Short chain fatty acid compounds and uses thereof

Abstract

The present disclosure describes methods comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition and a therapeutically-effective amount of an anti-cancer agent. The disclosed methods can comprise administering a pharmaceutical composition comprising a short chain fatty acid or a pharmaceutically-acceptable salt or ester thereof. The disclosed methods can be used to treat a cancer.

Description

Attomey Docket No.: 206017-0045-80WOSHORT CHAIN FATTY ACID COMPOUNDS AND USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 694,750 filed on September 13, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Short chain fatty acids (SCFAs) are saturated aliphatic acids consisting of one polar carboxylic acid moiety and hydrophobic hydrocarbon chain. Among these, acetate (C2), propionate (C3) and butyrate (C4) are the most common and well-studied molecules.INCORPORATION BY REFERENCE

[0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.SUMMARY OF THE DISCLOSURE

[0004] Disclosed herein is a method of treating a condition in a subject in need thereof, the method comprising: (a) administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and (b) administering to the subject a therapeutically effective amount of a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the pharmaceutical composition, and wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeutically effective for the condition in absence of the pharmaceutical composition.

[0005] Disclosed herein is a method of treating a condition in a subject in need thereof, the method comprising: (a) administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and (b) administering to the subject a therapeutically-Attorney Docket No.: 206017-0045-80WO effective amount of a second therapy that exhibits synergy with the pharmaceutical composition for the condition.

[0006] Disclosed herein is a method of inhibiting tumor growth in a subject having a tumor comprising: (a) administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and (b) administering to the subject a therapeutically- effective amount of a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the first pharmaceutical composition, wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeutically effective for the condition in absence of first pharmaceutical composition, and wherein the combination of the first pharmaceutical composition and the second therapy inhibits growth of the tumor in the subject.

[0007] Disclosed herein is a method of reducing size of a tumor in a subject having the tumor comprising: (a) administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and (b) administering to the subject a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the first pharmaceutical composition, wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeutically effective for the condition in absence of first pharmaceutical composition, and wherein the method reduces the size of the tumor in the subject.

[0008] Disclosed herein is a method of treating a cancer in a subject in need thereof, the method comprising:(a) administering to the subject a therapeutically-effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises a short chain fatty acid or a pharmaceutically-acceptable salt or ester thereof; and (b) orally, intraperitoneally, intratumorally, rectally, parenterally, topically, pulmonary, intranasally, or buccally administering to the subject a therapeutically-effective amount of an anti-cancer agent.

[0009] Disclosed herein is a kit comprising: (a) a pharmaceutical composition comprising a short chain fatty acid or a pharmaceutically-acceptable salt or ester thereof; and (b) an anti-cancer agent formulated for administration orally, intraperitoneally, intratumorally, rectally, parenterally, topically, pulmonary, intranasally, or buccally.Attorney Docket No.: 206017-0045-80WOBRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 shows tumor volume over time in a pancreatic ductal adenocarcinoma (PDAC) model mice following vehicle or treatment with a SCFA compound alone, chemotherapy alone, or a combination of a SCFA compound and chemotherapy.

[0011] FIG. 2 shows mouse weight over time in a pancreatic ductal adenocarcinoma (PDAC) model mice following vehicle or treatment with a SCFA compound alone, chemotherapy alone, or a combination of a SCFA compound and chemotherapy.

[0012] FIG. 3 shows tumor volume in a pancreatic ductal adenocarcinoma (PDAC) model mice at day 14 following vehicle or treatment with a SCFA compound alone, chemotherapy alone, or a combination of a SCFA compound and chemotherapy.

[0013] FIG. 4 shows tumor weight in a pancreatic ductal adenocarcinoma (PDAC) model mice at day 14 following vehicle or treatment with a SCFA compound alone, chemotherapy alone, or a combination of a SCFA compound and chemotherapy.DETAILED DESCRIPTIONShort chain fatty acid (SCFA)

[0014] Short chain fatty acids (SCFAs) are fatty acids with aliphatic tails shorter than aliphatic tails of long chain fatty acids. Short chain fatty acids can be derivatized to provide a salt or ester thereof, for example, pharmaceutically-acceptable salts and esters of fatty acids (e.g., sodium butyrate, arginine butyrate).

[0015] In some embodiments, a composition disclosed herein comprises at least one SCFA. In some embodiments, a composition disclosed herein comprises at least one short chain fatty acid (SCFA), SCFA precursor, SCFA biosynthesis precursor, a derivative thereof, a SCFA moiety, or a combination thereof.

[0016] In some embodiments, a composition disclosed herein comprises at least one SCFA, or a compound comprising a SCFA moiety. In some embodiments, a composition disclosed herein comprises at least two SCFAs. In some embodiments, a composition disclosed herein comprises at least three SCFAs.

[0017] Non-limiting examples of a SCFA or SCFA moiety include: acetic acid, butyric acid (BA), C3-C12 fatty acids, C3-C10 fatty acids, C3-C8 fatty acids, methoxyacetic acid, valproic acid (VP A),Attorney Docket No.: 206017-0045-80WO propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, N-acetylbutyrate (and other forms of butyrate, e.g., phenylbutyrate, isobutyrate, pivaloyloxymethyl butyrate, monoacetone glucose 3-butyrate), isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4- hydroxypentanoic acid, 2-ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3- methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3 -hydroxypentanoic acid, 3- methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, and a combination thereof.

[0018] Non-limiting examples of a SCFA or a SCFA moiety include: compounds or structures with at least 12 carbon atoms, at least 11 carbon atoms, at least 10 carbon atoms, at least 9 carbon atoms, at least 8 carbon atoms, at least 7 carbon atoms, at least 6 carbon atoms, at least 5 carbon atoms, at least 4 carbon atoms, at least 3 carbon atoms, and at least 2 carbon atoms. In some embodiments, the SCFA or SCFA moiety includes compounds or structures with no greater than 13 carbon atoms, no greater than 12 carbon atoms, no greater than 11 carbon atoms, no greater than 10 carbon atoms, no greater than 9 carbon atoms, no greater than 8 carbon atoms, or no greater than 7 carbon atoms.

[0019] In some embodiments, a SCFA or SCFA moiety is not a branched fatty acid. In some embodiments, a SCFA or SCFA moiety is a branched fatty acid.

[0020] In some embodiments, short chain fatty acids (SCFAs) modulate a cytokine. Non-limiting examples of cytokines include: TNFa, FFNy, IL-17A, IL-21, IL-22, IL-23, IL-27, IL-31, and MIP- 3a. Additional non-limiting examples of cytokines include: IL-10, IL-2, IL-18, IL-4, IL-12, IL-35, IL-36.

[0021] In some embodiments, the cytokine is a pro-inflammatory cytokine. In some embodiments, short chain fatty acids (SCFAs) decrease activity of a pro-inflammatory cytokine. Non-limiting examples of pro-inflammatory cytokines include: type 1 cytokines, IL-1 (e.g., IL-ip), IL-6, IL-8, IL- 9, IL-12, IL-15, IL-17, IL-18, IFN-y, and TNF-a. In some embodiments, the cytokine is an antiinflammatory cytokine. In some embodiments, short chain fatty acids (SCFAs) increase activity of an anti-inflammatory cytokine. Non-limiting examples of anti-inflammatory cytokines include IL-4, IL-10, IL-11, and IL-13.

[0022] In some embodiments, short chain fatty acids (SCFAs) modulate multiple cellular signaling proteins, including, but not limited to, IL-18, TLR3, IFN-y, TNFa, TGF-P, MyD88, PI3K / Akt, JAK / STAT, Smad 2 / 3, Smad 4, IL-10, Notch, hedgehog, Wnt (beta-catenin), matrixAttorney Docket No.: 206017-0045-80WO metalloproteinases 9 and 10, tissue inhibitor of metalloproteinases, nodal and NF-KB signaling. Tn some embodiments, the signaling proteins that are modulated by SCFAs modulate biological pathways or processes include, but are not limited to, inflammation, immunity, proliferation, differentiation, apoptosis, oncogenesis, transcription of DNA, cytokine production, cell survival, angiogenesis, fibrogenesis oxidative stress, and cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, and ultraviolet irradiation. For example, in some embodiments SCFAs reduce oxidative stress.

[0023] In some embodiments, short chain fatty acids (SCFAs) modulate multiple immune cells, including, but not limited to, macrophages, mast cells, neutrophils, Thl, Thl7, and Th22 lymphocytes.

[0024] In some embodiments, a method disclosed herein comprises treating or reducing a likelihood of developing medical diseases or disorders characterized by elevated levels or abnormal expression of at least one of IL-18, TLR3, IFN-y, TNFa, TGF-P, MyD88, PI3K / Akt, JAK / STAT, Smad 2 / 3, Smad 4 or IL- 10 signaling.

[0025] In some embodiments, a method disclosed herein comprises treating or reducing a likelihood of developing medical diseases or disorders characterized by decreased levels or abnormal expression of NF-KB signaling.

[0026] In some embodiments, administering a composition disclosed herein increases expression of IL-10 in the subject compared to baseline (e.g., compared to an IL-10 level prior to administration of the composition). In some embodiments, administering a composition disclosed herein to a subject increases expression of IL-10 in the subject by at least about 3%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more. In some embodiments, the increased expression of the antiinflammatory and immunosuppressive cytokine IL-10 following administration of SCFAs in a subject indicates a reduced inflammatory mechanism in the subject due to the SCFAs.

[0027] In some embodiments, a composition disclosed herein comprises at least one compound comprising a precursor of a SCFA, or a moiety thereof. Non-limiting examples of the precursor include plant cell-wall polysaccharides, dietary nonstarch polysaccharides (NSP) a salt of lactate, a salt of succinate, a salt of formate, 1,2-propenedol, trypamine, indole, indole-3 -acetate, and a combination thereof.Attorney Docket No.: 206017-0045-80WO

[0028] In some embodiments, a composition disclosed herein comprises at least one compound comprising a biosynthesis precursor of a SCFA, or a moiety thereof. Non-limiting examples of a biosynthesis precursor include acetyl-CoA carboxylase inhibitor, an adenosine monophosphate kinase (AMPK) activator, vitamin D, and a combination thereof.

[0029] In some embodiments, a composition disclosed herein comprises a salt of a SCFA, or a derivative thereof. Non-limiting examples of a salt of butyric acid include sodium butyrate, magnesium butyrate, and calcium butyrate. In some embodiments, the composition comprises one or more of magnesium butyrate and calcium butyrate.

[0030] In some embodiments, a composition disclosed herein comprises butyric acid or a pharmaceutically-acceptable salt thereof. In some embodiments, a composition disclosed herein comprises propionic acid or a pharmaceutically-acceptable salt thereof. In some embodiments, a composition disclosed herein comprises butyric acid or a pharmaceutically-acceptable salt thereof and propionic acid or a pharmaceutically-acceptable salt thereof.

[0031] In some embodiments, a composition disclosed herein comprises acetic acid or a pharmaceutically-acceptable salt thereof. In some embodiments, a composition disclosed herein comprises butyric acid or a pharmaceutically-acceptable salt thereof, propionic acid or a pharmaceutically-acceptable salt thereof, and acetic acid or a pharmaceutically-acceptable salt thereof.

[0032] In some embodiments, a composition disclosed herein comprises a derivative of a SCFA. In some embodiments, the derivative comprises at least one SCFA moiety linked to at least one additional moiety. In some embodiments, the derivative comprises at least one SCFA moiety linked to at least one polyethylene glycol (PEG) moiety. In some embodiments, the SCFA moiety linked to the PEG moiety hydrolyzes under a low pH condition to yield a SCFA molecule and a PEG molecule.

[0033] In some embodiments, a composition disclosed herein a combination of SCFAs, and / or derivatives thereof. In some embodiments, the composition is prepared at amounts of at least 10 mM, at least 20 mM, at least 30 mM, at least 40 mM, at least 50 mM, at least 60 mM, at least 70 mM, at least 80 mM, at least 90 mM, at least 100 mM, or more of each or all the compounds of the composition.

[0034] Derivatives of SCFAs, e.g., having substituents on the carbon chain such as OH, SH, NH2, methyl, ethyl, halogen, and other groups that do not interfere with the compound's therapeuticAttorney Docket No.: 206017-0045-80WO activity can also be used. In some embodiments, a compound disclosed herein comprises at least one SCFA linked to at least one additional moiety, such as OH, SH, NH2, methyl, ethyl, halogen, and other groups that do not interfere with the compound's therapeutic activity. In some embodiments, a SCFA is pegylated.

[0035] In some embodiments, a composition disclosed herein comprises a precursor of a SCFA alone or in combination with one or more SCFAs. Non-limiting examples of precursors of SCFAs include: a salt of formate, a salt of lactate, a salt of succinate, 1,2-propenedol, trypamine, indole, and indole-3 -acetate.

[0036] In some embodiments, a composition disclosed herein comprises a precursor of SCFA biosynthesis alone or in combination with one or more SCFA. Non-limiting examples of precursors of SCFA biosynthesis include: a salt of formate, a salt of lactate, a salt of succinate, acetyl-CoA carboxylase inhibitors, adenosine monophosphate kinase (AMPK) activators, and vitamin D.

[0037] In some embodiments, a compound comprising at least one SCFA, or a compound comprising a SCFA moiety disclosed herein is combined with one or more compounds, such as one or more additional therapeutic agent, for a particular disease or disorder. In some embodiments, the SCFA is in the same composition as one or more additional therapeutic agents. In some embodiments, the composition comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more than 10 additional therapeutic agents.Interleukin-10 (IL-10)

[0038] IL- 10 is a pleiotropic cytokine with effects on numerous cell populations, such as circulating and resident immune cells as well as epithelial cells. IL-10 is produced by monocytes and Th2 cells, mast cells and also in a subset of activated T cells and B cells.

[0039] IL- 10 can exert either immunosuppressive or immunostimulatory effects on a variety of cell types. Non-limiting examples of effects of IL-10 expression include: inhibiting monocyte / macrophage function, suppressing the production of a pro-inflammatory cytokine (e.g., TNF-a, IL-ip, IL-6,MIP-la and IL-8), increasing release of MCP-1, upregulating monocyte expression of an anti-inflammatory cytokine (e.g., IL-IRa), and suppressing the synthesis of superoxide anions and NO by activated monocytes / macrophages.

[0040] IL- 10 is also a growth co-stimulator for thymocytes and mast cells, and an enhancer of cytotoxic T cell development. In some embodiments, the elevated level of IL-10 activates theAttorney Docket No.: 206017-0045-80WO transcription of genes for mast cell derived proteases. In some embodiments, the elevated level of IL- 10 enhances the production of the tissue inhibitor of metalloproteinases of monocytes and tissue macrophages while decreasing metalloproteinase biosynthesis.

[0041] In some embodiments, a method disclosed herein comprises treating or reducing a likelihood of developing a condition characterized by reduced levels or abnormal expression of IL- 10 signaling. In some embodiments, the condition is a cancer. In some embodiments, the condition is pancreatic cancer. In some embodiments, a method disclosed herein comprises administering SCFAs to elevate the expression of an anti-inflammatory cytokine. In some embodiments, the anti-inflammatory cytokine is IL- 10.

[0042] Non-limiting examples of effects of IL-10 include: inhibiting the activity of Thl cells, NK cells, and macrophages, impeding pathogen clearance, and ameliorating immunopathology.

[0043] In some embodiments, an elevated level of IL- 10 exerts anti-cancer activity by effects on different cell populations, including but not limited to, antigen presenting cells, T-cells, or a combination thereof. In some embodiments, an elevated level of IL-10 results in attenuating a T- helper (Th)l / Th2 disbalance. In some embodiments, an elevated level of IL-10 results in a type 1 / type 2 cytokine balance shift. Non-limiting examples of effects of a type 1 / type 2 cytokine balance shift include: increasing proportion of IL-4, IL-5, and IL-10 producing T-cells, and selective increase in IgE serum levels.

[0044] In some embodiments, a method disclosed herein comprises obtaining a level of a biomarker in a subject, wherein the biomarker is an anti-inflammatory cytokine, wherein the subject is undergoing a regimen of short chain fatty acid therapy for an inflammatory condition.

[0045] In some embodiments, a method disclosed herein further comprises based on the level of the biomarker in the subject, continuing the short chain fatty acid therapy, wherein the level of the biomarker shows elevated expression of the biomarker in the subject.

[0046] In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject prior to the administering to the subject the short chain fatty acid therapy. In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject during initiation of the administering to the subject the short chain fatty acid therapy. In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject concurrently with the first administering to the subject the short chain fatty acid therapy.Attorney Docket No.: 206017-0045-80WO

[0047] In some embodiments, the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or greater than about 100% higher in comparison to a predetermined value. In some embodiments, the predetermined value is level of the biomarker determined prior to the administering to the subject a regimen of short chain fatty acid therapy. In some embodiments, the predetermined value is level of the biomarker determined during initiation of the administering to the subject a regimen of short chain fatty acid therapy.

[0048] In some embodiments, the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 0.5-fold, at least about 1-fold, at least about 1.5-fold, at least about 2 fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, at least about 6-fold, at least about 6.5- fold, at least about 7 fold, at least about 7.5-fold, at least about 8-fold, at least about 8.5-fold, at least about 9-fold, at least about 9.5-fold, at least about 10-fold, or greater than about 10-fold higher in comparison to a predetermined value. In some embodiments, the predetermined value is level of the biomarker determined prior to the administering to the subject a regimen of short chain fatty acid therapy. In some embodiments, the predetermined value is level of the biomarker determined during initiation of the administering to the subject a regimen of short chain fatty acid therapy.

[0049] In some embodiments, the level of the biomarker shows elevated expression of the biomarker in the subject over a period of about three days, about four days, about five days, about six days, about seven days, or greater than about seven days.

[0050] In some embodiments, the level of the biomarker shows elevated expression of the biomarker in the subject over a period of about three days to four days, about four to five days, about five to six days, about six to seven days, or greater than about seven days.

[0051] In some embodiments, a method disclosed herein comprises (a) administering a therapeutically-effective amount of a short chain fatty acid therapy for an inflammatory condition to a subject in need thereof; (b) after the administering, obtaining a level of a biomarker in a subject, wherein the biomarker is an anti-inflammatory cytokine; and (c) based on the level of the biomarker in the subject, continuing the short chain fatty acid therapy.Attorney Docket No.: 206017-0045-80WO

[0052] In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject prior to the administering to the subject the short chain fatty acid therapy. In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject during initiation of the administering to the subject the short chain fatty acid therapy. In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject concurrently with the first administering to the subject the short chain fatty acid therapy.

[0053] In some embodiments, the short chain fatty acid therapy is continued if the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or greater than about 100% higher in comparison to a predetermined value. In some embodiments, the predetermined value is the level of the biomarker determined prior to the administering to the subject a regimen of short chain fatty acid therapy. In some embodiments, the predetermined value is level of the biomarker determined during initiation of the administering to the subject a regimen of short chain fatty acid therapy.

[0054] In some embodiments, the short chain fatty acid therapy is continued if the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 0.5-fold, at least about 1-fold, at least about 1.5-fold, at least about 2 fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, at least about 6-fold, at least about 6.5-fold, at least about 7 fold, at least about 7.5-fold, at least about 8-fold, at least about 8.5-fold, at least about 9-fold, at least about 9.5-fold, at least about 10-fold, or greater than about 10-fold higher in comparison to a predetermined value. In some embodiments, the predetermined value is level of the biomarker determined prior to the administering to the subject a regimen of short chain fatty acid therapy. In some embodiments, the predetermined value is level of the biomarker determined during initiation of the administering to the subject a regimen of short chain fatty acid therapy.

[0055] In some embodiments, the short chain fatty acid therapy is continued if the level of the biomarker shows elevated expression of the biomarker in the subject over a period of about three days, about four days, about five days, about six days, about seven days, or greater than about seven days.Attorney Docket No.: 206017-0045-80WO

[0056] In some embodiments, the short chain fatty acid therapy is continued if the level of the biomarker shows elevated expression of the biomarker in the subject over a period of about three days to four days, about four to five days, about five to six days, about six to seven days, or greater than about seven days.Conditions

[0057] The present disclosure describes methods and systems for treating conditions comprising administering a pharmaceutical composition comprising at least one short chain fatty acid (SCFA), a SCFA precursor, a SCFA biosynthesis precursor, a compound comprising a SFCA moiety, a derivative thereof, and a combination thereof. In some embodiments, the condition is a cancer. In some embodiments, the condition is pancreatic cancer.

[0058] Disclosed herein is a method for the treatment or reducing a likelihood of developing at least one disease or disorder in a subject, comprising administering to the subject at least one composition comprising a SCFA or a compound comprising a SCFA, optionally in combination with at least one additional agent or therapy.

[0059] In some embodiments, a composition disclosed herein increases the number of disease-free days, reduce the severity of a disease or disorder, reduce the risk of developing a disease or disorder, reduce the risk of recurrence of a disease or disorder, or a combination thereof in the subject. In some embodiments, a composition disclosed herein increase the number of disease-free days by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more in the subject as compared to a subject who is not receiving treatment. In some embodiments, a composition disclosed herein reduce the severity of a disease or disorder by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more in the subject as compared to a subject who is not receiving treatment. In some embodiments, a composition disclosed herein reduce the risk of developing a disease orAttorney Docket No.: 206017-0045-80WO disorder by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more in the subject as compared to a subject who is not receiving treatment. In some embodiments, a composition disclosed herein reduce the risk of recurrence of a disease or disorder by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more in the subject as compared to a subject who is not receiving treatment.

[0060] Non-limiting examples of diseases and disorders that are treated, reduced in likelihood, or ameliorated include: inflammatory diseases and various cancer diseases.Pancreatic Cancer

[0061] Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body.

[0062] The most common type of pancreatic cancer is pancreatic adenocarcinoma. These adenocarcinomas start within the part of the pancreas that makes digestive enzymes. Other types of cancer, which collectively represent the majority of the non-adenocarcinomas, also arise from these cells. About 1-2% of cases of pancreatic cancer are neuroendocrine tumors, which arise from the hormone-producing cells of the pancreas. These can be less aggressive than pancreatic adenocarcinoma.

[0063] Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Available treatment modalities often show suboptimal or no clinical efficacy and survival remains poor. There is an urgent need for the development of novel therapeutic modalities and overcome the challenges with therapeutic resistance.

[0064] In some embodiments, SCFAs enhance an anti-tumor immune response.

[0065] In some embodiments, SCFAs decrease inflammation and / or exert anti-tumor efficacy inAttorney Docket No.: 206017-0045-80WO pancreatic cancer. In some embodiments, SCFAs inhibit tumor progression. In some embodiments, SCFAs have anti-inflammatory effects. In some embodiments, SCFAs reduce oxidative stress. In some embodiments, SCFAs decrease pro-inflammatory cytokines (e.g., IL-6 and IL-8 that promote carcinogenesis). In some embodiments, SCFAs increase anti-inflammatory cytokines (e.g., IL-10). In some embodiments, SCFAs promote immune homeostasis.

[0066] . In some embodiments, SCFAs may inhibit growth of cancer cells and / or promote apoptosis (programmed cell death) in certain cancer cell types. In some embodiments, SCFAs inhibit tumor proliferation. In some embodiments, SCFAs may induce apoptosis.

[0067] The gut microbiome may modulate the response to chemotherapy in pancreatic cancer. Specific gut bacteria can metabolize or interact with a chemotherapeutic agent, affecting efficacy or toxicity of the chemotherapeutic agent. An imbalanced gut microbiome can be associated with certain types of cancer. In some embodiments, SCFAs help maintain gut barrier integrity, reducing the potential spread of cancer cells. In some embodiments, SCFAs modulate the development of gastrointestinal (GI) toxicity through various mechanisms, including promoting the proliferation of crypt cells, modulating immune responses, and restoring and maintaining the integrity of the intestinal barrier and gut microbiota.Cancer and cancer therapy

[0068] In addition to pancreatic cancer, the cancer that is treated or immunized against (i.e., prophylactic treatment) by the methods disclosed herein can be a cancer selected from the group consisting of B cell lymphoma, T cell lymphoma, myeloma, leukemia, hematopoietic neoplasias, thymoma, lymphoma, sarcoma, lung cancer, non-Hodgkins lymphoma, Hodgkins lymphoma, uterine cancer, adenocarcinoma, breast cancer, hepatocellular cancer, lung cancer, renal cancer, bladder cancer, prostate cancer, ovarian cancer, primary or metastatic melanoma, squamous cell carcinoma, basal cell carcinoma, brain cancer, angiosarcoma, hemangiosarcoma, head and neck carcinoma, thyroid carcinoma, soft tissue sarcoma, bone sarcoma, testicular cancer, uterine cancer, cervical cancer, gastrointestinal cancer, and any other cancer now known or later identified (see, e g., Rosenberg (1996) Ann. Rev. Med. 47:481-491, the entire contents of which are incorporated by reference herein).

[0069] The methods and compositions disclosed herein can be used to prevent, abate, minimize, control, and / or lessen tumor metastasis in humans and animals. The methods and compositionsAttorney Docket No.: 206017-0045-80WO disclosed herein may be used to slow the rate of primary tumor growth. The methods and compositions disclosed herein can be used to stop the spread of cancer cells. In some embodiments, control of metastasis by methods and compositions disclosed herein can provide the subject a greater ability to concentrate the disease in one location.

[0070] Non-limiting examples of cancers that are treated by the methods and composition disclosed herein include: Acute Lymphoblastic; Acute Myeloid Leukemia; Adrenocortical Carcinoma;Adrenocortical Carcinoma, Childhood; Appendix Cancer; Basal Cell Carcinoma; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bone Cancer; Osteosarcoma and Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Central Nervous System Atypical Teratoid / Rhabdoid Tumor, Childhood; Central Nervous System Embryonal Tumors; Cerebellar Astrocytoma; Cerebral Astrocytotna / Malignant Glioma; Craniopharyngioma; Ependymoblastoma; Ependymoma; Medulloblastoma;Medulloepithelioma; Pineal Parenchymal Tumors of intermediate Differentiation; Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma; Visual Pathway and Hypothalamic Glioma; Brain and Spinal Cord Tumors; Breast Cancer; Bronchial Tumors; Burkitt Lymphoma; Carcinoid Tumor; Carcinoid Tumor, Gastrointestinal; Central Nervous System Atypical Teratoid / Rhabdoid Tumor; Central Nervous System Embryonal Tumors; Central Nervous System Lymphoma; Cerebellar Astrocytoma Cerebral Astrocytoma / Malignant Glioma, Childhood; Cervical Cancer; Chordoma, Childhood; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Colon Cancer; Colorectal Cancer; Craniopharyngioma; Cutaneous T- Cell Lymphoma; Esophageal Cancer; Ewing Family of Tumors; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastrointestinal Carcinoid Tumor; Gastrointestinal Stromal Tumor (GIST); Germ Cell Tumor, Extracranial; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma; Glioma, Childhood Brain Stem; Glioma, Childhood Cerebral Astrocytoma; Glioma, Childhood Visual Pathway and Hypothalamic;Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer; Histiocytosis, Langerhans Cell; Hodgkin Lymphoma; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma; intraocular Melanoma; Islet Cell Tumors; Kidney (Renal Cell) Cancer; Langerhans Cell Histocytosis; Laryngeal Cancer; Leukemia, Acute Lymphoblastic; Leukemia, Acute Myeloid;Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip andAttorney Docket No.: 206017-0045-80WOOral Cavity Cancer; Liver Cancer; Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoma, AIDS-Related; Lymphoma, Burkitt; Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin; Lymphoma, Non-Hodgkin; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom; Malignant Fibrous Histiocytoma of Bone and Osteosarcoma; Medulloblastoma; Melanoma; Melanoma, intraocular (Eye); Merkel Cell Carcinoma; Mesothelioma; Metastatic Squamous Neck Cancer with Occult Primary; Mouth Cancer; Multiple Endocrine Neoplasia Syndrome, (Childhood); Multiple Myeloma / Plasma Cell Neoplasm; Mycosis; Fungoides; Myelodysplastic Syndromes; Myelodysplastic Myeloproliferative Diseases; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Adult Acute; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Neuroblastoma; Non-Small Cell Lung Cancer; Oral Cancer; Oral Cavity Cancer; Oropharyngeal Cancer; Osteosarcoma and Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Islet Cell Tumors; Papillomatosis; Parathyroid Cancer; Penile Cancer; Pharyngeal Cancer; Pheochromocytoma; Pineal Parenchymal Tumors of Intermediate Differentiation; Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; Plasma Celt Neoplasm / Multiple Myeloma; Pleuropulmonary Blastoma; Primary Central Nervous System Lymphoma; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Pelvis and Ureter, Transitional Cell Cancer; Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15; Retinoblastoma; Rhabdomyosarcoma; Salivary Gland Cancer; Sarcoma, Ewing Family of Tumors; Sarcoma, Kaposi; Sarcoma, Soft Tissue; Sarcoma, Uterine; Sezary Syndrome; Skin Cancer (Nonmelanoma); Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma; Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Supratentorial Primitive Neuroectodermal Tumors; T-Cell Lymphoma, Cutaneous; Testicular Cancer; Throat Cancer; Thymoma and Thymic Carcinoma; Thyroid Cancer; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Urethral Cancer; Uterine Cancer, Endometrial; Uterine Sarcoma; Vaginal Cancer; Vulvar Cancer; Waldenstrom Macroglobulinemia; and Wilms Tumor.

[0071] Nonlimiting examples of chemotherapeutic agents include: Gemcitabine, Albumin-bound paclitaxel (Abraxane), 5-fluorouracil (5-FU) or capecitabine (an oral 5-FU drug), Platinum drugsAttorney Docket No.: 206017-0045-80WO(e g., cisplatin or oxaliplatin), and Irinotecan. In some embodiments, the chemotherapeutic agent is gemcitabine. In some embodiments, the chemotherapeutic agent is paclitaxel. In some embodiments, the chemotherapeutic agent is5-FU. In some embodiments, the chemotherapeutic agent iscisplatin. In some embodiments, the chemotherapeutic agent is oxaliplatin.

[0072] Additional nonlimiting examples of chemotherapeutic agents include cytotoxic agents (e.g., 5 -fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramucine phosphate sodium, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alfa-2a recombinant, paclitaxel, teniposide, and streptozoci), cytotoxic alkylating agents (e.g., busulfan, chlorambucil, cyclophosphamide, melphalan, or ethylesulfonic acid), alkylating agents (e.g., asaley, AZQ, BCNU, busulfan, bisulphan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cis-platinum, clomesone, cyanomorpholinodoxorubicin, cyclodisone, cyclophosphamide, dianhydrogalactitol, fluorodopan, hepsulfam, hycanthone, iphosphamide, melphalan, methyl CCNU, mitomycin C, mitozolamide, nitrogen mustard, PCNU, piperazine, piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin, teroxirone, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard, and Yoshi-864), antimitotic agents (e.g., allocolchicine, Halichondrin M, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, trityl cysteine, vinblastine sulfate, and vincristine sulfate), plant alkaloids (e.g., actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mitramycin, mitomycin, daunorubicin, VP-16-213, VM-26, navelbine and taxotere), biologicals (e.g., alpha interferon, BCG, G-CSF, GM-CSF, and interleukin-2), topoisomerase I inhibitors (e.g., camptothecin, camptothecin derivatives, and morpholinodoxorubicin), topoisomerase II inhibitors (e.g., mitoxantron, amonafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene HCL, daunorubicin, deoxy doxorubicin, menogaril, N,N-dibenzyl daunomycin, oxanthrazole, rubidazone, VM-26 and VP- 16), and synthetics (e g., hydroxyurea, procarbazine, o,p'-DDD, dacarbazine, CCNU, BCNU, cis- diamminedichloroplatimun, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid, gliadel and porfimer sodium).

[0073] Antiproliferative agents are compounds that decrease the proliferation of cells. Antiproliferative agents include alkylating agents, antimetabolites, enzymes, biological responseAttorney Docket No.: 206017-0045-80WO modifiers, miscellaneous agents, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and analogs thereof, toremifene, droloxifene and roloxifene), Additional examples of specific antiproliferative agents include, but are not limited to levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, and ondansetron.

[0074] Non-limiting examples of an anti-tumor agent include cytotoxic / antineoplastic agents and anti-angiogenic agents. For example, a cytotoxic / anti -neoplastic agent may be an agent which attacks and kills cancer cells. A non-limiting example of a cytotoxic / anti -neoplastic agent include an alkylating agent, which alkylates the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine. An additional non-limiting example of a cytotoxic / anti-neoplastic agent includes an antimetabolite for tumor cells, e g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopurine, azathioprime, and procarbazine. An additional non-limiting example of a cytotoxic / anti-neoplastic agent includes an antibiotic, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.

[0075] In some embodiments, a therapeutically-effective amount can be an amount effective in treating a cancer. In some embodiments, a therapeutically-effective amount can be an amount effective in treating a tumor. In some embodiments, a therapeutically-effective amount can be an amount effective in increasing subject survival.

[0076] In some embodiments, a therapeutically-effective amount can be an amount effective in shrinking a tumor. The tumor can be reduced in size by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%.

[0077] In some embodiments, a therapeutically effective amount is an amount effective to slow or reverse proliferation of the tumor.Dosing and Administration

[0078] In practicing the methods or use provided herein, therapeutically-effective amounts of the compounds described herein are administered to a subject having a disease or condition to be treated.Attorney Docket No.: 206017-0045-80WOA therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. Subjects can be, for example, humans, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, or neonates. A subject can be a patient.

[0079] The particular dosage of a compound required to treat the condition can depend on the severity of the condition, the route of administration, and related factors that can be decided by the attending physician.

[0080] A therapeutically-effective amount of a compound of the present disclosure can be expressed as mg of the compound per kg of subject body mass. In some embodiments, a therapeutically- effective amount is 1-1,000 mg / kg, 1-500 mg / kg, 1-250 mg / kg, 1-100 mg / kg, 1-50 mg / kg, 1-25 mg / kg, or 1-10 mg / kg. In some embodiments, a therapeutically-effective amount is about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1,000 mg / kg.

[0081] A compound described herein can be present in a composition in a range of from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to about 60 mg, from about 60 mg to about 65 mg, from about 65 mg to about 70 mg, from about 70 mg to about 75 mg, from about 75 mg to about 80 mg, from about 80 mg to about 85 mg, from about 85 mg to about 90 mg, from about 90 mg to about 95 mg, from about 95 mg to about 100 mg, from about 100 mg to about 125 mg, from about 125 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 225 mg, from about 225 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 325 mg, from about 325 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 425 mg, from about 425 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 525 mg, from about 525 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 625 mg, from about 625 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 725 mg, from about 725 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 825 mg, from about 825 mg to about 850 mg, from about 850 mg toAttorney Docket No.: 206017-0045-80WO about 900 mg, from about 900 mg to about 925 mg, from about 925 mg to about 950 mg, from about 950 mg to about 1000 mg, from about 1000 mg to about 1025 mg, from about 1025 mg to about 1050 mg, from about 1050 mg to about 1100 mg, from about 1100 mg to about 1125 mg, from about 1125 mg to about 1150 mg, from about 1150 mg to about 1200 mg, from about 1200 mg to about 1225 mg, from about 1225 mg to about 1250 mg, from about 1250 mg to about 1300 mg, from about 1300 mg to about 1325 mg, from about 1325 mg to about 1350 mg, from about 1350 mg to about 1400 mg, from about 1400 mg to about 1425 mg, from about 1425 mg to about 1450 mg, from about 1450 mg to about 1500 mg, from about 1500 mg to about 1525 mg, from about 1525 mg to about 1550 mg, from about 1550 mg to about 1600 mg, from about 1600 mg to about 1625 mg, from about 1625 mg to about 1650 mg, from about 1650 mg to about 1700 mg, from about 1700 mg to about 1725 mg, from about 1725 mg to about 1750 mg, from about 1750 mg to about 1800 mg, from about 1800 mg to about 1825 mg, from about 1825 mg to about 1850 mg, from about 1850 mg to about 1900 mg, 1900 mg to about 1925 mg, from about 1925 mg to about 1950 mg, or from about 1950 mg to about 2000 mg.

[0082] A compound described herein can be present in a composition in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg about 1925 mg, about 1950 mg, about 1975 mg, or about 2000 mg.Attorney Docket No.: 206017-0045-80WO

[0083] In some embodiments, a SCFA compound dose or a composition for gavage comprises a 4000 mg mixture / day (e.g., 60% Sodium Acetate, 25% Sodium Propionate, 15% Sodium Butyrate). In some embodiments, a SCFA compound comprises about 60% acetic acid or a pharmaceutically acceptable salt there of (e.g., sodium acetate), about 25% propionic acid or a pharmaceutically acceptable salt there of (e.g., sodium propionate), about 15% butyric acid or a pharmaceutically acceptable salt there of (e.g., sodium butyrate).

[0084] In some embodiments, a SCFA compound comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% acetic acid or a pharmaceutically acceptable salt there of (e.g., sodium acetate). In some embodiments, a SCFA compound comprises less than about 60% acetic acid or a pharmaceutically acceptable salt there of (e.g., sodium acetate). In some embodiments, the daily dose of SCFA compound comprises less than 8 g / day, less than 9 g / day, less than 10 g / day, less than 11 g / day, less than 12 g / day, less than 13 g / day, less than 14 g / day, less than 15 g / day.

[0085] In some embodiments, a SCFA compound comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% propionic acid or a pharmaceutically acceptable salt there of (e.g., sodium propionate).

[0086] In some embodiments, a SCFA compound comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% butyric acid or a pharmaceutically acceptable salt there of (e.g., sodium butyrate).

[0087] In some embodiments, a chemotherapy regimen is administered. In some embodiments, a chemotherapy regimen is administered biweekly. In some embodiments, a chemotherapy regimen is administered biweekly by IP injection. In some embodiments, a chemotherapy regimen is administered biweekly by IP injection following a FOLFIRINOX protocol (Leucovorin: 50 mg / kg, Oxaliplatin: 2.5 mg / kg, 5 -Fluorouracil: 25 mg / kg, Irinotecan: 25 mg / kg).

[0088] In some embodiments, a therapeutically-effective amount can be administered 1-35 times per week, 1-14 times per week, or 1-7 times per week. In some embodiments, a therapeutically- effective amount can be administered 1-10 times per day, 1-5 times per day, 1 time, 2 times, or 3 times per day.Attomey Docket No.: 206017-0045-80WO

[0089] In some embodiments, a number of doses for a therapeutically-effective amount can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10.

[0090] In some embodiments, a compound disclosed herein can be administered in therapeutically- effective amounts by various forms and routes including, for example, by intravenous, intravitreal, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, intraocular, and topical administration. Non-limiting examples of parenteral or systemic administration include subcutaneous, intravenous, intraperitoneal, and intramuscular injections.

[0091] In some embodiments, a pharmaceutical composition disclosed herein is generally formulated for oral or topical (i.e., skin, ocular and mucosal surfaces) administration, with the most suitable route in any given case depending on the nature and severity of the condition being treated and on the nature of the particular active agent which is being used.

[0092] Oral Formulations

[0093] In some embodiments, a pharmaceutical composition, composition, or compound disclosed herein, is administered orally, and thus be formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, and pellets. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, and oils. If formulated as a capsule, the compositions disclosed herein comprise, in addition to the active compound and the inert carrier or diluent, a hard gelating capsule. In some embodiments, a formulation for oral administration is an enteric coated, time release capsule.

[0094] Formulations suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations can be prepared by any suitable method of pharmacy, which includes bringing into association the active compound and a suitable carrier (which can contain one or more accessory ingredients as noted above). In general, the formulations disclosed herein are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet can be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-Attorney Docket No.: 206017-0045-80WO flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and / or surface active / dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.

[0095] The delayed release dosage units can be coated with the delayed release polymer coating using conventional techniques, e.g., using a conventional coating pan, an airless spray technique, fluidized bed coating equipment (with or without a Wurster insert).

[0096] An example method for preparing extended release tablets is by compressing a drugcontaining blend, e.g., blend of granules, prepared using a direct blend, wet-granulation, or drygranulation process. Extended release tablets can also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant. However, tablets are manufactured using compression rather than molding. A method for forming extended release drugcontaining blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants. As an alternative to direct blending, a drug-containing blend can be prepared by using wet-granulation or dry-granulation processes. Beads containing the active agent can also be prepared by any one of a number of techniques, starting from a fluid dispersion. For example, a method for preparing drug-containing beads involves dispersing or dissolving the active agent in a coating suspension or solution containing pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, silicone dioxide, or plasticizers. The admixture is used to coat a bead core such as a sugar sphere having a size of approximately 60 to 20 mesh.

[0097] An alternative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, a disintegrant, etc., extruding the blend, spheronizing the extrudate, drying and optionally coating to form the immediate release beads.

[0098] Delayed release formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, and soluble in the neutral environment of small intestines. The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drugcontaining composition can be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. Examples of coating materials includeAttorney Docket No.: 206017-0045-80WO bioerodible, gradually hydrolyzable, gradually water-soluble, and / or enzymatically degradable polymers, and can be enteric polymers. Enteric polymers become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Non-limiting examples of coating materials for effecting delayed release include cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, e.g., formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit®, including Eudragit® L3OD-55 and LI 00-55 (soluble at pH 5.5 and above), Eudragit®. L- 100 (soluble at pH 6.0 and above), Eudragit®. S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and Eudragits®. NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum, zein, and shellac. Combinations of different coating materials can be used. Multi-layer coatings using different polymers can be applied.

[0099] The coating composition can include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer reduces the fragility of the coating and can be represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Non-limiting examples of plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil, and acetylated monoglycerides. A stabilizing agent is used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants can reduce sticking effects during film formation and drying and can represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates can be used. Pigments such as titanium dioxide can be used. Small quantities of anAttorney Docket No.: 206017-0045-80WO anti-foaming agent, such as a silicone (e g., simethicone), can be added to the coating composition.

[0100] In addition to a therapeutic or diagnostic agent (or possibly other desired molecules for delivery), the particles can include excipients such as a sugar, such as lactose, a protein, such as albumin, and / or a surfactant.

[0101] In some embodiments, a treatment regimen comprises daily oral administration of a short chain fatty acid. In some embodiments, an amount of a form of butyric acid or a pharmaceutically- acceptable salt thereof, wherein the amount is therapeutically equivalent to about 600 mg of butyric acid or a pharmaceutically-acceptable salt thereof, such as sodium butyrate, calcium butyrate, or magnesium butyrate, is administered 3 times per day (a total of about 1800 mg / day) for at least one week. In some embodiments, a treatment regimen comprises oral administration of two capsules, each containing an amount of a form of butyric acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 600 mg of butyric acid or a pharmaceutically-acceptable salt thereof, such as sodium butyrate, calcium butyrate, or magnesium butyrate, 3 times per day (a total of about 3,600 mg / day) for at least one week. In some embodiments, a treatment regimen comprises oral administration of two capsules, each containing an amount of a form of butyric acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 600 mg of butyric acid or a pharmaceutically-acceptable salt thereof, such as sodium butyrate, calcium butyrate, or magnesium butyrate, 3 times per day (a total of about 3,600 mg / day) for at least one week followed thereafter by oral administration of capsules, each containing an amount of a form of butyric acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 600 mg of butyric acid or a pharmaceutically-acceptable salt thereof, such as sodium butyrate calcium butyrate, or magnesium butyrate, 3 times per day (a total of about 1800 mg / day) for at least one week.

[0102] Compounds of the present disclosure, whether administered alone, or in combination with a modulator of oxidative stress can be administered to a subject in need of such administration, for example a human or animal patient.Pharmaceutical Compositions

[0103] A pharmaceutical composition can be a combination of any compounds described herein with other chemical components, such as pharmaceutically acceptable carriers, stabilizers, binders, diluents, dispersing agents, suspending agents, thickening agents, solubilizing agents, or excipients.Attorney Docket No.: 206017-0045-80WOSuch compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions, or solutions. The pharmaceutical composition facilitates administration of the compound to an organism.

[0104] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0105] In some embodiments, the pharmaceutical composition provided herein comprises a buffer as an excipient. Non-limiting examples of buffers include potassium phosphate, sodium phosphate, phosphate buffer, citrate buffer, saline sodium citrate buffer (SSC), acetate, saline, physiological saline, phosphate buffer saline (PBS), 4-2-hy droxy ethyl- 1 -piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), and piperazine-N,N'-bis(2- ethanesulfonic acid) buffer (PIPES), citric acid monohydrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and any combination thereof.

[0106] In some embodiments, the pharmaceutical composition provided herein comprises an alcohol as an excipient. Non-limiting examples of alcohols include ethanol, propylene glycol, glycerol, polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol, threitol, arabitol, ribitol, mannitol, galactilol, fucitol, lactitol, and any combination thereof.

[0107] Pharmaceutical preparations can be formulated with polyethylene glycol (PEG). PEGs with molecular weights ranging from about 300 g / mol to about 10,000,000 g / mol can be used. Nonlimiting examples of PEGs include PEG 200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000, PEG 10,000, and PEG 20,000.

[0108] Further excipients that can be used in a composition described herein include, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin, glycerin, hypophosphorous acid, phenol, phenylethyl alcohol, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid,Attorney Docket No.: 206017-0045-80WO thimerasol, acetic acid, aluminum monostearate, boric acid, calcium hydroxide, calcium stearate, calcium sulfate, calcium tetrachloride, cellulose acetate pthalate, microcrystalline celluose, chloroform, citric acid, edetic acid, and ethylcellulose.

[0109] In some embodiments, the pharmaceutical composition provided herein comprises an aprotic solvent as an excipient. Non-limiting examples of aprotic solvents include perfluorohexane, a,a,a- trifluorotoluene, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, freon-11, benzene, toluene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate, 1,2-dimethoxy ethane, 2-methoxy ethyl ether, tetrahydrofuran, methylene chloride, pyridine, 2-butanone, acetone, N-methylpyrrolidinone, nitromethane, dimethylformamide, acetonitrile, sulfolane, dimethyl sulfoxide, and propylene carbonate.

[0110] The amount of the excipient in a pharmaceutical composition described herein can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% by mass of a compound in the pharmaceutical formulation.

[0111] The amount of the excipient in a pharmaceutical composition described herein can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% by mass or by volume of the unit dosage form.

[0112] In some embodiments, the addition of an excipient to a pharmaceutical composition described herein can increase or decrease the viscosity of the composition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, atAttorney Docket No.: 206017-0045-80WO least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the addition of an excipient to a pharmaceutical composition described herein can increase or decrease the viscosity of the composition by no greater than 5%, no greater than 10%, no greater than 15%, no greater than 20%, no greater than 25%, no greater than 30%, no greater than 35%, no greater than 40%, no greater than 45%, no greater than 50%, no greater than 55%, no greater than 60%, no greater than 65%, no greater than 70%, no greater than 75%, no greater than 80%, no greater than 85%, no greater than 90%, no greater than 95%, or no greater than 99%.

[0113] A composition disclosed herein can be used as a complete food product, as a component of a food product, as a dietary supplement, as part of a dietary supplement, or as a feed additive, and can be either in liquid, semisolid or solid form. A composition disclosed herein can be in the form of a pharmaceutical composition. The compositions, dietary supplements, food products, baby food products, feed additives, and / or pharmaceutical compositions disclosed herein can advantageously be utilized in methods for promoting the health of an individual.

[0114] A composition disclosed herein can be in liquid, semisolid, or solid form. For example, the compositions can be administered as tablets, gel packs, capsules, gelatin capsules, flavored drinks, as a powder that can be reconstituted into such a drink, cooking oil, salad oil or dressing, sauce, syrup, mayonnaise, or margarine. Non-limiting examples of the food product and dietary supplements can include dairy products, baby food, baby formula, beverages, bars, a powder, a food topping, a drink, a cereal, an ice cream, a candy, a snack mix, a baked food product, and a fried food product. Nonlimiting examples of beverages include energy drinks, nutraceutical drinks, smoothies, sports drinks, orange juice, and other fruit drinks. Non-limiting examples of a bar include a meal replacement, a nutritional bar, a snack bar, an energy bar, and an extruded bar. Non-limiting examples of a dairy product include yogurt, yogurt drinks, cheese, and milk.

[0115] In some embodiments, a food products or dietary supplements can further comprise herbals, herbal extracts, fungal extracts, enzymes, fiber sources, minerals, and vitamins. In some embodiments, a microalgal oils and microalgal biomass can be used in the compositions disclosed herein for both therapeutic and non-therapeutic uses. Thus, the compositions, food products, and animal feed additives disclosed herein can be used for therapeutic or non-therapeutic purposes.Pharmaceutically-A cceptable Salts.

[0116] The present disclosure provides the use of pharmaceutically-acceptable salts of anyAttorney Docket No.: 206017-0045-80WO compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a baseaddition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically- acceptable salt is a metal salt.

[0117] Metal salts can arise from the addition of an inorganic base to a compound described herein. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0118] In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0119] Ammonium salts can arise from the addition of ammonia or an organic amine to a compound described herein. In some embodiments, the organic amine is tri ethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, piprazole, imidazole, or pyrazine.

[0120] In some embodiments, an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N- methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a piprazole salt, an imidazole salt, or a pyrazine salt.

[0121] Acid addition salts can arise from the addition of an acid to a compound described herein. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicAttorney Docket No.: 206017-0045-80WO acid, citric acid, oxalic acid, or maleic acid.

[0122] In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt.Combinations

[0123] In some embodiments, a method disclosed herein further comprises administering a therapeutically-effective amount of a second therapy. In some embodiments, the second therapy exhibits synergy with a short chain fatty acid, for example as provided herein, or a pharmaceutically- acceptable salt thereof. In some embodiments, the second therapy exhibits an additive therapeutic effect to the short chain fatty, for example as provided herein, acid or a pharmaceutically-acceptable salt thereof. In some embodiments, the short chain fatty acid, for example as provided herein, or a pharmaceutically-acceptable salt thereof exhibits an additive therapeutic effect to the second therapy.

[0124] In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a therapeutically-effective amount of a short chain fatty acid, for example as provided herein, or a pharmaceutically-acceptable salt thereof and a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the therapeutically-effective amount of the short chain fatty acid, for example as provided herein, or a pharmaceutically-acceptable salt thereof, and wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeutically effective for the condition in absence of the therapeutically-effective amount of the short chain fatty acid, for example as provided herein, or a pharmaceutically-acceptable salt thereof.

[0125] In some embodiments, a combination can be in a single formulation or can be separate and administered in sequence (either a composition comprising at least one SCFA, for example as provided herein, or a molecule comprising a SCFA moiety, first and then a composition comprising an additional agent, or a composition comprising an additional agent first and then a composition comprising at least one SCFA, for example as provided herein, or a molecule comprising a SCFAAttorney Docket No.: 206017-0045-80WO moiety). In some embodiments, the SCFA, for example as provided herein, or a molecule comprising a SCFA moiety, can be administered to the subject about 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 0.25 hours, 0.5 hours, 0.75 hours, 1 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks before the composition comprising at least one additional agent is administered to the subject. In other embodiments, the composition comprising at least one additional agent can be administered to the subject about 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 0.25 hours, 0.5 hours, 0.75 hours, 1 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks before the composition comprising at least one SCFA, for example as provided herein, or a molecule comprising a SCFA moiety, is administered to the subject.

[0126] Magnesium, Vitamin D, and Vitamin E

[0127] In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, and additionally one or more of magnesium or a source of magnesium, vitamin D (e.g., vitamin D3), and vitamin E (e.g., d-a-tocopherol acetate). Magnesium is a co-factor for more than 300 enzymes that regulate diverse biochemical reactionsAttorney Docket No.: 206017-0045-80WO including regulation of blood glucose levels, detoxification, and others. Vitamin D3 deficiency is frequent in patients with immune disorders. Vitamin E has antioxidant activities. Non-limiting examples of a source of magnesium include magnesium chloride, magnesium hydroxide, magnesium carbonate, magnesium bicarbonate, magnesium sulfate, magnesium phosphate, and magnesium acetate.

[0128] In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, and additionally one or more of a source of magnesium, vitamin D (e.g., vitamin D3), and vitamin E. In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, in combination with a composition comprising one or more of a source of magnesium, vitamin D (e.g., vitamin D3), and vitamin E.

[0129] In some embodiments, a composition disclosed herein comprises a source of magnesium. In some embodiments, a composition disclosed herein comprises an inorganic magnesium salt such as magnesium chloride, magnesium carbonate, or magnesium phosphate. In some embodiments, a composition disclosed herein comprises vitamin D (e.g., vitamin D3). In some embodiments, a composition disclosed herein comprises vitamin E.

[0130] Any embodiments disclosed herein can be used in conjunction or individually. For example, any pharmaceutically-acceptable excipient, method, technique, solvent, or compound disclosed herein can be used together with any other pharmaceutically-acceptable excipient, method, technique, solvent, or compound disclosed herein to achieve any therapeutic result. Compounds, excipients, and other formulation components can be present at any amount, ratio, or percentage disclosed herein in any such formulation, and any such combination can be used therapeutically for any purpose described herein.EXAMPLESEXAMPLE 1: Treatment of Pancreatic Cancer with Short Chain Fatty Acids - assessment of pancreatic cancer mouse modelsAttorney Docket No.: 206017-0045-80WO

[0131] Various assays were designed and tested in serum as shown and described for FIGs. 1-4 and Tables 1 and 2. Assays included evaluations of tumor growth (e.g., tumor volume) in a mouse model of pancreatic cancer compared to a control group.

[0132] Study design

[0133] A xenograft mouse syngeneic pancreatic cancer model was generated using a flank xenograft pancreatic cancer with KPC cell line by injecting 104cells. In these mice, tumors typically developed in 7 days and when the volume of tumor(s) reached 50-100 mm3. Twenty-eight mice were randomly assigned to four groups (each group comprising eight mice) as follows: (1) Vehicle Gavage with carrier solution, (2) treatment with a SCFA compound alone, (3) treatment with a FOLFIRINOX (Ca+2 folinate 50 mg / kg, oxaliplatin 2.5 mg / kg, irinotecan 25 mg / kg and 5- fluorouracil 25 mg / kg), and (4) combination treatment with a SCFA compound + FOLFIRINOX. The SCFA compound was administered orally daily (5 days a week), and IP with each cycle of chemotherapy. FOLFIRINOX was administered on day 7 and day 14 by intravenous tail vein injection. Blood samples were drawn weekly and preserved. The animals were monitored for 21 days after injection and were then sacrificed for additional analysis. After sacrificing the mice, the abdomens were assessed for metastatic disease and tumor samples, liver, spleen, and intestines were collected for analysis of toxicity and microbiota.

[0134] Tumor volume

[0135] Tumor volume was determined in all mice over the period of each study (FIG. 1, FIG. 3, and Table 1)

[0136] FIG. 1 and Table 1 show tumor volume over time following treatment with vehicle gavage (control), a SCFA compound alone, chemotherapy along, and a combination of a SCFA compound and chemotherapy. FIG. 3 shows the tumor volume at day 14 for each group.

[0137] These experiments showed that mice treated with a SCFA compound alone exhibited a decreased tumor volume compared to control mice and mice treated with chemotherapy alone. Mice treated with a combination of a SCFA compound and chemotherapy exhibited also a decreased tumor volume compared to control mice and mice treated with chemotherapy alone or a SCFA compound alone.Table 1 Tumor Volume Over TimeAttorney Docket No.: 206017-0045-80WO

[0138] Body weight

[0139] Body weight was determined in all mice over the period of each study (FIG. 2 and Table 2). Both, SCFA and chemotherapy, whether in combination or alone showed no significant influence on body weight loss by treatment compared to vehicle-treated controls (FIG. 2 and Table 2).Table 2 Body Weight Over Time

[0140] Tumor weight

[0141] Tumor weight was determined in all mice at day 14 for each group (FIG. 4).

[0142] These experiments showed that mice treated with a SCFA compound alone exhibited a decreased tumor weight compared to control mice. Mice treated with a combination of a SCFAAttorney Docket No.: 206017-0045-80WO compound and chemotherapy exhibited also a decreased tumor weight compared to control mice and mice treated with chemotherapy alone or a SCFA compound alone.

[0143] With regards to observations of animal well-being, SCFA and all tested doses of chemotherapy or combination treatments were well tolerated during the study duration.EXAMPLE 2: Treatment of Pancreatic Cancer with Short Chain Fatty Acids - assessment of pancreatic cancer mouse models

[0144] Various assays were designed and tested in samples (e.g., blood, tumor samples, liver, spleen, and intestines) from mouse pancreatic cancer models and control mice as described in Example 1. Assays include evaluations of tumor growth (e.g., tumor volume), tumor toxicity, GI toxicity, RNA sequencing, and proteomics and metabolomics in a treated group compared to a control group. Additional assays, including evaluating tumor necrosis and apoptosis, are performed and assessed in the treated group compared to the control group.

[0145] Tumor toxicity: Tumor samples are used for microscopic analysis and immunohistochemistry (IHC) to assess tumor necrosis and apoptosis and immune infiltration.

[0146] GI toxicity: Intestines from treated mice and control mice are used for histopathologic assessment to determine GI toxicity.

[0147] RNA sequencing: RNA sequencing is performed to identify expression changes. Bioinformatic analysis of the RNA seq is used to identify signaling pathways. A comparative analysis of the various inflammatory and metabolic signaling pathways is performed between the treated and control groups.

[0148] Proteomics and metabolomics: For metabolomic analysis, an untargeted global metabolomics and a targeted analysis of energy and purine metabolism is performed. Deep metabolic profiling of polar and lipid fractions is used to identify potential metabolic biomarkers as well as specific metabolic pathways and their roles in response to treatment. Differential proteomic analysis is also performed to determine proteomic alternations, if any, using protein PTM analysis and functional proteomics, including changes in protein glycosylation, detect / quantify carbonylated proteins modified by oxidation, and identify and quantify free sulfhydryl groups and mixed disulfide formation.EXAMPLE 3: Treatment of Pancreatic Cancer with Short Chain Fatty Acids - assessmentAttorney Docket No.: 206017-0045-80WO pancreatic cancer cell lines

[0149] Various assays are designed and tested in pancreatic cancer cell lines (e.g., Panc-02 cell lines). Assays included evaluations of cancer cell growth and apoptosis.

[0150] Four groups will be treated as follows: (1) Vehicle, (2) treatment with a SCFA compound alone, (3) treatment with a FOLFIRINOX (Ca+2 folinate, oxaliplatin, irinotecan and 5 -fluorouracil), and (4) combination treatment with a SCFA compound + FOLFIRINOX.EXAMPLE 4: Treatment of Pancreatic Cancer with Short Chain Fatty Acids - assessment cytokines

[0151] Various assays were designed and tested in samples (e.g., blood,) from mouse pancreatic cancer models and control mice as described in Example 1. Assays include evaluations of cytokines in a treated group compared to a control group.

[0152] Cytokine analysis - Multiplex assay

[0153] Anti-inflammatory and pro-inflammatory cytokines (e.g., IL-6, 11-8, IL-10, IL-23, IL-17A, TNF-a, and IL-22) of each mouse are measured by multiplex ELISA in samples (e.g., plasma) collected after treatment as described in Example 1.

[0154] Blood samples are collected from various timepoints for each group (e.g., at study initiation and at the end of the study). For cytokine analysis in plasma, blood samples are collected, and separation is performed to separate serum from cells immediately following blood collection or within two hours of blood collection. For example, separation of plasma / serum from the red blood cells in the blood sample was achieved by centrifuging the blood sample for about 10 minutes at 3000 RPM.

[0155] Serum samples (approximately 0.4 mL to 1 mL serum) are transferred to a transport tube and frozen until analysis is performed. Samples and reference standards were assessed using a quantitative multiplex bead assay. The Cytokine Panel for various cytokines (e.g., IL- 10, IL-2, IL -4, IL-5, IL-12, IL-13, IL-17, IL-ip, IL-6, IL-8, IFN-y, and TNF-a) is used to assess cytokine release. Cytokine expression for each treatment group is assessed.EXAMPLE 5: Treatment of Pancreatic Cancer with Short Chain Fatty Acids - assessment of pancreatic cancer in a human subject

[0156] Various assays are designed and tested in samples (e.g., blood or tumor samples) from a human subject diagnosed with pancreatic cancer.Attorney Docket No.: 206017-0045-80WO

[0157] An example treatment includes: Abraxane (Paclitaxol); 80mg weekly, Eloxatin (Oxaliplatin): 70mg weekly, Xeloda (Oral 5-FU); 14 days, 2x a day.

[0158] An example regimen is:

[0159] • 2-4 capsules of Ca / Mg butyrate (600 mg of butyric acid in each capsule), BID

[0160] • 1 capsule of Ca-propionate (196 mg of propionic acid in capsule), QD

[0161] *6mL of distilled vinegar containing 5% of acetic acid (about 5 ml), thus about 260mg of acetic acid, with tea, or warm water, or juice, QD

[0162] Blood work (clinical chemistry, hematology and coagulation) is performed weekly (e.g., every 10 days) during treatment, and a week after the termination of treatment.

[0163] Assays include evaluations of tumor growth (e.g., tumor volume), tumor toxicity, GI toxicity, RNA sequencing, and proteomics and metabolomics are performed and assessed. Additional assays, including evaluating cytokines, tumor growth, and tumor necrosis and apoptosis, are performed and assessed.

[0164] These experiments show that after treatment, the subject has no metastasis. These experiments show that after treatment, the subject has tumor shrinkage.EXAMPLE 6: Treatment of Pancreatic Cancer with Short Chain Fatty Acids - assessment of pancreatic cancer mouse models

[0165] Various assays were designed and tested in serum as shown and described for FIGs. 5-7 and Tables 3 and 4. Assays included evaluations of tumor growth (e.g., tumor volume) in a mouse model of pancreatic cancer compared to a control group.

[0166] Study design

[0167] The therapeutic effects of daily oral administration of short-chain fatty acids (SCFAs) combined with standard FOLFIRINOX chemotherapy on tumor progression, systemic tissue pathology, and overall survival were evaluated in a murine model of pancreatic cancer. Forty Nude mice bearing subcutaneous MiaPaCa-2 tumors were treated over three weeks with vehicle control, a SCFA compound, chemotherapy, or a combination of the SCFA compound and chemotherapy. Treatments were followed by an additional two weeks of SCFA compound supplementation via drinking water for relevant groups, and subsequent monitoring for survival.

[0168] MethodsAttorney Docket No.: 206017-0045-80WO

[0169] A mouse pancreatic cancer model was generated using male Nude mice (n=40 mice) by subcutaneously inoculated in the right flank with (5 x 106) MiaPaCa-2 human pancreatic cancer cells. The average mouse weight was 30 g.

[0170] In these mice, tumors typically developed when the volume of tumor(s) reached 50-100 mm3. Once tumors were established (e.g., reaching 50-100 mm3), the mice were randomly assigned to four groups (n=5 / group). The groups were as follows: (1) Control (PBS gavage + PBS injections), (2) treatment with a SCFA compound alone (SCFA compound gavage + PBS injections), (3) treatment with chemotherapy (PBS gavage + FOLFIRINOX injections; Ca+2 folinate 50 mg / kg, oxaliplatin 2.5 mg / kg, irinotecan 25 mg / kg and 5 -fluorouracil 25 mg / kg), and (4) combination treatment with a SCFA compound and chemotherapy (SCFA compound gavage + FOLFIRINOX injections).

[0171] Treatment commenced immediately on the day of randomization and continued for three weeks, excluding weekends. Daily oral gavage volumes were 200 pL per mouse.

[0172] SCFA doses and composition for gavage were: 4000 mg mixture / mouse / day comprising: 60% Sodium Acetate, 25% Sodium Propionate, 15% Sodium Butyrate). Chemotherapy regimens were administered biweekly by IP injection, following the FOLFIRINOX protocol utilized: Leucovorin: 50 mg / kg, Oxaliplatin: 2.5 mg / kg, 5 -Fluorouracil: 25 mg / kg, Irinotecan: 25 mg / kg.

[0173] Control groups received corresponding volumes of PBS in place of chemotherapy or SCFA compound. The final dose of chemotherapy and gavage was given on Day 21. Then, for two weeks, SCFA with the same concentration was added to the water supply of the SCFA compound group and combination group, while the same amount of PBS was added to the water supply of the Control group and chemotherapy group. The SCFA mixture was prepared to be given with drinking water following the same dose. The water supplies were renewed every 5 days during the two weeks.Then, for the remainder of the experiment, the tumor sizes were monitored twice a week and the animals' weights were monitored weekly.

[0174] Post-treatment, tumor samples and key organs (e.g, liver, spleen, and intestines) were harvested for pathological assessment to investigate treatment efficacy and toxicity.

[0175] Body wei ht

[0176] Body weight was determined in all mice over the period of each study (FIG. 5 and Table 3). Both, SCFA and chemotherapy, whether in combination or alone showed no significant influence on body weight loss by treatment compared to vehicle-treated controls (FIG. 5 and Table 3).

[0177] Tumor volumeAttorney Docket No.: 206017-0045-80WO

[0178] Tumor volume was determined in all mice over the period of each study (FIG. 6 and Table 4).

[0179] FIG. 6 and Table 4 show tumor volume over time following treatment with vehicle gavage (control), a SCFA compound alone, chemotherapy alone, and a combination of a SCFA compound and chemotherapy.

[0180] These experiments showed that mice treated with a SCFA compound alone, chemotherapy alone, and a combination of a SCFA compound and chemotherapy exhibited a decreased tumor volume compared to control mice. Mice treated with a combination of a SCFA compound and chemotherapy exhibited also a decreased tumor volume compared to mice treated with chemotherapy alone or a SCFA compound alone.

[0181] With regards to observations of animal well-being, SCFA and all tested doses of chemotherapy or combination treatments were well tolerated during the study duration.

[0182] Mice in the combination group lived 30 days (75%) longer.Attorney Docket No.: 206017-0045-80WOTable 3 Body Weight Over TimeAttorney Docket No.: 206017-0045-80WOTable 3 (continued)Attorney Docket No.: 206017-0045-80WOTable 4 Tumor Volume Over TimeAttorney Docket No.: 206017-0045-80WOTable 4 (continued)Attorney Docket No.: 206017-0045-80WOTable 4 (continued)WSGR Docket No. 58347-711.601Table 5 Body Weight Over TimeAttorney Docket No.: 206017-0045-80WOTable 6 Tumor Volume Over TimeAttorney Docket No.: 206017-0045-80WOTable 4 (continued)Attorney Docket No.: 206017-0045-80WOTable 4 (continued)Attorney Docket No.: 206017-0045-80WOEXAMPLE 7: Treatment of Pancreatic Cancer with Short Chain Fatty Acids - assessment of pancreatic cancer mouse models

[0183] Various assays were designed and tested in serum as shown and described for FIGs. 8-9 and Tables 5 and 6. Assays included evaluations of tumor growth (e.g., tumor volume) in a mouse model of pancreatic cancer compared to a control group.

[0184] Study design

[0185] The therapeutic effects of daily oral administration of short-chain fatty acids (SCFAs) combined with standard FOLFIRINOX chemotherapy on tumor progression, systemic tissue pathology, and overall survival were evaluated in a murine model of pancreatic cancer. Forty C57BL / 6 mice bearing subcutaneous KPC tumors were treated over three weeks with vehicle control, a SCFA compound, chemotherapy, or a combination of the SCFA compound and chemotherapy.

[0186] Methods

[0187] A mouse pancreatic cancer model was generated using male C57BL / 6 mice (n=40 mice) by subcutaneously inoculated in the right flank with (1 x 106) KPC murine pancreatic cancer cells to establish tumor xenografts.

[0188] In these mice, tumors typically developed when the volume of tumor(s) reached 50-100 mm3. Once tumors were established (e.g., reaching 50-100 mm3), the mice were randomly assigned to four groups (n=7 / group), housed in pairs across two cages per group due to cage capacity regulations (maximum five mice per cage). The groups were as follows: (1) Control (PBS gavage + PBS injections), (2) treatment with a SCFA compound alone (SCFA compound gavage + PBS injections), (3) treatment with chemotherapy (PBS gavage + FOLFIRINOX injections; Ca+2 folinate 50 mg / kg, oxaliplatin 2.5 mg / kg, irinotecan 25 mg / kg and 5-fluorouracil 25 mg / kg), and (4) combination treatment with a SCFA compound and chemotherapy (SCFA compound gavage + FOLFIRINOX injections).

[0189] Treatment commenced immediately on the day of randomization and continued for three weeks, excluding weekends. Daily oral gavage volumes were 200 pL per mouse.- SCFA doses and composition for gavage were: 4000 mg mixture / mouse / day comprising: 60% Sodium Acetate, 25% Sodium Propionate, 15% Sodium Butyrate). During the initial two days, SCFAs were prepared by dissolving in 10 mL PBS: Sodium Acetate: 2400 mg, Sodium Propionate: 1000 mg, Sodium Butyrate: 600 mg.Attorney Docket No.: 206017-0045-80WO

[0190] Chemotherapy regimens were administered biweekly by IP injection, following the FOLFIRINOX protocol utilized: Leucovorin: 50 mg / kg, Oxaliplatin: 2.5 mg / kg, 5 -Fluorouracil: 25 mg / kg, Irinotecan: 25 mg / kg.

[0191] Control groups received corresponding volumes of PBS in place of chemotherapy or SCFA compound.- The final dose of chemotherapy and gavage was given on Day 21. Then, mice were sacrificed in accordance with ethical guidelines, and specimens were collected for histopathological analysis. Organs harvested (e.g., tumor tissue, spleen, liver, intestines, and colon) were harvested for pathological assessment to investigate treatment efficacy and toxicity. All samples were fixed in 10% formaldehyde before submission to pathology.

[0192] Body wei ht

[0193] Body weight was determined in all mice over the period of each study (FIG. 8 and Table 5). Both, SCFA and chemotherapy, whether in combination or alone showed no significant influence on body weight loss by treatment compared to vehicle-treated controls (FIG. 8 and Table 5).

[0194] Tumor volume

[0195] Tumor volume was determined in all mice over the period of each study (FIG. 9 and Table 6)

[0196] FIG. 9 and Table 6 show tumor volume over time following treatment with vehicle gavage (control), a SCFA compound alone, chemotherapy alone, and a combination of a SCFA compound and chemotherapy.

[0197] These experiments showed that mice treated with a SCFA compound alone, chemotherapy alone, and a combination of a SCFA compound and chemotherapy exhibited a decreased tumor volume compared to control mice. Mice treated with a combination of a SCFA compound and chemotherapy exhibited also a decreased tumor volume compared to mice treated with chemotherapy alone or a SCFA compound alone.

[0198] With regards to observations of animal well-being, SCFA and all tested doses of chemotherapy or combination treatments were well tolerated during the study duration.EMBODIMENTS

[0199] The following non-limiting embodiments provide illustrative examples of the disclosure, but do not limit the scope of the disclosure.Attorney Docket No.: 206017-0045-80WO

[0200] Embodiment 1 . A method of treating a condition in a subject in need thereof, the method comprising: (a) administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and (b) administering to the subject a therapeutically effective amount of a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the pharmaceutical composition, and wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeutically effective for the condition in absence of the pharmaceutical composition.

[0201] Embodiment 2. The method of embodiment 1, wherein the condition is a cancer.

[0202] Embodiment 3. The method of embodiment 1 or 2, wherein the condition is pancreatic cancer.

[0203] Embodiment 4. The method of any one of embodiments 1-3, wherein the short chain fatty acid is butyric acid or a pharmaceutically acceptable salt thereof.

[0204] Embodiment 5. The method of any one of embodiments 1-4, wherein the first pharmaceutical composition comprises at least two short chain fatty acids.

[0205] Embodiment 6. The method of any one of embodiments 1-5, wherein the first pharmaceutical composition comprises butyric acid or a pharmaceutically acceptable salt thereof and propionic acid or a pharmaceutically acceptable salt thereof.

[0206] Embodiment 7. The method of any one of embodiments 1-6, wherein the pharmaceutically acceptable salt of butyric acid is sodium butyrate.

[0207] Embodiment 8. The method of any one of embodiments 1-7, wherein the pharmaceutically acceptable salt of propionic acid is sodium propionate.

[0208] Embodiment 9. The method of any one of embodiments 1-8, wherein the butyric acid or the pharmaceutically-acceptable salt thereof is present in an amount of about 800 mg to about 1800 mg butyric acid or a pharmaceutically-acceptable salt thereof.

[0209] Embodiment 10. The method of any one of embodiments 1-9, wherein the propionic acid or the pharmaceutically-acceptable salt thereof is present in an amount of about 20 mg to about 200 mg.

[0210] Embodiment 11. The method of any one of embodiments 1-10, wherein the first pharmaceutical composition further comprises vitamin D.Attorney Docket No.: 206017-0045-80WO

[0211] Embodiment 12. The method of embodiment 11, wherein the vitamin D is vitamin D3.

[0212] Embodiment 13. The method of embodiment 11 or 12, wherein the vitamin D is present in an amount of from about 50 IU to about 200 IU.

[0213] Embodiment 14. The method of any one of embodiments 1-13, wherein the first pharmaceutical composition further comprises a source of magnesium.

[0214] Embodiment 15. The method of any one of embodiments 14, wherein the source of magnesium is an inorganic magnesium salt.

[0215] Embodiment 16. The method of embodiment 14 or 15, wherein the source of magnesium is present in an amount of about 10 mg.

[0216] Embodiment 17. The method of any one of embodiments 1-16, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0217] Embodiment 18. The method of any one of embodiments 1-17, wherein the pharmaceutical composition is formulated for oral administration.

[0218] Embodiment 19. The method of any one of embodiments 1-18, wherein the pharmaceutical composition is formulated as a capsule.

[0219] Embodiment 20. The method of any one of embodiments 1-19, wherein the pharmaceutical composition is formulated as a tablet.

[0220] Embodiment 21. The method of any one of embodiments 1-20, wherein the pharmaceutical composition is administered with food or drink.

[0221] Embodiment 22. The method of any one of embodiments 1-21, wherein the second therapy comprises a chemotherapeutic agent.

[0222] Embodiment 23. The method of any one of embodiments 1-22, wherein the second therapy comprises abraxane.

[0223] Embodiment 24. The method of any one of embodiments 1-23, wherein the second therapy comprises el oxatin.

[0224] Embodiment 25. The method of any one of embodiments 1-24, wherein the second therapy comprises xeloda.

[0225] Embodiment 26. The method of any one of embodiments 1-25, wherein the second therapy comprises FOLFIRINOX.

[0226] Embodiment 27. The method of any one of embodiments 1-26, wherein the second therapy comprises a radiation therapy.Attorney Docket No.: 206017-0045-80WO

[0227] Embodiment 28. The method any one of embodiments 1 -27, wherein the second therapy exhibits synergy with the pharmaceutical composition.

[0228] Embodiment 29. The method of any one of embodiments 1-28, wherein the administering of the reduced amount of the second therapy comprises administering the second therapy to the subject at a reduced frequency.

[0229] Embodiment 30. The method of any one of embodiments 1-29, wherein the administering of the reduced amount of the second therapy comprises administering a reduced dosage of the second therapy to the subject at a reduced frequency.

[0230] Embodiment 31. The method of any one of embodiments 1-30, wherein the reduced amount of the second therapy has a decreased toxicity profile compared to a toxicity profile of an amount of the second therapy that is therapeutically effective for the condition in absence of the pharmaceutical composition.

[0231] Embodiment 32. The method of any one of embodiments 1-31, wherein the administering of the pharmaceutical composition is oral.

[0232] Embodiment 33. The method of any one of embodiments 1-32, wherein the administering of the pharmaceutical composition is intravenous.

[0233] Embodiment 34. The method of any one of embodiments 1-33, wherein the administering of the pharmaceutical composition is prior to the administering of the second therapy.

[0234] Embodiment 35. The method of any one of embodiments 1-34, wherein the administering of the second therapy is prior to the administering of the pharmaceutical composition.

[0235] Embodiment 36. The method of any one of embodiments 1-35, wherein the administering of the pharmaceutical composition is concurrently with the administering of the second therapy.

[0236] Embodiment 37. The method of any one of embodiments 1-36, wherein the subject received a therapy other than the second therapy prior to the administering of the pharmaceutical composition.

[0237] Embodiment 38. The method of embodiment 37, wherein the therapy other than the second therapy was received after the subject was diagnosed with the condition.

[0238] Embodiment 39. The method of embodiment 37 or 38, wherein the subject has not responded to the therapy other than the second therapy.

[0239] Embodiment 40. The method of any one of embodiments 37-39, wherein the subject experienced a relapse of the condition after the therapy other than the second therapy.Attorney Docket No.: 206017-0045-80WO

[0240] Embodiment 41 . The method of any one of embodiments 1-40, wherein the method ameliorates a physiological symptom associated with the condition.

[0241] Embodiment 42. A method of treating a condition in a subject in need thereof, the method comprising: (a) administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and (b) administering to the subject a therapeutically- effective amount of a second therapy that exhibits synergy with the pharmaceutical composition for the condition.

[0242] Embodiment 43. The method of embodiment 42, wherein the condition is a cancer.

[0243] Embodiment 44. The method of embodiment 42 or 43, wherein the condition is pancreatic cancer.

[0244] Embodiment 45. The method of any one of embodiments 42-44, wherein the short chain fatty acid is butyric acid or a pharmaceutically acceptable salt thereof.

[0245] Embodiment 46. The method of any one of embodiments 42-45, wherein the first pharmaceutical composition comprises at least two short chain fatty acids.

[0246] Embodiment 47. The method of any one of embodiments 42-46, wherein the pharmaceutical composition comprises butyric acid or a pharmaceutically acceptable salt thereof and propionic acid or a pharmaceutically acceptable salt thereof.

[0247] Embodiment 48. The method of any one of embodiments 42-47, wherein the pharmaceutically acceptable salt of butyric acid is sodium butyrate.

[0248] Embodiment 49. The method of any one of embodiments 42-48, wherein the pharmaceutically acceptable salt of propionic acid is sodium propionate.

[0249] Embodiment 50. The method of any one of embodiments 42-49, wherein the butyric acid or the pharmaceutically-acceptable salt thereof is present in an amount of about 800 mg to about 1800 mg butyric acid or a pharmaceutically-acceptable salt thereof.

[0250] Embodiment 51. The method of any one of embodiments 42-50, wherein the propionic acid or the pharmaceutically-acceptable salt thereof is present in an amount of about 20 mg to about 200 mg.

[0251] Embodiment 52. The method of any one of embodiments 42-51, wherein the pharmaceutical composition further comprises vitamin D.

[0252] Embodiment 53. The method of embodiment 52, wherein the vitamin D is vitamin D3.Attorney Docket No.: 206017-0045-80WO

[0253] Embodiment 54. The method of embodiment 52 or 53, wherein the vitamin D is present in an amount of from about 50 IU to about 200 IU.

[0254] Embodiment 55. Embodiment 50. The method of any one of embodiments 42-54, wherein the pharmaceutical composition further comprises a source of magnesium.

[0255] Embodiment 56. The method of embodiment 55, wherein the source of magnesium is an inorganic magnesium salt.

[0256] Embodiment 57. The method of embodiment 55 or 56, wherein the source of magnesium is present in an amount of about 10 mg.

[0257] Embodiment 58. The method of any one of embodiments 42-57, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0258] Embodiment 59. The method of any one of embodiments 42-58, wherein the pharmaceutical composition is formulated for oral administration.

[0259] Embodiment 60. The method of any one of embodiments 42-59, wherein the pharmaceutical composition is formulated as a capsule.

[0260] Embodiment 61. The method of any one of embodiments 42-60, wherein the pharmaceutical composition is formulated as a tablet.

[0261] Embodiment 62. The method of any one of embodiments 42-61, wherein the first pharmaceutical composition is administered with food or drink.

[0262] Embodiment 63. The method of any one of embodiments 42-62, wherein the second therapy comprises a chemotherapeutic agent.

[0263] Embodiment 64. The method of any one of embodiments 42-63, wherein the second therapy comprises abraxane.

[0264] Embodiment 65. The method of any one of embodiments 42-64, wherein the second therapy comprises el oxatin.

[0265] Embodiment 66. The method of any one of embodiments 42-65, wherein the second therapy comprises xeloda.

[0266] Embodiment 67. The method of any one of embodiments 42-65, wherein the second therapy comprises FOLFIRINOX.

[0267] Embodiment 68. The method of any one of embodiments 42-67, wherein the second therapy comprises a radiation therapy.Attorney Docket No.: 206017-0045-80WO

[0268] Embodiment 69. The method of any one of embodiments 42-68, wherein the reduced amount of the second therapy comprises administering the second therapy to the subject at a reduced frequency.

[0269] Embodiment 70. The method of any one of embodiments 42-69, wherein the reduced amount of the second therapy comprises administering a reduced dosage of the second therapy to the subject at a reduced frequency.

[0270] Embodiment 7E The method of any one of embodiments 42-69, wherein the reduced amount of the second therapy has a decreased toxicity profile compared to a toxicity profile of an amount of the second therapy that is therapeutically effective for the condition in absence of first pharmaceutical composition.

[0271] Embodiment 72. The method of any one of embodiments 42-71, wherein the administering of the pharmaceutical composition is oral.

[0272] Embodiment 73. The method of any one of embodiments 42-72, wherein the administering of the pharmaceutical composition is intravenous.

[0273] Embodiment 74. The method of any one of embodiments 42-73, wherein the administering of the pharmaceutical composition is prior to the administering of the second therapy.

[0274] Embodiment 75. The method of any one of embodiments 42-74, wherein the administering of the second therapy is prior to the administering of the pharmaceutical composition.

[0275] Embodiment 76. The method of any one of embodiments 42-75, wherein the administering of the pharmaceutical composition is concurrently with the administering of the second therapy.

[0276] Embodiment 77. The method of any one of embodiments 42-76, wherein the subject received a therapy other than the second therapy prior to the administering of the pharmaceutical composition.

[0277] Embodiment 78. The method of embodiment 77, wherein the therapy other than the second therapy was received after the subject was diagnosed with the condition.

[0278] Embodiment 79. The method of embodiment 77 or 78, wherein the subject has not responded to the therapy other than the second therapy.

[0279] Embodiment 80. The method of any one of embodiments 77-79, wherein the subject experienced a relapse of the condition after the therapy other than the second therapy.

[0280] Embodiment 81. The method of any one of embodiments 42-80, wherein the method ameliorates a physiological symptom associated with the condition.Attorney Docket No.: 206017-0045-80WO

[0281] Embodiment 82. A method of inhibiting tumor growth in a subject having a tumor comprising: (a) administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and (b) administering to the subject a therapeutically- effective amount of a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the first pharmaceutical composition, wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeutically effective for the condition in absence of first pharmaceutical composition, and wherein the combination of the first pharmaceutical composition and the second therapy inhibits growth of the tumor in the subject.

[0282] Embodiment 83. The method of embodiment 82, wherein the inhibition of growth of the tumor in the subject is greater than an inhibition of growth of the tumor in a control subject administered an amount of the second therapy that is therapeutically effective for the condition in absence of first pharmaceutical composition.

[0283] Embodiment 84. The method of embodiment 82 or 83, wherein the combination of the pharmaceutical composition and the reduced amount of a second therapy exhibits a synergistic effect on inhibiting tumor growth compared to a tumor growth inhibition exhibited in a control subject administered a therapeutic dose of the first pharmaceutical composition alone or a therapeutic dose of the second therapy alone.

[0284] Embodiment 85. The method of any one of embodiments 82-84, wherein the subject exhibits a reduction of size of a tumor in the subject.

[0285] Embodiment 86. The method of any one of embodiments 82-85, wherein the subject exhibits a decrease in number of tumor cells in the subject.

[0286] Embodiment 87. A method of reducing size of a tumor in a subject having the tumor comprising:(a) administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and (b) administering to the subject a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the first pharmaceutical composition, wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeuticallyAttorney Docket No.: 206017-0045-80WO effective for the condition in absence of first pharmaceutical composition, and wherein the method reduces the size of the tumor in the subject.

[0287] Embodiment 88. The method of embodiment 87, wherein the reduction of the size of the tumor in the subject is greater than a reduction of the size of the tumor in a control subject administered an amount of the second therapy that is therapeutically effective for the condition in absence of the pharmaceutical composition.

[0288] Embodiment 89. The method of embodiment 87 or 88, wherein the pharmaceutical composition and the reduced amount of a second therapy exhibit a synergistic effect on inhibiting tumor growth compared to tumor growth inhibition exhibited in a control subject administered a therapeutic dose of the pharmaceutical composition alone or a therapeutic dose of the second therapy alone.

[0289] Embodiment 90. The method of any one of embodiments 87-89, wherein the subject exhibits an inhibition of tumor growth.

[0290] Embodiment 91. The method of any one of embodiments 87-90, wherein the subject exhibits a decrease in the number of tumor cells in the subject.

[0291] Embodiment 92. A method of treating a cancer in a subject in need thereof, the method comprising: (a) administering to the subject a therapeutically-effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises a short chain fatty acid or a pharmaceutically-acceptable salt or ester thereof; and (b) orally, intraperitoneally, intratumorally, rectally, parenterally, topically, pulmonary, intranasally, or buccally administering to the subject a therapeutically-effective amount of an anti-cancer agent.

[0292] Embodiment 93. The method of embodiment 92, wherein the short chain fatty acid is butyric acid.

[0293] Embodiment 94. The method of embodiment 92 or 93, wherein the pharmaceutical composition further comprises propionic acid or a pharmaceutically-acceptable salt or ester thereof.

[0294] Embodiment 95. The method of any one of embodiments 92-94, wherein the pharmaceutical composition further comprises a source of magnesium.

[0295] Embodiment 96. The method of any one of embodiments 92-95, wherein the pharmaceutical composition further comprises magnesium chloride.

[0296] Embodiment 97. The method of any one of embodiments 92-96, wherein the pharmaceutical composition further comprises vitamin D.Attorney Docket No.: 206017-0045-80WO

[0297] Embodiment 98. The method of any one of embodiments 92-97, wherein the pharmaceutical composition further comprises vitamin D3.

[0298] Embodiment 99. The method of any one of embodiments 92-98, wherein the anti-cancer agent is chemotherapy.

[0299] Embodiment 100. The method of any one of embodiments 92-99, wherein the anti-cancer agent comprises FOLFIRINOX.

[0300] Embodiment 101. The method of any one of embodiments 92-100, wherein the anti-cancer agent comprises folinate.

[0301] Embodiment 102. The method of any one of embodiments 92-101, wherein the anti-cancer agent comprises oxaliplatin.

[0302] Embodiment 103. The method of any one of embodiments 92-102, wherein the anti-cancer agent comprises irinotecan.

[0303] Embodiment 104. The method of any one of embodiments 92-103, wherein the anti-cancer agent comprises 5 -fluorouracil.

[0304] Embodiment 105. The method of any one of embodiments 92-104, wherein the anti-cancer agent comprises folinate, oxaliplatin, irinotecan, and 5 -fluorouracil.

[0305] Embodiment 106. The method of any one of embodiments 92-105, wherein the administering of the anti-cancer agent is oral.

[0306] Embodiment 107. The method of any one of embodiments 92-106, wherein the administering of the anti-cancer agent is intraperitoneal.

[0307] Embodiment 108. A kit comprising: (a) a pharmaceutical composition comprising a short chain fatty acid or a pharmaceutically-acceptable salt or ester thereof; and (b) an anti-cancer agent formulated for administration orally, intraperitoneally, intratum orally, rectally, parenterally, topically, pulmonary, intranasally, or buccally.

[0308] Embodiment 109. The kit of embodiment 1, wherein the short chain fatty acid is butyric acid.

[0309] Embodiment 110. The kit of embodiment 2, wherein the pharmaceutical composition further comprises propionic acid or a pharmaceutically-acceptable salt or ester thereof.

[0310] Embodiment 111. The kit of embodiment 1, wherein the pharmaceutical composition further comprises a source of magnesium.

[0311] Embodiment 112. The kit of embodiment 1, wherein the pharmaceutical composition further comprises magnesium chloride.Attorney Docket No.: 206017-0045-80WO

[0312] Embodiment 1 13. The kit of embodiment 1, wherein the pharmaceutical composition further comprises vitamin D.

[0313] Embodiment 114. The kit of embodiment 1, wherein the pharmaceutical composition further comprises vitamin D3.

[0314] Embodiment 115. The kit of embodiment 1, wherein the anti-cancer agent is chemotherapy.

[0315] Embodiment 116. The kit of embodiment 1, wherein the anti-cancer agent comprises FOLFIRINOX.

[0316] Embodiment 117. The kit of embodiment 1, wherein the anti-cancer agent comprises folinate.

[0317] Embodiment 118. The kit of embodiment 1, wherein the anti-cancer agent comprises oxaliplatin.

[0318] Embodiment 119. The kit of embodiment 1, wherein the anti-cancer agent comprises irinotecan.

[0319] Embodiment 120. The kit of embodiment 1, wherein the anti-cancer agent comprises 5- fluorouracil.

[0320] Embodiment 121. The kit of embodiment 1, wherein the anti-cancer agent comprises folinate, oxaliplatin, irinotecan, and 5 -fluorouracil.

Claims

Attorney Docket No.: 206017-0045-80WOCLAIMSWHAT IS CLAIMED IS:

1. A method of treating a condition in a subject in need thereof, the method comprising: a. administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and b. administering to the subject a therapeutically effective amount of a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the pharmaceutical composition, and wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeutically effective for the condition in absence of the pharmaceutical composition.

2. The method of claim 1, wherein the condition is a cancer.

3. The method of claim 1 or 2, wherein the condition is pancreatic cancer.

4. The method of any one of claims 1-3, wherein the short chain fatty acid is butyric acid or a pharmaceutically acceptable salt thereof.

5. The method of any one of claims 1-4, wherein the first pharmaceutical composition comprises at least two short chain fatty acids.

6. The method of any one of claims 1-5, wherein the first pharmaceutical composition comprises butyric acid or a pharmaceutically acceptable salt thereof and propionic acid or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1-6, wherein the pharmaceutically acceptable salt of butyric acid is sodium butyrate.

8. The method of any one of claims 1-7, wherein the pharmaceutically acceptable salt of propionic acid is sodium propionate.

9. The method of any one of claims 1-8, wherein the butyric acid or the pharmaceutically- acceptable salt thereof is present in an amount of about 800 mg to about 1800 mg butyric acid or a pharmaceutically-acceptable salt thereof.

10. The method of any one of claims 1-9, wherein the propionic acid or the pharmaceutically- acceptable salt thereof is present in an amount of about 20 mg to about 200 mg.Attorney Docket No.: 206017-0045-80WO11 . The method of any one of claims 1-10, wherein the first pharmaceutical composition further comprises vitamin D.

12. The method of claim 11, wherein the vitamin D is vitamin D3.

13. The method of claim 11 or 12, wherein the vitamin D is present in an amount of from about 50 IU to about 200 IU.

14. The method of any one of claims 1-13, wherein the first pharmaceutical composition further comprises a source of magnesium.

15. The method of claim 14, wherein the source of magnesium is an inorganic magnesium salt.

16. The method of claim 14 or 15, wherein the source of magnesium is present in an amount of about 10 mg.

17. The method of any one of claims 1-16, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

18. The method of any one of claims 1-17, wherein the pharmaceutical composition is formulated for oral administration.

19. The method of any one of claims 1-18, wherein the pharmaceutical composition is formulated as a capsule.

20. The method of any one of claims 1-19, wherein the pharmaceutical composition is formulated as a tablet.

21. The method of any one of claims 1-20, wherein the pharmaceutical composition is administered with food or drink.

22. The method of any one of claims 1-21, wherein the second therapy comprises a chemotherapeutic agent.

23. The method of any one of claims 1-22, wherein the second therapy comprises abraxane.

24. The method of any one of claims 1-23, wherein the second therapy comprises eloxatin.

25. The method of any one of claims 1-24, wherein the second therapy comprises xeloda.

26. The method of any one of claims 1-25, wherein the second therapy comprisesFOLFIRINOX.

27. The method of any one of claims 1-26, wherein the second therapy comprises a radiation therapy.

28. The method any one of claims 1-27, wherein the second therapy exhibits synergy with the pharmaceutical composition.Attorney Docket No.: 206017-0045-80WO29. The method of any one of claims 1-28, wherein the administering of the reduced amount of the second therapy comprises administering the second therapy to the subject at a reduced frequency.

30. The method of any one of claims 1-29, wherein the administering of the reduced amount of the second therapy comprises administering a reduced dosage of the second therapy to the subject at a reduced frequency.

31. The method of any one of claims 1-30, wherein the reduced amount of the second therapy has a decreased toxicity profde compared to a toxicity profile of an amount of the second therapy that is therapeutically effective for the condition in absence of the pharmaceutical composition.

32. The method of any one of claims 1-31, wherein the administering of the pharmaceutical composition is oral.

33. The method of any one of claims 1-32, wherein the administering of the pharmaceutical composition is intravenous.

34. The method of any one of claims 1-33, wherein the administering of the pharmaceutical composition is prior to the administering of the second therapy.

35. The method of any one of claims 1-34, wherein the administering of the second therapy is prior to the administering of the pharmaceutical composition.

36. The method of any one of claims 1-35, wherein the administering of the pharmaceutical composition is concurrently with the administering of the second therapy.

37. The method of any one of claims 1-36, wherein the subject received a therapy other than the second therapy prior to the administering of the pharmaceutical composition.

38. The method of claim 37, wherein the therapy other than the second therapy was received after the subject was diagnosed with the condition.

39. The method of claim 37 or 38, wherein the subject has not responded to the therapy other than the second therapy.

40. The method of any one of claims 37-39, wherein the subject experienced a relapse of the condition after the therapy other than the second therapy.

41. The method of any one of claims 1-40, wherein the method ameliorates a physiological symptom associated with the condition.

42. A method of treating a condition in a subject in need thereof, the method comprising:Attorney Docket No.: 206017-0045-80WO a. administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and b. administering to the subject a therapeutically-effective amount of a second therapy that exhibits synergy with the pharmaceutical composition for the condition.

43. The method of claim 42, wherein the condition is a cancer.

44. The method of claim 42 or 43, wherein the condition is pancreatic cancer.

45. The method of any one of claims 42-44, wherein the short chain fatty acid is butyric acid or a pharmaceutically acceptable salt thereof.

46. The method of any one of claims 42-45, wherein the first pharmaceutical composition comprises at least two short chain fatty acids.

47. The method of any one of claims 42-46, wherein the pharmaceutical composition comprises butyric acid or a pharmaceutically acceptable salt thereof and propionic acid or a pharmaceutically acceptable salt thereof.

48. The method of any one of claims 42-47, wherein the pharmaceutically acceptable salt of butyric acid is sodium butyrate.

49. The method of any one of claims 42-48, wherein the pharmaceutically acceptable salt of propionic acid is sodium propionate.

50. The method of any one of claims 42-49, wherein the butyric acid or the pharmaceutically- acceptable salt thereof is present in an amount of about 800 mg to about 1800 mg butyric acid or a pharmaceutically-acceptable salt thereof.

51. The method of any one of claims 42-50, wherein the propionic acid or the pharmaceutically- acceptable salt thereof is present in an amount of about 20 mg to about 200 mg.

52. The method of any one of claims 42-51, wherein the pharmaceutical composition further comprises vitamin D.

53. The method of claim 52, wherein the vitamin D is vitamin D3.

54. The method of claim 52 or 53, wherein the vitamin D is present in an amount of from about 50 IU to about 200 IU.

55. The method of any one of claims 42-54, wherein the pharmaceutical composition further comprises a source of magnesium.

56. The method of claim 55, wherein the source of magnesium is an inorganic magnesium salt.Attorney Docket No.: 206017-0045-80WO57. The method of claim 55 or 56, wherein the source of magnesium is present in an amount of about 10 mg.

58. The method of any one of claims 42-57, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

59. The method of any one of claims 42-58, wherein the pharmaceutical composition is formulated for oral administration.

60. The method of any one of claims 42-59, wherein the pharmaceutical composition is formulated as a capsule.

61. The method of any one of claims 42-60, wherein the pharmaceutical composition is formulated as a tablet.

62. The method of any one of claims 42-61, wherein the first pharmaceutical composition is administered with food or drink.

63. The method of any one of claims 42-62, wherein the second therapy comprises a chemotherapeutic agent.

64. The method of any one of claims 42-63, wherein the second therapy comprises abraxane.

65. The method of any one of claims 42-64, wherein the second therapy comprises eloxatin.

66. The method of any one of claims 42-65, wherein the second therapy comprises xeloda.

67. The method of any one of claims 42-65, wherein the second therapy comprisesFOLFIRINOX.

68. The method of any one of claims 42-67, wherein the second therapy comprises a radiation therapy.

69. The method of any one of claims 42-68, wherein the reduced amount of the second therapy comprises administering the second therapy to the subject at a reduced frequency.

70. The method of any one of claims 42-69, wherein the reduced amount of the second therapy comprises administering a reduced dosage of the second therapy to the subject at a reduced frequency.

71. The method of any one of claims 42-69, wherein the reduced amount of the second therapy has a decreased toxicity profile compared to a toxicity profile of an amount of the second therapy that is therapeutically effective for the condition in absence of first pharmaceutical composition.Attorney Docket No.: 206017-0045-80WO72. The method of any one of claims 42-71, wherein the administering of the pharmaceutical composition is oral.

73. The method of any one of claims 42-72, wherein the administering of the pharmaceutical composition is intravenous.

74. The method of any one of claims 42-73, wherein the administering of the pharmaceutical composition is prior to the administering of the second therapy.

75. The method of any one of claims 42-74, wherein the administering of the second therapy is prior to the administering of the pharmaceutical composition.

76. The method of any one of claims 42-75, wherein the administering of the pharmaceutical composition is concurrently with the administering of the second therapy.

77. The method of any one of claims 42-76, wherein the subject received a therapy other than the second therapy prior to the administering of the pharmaceutical composition.

78. The method of claim 77, wherein the therapy other than the second therapy was received after the subject was diagnosed with the condition.

79. The method of claim 77 or 78, wherein the subject has not responded to the therapy other than the second therapy.

80. The method of any one of claims 77-79, wherein the subject experienced a relapse of the condition after the therapy other than the second therapy.

81. The method of any one of claims 42-80, wherein the method ameliorates a physiological symptom associated with the condition.

82. A method of inhibiting tumor growth in a subject having a tumor comprising: a. administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and b. administering to the subject a therapeutically-effective amount of a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the first pharmaceutical composition, wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeutically effective for the condition in absence of first pharmaceutical composition, andAttorney Docket No.: 206017-0045-80WO wherein the combination of the first pharmaceutical composition and the second therapy inhibits growth of the tumor in the subject.

83. The method of claim 82, wherein the inhibition of growth of the tumor in the subject is greater than an inhibition of growth of the tumor in a control subject administered an amount of the second therapy that is therapeutically effective for the condition in absence of first pharmaceutical composition.

84. The method of claim 82 or 83, wherein the combination of the pharmaceutical composition and the reduced amount of a second therapy exhibits a synergistic effect on inhibiting tumor growth compared to a tumor growth inhibition exhibited in a control subject administered a therapeutic dose of the first pharmaceutical composition alone or a therapeutic dose of the second therapy alone.

85. The method of any one of claims 82-84, wherein the subject exhibits a reduction of size of a tumor in the subject.

86. The method of any one of claims 82-85, wherein the subject exhibits a decrease in number of tumor cells in the subject.

87. A method of reducing size of a tumor in a subject having the tumor comprising: a. administering to the subject a therapeutically-effective amount of a pharmaceutical composition, the pharmaceutical composition comprising at least one short chain fatty acid or a pharmaceutically-acceptable salt thereof; and b. administering to the subject a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the first pharmaceutical composition, wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeutically effective for the condition in absence of first pharmaceutical composition, and wherein the method reduces the size of the tumor in the subject.

88. The method of claim 87, wherein the reduction of the size of the tumor in the subject is greater than a reduction of the size of the tumor in a control subject administered an amount of the second therapy that is therapeutically effective for the condition in absence of the pharmaceutical composition.Attorney Docket No.: 206017-0045-80WO89. The method of claim 87 or 88, wherein the pharmaceutical composition and the reduced amount of a second therapy exhibit a synergistic effect on inhibiting tumor growth compared to tumor growth inhibition exhibited in a control subject administered a therapeutic dose of the pharmaceutical composition alone or a therapeutic dose of the second therapy alone.

90. The method of any one of claims 87-89, wherein the subject exhibits an inhibition of tumor growth.

91. The method of any one of claims 87-90, wherein the subject exhibits a decrease in the number of tumor cells in the subject.

92. A method of treating a cancer in a subject in need thereof, the method comprising: a. administering to the subject a therapeutically-effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises a short chain fatty acid or a pharmaceutically-acceptable salt or ester thereof; and b. orally, intraperitoneally, intratumorally, rectally, parenterally, topically, pulmonary, intranasally, or buccally administering to the subject a therapeutically-effective amount of an anti-cancer agent.

93. The method of claim 92, wherein the short chain fatty acid is butyric acid.

94. The method of claim 92 or 93, wherein the pharmaceutical composition further comprises propionic acid or a pharmaceutically-acceptable salt or ester thereof.

95. The method of any one of claims 92-94, wherein the pharmaceutical composition further comprises a source of magnesium.

96. The method of any one of claims 92-95, wherein the pharmaceutical composition further comprises magnesium chloride.

97. The method of any one of claims 92-96, wherein the pharmaceutical composition further comprises vitamin D.

98. The method of any one of claims 92-97, wherein the pharmaceutical composition further comprises vitamin D3.

99. The method of any one of claims 92-98, wherein the anti-cancer agent is chemotherapy.

100. The method of any one of claims 92-99, wherein the anti-cancer agent comprises FOLFIRINOX.

101. The method of any one of claims 92-100, wherein the anti-cancer agent comprises folinate.Attorney Docket No.: 206017-0045-80WO102. The method of any one of claims 92-101, wherein the anti-cancer agent comprises oxaliplatin.

103. The method of any one of claims 92-102, wherein the anti-cancer agent comprises irinotecan.

104. The method of any one of claims 92-103, wherein the anti-cancer agent comprises 5- fluorouracil.

105. The method of any one of claims 92-104, wherein the anti-cancer agent comprises folinate, oxaliplatin, irinotecan, and 5 -fluorouracil.

106. The method of any one of claims 92-105, wherein the administering of the anti-cancer agent is oral.

107. The method of any one of claims 92-106, wherein the administering of the anti-cancer agent is intraperitoneal.

108. A kit compri si ng : a. a pharmaceutical composition comprising a short chain fatty acid or a pharmaceutically-acceptable salt or ester thereof; and b. an anti-cancer agent formulated for administration orally, intraperitoneally, intratumorally, rectally, parenterally, topically, pulmonary, intranasally, or buccally.

109. The kit of claim 1, wherein the short chain fatty acid is butyric acid.

110. The kit of claim 2, wherein the pharmaceutical composition further comprises propionic acid or a pharmaceutically-acceptable salt or ester thereof.

111. The kit of claim 1, wherein the pharmaceutical composition further comprises a source of magnesium.

112. The kit of claim 1, wherein the pharmaceutical composition further comprises magnesium chloride.

113. The kit of claim 1, wherein the pharmaceutical composition further comprises vitamin D.

114. The kit of claim 1, wherein the pharmaceutical composition further comprises vitamin D3.

115. The kit of claim 1, wherein the anti-cancer agent is chemotherapy.

116. The kit of claim 1, wherein the anti-cancer agent comprises FOLFIRINOX.

117. The kit of claim 1, wherein the anti-cancer agent comprises folinate.

118. The kit of claim 1, wherein the anti-cancer agent comprises oxaliplatin.

119. The kit of claim 1, wherein the anti-cancer agent comprises irinotecan.

120. The kit of claim 1, wherein the anti-cancer agent comprises 5 -fluorouracil.Attorney Docket No.: 206017-0045-80WO121 . The kit of claim 1, wherein the anti-cancer agent comprises folinate, oxaliplatin, irinotecan, and 5 -fluorouracil.

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