective amount of a composition comprising canrenoate. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate. In some embodiments, there is provided a method of improving fatigue and dyspnea in an individual having liver cancer (such as HCC), comprising administering (such as orally administering) to the individual an effective amount of a composition comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition is about 10 mg to about 200 mg (such as about 20 to about 50 mg, for example) per day. In some embodiments, the individual has no symptom of cancer cachexia.
[0098] In some embodiments, the individual being treated is no more than about 18 years old. For example, in some embodiments, there is provided a method of treating a cancer in an individual having pediatric cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate, wherein the individual is no more than about 18 years old. In some embodiments, there is provided a method of promoting growth in an individual having a cancer, wherein the individual is no more than about 18 years old. In some embodiments, there is provided a method of preventing loss of growth in an individual having cancer, wherein the individual is no more than about 1 8 years old. In some embodiments, there is provided a method of treating muscle wasting in an indi vidual having cancer, wherein the individual is no more than about 18 years old. In some embodiments, there is provided a method of prolonging survival of an individual having cancer, wherein the individual is no more than about 18 years old. In some embodiments, there is provided a method of improving quality of life in an individual having cancer, wherein the individual is no more man about 18 years old. In some embodiments, the individual is no more than about any of 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2. or 1 year old. In some embodiments, the individual is about 9 to about 15 years old. In some embodiments, the individual is about 5 to about 9 years old. In some embodiments, the individual is about 1 to about 5 years old. In some embodiments, the individual is no more than about 1 year old, such as about 6 months old to about 1 year old, less than about 6 months old, or less than about 3 months old. In some embodiments, the composition comprises a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition comprises a canrenoate selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate. In some embodiments, the composition comprises cesium canrenoate.
[0099] In some embodiments, the individual no more than about 18 years old for the methods described herein has a solid tumor. In some embodiments, the solid tumor is sarcoma. In some embodiments, the solid tumor is carcinoma (such as adenocarcinoma). In some embodiments, the solid tumor is a neuroendocrine tumor. In some embodiments, the solid tumor is a cancer of the connectt\'e tissue. In some embodiments, the solid tumor is a cancer arising from mesenchymal cells (e.g., skeletal muscle progenitor cells). In some embodiments, the solid tumor is a soft tissue tumor (such as soft tissue sarcoma). In some embodiments, the solid tumor is selected from the group consisting of neuroblastoma, rhabdomyosarcoma, osteosarcoma, retinoblastoma, CNS tumor, Wilm's tumor, and E wing's sarcoma. In some embodiments, the solid tumor is an abdominal tumor, a soft tissue tumor, a bone tumor, or an eye tumor. In some embodiments, the solid tumor is a brain tumor. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is a soft tissue sarcoma, such as rhabdomyosarcoma. In some embodiments, the solid tumor is neuroblastoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is retinoblastoma. In some embodiments, the solid tumor is a heritable retinoblasmoma.
[0100] In some embodiments, the individual no more than about 18 years old for the methods described herein has a central nervous system (CNS) tumor, such as an astrocytoma, a brain stem glioma, an ependymoma, a germ cell tumor, or a medulloblastoma. Childhood central nervous system tumors do not typically spread outside the brain and spinal cord. In some embodiments, the CNS tumor is a recurrent CNS tumor.
[0101 ] In some embodiments, the individual no more than 18 years old for the methods described herein has Wilms' tumor (also known as nephroblastoma). In some embodiments, the individual has Stage I Wilms' tumor. In some embodiments, the mdividual has Stage II Wilms' tumor. In some embodiments, the individual has Stage III Wilms' tumor. In some embodiments, the mdividual has Stage IV Wilms' tumor. In some embodiments, the individual has Stage V Wilms' tumor. In some embodiments, the individual has recurrent Wilms' tumor.
101021 In some embodiments, the individual no more than 18 years old for the metiiods described herein has soft tissue sarcoma. In some embodiments, the individual has Stage 1 soft tissue sarcoma. In some embodiments, the individual has Stage II soft tissue sarcoma. In some embodiments, the individual has Stage III soft tissue sarcoma. In some embodiments, the individual has Stage IV soft tissue sarcoma. In some embodiments, the individual has recurrent soft tissue sarcoma.
[0103] In some embodiments, the individual no more than about 18 years old for the methods described herein has Ewing's sarcoma. In some embodiments, the individual has localized Ewing's sarcoma. In some embodiments, the individual has metastatic Ewing's sarcoma. In some embodiments, the individual has Stage 1 Ewing's sarcoma. In some embodiments, the individual lias Stage 2 Ewing's sarcoma. In some embodiments, the individual has Stage 3 Ewmg's sarcoma. In some embodiments, the individual has Stage 4 Ewmg's sarcoma. In some embodiments, the individual has recurrent Ewing's sarcoma.
[0104] In some embodiments, the individual no more than about 18 years old for the methods described herein has hepatoblastoma.
[0105] In some embodiments, the individual no more than about 18 years old for the methods described herein has a haematological disease, such as leukemia (for example acute leukemia).
Canrenoate compositions
[0106] The methods described herein comprise administration of compositions comprising a pharmaceutically acceptable salt of canrenoate or canrenoic acid:
Figure imgf000029_0001
wherein Ivf is an ion of an alkali metal (Group 1), such as Li1 (lithium), Na* (sodium), K f (potassium), Rb+ (rubidium), and Cs+ (cesium). As used herein, "canrenoate" or "a canrenoate composition" comprises a pharmaceutically acceptable salt of canrenoate and/or canrenoic acid. In some embodiments, for the use in methods, a pharmaceutically acceptable salt of canrenoate is provided. In some embodiments, for the use in methods, cesium canrenoate is provided. The present disclosure also provides such compositions which are useful for the methods disclosed herein.
[0107] The present disclosure, in one aspect, provides a compound of the formula:
Figure imgf000029_0002
wherein M : is an ion of an alkali metal (Group 1) selected from the group consisting of Li4 (lithium), Na+ (sodium), Rb+ (rubidium), and Cs' (cesium), in some embodiments, JVT is Li+ (lithium). In some embodiments, M1 is Na1 (sodium). In some embodiments, M1 is Rb1 (rubidium). In some embodiments, M÷ is Cs+ (cesium).
[0108] The present disclosure, in one aspect, provides a compound of the formula:
Figure imgf000030_0001
(cesium canrenoate).
[0109] The systemic (IUPAC) name for cesium canrenoate is cesium 3-
Figure imgf000030_0002
7-hydroxy 0J3<limethyl-3-oxo-2,8.9,l l J2,14,15,16- octahydro-1 /-/-cyclopenta[a |phenanthren-l 7-yl]propanoate. Caesium canrenoate has the chemical formula: C22II29O CS. The molecular weight is 490.37.
[0110] The pharmaceutical salts of canrenoate can be obtained commercially or through synthesis with procedures known in the art.
Figure imgf000030_0003
[0111] In some embodiments, pharmaceutical salts of canrenoate can be synthesized from camenoic acid. Referring to the scheme above, potassium canrenoate can be obtained commercially. Canrenoic acid can be synthesized from potassium canrenoate, such as with adjustment of the pli of the reaction solution. Reaction of camenoic acid with an electrolyte having an alkali metal (Group 1) would yield a pharmaceutical salt of canrenoate. In some embodiments, the electrolyte contains Li+ (lithium), Na÷ (sodium), Rb+ (rubidium), or Cs" (cesium). In some embodiments, cesium hydroxide (CsOH) can be used to prepare cesium canrenoate.
[01121 The present disclosure provides, in some embodiments, a compound having the characteristics of a compound prepared by reaction of canrenoic acid and a cesium electrolyte (such as cesium hydroxide). By having the characteristics of a compound prepared by certain processes, the resulting compound has properties that are the same or similar to a compound prepared by the process. In some embodiments, the properties that can be measured and compared are molecular weight, Ή-NMR spectrum, IR spectrum, and melting point.
[0113] The present disclosure provides a compound of the formula:
Figure imgf000031_0001
[01 14] The present disclosure provides a composition comprising a compound formula:
Figure imgf000031_0002
[0115] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition further comprises other salt forms of canrenoate, such as lithium canrenoate, sodium canrenoate, potassium canrenoate, or rubidium canrenoate. In some embodiments, the composition further comprises potassium canrenoate. In compositions comprising mixtures of salt forms of canrenoate, in some embodiments, the composition comprises at least 50. 60, 70, 80, 90, 91. 92, 93, 94, 95, 96, 97, 98, or 99% w/w of cesium canrenoate, where the percentage w/w is calculated by using the weight of cesium canrenoate and the total weight of canrenoate with the other salt form. In some embodiments, the composition comprises both cesium canrenoate and potassium canrenoate, wherein the weight ratio of the cesium canrenoate and the potassium canrenoate in the composition is more than about any of 2: 1 , 5:1 ,10:1 , 20:1 , 30: 1 , 40: 1, 50:1, 60:1 , 70: 1 , 80: 1 , 90: 1 , or 100: 1.
[0116] The compositions described herein, in some embodiments, are present in pharmaceutical compositions. The pharmaceutical compositions may further comprise one or more pharmaceutically acceptable carrier (or excipients). A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In some embodiments, the pharmaceutical composition is sterile.
[Oil 7] Also provided herein are unit dosage forms comprising a pharmaceutical composition described herein. These unit dosage forms can be stored in a suitable packaging in single or multiple unit dosages and may also be further sterilized and sealed. Unit dosage forms can be provided, for example, in the form of tablets, capsules, vials, and any other forms described herein.
[01 8] In some embodiments, there is provided a composition (such as a pharmaceutical composition, for example a unit dosage) comprising canrenoate (such as cesium canrenoate), wherein the amount of canrenoate in the composition (such as pharmaceutical composition) is included in any of the following ranges: about 5 to about 10 mg, about 10 to about 20 mg, about 20 to about 30 mg, about 30 to about 40 mg, about 40 to abotit 50 mg, about 50 to about 60 mg, about 60 to about 70 mg, about 70 to about 80 mg, about 80 to about 90 mg, about 90 to about 100 mg, about 100 to about 1 10 mg, about 1 10 to about 120 mg, about 120 to about 130 mg, about 130 to about 140 mg, about 140 to about 150 mg, about 150 to about 160 mg. In some embodiments, the amount of canrenoate in the composition is about 20 to about 160 mg, including for example about 50 to about 150 mg, 80 to about 150 mg, about 90 to about 140 mg, about 100 to about 120 mg. In some embodiments, the composition is suitable for oral administration. In some embodiments, the composition is a pharmaceutically acceptable salt of canrenoate. In some embodiments, the composition is cesium canrenoate.
[0119] In some embodiments, the composition is provided in a slow release form.
[0120] Also provided are articles of manufacture comprising the compositions, formulations, and unit dosages described herein in suitable packaging for use in the methods of treatment, methods of administration, and dosage regimens described herein. Suitable packaging for compositions described herein are known in the art, and include, for example, vial (such as sealed vials), vessels (such as sealed vessels), ampules, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. These articles of manufacture may further be sterilized and/or sealed. Dosages and Administration Route
[0121] The dosage of the compositions described herein administered to an individual (such as a human) may vary with the particular composition, the method of administration, and the particular stage of cancer. The amount should be sufficient to produce a desirable response, such as a therapeutic or prophylactic response against cancer. In some embodiments, the amount of the composition is a therapeutically effective amount. In some embodiments, that amount of the composition is a prophvlactically effective amount. In some embodiments, the amount of total canrenoate in the composition is below the level that induces a toxicological effect (i.e., an effect above a clinically acceptable level of toxicity) or is at a level where a potential side effect can be controlled or tolerated when the composition is administered to the individual.
[0122] in some embodiments, the amount of canrenoate (such as cesium canrenoate) in the composition is included in any of the following ranges: about 0.5 to about 5 mg, about 5 to about 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 1 50 to about 1 75 mg, about 1 75 to about 200 mg. In some embodiments, the amount of canrenoate in the composition is included in any of the following ranges: about 5 to about 10 mg, about 10 to about 20 mg, about 20 to about 30 mg, about 30 to about 40 mg, about 40 to about 50 mg, about 50 to about 60 mg, about 60 to about 70 mg, about 70 to about 80 mg, about 80 to about 90 mg, about 90 to about 100 mg, about 100 to about 110 mg, about 1 10 to about 120 mg, about 120 to about 1 30 mg, about 1 0 to about 140 mg, about 140 to about 1 50 mg, about 150 to about 160 mg. In some embodiments, the amount of canrenoate (such as cesium canrenoate) in the composition is about 20 to about 160 mg. including for example about 50 to about 150 mg, 80 to about 150 mg, about 90 to about 140 mg, about 100 to about 120 mg.
[0123] In some embodiments, the amount of canrenoate (such as cesium canrenoate) in the composition includes at least about any of 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg. In some embodiments, the amount of canrenoate (such as cesium canrenoate) in the composition includes less than about any of 35 mg/kg, 30 mg/kg, 25 mg/kg, 20 mg/kg, 1 5 mg/kg, 1 0 mg/kg, 5 mg/kg, 2.5 mg kg, 2 mg/kg, 1 mg''kg, 0.5 mg/kg, or 0.1 mg/kg. [012 1 Exemplary dosing frequencies include, but are not limited to, weekly without break; weekly, three out of four weeks; once every three weeks; once every two weeks; weekly, two out of three weeks. In some embodiments, the composition is administered about once e er)' 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some embodiments, the composition is administered at least about any of 1 x, 2x, 3x, 4x, 5x, 6x, or 7x (i.e. , daily) a week. In some embodiments, the intervals between each administration are less than about any of 6 months, 3 months, I month, 20 days, 15, days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days. 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, the intervals belvveen each administration are more than about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, there is no break in the dosing schedule. In some embodiments, the interval between each administration is no more than about a week. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered at least once (such as at least any of 2x, 3x, or 4x) daily.
[0125] The administration of the composition can be extended over an extended period of time, such as from about a month up to about seven years or life-long. In some embodiments, the composition is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 18, 24, 30, 36, 48, 60, 72, or 84 months or life-long. In some embodiments, the composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week.
101261 The compositions described herein can be administered to an individual (such as human) via various routes, including, for example, intravenous, intra-arterial, intraperitoneal, intraportal, intrapulmonary, oral, inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, intraocular, intrathecal, transmucosal, and transdermal. In some embodiments, sustained continuous release formulation of the composition may be used.
[0127] Once improvement of the patient's disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic e ffect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis. Pharmaceutical Formulations and Administration
[0128] The pharmaceutical compositions described herein may be formulated as solutions, emulsions, suspensions, dispersions, or inclusion complexes such as cyclodextrins in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the embodiments may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.
[0129] For oral administration, the compositions may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP). sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or tale. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. The oral formulations may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
[0130] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di- glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
[0131] A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.
[0132] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaeeutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose,
carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
[0133] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the compositions may be provided in sterile aqueous solutions or suspensions, buff ered to an appropriate pH and isotonicity or in parenteral ly acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Formulations suitable for parenteral including intravenous administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[0134] Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose or an appropriate fraction thereof, of an active ingredient.
Drug Combinations
[0135] The methods of the embodiments comprise administering an effective amount of at least one compound of the embodiments; optionally the compound may be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful for treating a cancer afflicting the subject.
[0136] The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the embodiments or may be included with a compound of the embodiments in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to. or after administration of a compound of the embodiments.
[0137] In certain embodiments, the additional therapeutic agent is selected from the group consisting of progestins, corticosteroids, metoclopramide, cannabinoids, thalidomide, melatonin, clenbuterol, anabolic steroids, omega 3 fatty acids, NSAlDs, beta-blocking agents, 5H T-modulating agents. SARMs, ghrelin, growth hormone, IGF-1, myostatin antibody, activin receptor antagonist, and agents which inhibit the renin-angiotensin systems (such as renin inhibitor, ACE inhibitors, and angiotensin receptor antagonists).
Kits
[0138] The present application also provides kits, medicines, compositions, and unit dosage forms for use in any of the methods described herein.
[0139] Kits provided herein include one or more containers comprising any one of the compositions described herein and/or other agent(s), and in some embodiments, further comprise instructions for use in accordance with any of the methods described herein. The kit may further comprise a description of selection of individual suitable for treatment. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert, (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
[0140] For example, in some embodiments, the kit comprises a) a composition comprising canrenoate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and b) instructions for administering the composition for treatment of cancer (such as liver cancer).
[0141] The kits of the invention are in suitable packaging. Suitable packaging include, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed N ylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information. The present application thus also provides articles of manufacture, which include vials (such as sealed vials), bottles, jars, flexible packaging, and the like.
[0142] The instructions relating to the use of the compositions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of canrenoate as disclosed herein to provide effective treatment of an individual for an extended period, such as any of a week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the pharmaceutical compositions and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
[0143] Also provided are medicines, compositions, and unit dosage forms useful for the methods described herein. For example, the present disclosure provides, in some embodiments, a composition compri ing canrenoate for treating cancer in an individual having cancer. The present disclosure provides, in some embodiments, a composition comprising canrenoate for prolonging survival of an individual having cancer. The present disclosure provides, in some embodiments, a composition comprising canrenoate for preventing body weight loss of an individual having cancer.
[0144] For example, the present disclosure provides, in some embodiments, a composition comprising canrenoate for the manufacture of a medicament for treating cancer in an individual having cancer. The present disclosure provides, in some embodiments, a composition comprising canrenoate for the manufacture of a medicament for prolonging survival of an individual having cancer. The present disclosure provides, in some embodiments, a composition comprising canrenoate for the manufacture of a medicament for preventing body weight loss of an individual having cancer.
[0145] Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of this invention . The invention will now be described in greater detail by reference to the following non-limiting examples. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
Examples
Example 1. Synthesis of Cesium Canrenoate
1.
Figure imgf000039_0001
Scheme 1
[0147] Potassium canrenoate (5.23 g, 13.2 mmol) was dissolved in water (200 ml.) and the pTI adjusted to pH 4 with IICl (0.125 M). The resultant precipitate was collected by filtration, washed with water ( 100 ml,), then IMS (25 mL) and DCM (50 mL) and dried at 40 °C for 30 minutes to give the free acid (4.55 g, 96% recovery). CsOII.TLO (2.02 g, 12.1 mmol) was added to the solid as a solution in water (200 mL). The solution was filtered through Celite and freeze-dried to give cesium canrenoate (5.84 g, 90%) as an off white solid.
[0148] Ή NMR (DMSO-d6) 6.09 (s, 2H), 5.55 (s, 1 IT), 2.00 (m, 5H), 1.50 (m, 12H), 1.02 (s, 3H), 0.81 (s, 3H).
[0149] LCMS: Rt 8.24 min, [M HTf 359.4, 99%.
Example 2. Study Protocol with Yoshidu Hepatoma Model
[0150] Ascites hepatoma Yoshida AH-130 cells (10s cells) were inoculated into about 200 gram male istar rats by i.p. injection. Alternatively animals received saline injection only (sham). The day after inoculation animals were randomized into various groups and then received twice daily treatment with either placebo or various test compositions by oral gavage over a period of up to 17 days. The primary endpoints of the study included assessment of body weight, body composition (with and without tumor), and survival. Body composition was monitored by NMR. Echocardiography was used in instances to monitor condition of the heart. Organ weight was assessed at the end of the study (or after death) as a secondary endpoint. In addition, locomotor activity and food intake were also assessed. Figure 1 provides a diagram showing the design study.
Example 3. Effect of Cesium Canrenoate on Survival
[0151 ] To study the effect of the test compounds on survival, survival was monitored over time. Figure 2 shows the percent survival of rats that were admini stered with cesium canrenoate (Cs-can) at dosages of 0.2, 1, 2.5, or 10 mg/kg/day. One control group received a placebo (plac). Figure 3 further shows the percent survival of rats that were administered with cesium canrenoate at dosages of 0.2, 1 , 10, or 20 mg kg/day. As shown in both Figures 2 and 3, 1 mg/kg/day of cesium canrenoate had the best effect on survival among all dosages tested. Furthermore, as shown in Figures 2 and 3, cesium canrenoate was significantly superior to placebo.
Example 4. Effect of Cesium Canrenoate on Body Weight
[0152] To study the effect of the test compounds on body weight, body weight was monitored over time. The sham body weight was 71.6±1.8 g.
[0153] Figure 4 shows the change of body weight (in grams) in rats administered with cesium canrenoate (Cs-can) at dosage of 0.2, 1, 10, or 20 mg/kg/day. As shown in Figure 4, rats receiving 0.2, 1 or 10 mg/kg/day of cesium canrenoate had less body weight loss than those in the placebo group.
Example 5. Effects of Cesium Canrenoate on Preserving Lean Body Mass
[0154] To study the effect of the test compounds on lean body mass, lean mass was determined at the end of the study. The sham lean body mass was 48.6± 1.5 grams.
[0155] Figure 5 shows the change in lean body mass (in grams) of rats that were administered with cesium canrenoate at dosages of 0.2, 1 . 10, or 20 mg/kg/day. As shown in
Figure 5, rats receiving cesium canrenoate at doses of 0.2, 1 , or 10 mg kg/day had less change in lean body mass than those receiving the placebo. Example 6. Effects of Cesium Canrenoate on Preserving Fat Mass
[0156] To study the effect of the test compounds on fat mass, the fat mass were determined at the end of the study. The sham fat mass was 13.2=1 .1 grams.
[0157] Figure 6 shows the change in fat mass (in grams) of rats administered with cesium canrenoate at dosages of 0.2, 1, 10, or 20 mg/kg/day. As shown in Figure 6, rats receiving cesium canrenoate at 0.2, 1, 10, or 20 mg/kg/day or higher had less fat mass loss than those in the placebo group.
[0158] Figure 7A shows the weight of white adipose tissue (WAT) (in grams) of rats administered with cesium canrenoate al dosages of 0.2, 1 . 10, or 20 mg/kg/day. As shown in Figure 8 A, cesium canrenoate at dosages of 0.2, 1, or 10 mg/kg/day had better effects in reducing fat wasting than the placebo group.
[0159] Figure 7B shows the weight of brown adipose tissue (BAT) (in grams) of rats administered with cesium canrenoate at dosages of 0.2, 1 , 10, or 20 mg/kg/day. As shown in Figure 8B, cesium canrenoate at dosages of 0.2, 1, 10, or 20 mg/kg/day and the placebo had effects in reducing fat wasting with respect to brown adipose tissue. Cesium canrenoate at dosages of 0.2, I, 10, or 20 mg/kg/day protect BAT mass and thus treated rats retained better control of thermogenesis.
Example 7. Effect of Cesium Canrenoate on Tumor Growth
|0160| To study the effect of the test compounds on tumor growth, tumor growth was assessed at the end of the study.
[01611 Figure 8A shows the tumor volume (in ml) of rats administered with cesium canrenoate at dosages of 0.2, 1 , 10, or 20 mg/kg/day. Figure 8B shows the total number of cells in a tumor of rats administered with cesium canrenoate at dosages of 0.2, 1, 10, or 20 mg/kg/day. As shown in Figures 8A and 8B, rats receiving cesium canrenoate did not have any signi [leant effects on tumor growth compared to those in the placebo group.
[0162] The effect of the test compounds on tumor growth was also evaluated in an in vitro experiment with various tumor cells, namely, Kelly (neuroblastoma), IIela-93 (cervix carcinoma), and Bl 6V (melanoma). Cell growth was assessed by Brdli incorporation (left of Figure 9) and XTT assay (right of Figure 9). Doxorubicin was used as a positive control. As shown in Figure 9, cesium canrenoate did not show any inhibitor effects on tumor cell proliferation.

Claims

1 . A compound of the formula:
Figure imgf000042_0001
wherein M~ is an ion of an alkali metal (Group 1 ) selected from the group consisting of Li" (lithium), Na (sodium), Rb' (rubidium), and Cs' (cesium).
2. A compound of the formula:
Figure imgf000042_0002
(cesium canrenoate).
3. A pharmaceutical composition comprising the compound of claim 1 or 2.
4. A method of treating cancer in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
5. A method of prolonging survival of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
6. A method of preventing body weight loss of an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
7. A method of improving quality of life in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
8. A method of preventing and treating muscle wasting in an individual having cancer, comprising administering to the individual an effective amount of a composition comprising canrenoate.
9. The method of any one of claims 4-8, wherein the canrenoate is a pharmaceutically acceptable salt of canrenoate.
10. The method of any one of claims 4-8, wherein the canrenoate is selected from the group consisting of cesium canrenoate, lithium canrenoate, sodium canrenoate, and rubidium canrenoate.
11. The method of any one of claims 4-8, wherein the canrenoate is cesium canrenoate.
12. The method of any one of claims 4-11 , wherein the individual has no symptom of cancer cachexia.
13. The method of any one of claims 4-11 , wherein the individual has one or more symptoms of cancer cachexia.
14. The method of any one of claims 4-13, wherein the cancer is selected from the group consisting of liver cancer, lung cancer, ovarian cancer, pancreatic cancer, melanoma, and brain cancer.
15. The method of any one of claims 4-13, wherein the cancer is selected from the group consisting of gastric cancer, pancreatic cancer, lung, esophageal, colorectal, head and neck cancer, and hematological malignancy.
16. The method of claim 14, wherein the cancer is liver cancer.
17. The method of any one of claims 4-16, wherein the cancer is an early stage cancer.
18. The method of any one of claims 4-16, wherein the cancer is a late stage cancer.
19. The method of any one of claims 4-18, wherein the composition is administered orally.
20. The method of any one of claims 4-19, wherein the amount of canrenoate in the composition is about 10 to about 200 mg daily.
21. The method of any one of claims 4-20, wherein the composition is administered daily or twice daily.
22. A kit comprising the pharmaceutical composition of claim 3 and instruction for using the pharmaceutical composition for treating cancer.
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