Methods for treating or preventing prostate cancer

Abstract

The present invention relates, in part, to methods of treating or preventing prostate cancer in a subject in need thereof, wherein the method comprises combining dietary intervention with administration of at least one omega-3 fatty acid.

Description

[0001] Atorney Docket No.: 206030-0331-OOWO

[0002] METHODS FOR TREATING OR PREVENTING PROSTATE CANCER

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Application No. 63 / 716,941, filed November 06, 2024, and U.S. Provisional Application No. 63 / 802,041, filed May 08, 2025, all of which applications are incorporated herein by reference in their entireties.

[0005] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0006] This invention was made with government support under CA231219 awarded by the National Institutes of Health. The government has certain rights in the invention. This work was supported by the U.S. Department of Veterans Affairs, and the Federal government has certain rights in the invention.

[0007] BACKGROUND OF THE INVENTION

[0008] Active surveillance (AS) is an established option for men with low risk or favorable intermediate-risk prostate cancer. However, approximately 50% of men that elect AS ultimately undergo therapy with either surgery or radiation within 5-years of the diagnosis (Timilshina et al., 2023, J Urol, (209)540-548; Simpkin et al., 2015, Eur Urol, (67)993-1005). Prostate cancer patients in all stages of the disease, including those on AS, are highly interested in dietary approaches and supplements they can take to delay the progression of their disease. So far, however, specific guidelines in this regard have not been established. The MEAL clinical trial evaluated increased vegetable intake over 2-years in men on AS and reported no effect on prostate cancer progression (Parsons et al., 2020, JAMA, (323)140-148). The CANARY prostate cancer AS study evaluated healthy diet patterns with a median follow-up of 7.8 years and reported no effect on upgrading of the cancer (Schenk et al., 2023, Nutr Cancer, (75)618-626).

[0009] Thus, there is a need in the art for improved compositions and methods for treating or preventing prostate cancer and improving prostate health through dietary intervention. This invention addresses this unmet need.

[0010] SUMMARY OF THE INVENTION Atorney Docket No.: 206030-0331-OOWO

[0011] In some embodiments, the invention relates to a method of treating or preventing prostate cancer in a subject in need thereof, wherein the method comprises combining dietary intervention with administration of at least one omega-3 faty acid.

[0012] In some embodiments, the method comprises: a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 fatty acid intake in the subject; and c) decreasing dietary omega-6 fatty acid intake in the subject.

[0013] In some embodiments, the at least one omega-3 fatty acid is at least one selected from the group consisting of eicosapentaenoic acid (EP A), docosahexaenoic acid (DHA), a-linolenic acid (ALA), stearidonic acid (SDA), eicosatetraenoic acid (ETA), and docosapentaenoic acid (DPA), and combinations thereof.

[0014] In some embodiments, the at least one omega-3 fatty acid is administered in a dose of at least 1 g daily. In some embodiments, the at least one omega-3 fatty acid is administered in a dose of about 2.2 g daily.

[0015] In some embodiments, the at least one omega-3 fatty acid comprises EPA and DHA. In some embodiments, the at least one omega-3 fatty acid comprises about 1 part EPA and about 2 parts DHA. In some embodiments, the at least one omega-3 fatty acid comprises about 730 mg EPA and about 1470 mg DHA.

[0016] In some embodiments, the method further comprises reducing the ratio of omega-6 to omega-3 fatty acid in the subject’s red blood cells. In some embodiments, the ratio of omega-6 to omega-3 fatty acids is reduced to 4: 1 or lower.

[0017] In some embodiments, treating or preventing prostate cancer is determined by an improvement in at least one symptom, metric, or score for prostate cancer.

[0018] In some embodiments, the improvement in at least one symptom, metric, or score is determined about 3 months, about 6 months, about 9 months, or about one year after initiation of treatment.

[0019] In some embodiments, the improvement in at least one symptom, metric, or score is selected from Ki-67 index, prostate specific antigen (PSA) level, tumor grade, tumor length, tumor volume, and Decipher genomic classifier score.

[0020] In some embodiments, there is at least a 10% decrease in the subject’s Ki-67 index about one year after initiation of treatment. In some embodiments, there is an about 30% decrease in the subject’s Ki-67 index about one year after initiation of treatment. Atorney Docket No.: 206030-0331-OOWO

[0021] In some embodiments, the invention relates to a method of maintaining or improving prostate health in a subject in need thereof, wherein the method comprises: a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 fatty acid intake in the subject; and c) decreasing dietary omega-6 fatty acid intake in the subject.

[0022] In some embodiments, the at least one omega-3 fatty acid is at least one selected from the group consisting of eicosapentaenoic acid (EP A), docosahexaenoic acid (DHA), a-linolenic acid (ALA), stearidonic acid (SDA), eicosatetraenoic acid (ETA), and docosapentaenoic acid (DPA), and combinations thereof.

[0023] In some embodiments, the at least one omega-3 fatty acid is administered in a dose of at least 1 g daily.

[0024] In some embodiments, the at least one omega-3 fatty acid is administered in a dose of about 2.2 g daily.

[0025] In some embodiments, the at least one omega-3 fatty acid comprises EPA and DHA.

[0026] In some embodiments, the at least one omega-3 fatty acid comprises about 1 part EPA and about 2 parts DHA.

[0027] In some embodiments, the at least one omega-3 fatty acid comprises about 730 mg EPA and about 1470 mg DHA.

[0028] In some embodiments, the method further comprises reducing the ratio of omega-6 to omega-3 fatty acid in the subject’s red blood cells.

[0029] In some embodiments, the ratio of omega-6 to omega-3 fatty acids is reduced to 4: 1 or lower.

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The following detailed description of embodiments of the invention will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0032] Figure 1 depicts a representative flow chart diagram for the study.

[0033] Figure 2 depicts representative data demonstrating the red blood cell fatty acid composition at baseline, 6 and 12 months. The data is presented as percent of total fat.# data in the control group were collected from n=46 (baseline), n=42 (6 mon) and n=44 (12 mon); D+FO Atorney Docket No.: 206030-0331-OOWO group from n=45 (baseline), n=39 (6 mon) and n=44 (12 mon). Abbreviations: DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; LA: linoleic acid; AA: arachidonic acid.

[0034] * compared to baseline; p< 0.001. p-values were assessed from the interaction term for differential changes between groups using linear mixed effects models.

[0035] Figure 3A and Figure 3B depict representative data demonstrating prostate Ki-67 protein expression in same site biopsies at baseline and 12 months by multiplex fluorescence staining analysis. Among the 44 patients in the D+FO group and 47 patients in the control group, 40 patients in each group had evaluable cancer tissue for Ki-67 analysis. Prostate Ki-67 was assessed using a negative binomial mixed effects model. The outcome variable in the model was the number of Ki-67-positive stained nuclei with an offset term to control for the number of cells evaluated (total DAPI-stained nuclei in prostate cancer glands). The terms in the model included fixed effects for treatment (D+FO / control), time (baseline / 12 month), and the treatment by time interaction with a patient random effect.

[0036] Figure 4A and Figure 4B depict representative data demonstrating Ki-67 in prostate biopsy tissue via multiplex immunofluorescence. Figure 4A depicts low Ki-67 expression and Figure 4B depicts high Ki-67 expression. Ki-67 positive nuclei are colored light gray. Total nuclei (DAPI) are colored dark gray.

[0037] DETAILED DESCRIPTION

[0038] The present invention is based, in part, on the discovery that dietary intervention in combination with omega-3 fatty acid administration significantly reduced prostate cancer cell proliferation. Provided herein are methods for treating or preventing prostate cancer in a subject in need thereof. In certain embodiments, the invention, in part, relates to methods comprising dietary intervention in combination with administration of omega-3 fatty acids for the treatment or prevention of prostate cancer. In some embodiments, the invention provides administration of at least one omega-3 fatty acid in combination with dietary intervention such as, but not limited to, increasing dietary omega-3 fatty acids and decreasing dietary omega-6 fatty acids.

[0039] In one aspect, the present invention relates to methods of maintaining or improving prostate health. In certain embodiments, the invention, in part, relates to methods comprising dietary intervention in combination with administration of omega-3 fatty acids for maintaining or improving prostate health. Atorney Docket No.: 206030-0331-OOWO

[0040] Definitions

[0041] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Any methods and materials similar or equivalent to those described herein can be used in the practice of and / or for the testing of the present invention. In describing and claiming the present invention, the following terminology will be used according to how it is defined, where a definition is provided.

[0042] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0043] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0044] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0045] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0046] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0047] The terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In some embodiments, the patient, subject or individual is a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) and a primate (e.g., monkey and human). In certain non-limiting embodiments, the patient, subject or individual is a human.

[0048] By the term “modulating,” as used herein, is meant mediating a detectable increase or decrease in the level of a response in a subject compared with the level of a response in the Atorney Docket No.: 206030-0331-OOWO subject in the absence of a treatment or compound, and / or compared with the level of a response in an otherwise identical but untreated subject. The term encompasses perturbing and / or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject (e.g., a human.)

[0049] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.

[0050] As used herein, “treating a disease or disorder” means reducing the frequency with which a symptom of the disease or disorder is experienced by a patient. Disease and disorder are used interchangeably herein.

[0051] The phrase “therapeutically effective amount,” as used herein, refers to an amount that is sufficient or effective to prevent or treat (delay or prevent the onset of, prevent the progression of, inhibit, decrease or reverse) a disease or condition, including alleviating symptoms of such diseases.

[0052] To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject.

[0053] As used herein, the term “preventing a disease or disorder” refers to reducing the likelihood, incidence, or severity of the onset or development of the disease or disorder in a subject who is at risk of developing it, but who does not yet exhibit clinical symptoms thereof. This may include the likelihood, incidence or severity of developing prostate cancer or a disease or disorder related to prostate function.

[0054] As used herein, the term “maintaining or improving prostate health” refers to sustaining or enhancing the normal structure and / or function of the prostate tissue and / or gland. This may include sustaining or enhancing urinary function, and mitigating age-related or physiological decline in prostate function, whether by structural, biochemical, or functional means. This may include preventing, reducing, or delaying the onset or progression of prostate-related conditions or symptoms, such as prostate enlargement, inflammation, or impaired urinary function.

[0055] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For Atorney Docket No.: 206030-0331-OOWO example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0056] Description

[0057] The present invention provides methods for treating or preventing prostate cancer in a subject in need thereof. In certain embodiments, the invention relates to methods of treating or preventing prostate cancer, the method comprising administering at least one omega-3 fatty acids, increasing dietary omega-3 faty acids, and decreasing omega-6 faty acids.

[0058] In one aspect, the invention relates to the discovery that a low omega-6, high omega-3 diet in combination with omega-3 fatty acid supplementation significantly reduced prostate cancer cell proliferation as measured by the Ki-67 index.

[0059] In some embodiments, the method of treating or preventing prostate cancer in a subject in need thereof comprises administering to the subject at least one omega-3 fatty acid. In some embodiments, the method comprises increasing dietary omega-3 faty acids and decreasing omega-6 fatty acids. In some embodiments, the method comprises instructing the subject to decrease dietary omega-6 intake and increase dietary omega-3 intake. In some embodiments, the method comprises administering at least one omega-3 fatty acid in combination with increasing dietary omega-3 fatty acids and decreasing omega-6 fatty acids for treating or preventing prostate cancer. In some embodiments, the method comprises reducing the ratio of omega-6 to omega-3 fatty acids to 4: 1 or lower.

[0060] In some embodiments, the method comprises treating or preventing prostate cancer, wherein the treatment or prevention of prostate cancer is determined by an improvement in at least one symptom, metric, or score for prostate cancer. In some embodiments, the improvement in at least one symptom, metric, or score is determined about 3 months, about 6 months, about 9 months, or about one year after initiation of treatment. In some embodiments, the improvement in at least one symptom, metric, or score is selected from Ki-67 index, prostate specific antigen (PSA) level, tumor grade, tumor length, tumor volume, and Decipher genomic classifier score.

[0061] In one aspect, the present invention relates to methods of maintaining or improving prostate health. In certain embodiments, the invention relates to methods of maintaining or Atorney Docket No.: 206030-0331-OOWO improving prostate health, the method comprising administering at least one omega-3 fatty acids, increasing dietary omega-3 fatty acids, and decreasing omega-6 fatty acids. In some embodiments, the method of maintaining or improving prostate health in a subject in need thereof comprises administering to the subject at least one omega-3 fatty acid. In some embodiments, the method comprises increasing dietary omega-3 faty acids and decreasing omega-6 fatty acids. In some embodiments, the method comprises instructing the subject to decrease dietary omega-6 intake and increase dietary omega-3 intake. In some embodiments, the method comprises administering at least one omega-3 fatty acid in combination with increasing dietary omega-3 fatty acids and decreasing omega-6 fatty acids for treating or preventing prostate cancer. In some embodiments, the method comprises reducing the ratio of omega-6 to omega-3 fatty acids to 4: 1 or lower.

[0062] Method of Preventing or Treating a Disease or Disorder

[0063] The present invention relates, in part, to methods of treating or preventing prostate cancer in a subject in need thereof. In some embodiments, the method comprises treating or preventing the progression of prostate cancer. In some embodiments, the method comprises administering to the subject at least one omega-3 fatty acid in combination with increasing dietary omega-3 fatty acids and decreasing omega-6 fatty acids. In some embodiments, the at least one omega-3 fatty acid is at least one selected from the group consisting of eicosapentaenoic acid (EP A), docosahexaenoic acid (DHA), a-linolenic acid (ALA), stearidonic acid (SDA), eicosatetraenoic acid (ETA), and docosapentaenoic acid (DPA), and combinations thereof.

[0064] In some embodiments, the method comprises administering at least one omega-3 fatty acid daily. In some embodiments, the daily dose of the at least one omega-3 fatty acid is at least 1 g. In some embodiments, the at least one omega-3 fatty acid is administered at a dose of about 2.2 g daily.

[0065] In some embodiments, the method comprises administering at least one omega-3 fatty acid, wherein the at least one omega-3 fatty acid comprises EPA and DHA. In some embodiments, the at least one omega-3 fatty acid comprises 1 part EPA and 2 parts DHA. In some embodiments, the at least one omega-3 fatty acid comprises about 730 mg EPA and about 1470 mg DHA. Atorney Docket No.: 206030-0331-OOWO

[0066] In some embodiments, the method comprises combining dietary intervention with administration of at least one omega-3 fatty acid. In some embodiments, the method comprises increasing dietary omega-3 intake and decreasing dietary omega-6 intake. In some embodiments, the method comprises reducing the ratio of omega-6 to omega-3 fatty acid in the subject’s red blood cells. In some embodiments, the ratio of omega-6 to omega-3 fatty acids is reduced to 4: 1 or lower.

[0067] In some embodiments, the method comprises instructing the subject to decrease dietary omega-6 intake and increase dietary omega-3 intake. In some embodiments, the subject was instructed to consume less than 30% of calories from fat. In some embodiments, the subject was instructed decrease the consumption of foods high in omega-6 faty acids. Exemplary foods high in omega-6 fatty acids include, but are not limited to, fried foods, highly processed foods, chips and baked goods. In some embodiments, the subject was instructed to increase the consumption of foods high in omega-3 fatty acids. Exemplary foods high in omega-3 include, but are not limited to, salmon and tuna.

[0068] In some embodiments, the method comprises: a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 intake; and c) decreasing dietary omega-6 intake. In some embodiments, the method comprises a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 intake; and c) decreasing dietary omega-6 intake daily for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17, months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, or 36 months.

[0069] In some embodiments, treating and preventing prostate cancer is determined by an improvement in at least one symptom, metric, or score for prostate cancer. In some embodiments, the improvement in at least one symptom, metric, or score is determined about 3 months, about 6 months, about 9 months, or about one year after initiation of treatment. In some embodiments, the improvement in at least one symptom, metric, or score is selected from Ki-67 index, prostate specific antigen (PSA) level, tumor grade, tumor length, tumor volume, and Decipher genomic classifier score. In some embodiments, there is at least a 10% decrease in the subject’s Ki-67 index about one year after initiation of treatment. In some embodiments, there is an about 30% decrease in the subject’s Ki-67 index about one year after initiation of treatment. Atorney Docket No.: 206030-0331-OOWO

[0070] In some embodiments, treating or preventing progression of prostate cancer is determined by an improvement in at least one symptom, metric, or score for prostate cancer. In some embodiments, the improvement in at least one symptom, metric, or score is determined about 3 months, about 6 months, about 9 months, or about one year after initiation of treatment.

[0071] In some embodiments, the improvement in at least one symptom, metric, or score is selected from Ki-67 index, prostate specific antigen (PSA) level, tumor grade, tumor length, tumor volume, and Decipher genomic classifier score. In some embodiments, there is at least a 10% decrease in the subject’s Ki-67 index about one year after initiation of treatment. In some embodiments, there is an about 30% decrease in the subject’s Ki-67 index about one year after initiation of treatment.

[0072] In some embodiments, the subject is at risk of developing prostate cancer. In some embodiments, the subject is undergoing active surveillance. In some embodiments, the subject has prostate cancer.

[0073] In some embodiments, the method comprises: a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 intake; and c) decreasing dietary omega-6 intake in a subject in need thereof for about one year. In some embodiments, the ratio of omega- 6 to omega-3 fatty acids is reduced to 4: 1 or lower. In some embodiments, there is at least a 10% decrease in the subject’s Ki-67 index about one year after initiation of treatment.

[0074] In some embodiments, the method comprises administration of a capsule comprising omega-3 fatty acids. Any suitable format of delivery vehicle is contemplated. In some embodiments, the composition is for oral administration. In some embodiments, the composition is a discrete solid dose unit including, but not limited to, a hard or soft capsule, a tablet, a cachet, a troche, or a lozenge, each containing a predetermined amount of the omega-3 fatty acid.

[0075] In some embodiments, the method can be combined with administration of one or more additional therapeutic agents. Additional therapeutic agents include but are not limited to cytotoxic / anti -neoplastic agents, anti-angiogenic agents, or other anti-cancer agents.

[0076] Cytotoxic / anti-neoplastic agents are defined as agents which atack and kill cancer cells. Some cytotoxic / anti-neoplastic agents are alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine. Other cytotoxic / anti-neoplastic agents are antimetabolites for Atorney Docket No.: 206030-0331-OOWO tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine. Other cytotoxic / anti -neoplastic agents are antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulations commercially available for these compounds. Still other cytotoxic / anti-neoplastic agents are mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine and etoposide. Miscellaneous cytotoxic / anti-neoplastic agents include taxol and its derivatives, L-asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0077] Anti-angiogenic agents are well known to those of skill in the art. Suitable anti- angiogenic agents for use in the methods of the present disclosure include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides. Other known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 (including alpha and beta) interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinase- 1 and -2. (TIMP-1 and -2). Small molecules, including topoisomerases such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity, can also be used.

[0078] Other anti-cancer agents that can be used in combination with the disclosed methods include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; Atorney Docket No.: 206030-0331-OOWO fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfm; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL- TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL Atorney Docket No.: 206030-0331-OOWO antagonists; benzochlorins; benzoyl staurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide- amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophy cin 8; cryptophy cin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; Atorney Docket No.: 206030-0331-OOWO meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1- based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras- GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B 1 ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenyl acetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stemcell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; Atorney Docket No.: 206030-0331-OOWO tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin; stimalamer; apalutamide; enzalutamide; and darolutamide. In some embodiments, the anti-cancer agent is apalutamide, enzalutamide, or darolutamide.

[0079] In some embodiments, the anti-cancer agent may be a prodrug form of an anti-cancer agent. As used herein, the term “prodrug form” and its derivatives is used to refer to a drug that has been chemically modified to add and / or remove one or more substituents in such a manner that, upon introduction of the prodrug form into a subject, such a modification may be reversed by naturally occurring processes, thus reproducing the drug. The use of a prodrug form of an anti-cancer agent in the compositions, among other things, may increase the concentration of the anti-cancer agent in the compositions of the present disclosure. In certain embodiments, an anticancer agent may be chemically modified with an alkyl or acyl group or some form of lipid. The selection of such a chemical modification, including the substituent(s) to add and / or remove to create the prodrug, may depend upon a number of factors including, but not limited to, the particular drug and the desired properties of the prodrug. One of ordinary skill in the art, with the benefit of this disclosure, will recognize suitable chemical modifications^

[0080] One of skill in the art will appreciate that the described methods herein can be administered acutely (e.g., over a short period of time, such as a day, a week or a month) or chronically (e.g., over a long period of time, such as several months or a year or more). One of ordinary skill in the art will appreciate, based on the disclosure provided herein, that the methods for a) administering to the subject at least one omega-3 faty acid; b) increasing dietary omega-3 intake; and c) decreasing dietary omega-6 intake can be used to treat or prevent prostate cancer. Atorney Docket No.: 206030-0331-OOWO

[0081] The present invention relates, in part, to methods of treating or preventing prostate cancer in subjects in need thereof, the method comprising: a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 intake; and c) decreasing dietary omega-6 intake.

[0082] It will be appreciated by one of skill in the art, when armed with the present disclosure including the methods detailed herein, that the invention is not limited to the treatment of prostate cancer that is already established. Particularly, the disease or disorder need not have manifested to the point of detriment to the subject; indeed, the disease or disorder need not be detected in a subject before treatment is administered. That is, significant signs or symptoms of a disease or disorder do not have to occur before the present invention may provide benefit. Therefore, the present invention includes a method for preventing a disease or disorder, in that a composition, as discussed previously elsewhere herein, can be administered to a subject prior to the onset of the disease or disorder, thereby preventing the disease or disorder.

[0083] One of skill in the art, when armed with the disclosure herein, would appreciate that the prevention of a disease or disorder, encompasses administering to a subject a composition as a preventative measure against the development of, or progression of, a disease or disorder.

[0084] To practice the methods of the invention; the skilled artisan would understand, based on the disclosure provided herein, how to formulate and administer the appropriate composition to a subject. The present invention is not limited to any particular method of administration or treatment regimen.

[0085] One of skill in the art will appreciate that the compositions of the invention can be administered singly or in any combination. Further, the compositions of the invention can be administered singly or in any combination in a temporal sense, in that they may be administered concurrently, or before, and / or after each other. One of ordinary skill in the art will appreciate, based on the disclosure provided herein, that the compositions of the invention can be used to prevent or to treat a disease or disorder, and that a composition can be used alone or in any combination with another composition to affect a therapeutic result. In various embodiments, any of the compositions of the invention described herein can be administered alone or in combination with at least one modulator of an additional molecule associated with a disease or disorder. Atorney Docket No.: 206030-0331-OOWO

[0086] Method of Maintaining or Improving Prostate Health

[0087] The present invention relates, in part, to methods of maintaining or improving prostate health in a subject in need thereof. In some embodiments, the method comprises administering to the subject at least one omega-3 fatty acid in combination with increasing dietary omega-3 fatty acids and decreasing omega-6 fatty acids. In some embodiments, the at least one omega-3 fatty acid is at least one selected from the group consisting of eicosapentaenoic acid (EP A), docosahexaenoic acid (DHA), a-linolenic acid (ALA), stearidonic acid (SDA), eicosatetraenoic acid (ETA), and docosapentaenoic acid (DPA), and combinations thereof.

[0088] In some embodiments, the method comprises administering at least one omega-3 fatty acid daily. In some embodiments, the daily dose of the at least one omega-3 fatty acid is at least 1 g. In some embodiments, the at least one omega-3 fatty acid is administered at a dose of about 2.2 g daily.

[0089] In some embodiments, the method comprises administering at least one omega-3 fatty acid, wherein the at least one omega-3 fatty acid comprises EPA and DHA. In some embodiments, the at least one omega-3 fatty acid comprises 1 part EPA and 2 parts DHA. In some embodiments, the at least one omega-3 fatty acid comprises about 730 mg EPA and about 1470 mg DHA.

[0090] In some embodiments, the method comprises combining dietary intervention with administration of at least one omega-3 fatty acid. In some embodiments, the method comprises increasing dietary omega-3 intake and decreasing dietary omega-6 intake. In some embodiments, the method comprises reducing the ratio of omega-6 to omega-3 fatty acid in the subject’s red blood cells. In some embodiments, the ratio of omega-6 to omega-3 fatty acids is reduced to 4: 1 or lower.

[0091] In some embodiments, the method comprises instructing the subject to decrease dietary omega-6 intake and increase dietary omega-3 intake. In some embodiments, the subject was instructed to consume less than 30% of calories from fat. In some embodiments, the subject was instructed decrease the consumption of foods high in omega-6 faty acids. Exemplary foods high in omega-6 fatty acids include, but are not limited to, fried foods, highly processed foods, chips and baked goods. In some embodiments, the subject was instructed to increase the consumption of foods high in omega-3 fatty acids. Exemplary foods high in omega-3 include, but are not limited to, salmon and tuna. Atorney Docket No.: 206030-0331-OOWO

[0092] In some embodiments, the method comprises: a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 intake; and c) decreasing dietary omega-6 intake. In some embodiments, the method comprises a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 intake; and c) decreasing dietary omega-6 intake daily for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17, months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, or 36 months.

[0093] In some embodiments, the method comprises: a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 intake; and c) decreasing dietary omega-6 intake in a subject in need thereof for about one year. In some embodiments, the ratio of omega- 6 to omega-3 fatty acids is reduced to 4: 1 or lower.

[0094] In some embodiments, the method comprises administration of a capsule comprising omega-3 fatty acids. Any suitable format of delivery vehicle is contemplated. In some embodiments, the composition is for oral administration. In some embodiments, the composition is a discrete solid dose unit including, but not limited to, a hard or soft capsule, a tablet, a cachet, a troche, or a lozenge, each containing a predetermined amount of the omega-3 fatty acid.

[0095] In one aspect, the invention provides methods of maintaining or improving prostate health in a subject in need thereof. In some embodiments, maintaining or improving prostate health relates to improving prostate function or preventing prostate related diseases or disorders. Exemplary functions of the prostate can include, but is not limited to, producing prostatic fluid, regulating urine flow, supporting sperm health, ejaculation, and hormonal regulation. In some embodiments, the subject has a disease or disorder related to the prostate or is at risk of developing a disease or disorder related to the prostate. In some embodiments, the disease or disorder is benign prostatic hyperplasia (BPH), prostatitis, or prostate cancer. In some embodiments, the subject has frequent urination, difficulty starting or stopping urination, a weak urination stream, pain or discomfort while urinating or incontinence. In some embodiments, the present invention provides methods for improving prostate-related sexual dysfunction in a subject. In some embodiments, the subject has erectile dysfunction, painful ejaculation, and decreased volume of ejaculate. Atorney Docket No.: 206030-0331-OOWO

[0096] In some embodiments, the present invention provides methods of preventing prostate diseases or disorders in a subject. In some embodiments, the subject is at risk of developing a prostate disease or disorder. In some embodiments, the subject has family history of prostate disease. In some embodiments, the subject is obese. In some embodiments, the subject is over the age of 50. In some embodiments, the subject smokes. In some embodiments, the subject is determined to be at risk of developing a prostate disease or disorder based on genetic studies, a strong family history of prostate cancer, an elevated prostate specific antigen (PSA) blood level, or findings from a prior prostate biopsy. In some embodiments, the subject has a Gleason score of a 6 or above. In some embodiments, the subject is determined to be at risk of developing a prostate disease or disorder based the presence of at least one prostate cancer genetic biomarker. In some embodiments, the at least one prostate cancer genetic biomarker is a biomarker in the cell cycle progression (CCP) gene list. In some embodiments, the at least one prostate cancer genetic biomarker is selected from the group consisting of: F0XM1, CDC20, CDKN3, CDC2, KIF11, KIAA0101, NUSAP1, CENPF, ASPM, BUB IB, RRM2, DLGAP5, BIRC5, KIF20A, PLK1, TOP2A, TK1, PBK, ASF1B, C18orf24, RAD54L, PTTG1, CDCA3, MCM10, PRC1, DTL, CEP55, RAD51, CENPM, CDCA8, and ORC6L.

[0097] In some embodiments, improving prostate health is determined by an improvement in at least one symptom, metric, or score for prostate function. In some embodiments, the improvement in at least one symptom, metric, or score is determined about 3 months, about 6 months, about 9 months, or about one year after initiation of treatment. In some embodiments, the improvement is determined by a decreased Gleason score. In some embodiments, the improvement is determined by a decreased PSA blood level. In some embodiments, the improvement is determined by the change of at least one prostate cancer genetic biomarker. In some embodiments, the at least one prostate cancer genetic biomarker is a biomarker selected from the list consisting of: FOXM1, CDC20, CDKN3, CDC2, KIF11, KIAA0101, NUSAP1, CENPF, ASPM, BUB1B, RRM2, DLGAP5, BIRC5, KIF20A, PLK1, TOP2A, TK1, PBK, ASF1B, C18orf24, RAD54L, PTTG1, CDCA3, MCM10, PRC1, DTL, CEP55, RAD51, CENPM, CDCA8, and ORC6L. In some embodiments, the improvement is determined by a combination of Gleason score, PSA blood level, and prostate cancer genetic biomarkers.

[0098] EMBODIMENTS Atorney Docket No.: 206030-0331-OOWO

[0099] This invention provides the following non-limiting embodiments,

[0100] Embodiment 1 is a method of treating or preventing prostate cancer in a subject in need thereof, wherein the method comprises combining dietary intervention with administration of at least one omega-3 fatty acid.

[0101] Embodiment 2 is method of embodiment 1, wherein the method comprises: a) administering to the subject at least one omega-3 faty acid; b) increasing dietary omega-3 fatty acid intake in the subject; and c) decreasing dietary omega-6 fatty acid intake in the subject.

[0102] Embodiment 3 is the method of embodiment 1 or 2, wherein the at least one omega-3 fatty acid is at least one selected from the group consisting of eicosapentaenoic acid (EP A), docosahexaenoic acid (DHA), a-linolenic acid (ALA), stearidonic acid (SDA), eicosatetraenoic acid (ETA), and docosapentaenoic acid (DPA), and combinations thereof.

[0103] Embodiment 4 is the method of any one of embodiments 1 through 3, wherein the at least one omega-3 fatty acid is administered in a dose of at least 1 g daily.

[0104] Embodiment 5 is the method of any one of embodiments 1 through 4, wherein the at least one omega-3 fatty acid is administered in a dose of about 2.2 g daily.

[0105] Embodiment 6 is the method of any one of embodiments 1 through 5, wherein the at least one omega-3 fatty acid comprises EPA and DHA.

[0106] Embodiment 7 is the method of any one of embodiments 1 through 6, wherein the at least one omega-3 fatty acid comprises about 1 part EPA and about 2 parts DHA.

[0107] Embodiment 8 is the method of any one of embodiments 1 through 7, wherein the at least one omega-3 fatty acid comprises about 730 mg EPA and about 1470 mg DHA.

[0108] Embodiment 9 is method of any one of embodiments 1 through 8, wherein the method further comprises reducing the ratio of omega-6 to omega-3 fatty acid in the subject’s red blood cells.

[0109] Embodiment 10 is the method of any one of embodiments 1 through 9, wherein the ratio of omega-6 to omega-3 fatty acids is reduced to 4: 1 or lower.

[0110] Embodiment 11 is the method of any one of embodiments 1 through 10, wherein treating or preventing prostate cancer is determined by an improvement in at least one symptom, metric, or score for prostate cancer. Atorney Docket No.: 206030-0331-OOWO

[0111] Embodiment 12 is the method of any one of embodiments claim 1 through 1 1, wherein the improvement in at least one symptom, metric, or score is determined about 3 months, about 6 months, about 9 months, or about one year after initiation of treatment.

[0112] Embodiment 13 is the method of any one of embodiments 1 through 12, wherein the improvement in at least one symptom, metric, or score is selected from Ki-67 index, prostate specific antigen (PSA) level, tumor grade, tumor length, tumor volume, and Decipher genomic classifier score.

[0113] Embodiment 14 is the method of any one of embodiments 1 through 13, wherein there is at least a 10% decrease in the subject’s Ki -67 index about one year after initiation of treatment.

[0114] Embodiment 15 is the method of any one of embodiments 1 through 14, wherein there is an about 30% decrease in the subject’s Ki-67 index about one year after initiation of treatment.

[0115] Embodiment 16 is a method of maintaining or improving prostate health in a subject in need thereof, wherein the method comprises: a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 fatty acid intake in the subject; and c) decreasing dietary omega-6 fatty acid intake in the subject.

[0116] Embodiment 17 is the method of embodiment 16, wherein the at least one omega-3 fatty acid is at least one selected from the group consisting of eicosapentaenoic acid (EP A), docosahexaenoic acid (DHA), a-linolenic acid (ALA), stearidonic acid (SDA), eicosatetraenoic acid (ETA), and docosapentaenoic acid (DPA), and combinations thereof.

[0117] Embodiment 18 is the method of embodiment 16 or 17, wherein the at least one omega-3 fatty acid is administered in a dose of at least 1 g daily.

[0118] Embodiment 19 is the method of any one of embodiments 16 through 18, wherein the at least one omega-3 fatty acid is administered in a dose of about 2.2 g daily.

[0119] Embodiment 20 is the method of any one of embodiments 16 through 19, wherein the at least one omega-3 fatty acid comprises EPA and DHA.

[0120] Embodiment 21 is the method of any one of embodiments 16 through 20, wherein the at least one omega-3 fatty acid comprises about 1 part EPA and about 2 parts DHA.

[0121] Embodiment 22 is the method of any one of embodiments 16 through 21, wherein the at least one omega-3 fatty acid comprises about 730 mg EPA and about 1470 mg DHA. Atorney Docket No.: 206030-0331-OOWO

[0122] Embodiment 23 is the method of any one of embodiments 16 through 22, wherein the method further comprises reducing the ratio of omega-6 to omega-3 fatty acid in the subject’s red blood cells.

[0123] Embodiment 24 is the method of any one of embodiments 16 through 24, the ratio of omega-6 to omega-3 fatty acids is reduced to 4:1 or lower.

[0124] EXPERIMENTAL EXAMPLES

[0125] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0126] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore are not to be construed as limiting in any way the remainder of the disclosure.

[0127] Example 1 : A High Omega-3, Low Omega-6 Diet with Fish Oil for Men with Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial

[0128] Men on active surveillance for prostate cancer are extremely interested in dietary changes or supplements to prevent progression of their disease. There are presently no prospective trials supporting such changes. This study sought to determine if a high omega-3, low omega-6 fatty acid diet with fish oil capsules (D+FO) decreases proliferation (Ki-67) in prostate biopsies in men with prostate cancer on active surveillance over a 1-year time period.

[0129] The Western diet is notably high in omega-6 fatty acids found in corn, soy, and safflower oil, and low in omega-3 fatty acids found in fatty cold-water fish such as salmon, mackerel, herring and sardines (Simopoulos AP., 2016, Nutrients, (8)128; Saini et al., 2018, Life Sci, (203)255-267). In preclinical models of prostate cancer, lowering omega-6 and raising omega-3 dietary intake delayed prostate cancer progression, however epidemiologic studies have shown mixed results (Liang et al., 2019, J Natl Cancer Inst, (111)52-59; Lovegrove et al., 2015, Int J Clin Pract, (69)87-105; Lee et al., 2020, Adv Nutr, (11)1134-1149; Bilodeau et al., 2021, Atorney Docket No.: 206030-0331-OOWO

[0130] Prostaglandins Leukot Essent Fatty Acids, (164)102215; Ngo et al., 2004, Cancer Res, (64)1252- 4). In a cross-sectional study nested within a Phase II clinical trial in men on AS, higher prostate tissue eicosapentaenoic acid (EP A, omega-3) levels correlated with less clinical-upgrading on subsequent biopsies (Moussa et al., 2019, Nutrients, 11). In a short-term pre-prostatectomy study, combining a low-fat diet with fish oil (FO) supplementation was found to decrease tissue biomarkers associated with prostate cancer progression (Ki-67-index and the cell-cycle progression score) (Galet et al., 2014, Cancer Prev Res (Phila), (7)97-104; Aronson et al., 2011, Cancer Prev Res (Phila), (4)2062-71). Based on these prior preclinical and clinical studies, the CAPFISH-3 trial was conducted. This trial is a 1-year prospective randomized trial in men with Grade Group 1 or 2 prostate cancer on AS with randomization to either no treatment (control group) or to a high omega-3, low omega-6 diet with FO supplements. The primary endpoint was Ki-67 index in targeted same site prostate biopsy tissue (based on location coordinates). Ki-67 index is a marker of proliferation and is known to predict progression, metastasis, and death from prostate cancer (Berlin et al., 2017, Urol Oncol, (35)499-506; Kammerer-Jacquet et al., 2019, Mod Pathol, (32)1303-1309).

[0131] The methods and materials are now described.

[0132] Trial Design and Conduct

[0133] The CAPFISH-3 trial was a single center phase II, randomized, open label, two-arm study in men on active surveillance for prostate cancer and was performed at the University of California Los Angeles. Men were randomized either to a control (no dietary intervention) group or to a group receiving dietary counseling to lower dietary omega-6 fat intake and increase dietary omega-3 fat intake combined with daily FO capsule supplements. Randomization (1: 1) was by a permuted random block design stratified by Gleason score 3+3 or 3+4.

[0134] Patients and Interventions

[0135] Eligible patients had biopsy-confirmed adenocarcinoma of the prostate (minimum 5% cancer in one core); Gleason score of 3+4 or less; clinical stage T2c or less; serum PSA of 25 or less; agree to not consume FO capsules if randomized to the control group; and were participating in the UCLA active surveillance program. Exclusion criteria were intake of Atorney Docket No.: 206030-0331-OOWO finasteride or dutasteride during the prior 6 months, prior treatment for prostate cancer, patients having an allergy to fish, and patients with a vegetarian diet.

[0136] Participants in the intervention arm received dietary counseling by the study registered dietician nutritionist consisting of monthly individualized counseling sessions in-person, via telehealth, or by telephone. Subjects were counseled to consume less than 30% of calories from fat with decreased consumption of foods high in omega-6 fatty acids such as fried foods, highly processed foods, chips and baked goods, and to increase intake of omega-3 rich foods (e.g. salmon, tuna). The goal was to decrease the ratio of omega-6 to omega-3 fat intake to achieve a ratio of less than 4: 1. FO capsules (Pharmavite LLC, West Hills, CA) were utilized, providing a daily dose of approximately 2.2 g of omega-3 fatty acids (DHA and EP A). The control group did not receive dietary counseling and was instructed to refrain from taking FO.

[0137] Prior to enrollment, a prostate biopsy was obtained and the coordinates of each core were recorded and tracked using an image-fusion device (Artemis, Eigen Health, Grass Valley, CA) (Natarajan et al., 2011, Urol Oncol, (29)334-42). Twelve months from the initial biopsy, all participants underwent same site biopsies at the coordinates where cancer was previously located (MRI and / or non-MRI targets, minimum of 3 cores per site). In addition, systematic 12-core biopsies were performed. Using the tracking technology, repeat sampling of a specific site is spatially accurate within several mm and has been employed successfully in previous studies (Natarajan et al., 2011, Urol Oncol, (29)334-42; Salami et al., 2021, Eur Urol, (79)456-465).

[0138] Assessments

[0139] Dietary intake was assessed at baseline and every 3 months (intervention arm) and every 6 months (control arm) by 3-day food records.

[0140] Fasting blood was collected at baseline, 6-months, and 1-year. Height was measured at baseline and anthropometries (weight, waist and hip circumference) were measured at baseline, 6-months, and 1-year in both groups, and at 3 and 9 months in the intervention group.

[0141] Plasma lipids (total cholesterol, HDL-cholesterol, triglyceride), testosterone, and PSA were measured. Red blood cell (RBC) fatty acid analyses were measured as previously described (Bagga et al., 1997, J Natl Cancer Inst, (89)1123-31). Serum cytokines were measured as previously described (Kim et al., 2018, Aging (Albany NY), (10)1239-1256). Atorney Docket No.: 206030-0331-OOWO

[0142] Slides from archived formalin-fixed, paraffin-embedded biopsy tissue were cut and either used for H&E staining, multiplex immunofluorescence analysis, or determination of Decipher genomic classifier score (Veracyte Inc. San Diego, CA), a 22 gene panel (Press et al., 2022, Eur Urol Open Sci, (37)113-119). Ki-67 in prostate biopsy tissue was analyzed using multiplex immunofluorescence analysis (Figure 4) (Mori et al., 2020, J Mammary Gland Biol Neoplasia, (25)417-432).

[0143] Endpoints and Statistical Analyses

[0144] Patient characteristics and study variables were summarized using means / standard deviations or frequencies / percentages. The analyses were conducted with an intention to treat framework (as randomized) for patients who completed the study. The primary endpoint was the change in Ki -67 index from baseline to 1-year from same site biopsies with cancer compared between the groups. In order to estimate this effect, a negative binomial mixed effects model was constructed. The outcome variable in the model was the number of Ki-67-positive stained nuclei with an offset term to control for the number of cells evaluated (total DAPI-stained nuclei in prostate cancer glands). The terms in the model included fixed effects for treatment (D+FO / control), time (baseline / 12 month), and the treatment by time interaction with a patient random effect and the number of prostate cancer gland nuclei (log scale) as an offset variable. Secondary outcome measures included pathologic features (Grade Group, maximum tumor length), Decipher 22 gene classifier score, serum PSA, testosterone, and lipid levels. For the primary PSA assessment, the PSA values collected during the study were utilized (baseline and 12 month). Additionally, as a sensitivity analysis, PSA was utilized at screening. Other secondary outcomes included RBC omega-3 and omega-6 fatty acid levels, compliance with the diet and FO capsules, and adverse events. These outcomes were largely assessed using linear mixed effects models with a similar structure to the primary outcome analysis, which allowed for the use of all available data from patients that completed the trial, even if a patient was missing follow-up or baseline data (due to non-evaluable biopsies). These analyses were presented using means / SDs at each time point as well as the p-value from the interaction term to assess for differential changes between groups. Prior to analysis, normality was assessed through visual inspections and drew on the clinical understanding of the variables. For cytokine data (Table 1) and PSA these analyses were run after performing a logarithmic transformation to better meet Atorney Docket No.: 206030-0331-OOWO statistical assumptions. For Grade Group progression, progression rate was compared between groups using the chi-square test. The statistical analyses were run using the Glimmix procedure in SAS V9.4 (SAS Institute, Cary, NC) and p-values <0.05 were considered statistically significant.

[0145] Table 1. Serum Cytokine Concentration (log scale) at Baseline, 6 and 12 Months. Values in Parenthesis Present SD.*#

[0146] * Abbreviations: IFN- y: interferon gamma; IL-10: interferon 10; IL-6: interferon 6; IL-8: interferon 8; MCP-1: monocyte chemoattractant protein- 1; M-CSF: macrophage colony-stimulating factor; TNF-a: tumor necrosis factor alpha. Statistical analysis used log transformation. #D+FO group n=46 (baseline). n=37 (6 mon) and n=45 (12 mon); Control group n=48 (baseline), n=43 (6 mon) and n=46 (12 mon). P- values were assessed from the interaction term treatment by time using linear mixed effects models.

[0147] Based on the treatment effect from a prior study incorporating a low-fat FO diet, it was estimated that a sample size of 35 evaluable subjects per treatment group would have 80% power for finding a 37% difference in log Ki-67 assuming a two-sample two tailed t-test with a 0.05 level of significance (means on log scale of 1.80 vs 1.43, SD=0.54). In this study, 100 randomized subjects anticipating a 10% dropout rate and anticipating 20% of subjects would have non-evaluable biopsy samples thus leaving 35 evaluable subjects per treatment group.

[0148] Demographics Attorney Docket No.: 206030-0331-00WO

[0149] The CAPFISH-3 trial was conducted from December 2014 to September 2022. One hundred and seven patients signed the consent form, seven of which failed screening, leaving 100 patients that were randomized (50 to the control group and 50 to the intervention group) (Figure 1). The majority of patients had Grade Group 1 (Gleason grade 3+3) prostate cancer and approximately one in four patients that entered the trial had Grade Group 2 (Gleason grade 3+4) prostate cancer (Table 2). The majority of patients in both groups had cTIC prostate cancer (elevated PSA with normal digital rectal exam - data not shown). The reasons for drop out are listed in Figure 1. squared).

[0150] Dietary and Fish Oil Capsule Intake Attorney Docket No.: 206030-0331-OOWO

[0151] Based on analyses of the 3-day food records, subjects in the D+FO group had a significant reduction in dietary omega-6 fatty acid intake and omega-6 to omega-3 dietary ratio as compared to the control group, whereas there was no significant difference in dietary intake (excluding FO supplements) of omega-3 fatty acids between the groups (Table 3). There was no difference in weight change between the groups and there was no significant change within group weight loss (Table 4). FO capsule compliance was computed for each patient as the number of pills consumed over the number of pills prescribed, resulting in an average overall compliance rate of 90.5% (SD 12.5%) for prescribed capsules consumed in the D+FO group. Table 3. 3 -Day Diet Records at Baseline, 6 and 12 Months. Values in Parenthesis are Standard Deviations.* Attorney Docket No.: 206030-0331-OOWO

[0152] * Control group baseline n=48, six month n=43, twelve month n=41. D+FO group baseline n=49, six month n=41 , twelve month n=33;#Control group did not consume fish oil and therefore the fields in the table were left blank. The fish oil capsules provided ~2.2 g of omega-3 fatty acids (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EP A)). Abbreviations: SatFat: saturated fat; MonoFat: monounsaturated fat; PolyFat: polyunsaturated fat. P-values were assessed from the interaction term for differential changes between groups using linear mixed effects models.

[0153] Table 4. Weight, BMI, Serum Lipids, Testosterone and PSA at Baseline, 6 and 12 Months. Values in Parenthesis are Standard Deviations.*

[0154] * Control group baseline n=50, six month n=46, twelve month n=46; D+FO group baseline n=50, six month n=37, twelve month n=43. # PSA not collected at 6-month time point Atorney Docket No.: 206030-0331-OOWO

[0155] **PSA median (IQR). Abbreviations: BMP body mass index (calculated as weight in kilograms divided by height in meters squared); LDL: low density lipoprotein; HDL: high density lipoprotein. P-values were assessed from the interaction term for differential changes between groups using linear mixed effects models.

[0156] Reduction in dietary omega-6 intake was confirmed by RBC fatty acid measurements, which are a measure of long-term dietary intake (Figure 2). DHA (omega-3), EPA (omega-3) and total omega-3 RBC levels were all significantly increased in the D+FO group but not in the control group (Figure 2, Table 5).

[0157] Table 5. Red Blood Cell Fatty Acid Composition. Values are Expressed as Percent of Total Fat. Values in Parenthesis Present SD.*#

[0158] Control D+FO

[0159] Time 0 6 12 0 6 12 Group

[0160] (mon)

[0161] Time

[0162] MA 0.4 (0.1) 0.4 (0.1) 0.3 (0.1) 0.4 (0.1) 0.4 (0.3) 0.4 (0.2) 0.987

[0163] PA 24.3 (1.6) 24.5 (1.9) 24.5 (1.7) 24.5 (2.5) 24.7 (2.7) 24.9 (2.8) 0.75

[0164] POA 0.5 (0.2) 0.5 (0.2) 0.5 (0.2) 0.5 (0.2) 0.5 (0.2) 0.5 (0.1) 0.867

[0165] SA 20.4 (1.5) 20.5 (1.5) 20.6 (1.4) 20.8 (1.8) 20.2 (2.0) 20.3 (2.1) 0.014

[0166] OA 13.9 (1.5) 14.0 (1.3) 14.1 (1.1) 13.9 (1.3) 13.5 (1.4) 13.4 (1.2) <0.001

[0167] LA 10.8 (1.5) 10.7 (1.5) 10.3 (1.2) 10.8 (1.4) 9.6 (1.3) 9.4 (1.4) <0.001

[0168] LNA 0.2 (0.1) 0.2 (0.3) 0.2 (0.1) 0.2 (0.1) 0.2 (0.1) 0.2 (0.1) 0.627

[0169] EDA 0.4 (0.1) 0.4 (0.2) 0.4 (0.2) 0.5 (0.2) 0.4 (0.1) 0.5 (0.1) 0.986

[0170] AA 19.2 (1.9) 19.3 (2.1) 19.3 (2.4) 18.9 (2.6) 15.3 (2.6) 15.0 (2.5) <0.001

[0171] EPA 1.0 (0.4) 1.0 (0.4) 1.0 (0.5) 1 1 (0.5) 2.3 (0.9) 2.6 (0.8) <0.001

[0172] DPA 3.2 (0.7) 3 1 (0.7) 3.1 (0.6) 3.1 (0 6) 3.3 (0 6) 3.3 (0 6) <0.001

[0173] DHA 5.6 (1.5) 5.5 (1.6) 5.6 (1.4) 5.4 (1.6) 9.6 (2.1) 9.6 (2.0) <0.001

[0174] 06 30.1 (1.8) 30.0 (1.8) 29.6 (2.2) 29.6 (2.8) 24.9 (2.9) 24.4 (2.8) <0.001

[0175] 03 9.9 (2.0) 9.6 (2.4) 9.7 (2.0) 9.6 (2.1) 15.2 (2.8) 15.5 (2.8) <0.001 ratio 06 / 3 3.2 (0.7) 3.3 (0.9) 3.2 (0.7) 3 3 (0.8) 1.7 (0.5) 1.7 (0.6) <0.001

[0176] * Abbreviations: MA: myristic acid; PA: palmitic acid; POA: palmitoleic acid; SA: stearic acid; OL: oleic acid; LA: linoleic acid; LNA: linolenic acid; EDA: eicosadienoic acid; AA: arachidonic acid; EPA: eicosapentaenoic acid; DPA: docosapentaenoic acid; DHA: docosahexaenoic acid; o-6: omega-6; o-3: omega-3. #D-FO group n=45 (baseline), n=39 (6 mon) and n=43 (12 mon); Control group n=46 (baseline), n=42 (6 mon) and n=43 (12 mon).

[0177] Primary Endpoint

[0178] A statistically significant 31% reduction in Ki-67 index was observed when comparing baseline to 1-year same site prostate biopsy cancer tissue between the D+FO vs control group (95% CI 52% -2.0%, p=0.043) (Figure 3). The Ki-67 index decreased in the D+FO group by Atorney Docket No.: 206030-0331-OOWO approximately 15% (from 1 .34% at baseline to 1 .14% at 12 months) and increased in the control group by approximately 24% (from 1.23% at baseline to 1.52% at 12 months).

[0179] Secondary Endpoints

[0180] Among the patients that completed the 1-year biopsy, there was no significant difference in same site Grade Group progression (17 (38.6%) in the D+FO group as compared to 17 (36.2%) in the control group, p=0.81). For maximal tumor length (surrogate for tumor volume) there was no significant difference in change from baseline (Control group: mean 3.12, SD 2.28, FO group: mean 3.06, SD 1.94) to 12 months (Control group: mean 3.96, SD 3.12, FO group: mean 3.43, SD 2.81) between groups (p=0.40) for same site biopsies. For the Decipher genomic classifier score, there was no significant difference in change from baseline (Control group: mean 0.23, SD 0.19, FO group: mean 0.18, SD 0.10) to 12 months (Control group: mean 0.22, SD 0.11, FO group: mean 0.24, SD 0.18) between groups (p=0.09) for same site biopsies.

[0181] Testosterone, PSA, Lipids and Cytokines

[0182] Comparing baseline to 1-year, there was no significant difference between the groups in testosterone or PSA levels (Table 4). There was a significant decrease in triglyceride levels between the groups (Table 4). Comparing baseline to 1-year serum cytokines, macrophage colony stimulating factor, also known as colony stimulating factor- 1, was significantly decreased in the D+FO group compared to control group (p=0.017, Table 1). Since PSA levels drawn during the trial were collected at patient entry (after the baseline prostate biopsy), and could potentially be affected by proximity to the biopsy, a post hoc, sensitivity analysis was performed ono PSA values collected prior to the biopsy that were used for screening. For this analysis, when comparing baseline to 1-year, there was also no significant difference between the groups (p=0.203), with PSA values at eligibility measured as 5.6 (4.1-7.0) and 5.9 (4.9-7.7) for control and D+FO, respectively (median Q1-Q3).

[0183] Safety

[0184] Four of the 50 patients randomized to the D+FO group were withdrawn by the principal investigator due to adverse events attributed to the FO. One patient had grade 2 flatulence, Atorney Docket No.: 206030-0331-OOWO constipation and bloating. Another was withdrawn due to grade 2 diarrhea, gastrointestinal discomfort and eructation. The two other patients were withdrawn due to grade 1 adverse events (loose stools in 1 patient and loose stools, eructation and nausea in the other).

[0185] CAPFISH-3, a randomized trial, demonstrated that intake of a high omega-3, low omega- 6 diet with FO supplements compared to a control group significantly decreased the Ki-67 index (primary endpoint) in tumor biopsy 12 month tissue compared to baseline tissue. In a metaanalysis of prostate cancer patients treated with curative intent, Ki-67 index was a predictor of biochemical failure, distant metastasis, and overall survival (Berlin et al., 2017, Urol Oncol, (35)499-506). Moreover, a recent study by Kammerer-Jacquet et al. reported Ki-67 in prostate needle biopsy tissue was an independent predictor of overall survival in conservatively managed patients with Grade Group 1 and 2 prostate cancer (Kammerer-Iacquet et al., 2019, Mod Pathol, (32)1303-1309). This finding is directly applicable to the trial in which patients also had Grade Group 1 and 2 prostate cancer. Kammerer-Jacquet et al. concluded that Ki-67 in prostate biopsy tissue should be utilized as a viable biomarker for prognostication in patients on active surveillance (Kammerer-Jacquet et al., 2019, Mod Pathol, (32)1303-1309).

[0186] The intervention used in the present trial is based on prior preclinical studies and a prospective clinical trial. Omega-6 polyunsaturated fat found in com oil, soy oil, and safflower oil present in fried foods, highly processed foods, chips and baked goods is consumed in high quantities in the typical western diet and is known to stimulate prostate cancer progression in preclinical models (Saini et al., 2018, Life Sci, (203)255-267; Ngo et al., 2004, Cancer Res, (64)1252-4). Likewise, omega-3 fatty acids found in cold-water fish such as salmon and sardines are low in the typical western diet and are known to delay the progression of prostate cancer In preclinical models (Saini et al., 2018, Life Sci, (203)255-267; Liang et al., 2019, J Natl Cancer Inst, (111)52-59; Bilodeau et al., 2021, Prostaglandins Leukot Essent Faty Acids, (164)02215). Moreover, a short-term randomized pre-prostatectomy trial combining a low fat diet low in omega-6 fatty acids with FO supplements reported a significant reduction in radical prostatectomy cancer Ki-67 and reduction in a cell cycle progression genetic risk score in the intervention vs the control Western group (Galet et al., 2014, Cancer Prev Res (Phila), (7)97- 104). Noteworthy is the cell cycle progression score incorporates gene expression of Ki-67 in the Atorney Docket No.: 206030-0331-OOWO

[0187] 31 gene panel and, when combined with clinical data, is a predictor of prostate cancer progression (Sommariva et al., 2016, Eur Urol, (69)107-15). To achieve a favorable ratio of omega-6 to omega-3 fatty acids in the present trial dietary intervention was combined with FO supplements. The outpatient diet intervention achieved the goal of lowering omega-6 intake based on analyses of the 3-day food records and RBC fatty acid levels. However, FO supplements were required to raise the omega-3 levels as this was not achieved by the diet alone (as measured by the 3-day food records), but there was a significant increase in the RBC omega- 3 fatty acid levels.

[0188] There are numerous underlying mechanisms supporting the intervention used in the present trial. The omega-6 fatty acid arachidonic acid (significantly reduced in this trial) is known to stimulate prostate cancer growth through a number of mechanisms including increasing pro-carcinogenic arachidonic acid metabolite levels and activation of phosphatidylinositol 3-kinase signaling (Hughes-Fulford et al., 2006, Cancer Res, (66)1427-33; Yang et al., 2012, Int J Oncol, (41)1495-503; Oktem et al., 2023, OMICS, (27)127-138). In addition, dietary omega-3 fatty acids have been shown to decrease the number of M2-like macrophages through binding to G-protein coupled receptors (Liang et al., 2023, Prostate Cancer Prostatic Dis). M2-like macrophages are immunosuppressive and promote angiogenesis, tumor progression and metastases (Liang et al., 2023, Prostate Cancer Prostatic Dis) and are associated with poor outcome and increased risk of nodal and distant metastasis (Hadimani et al., 2023, J Cancer Res Ther, (19)S300-S305; Han et al., 2022, J Oncol, 8580043). Consistent with this mechanism, in the present trial, serum levels of the cytokine macrophage colony stimulating factor, which is known to play a role in stimulating macrophages and prostate cancer progression, was significantly reduced in the intervention group (relative to the control group) (Mougel et al., 2022, Int J Mol Sci, 23).

[0189] Longer term and Phase III trials are ongoing to determine effects of the intervention on clinical endpoints. Further studies are also ongoing to determine the optimal dosing of omega-3 fatty acids. The dosing chosen for this trial was based on dosing used in prior prospective preprostatectomy trial that demonstrated inhibitory effects on Ki-67 and a cell cycle progression score (Aronson et al., 2011, Cancer Prev Res (Phila), (4)2062-71). A strength of the trial is that it established the feasibility of performing same site prostate biopsies for future dietary intervention trials, thus allowing longitudinal evaluation of tissue biomarkers. The Ki-67 index Attorney Docket No.: 206030-0331-00WO values from this trial will potentially provide useful data for planning future prospective active surveillance trials.

[0190] In summary, CAPFISH-3, a 1-year high omega-3, low omega-6 diet + FO intervention trial, resulted in a significant reduction in prostate cancer tissue Ki-67 index, a biomarker for prostate cancer progression, metastasis and death. Patients in the trial were compliant with the intervention which was well tolerated. Moreover, obtaining serial same site prostate biopsy tissue is feasible for future biomarker intervention trials. Based on the underlying anti-prostate cancer mechanisms of a high omega-3, low omega-6 diet with FO supplements, future trials are warranted evaluating this intervention in varying stages of prostate cancer. It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0191] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

Attorney Docket No.: 206030-0331-OOWOCLAIMSWhat is claimed is:

1. A method of treating or preventing prostate cancer in a subject in need thereof, wherein the method comprises combining dietary intervention with administration of at least one omega- 3 fatty acid.

2. The method of claim 1, wherein the method comprises: a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 fatty acid intake in the subject; and c) decreasing dietary omega-6 fatty acid intake in the subject.

3. The method of claim 2, wherein the at least one omega-3 fatty acid is at least one selected from the group consisting of eicosapentaenoic acid (EP A), docosahexaenoic acid (DHA), a- linolenic acid (ALA), stearidonic acid (SDA), eicosatetraenoic acid (ETA), and docosapentaenoic acid (DPA), and combinations thereof.

4. The method of claim 2, wherein the at least one omega-3 fatty acid is administered in a dose of at least 1 g daily.

5. The method of claim 2, wherein the at least one omega-3 fatty acid is administered in a dose of about 2.2 g daily.

6. The method of claim 2, wherein the at least one omega-3 fatty acid comprises EPA and DHA.

7. The method of claim 2, wherein the at least one omega-3 fatty acid comprises about 1 part EPA and about 2 parts DHA.Attorney Docket No.: 206030-0331-00WO8. The method of claim 2, wherein the at least one omega-3 fatty acid comprises about 730 mg EPA and about 1470 mg DHA.

9. The method of claim 2, wherein the method further comprises reducing the ratio of omega-6 to omega-3 fatty acid in the subject’s red blood cells.

10. The method of claim 9, wherein the ratio of omega-6 to omega-3 fatty acids is reduced to 4: 1 or lower.

11. The method of claim 2, wherein treating or preventing prostate cancer is determined by an improvement in at least one symptom, metric, or score for prostate cancer.

12. The method of claim 11, wherein the improvement in at least one symptom, metric, or score is determined about 3 months, about 6 months, about 9 months, or about one year after initiation of treatment.

13. The method of claim 12, wherein the improvement in at least one symptom, metric, or score is selected from Ki-67 index, prostate specific antigen (PSA) level, tumor grade, tumor length, tumor volume, and Decipher genomic classifier score.

14. The method of claim 13, wherein there is at least about a 10% decrease in the subject’s Ki-67 index about one year after initiation of treatment.

15. The method of claim 13, wherein there is an about 30% decrease in the subject’s Ki-67 index about one year after initiation of treatment.

16. A method of maintaining or improving prostate health in a subject in need thereof, wherein the method comprises: a) administering to the subject at least one omega-3 fatty acid; b) increasing dietary omega-3 fatty acid intake in the subject; andAttorney Docket No.: 206030-0331-OOWO c) decreasing dietary omega-6 fatty acid intake in the subject.

17. The method of claim 16, wherein the at least one omega-3 fatty acid is at least one selected from the group consisting of eicosapentaenoic acid (EP A), docosahexaenoic acid (DHA), a-linolenic acid (ALA), stearidonic acid (SDA), eicosatetraenoic acid (ETA), and docosapentaenoic acid (DPA), and combinations thereof.

18. The method of claim 16, wherein the at least one omega-3 fatty acid is administered in a dose of at least 1 g daily.

19. The method of claim 16, wherein the at least one omega-3 fatty acid is administered in a dose of about 2.2 g daily.

20. The method of claim 16, wherein the at least one omega-3 fatty acid comprises EPA and DHA.

21. The method of claim 16, wherein the at least one omega-3 fatty acid comprises about 1 part EPA and about 2 parts DHA.

22. The method of claim 16, wherein the at least one omega-3 fatty acid comprises about 730 mg EPA and about 1470 mg DHA.

23. The method of claim 16, wherein the method further comprises reducing the ratio of omega-6 to omega-3 fatty acid in the subject’s red blood cells.

24. The method of claim 23, wherein the ratio of omega-6 to omega-3 fatty acids is reduced to 4: 1 or lower.

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