Use of urolithins during remission of prior cancer treatment

Abstract

The present invention relates to the therapeutic use of a composition comprising a therapeutically effective amount of a urolithin or a precursor thereof, preferably a composition suitable for use in reducing the risk of recurrence of cancer or tumorigenesis in a patient in need thereof when the patient is in remission from a prior cancer treatment.

Description

[Technical field]

[0001] The present invention relates to therapeutic uses of compositions comprising a therapeutically effective amount of a urolithin or a precursor thereof, preferably compositions suitable for use in reducing the risk of recurrence of cancer or tumorigenesis in a patient in need thereof when said patient is in remission from a prior cancer treatment. The present invention further relates to corresponding compositions, methods for their preparation and methods for reducing the risk of recurrence of cancer or tumorigenesis in a patient in need thereof when said patient is in remission after a prior cancer treatment, comprising the steps of: a) providing a composition comprising a therapeutically effective amount of a urolithin or a precursor thereof, said composition preferably as defined herein above, b) administering to a patient in need thereof a composition comprising a therapeutically effective amount of a urolithin or a precursor thereof, wherein the patient is in remission after the prior cancer treatment, and c) optionally following up the patient periodically, preferably at predetermined intervals, preferably simultaneously with administration of the composition according to step b), for possible recurrence of the cancer treated with the prior cancer treatment, preferably by using cancer-specific biomarkers.

[0002] [Background technology] Cancer is the leading cause of death worldwide, responsible for nearly 10 million deaths in 2020 (see, for example, Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Pineros M, et al. Global Cancer Observatory: Cancer Today. Lyon: International Agency for Research on Cancer; 2020 (https: / / gco.iarc.fr / today (accessed February 2021)). The most common new cases of cancer in 2020 were breast cancer (2,260,000 cases); lung cancer (2,210,000 cases); colorectal cancer (1,930,000 cases); prostate cancer (1,410,000 cases); skin cancer (non-melanoma) (1,200,000 cases); and gastric cancer (1,090,000 cases). The most common causes of cancer deaths in 2020 were lung cancer (1,800,000 deaths); colorectal cancer (935,000 deaths); liver cancer (830,000 deaths); stomach cancer (769,000 deaths); and breast cancer (685,000 deaths) (see, for example, https: / / www.who.int / news-room / fact-sheets / detail / cancer).

[0003] Cancer is generally treated, typically by using radiation therapy, chemotherapy, surgery, and / or in recent years also by cancer immunotherapy. Although chemotherapy has been used for many years as a therapeutic intervention against a great many types of cancer, with considerable success, and will most likely become an important treatment in the future, the use of chemotherapy is always accompanied by significant toxic side effects. Therefore, in order to identify suitable compounds, preferably with lower toxic side effects, cancer research has also been working on applying other compounds, such as phytonutrients, especially plant polyphenols, to such treatments, either as adjuvant therapy added as part of classical cancer treatment, or even, in a smaller number of cases, as monotherapy, for example in the field of cancer immunotherapy. Polyphenols are phytochemicals that are typically present in food, and therefore are considered to be less likely to show significant toxic side effects compared to classical chemotherapy agents. In addition, polyphenols are usually abundant in various fruits and vegetables, making such compounds available at low cost. Recently discovered types of phytochemicals include gut polyphenol metabolites of ellagitannins, which have been shown to be effective in treating several types of cancer, such as prostate, uterine, hepatocellular, colon, bladder, or breast cancer (see Al-Harbi SA, Abdulrahman AO, Zamzami MA and Khan MI (2021), Urolithins: The Gut Based Polyphenol, Metabolites of Ellagitannins in Cancer Prevention, a Review., Front. Nutr. 8: 647582, doi:10.3389 / fnut.2021.647582).

[0004] Cancer treatment often focuses disproportionately on the early and clinical stages of cancer treatment, such as early treatment and pathological staging before surgery, and immediate clinical steps such as chemotherapy, surgery, etc., but important stages of cancer treatment also include the post-treatment stage. In the post-treatment stage, patients are usually followed up with biomarkers to detect recurrent tumors early in case the initial treatment was not successful or sufficient, and to resume further cancer treatment of the patient as soon as possible if necessary. Such biomarker detection is usually performed in the first 5 years after the initial cancer treatment to make a reliable prediction of the possibility of tumor recurrence and the possibility of completion of the prior cancer treatment.

[0005] However, this approach allows tumor levels to build up again to a high enough level to make a valid diagnosis, so that much of the cancer treatment that needs to be continued after the first round of treatment is resumed much too late in the post-treatment phase, however, this approach also unnecessarily limits the time frame for post-treatment steps, ultimately decreasing the patient's chances of successfully fighting cancer.

[0006] In view of the above, and with global health facing the significant adverse impact of cancer, there is an increasing need to more effectively accompany the post-treatment phase of upfront cancer treatment, as well as to improve the success rate of upfront cancer treatment in later stages of follow-up, preferably beyond the five years that are typical for follow-up in the post-treatment or remission phase of patients.

[0007] [Summary of the invention] The inventors have surprisingly found that the above needs can be met for various cancer types by the provision and use of the compositions of the invention as defined in this specification and the accompanying independent claims, and by methods of using such compositions. Further preferred embodiments are defined in the accompanying dependent claims and in the following specification.

[0008] According to a first embodiment, the present invention relates to a composition comprising a therapeutically effective amount of a urolithin or a precursor thereof, preferably suitable for use in reducing the risk of recurrence of cancer or tumor formation in a patient in need thereof during remission of said patient's prior cancer treatment (after completion). Preferably, the patient is a human or non-human mammal, preferably a human, optionally a human adult, child or infant. More preferably, the patient is an immunocompromised patient.

[0009] According to one aspect, the urolithin or precursor thereof is selected from the group consisting of urolithin, ellagic acid, and ellagitannin, more preferably selected from urolithin A, urolithin B, urolithin C, or urolithin D, or a combination thereof. Even more preferably, the urolithin is urolithin A, or a combination of urolithin A and at least one of urolithin B, urolithin C, or urolithin D. Most preferably, the urolithin is urolithin A.

[0010] According to a further aspect, the urolithin is administered in an amount of about 500-2000 mg / day, preferably 750-1500 mg / day, which may be administered once, twice or three or more times per day.

[0011] According to further aspects, administration of the composition comprising a urolithin is initiated on day 0 of the remission phase or at a subsequent stage, e.g., about 1, 2, 3, 4, 5, 6, or 7 days after the onset of the remission phase, or 1-2 or 2-3 weeks after the onset of the remission phase, e.g., administration is initiated in a time frame from day 0 (or day 1, 2, 3, 4, 5, 6, or 7) of the remission phase to about 2 months after the onset of the remission phase, preferably from about 1-2 weeks to 2 months after the onset of the remission phase, and preferably is carried out for a period of about 2-12 months or more, as defined below. Administration during the remission phase is preferably continuous.

[0012] According to one embodiment, the prior cancer treatment of the patient to be treated relates to treatment of a solid or liquid tumor, preferably a solid tumor, more preferably a tumor selected from lymphoma, carcinoma or sarcoma, even more preferably breast cancer, prostate cancer, uterine cancer, hepatocellular carcinoma, pancreatic cancer, cervical cancer, colon cancer, colorectal cancer, gastric cancer, bladder cancer, skin cancer, lung cancer or head and neck cancer, most preferably pancreatic cancer, colorectal cancer, skin cancer or breast cancer.

[0013] In certain embodiments, the prior cancer treatment is cancer surgery, radiation therapy, chemotherapy, targeted cancer therapy, immunotherapy, hormonal therapy, or phytochemical-based cancer therapy.

[0014] According to a further aspect, the prior cancer treatment comprises the use of a urolithin, preferably urolithin A, or chemotherapy.

[0015] In one embodiment, the composition is administered enterally or orally, preferably orally.

[0016] In a further aspect, the composition is in the form of a pharmaceutical or nutritional composition, optionally in the form of a food product, dietary supplement, nutraceutical, food for specific medical purposes (FSMP), nutritional supplement, dairy drink, small volume liquid nutritional supplement or meal replacement drink, botanical drink, gummy, or combinations thereof.

[0017] In one other embodiment, the composition includes a pomegranate extract, a tamarind extract, or a shilajit (mumijo) extract, which provides at least a portion of at least one urolithin or a precursor thereof. Alternatively or additionally, the composition includes an isolated form of the urolithin. Preferably, the composition includes an isolated form of the urolithin.

[0018] According to a second embodiment, the invention relates to a therapeutic or second medical use of a composition as defined above, preferably a composition comprising a therapeutically effective amount of a urolithin or a precursor thereof, for use in reducing the risk of recurrence of cancer or tumorigenesis in a patient in need thereof during remission of said patient's prior cancer treatment (after completion). All aspects of the first embodiment also apply to the therapeutic or second medical use according to the second embodiment.

[0019] According to a third aspect, the present invention also relates to a method for preparing a composition of the invention as defined above, preferably a composition comprising a therapeutically effective amount of a urolithin or a precursor thereof.

[0020] Furthermore, according to a fourth aspect, the present invention provides a method for reducing a risk of recurrence of cancer or tumor formation in a patient in need thereof when the patient is in remission following a prior cancer treatment, comprising: a) providing a composition comprising a therapeutically effective amount of a urolithin or a precursor thereof, the composition preferably being a composition of the invention as defined herein; b) administering a composition according to step a) comprising a therapeutically effective amount of a urolithin or a precursor thereof to a patient in need thereof, wherein the patient is in remission following a prior cancer treatment; and c) optionally following up the patient periodically, preferably at predetermined intervals, preferably simultaneously with administration of the composition according to step b), for possible recurrence of the cancer treated in the prior cancer treatment, preferably by using cancer-specific biomarkers; The present invention relates to a method comprising the steps of:

[0021] According to one aspect of the method of the invention, the composition administered is a composition as defined above according to the first embodiment. All embodiments defined herein for the first aspect are provided herein and apply also to the composition administered.

[0022] According to a further aspect, the patient treated in step b) of the method of the invention is a human or non-human mammal, preferably a human, optionally a human adult, child or infant. Preferably, the patient treated in step b) of the method of the invention is an immunocompromised patient.

[0023] According to one aspect, the urolithin or precursor thereof provided in step a) of the method of the invention is selected from the group consisting of urolithin, ellagic acid and ellagitannin, more preferably selected from urolithin A, urolithin B, urolithin C or urolithin D, or a combination thereof. More preferably, the urolithin is urolithin A or a combination of urolithin A with at least one of urolithin B, urolithin C or urolithin D. Even more preferably, the urolithin is urolithin A.

[0024] According to a further aspect, the urolithin provided with the composition in step a) and administered in step b) of the method of the invention is present in the composition in an amount of about 500-2000 mg / day, preferably 750-1500 mg / day. Administration may be in one, two or three or more doses per day.

[0025] According to a further aspect, administration of the composition comprising a urolithin in step b) of the method of the invention is initiated on day 0 of the remission phase or at a later stage, such as about 1, 2, 3, 4, 5, 6, or 7 days after the onset of the remission phase, or 1-2 or 2-3 weeks after the onset of the remission phase, for example administration is initiated from day 0 (or day 1, 2, 3, 4, 5, 6, or 7) of the remission phase to about 2 months after the onset of the remission phase, preferably in a time frame of about 1-2 weeks to 2 months after the onset of the remission phase, preferably for about 2-12 months or more as defined below. Administration during the remission phase is preferably continuous.

[0026] According to one embodiment, the prior cancer treatment of the patient to be treated relates to treatment of a solid or liquid tumor, preferably a solid tumor, more preferably a lymphoma, carcinoma or sarcoma, even more preferably breast cancer, prostate cancer, uterine cancer, hepatocellular carcinoma, pancreatic cancer, cervical cancer, colon cancer, colorectal cancer, gastric cancer, bladder cancer, skin cancer, lung cancer or head and neck cancer, most preferably pancreatic cancer, colorectal cancer, skin cancer or breast cancer.

[0027] In certain embodiments, the patient's prior cancer treatment as defined in the methods of the present invention is cancer surgery, radiation therapy, chemotherapy, targeted cancer therapy, immunotherapy, hormonal therapy, or phytochemical-based cancer therapy.

[0028] According to a further aspect, the patient's prior cancer treatment defined in the methods of the invention comprised the use of a urolithin, preferably urolithin A, or chemotherapy.

[0029] In one embodiment, the composition administered in step b) of the method of the invention is administered enterally or orally, preferably orally.

[0030] In a further aspect, the composition provided in step a) or administered in step b) of the method of the invention is in the form of a pharmaceutical or nutritional composition, optionally in the form of a food product, a dietary supplement, a nutraceutical, a food for special medical purpose (FSMP), a nutritional supplement, a dairy drink, a small volume liquid nutritional supplement or meal replacement drink, a botanical drink, a gummy, or a combination thereof.

[0031] In one other embodiment, the composition provided in step a) or administered in step b) of the method of the invention comprises a pomegranate extract, a tamarind extract, or a shilajit extract, which provides at least one urolithin or at least a portion of a precursor thereof. Alternatively or additionally, the composition provided in step a) or administered in step b) of the method of the invention comprises a urolithin in isolated form. Preferably, the composition provided in step a) or administered in step b) of the method of the invention comprises a urolithin in isolated form.

[0032] In a further aspect, the composition administered in step a) comprises a combination of a urolithin, preferably as defined herein above, with an NAD+ precursor and / or vitamin B12.

[0033] The inventors have surprisingly found that the prevention of tumor recurrence or tumor formation is highly effective when a composition comprising a therapeutically effective amount of a urolithin or precursor thereof as defined herein is administered to patients who have undergone prior cancer treatment. What is particularly surprising to the inventors is that such post-therapy type intervention is particularly effective not only in patients who still have a functioning immune system, but also in immunocompromised patients when applied during the remission phase.

[0034] Without wishing to be bound by theory, the inventors believe that the underlying effect of the current therapy is based on the effect of dietary supplementation with UroA in impeding tumor growth through the establishment of an enhanced adaptive immune response.

[0035] The present invention makes it possible to address remission in particular in patients who have completed prior cancer treatment, beneficially influencing their outcome, increasing survival rates, and even supporting the body's own immune response to combat the possibility of tumor recurrence. The present invention achieves this by intervening early at the onset of remission, without waiting too long for positive detection of biomarkers, which may occur during long remission periods, usually 5 years, after the completion of prior cancer treatment. This also significantly increases the informative diagnosis of long-term remission periods. A particular advantage of the treatment of the present invention is the effective re-stimulation of T cell function, especially in patients recovering from cancer, especially when the composition of the present invention is administered during remission periods as described below. [Brief description of the drawings]

[0036] [Figure 1-1] Analysis of tumor growth and survival rate of mice fed UroA-enriched diet in the MC38 model. Figure 1A shows a schematic of the dosing schedule in the analysis. Mice were fed UroA diet (UA diet) ad libitum for 4 weeks. Colorectal cancer cells MC38 were subcutaneously injected into the right flank of the mice. Mice fed a control diet (DMSO diet) were treated similarly. Both groups of mice were sacrificed at a humane endpoint. Figures 1B and 1C show tumor engraftment and growth in two separate experiments (referred to as experiment 1 and experiment 2). In both experiment 1 and experiment 2, tumor engraftment and growth were significantly reduced in mice exposed ad libitum to UroA-enriched diet. In experiment 1 (Figure 1B, left panel: mean values, right panel: individual data curves), five mice fed DMSO diet showed an average tumor size of 500 mm3 (black circles) and five mice fed urolithin A-enriched diet showed an average tumor size of 50 mm3 (white circles). In experiment 2 (Figure 1C), two of three mice fed the DMSO diet developed tumors larger than 100 mm3, whereas only one of three mice fed the Urolithin A-enriched diet developed a tumor larger than 100 mm3. Figure 1D shows predicted survival. The UroA diet (open circles) improved overall survival compared to the control (DMSO diet, filled circles) (Figure 1D). [Figure 1-2]Analysis of tumor growth and survival rate of mice fed UroA-enriched diet in the MC38 model. Figure 1A shows a schematic of the dosing schedule in the analysis. Mice were fed UroA diet (UA diet) ad libitum for 4 weeks. Colorectal cancer cells MC38 were subcutaneously injected into the right flank of the mice. Mice fed a control diet (DMSO diet) were treated similarly. Both groups of mice were sacrificed at a humane endpoint. Figures 1B and 1C show tumor engraftment and growth in two separate experiments (referred to as experiment 1 and experiment 2). In both experiment 1 and experiment 2, tumor engraftment and growth were significantly reduced in mice exposed ad libitum to UroA-enriched diet. In experiment 1 (Figure 1B, left panel: mean values, right panel: individual data curves), five mice fed DMSO diet showed an average tumor size of 500 mm3 (black circles) and five mice fed urolithin A-enriched diet showed an average tumor size of 50 mm3 (white circles). In experiment 2 (Figure 1C), two of three mice fed the DMSO diet developed tumors larger than 100 mm3, whereas only one of three mice fed the Urolithin A-enriched diet developed a tumor larger than 100 mm3. Figure 1D shows predicted survival. The UroA diet (open circles) improved overall survival compared to the control (DMSO diet, filled circles) (Figure 1D). [Diagram 2] Analysis of tumor rechallenge in the MC38 model. Figure 2A shows the dosing schedule for the analysis in the MC38 rechallenge model. Mice from the aforementioned UroA-treated groups that survived the MC38 tumor challenge (see Figure 1, experiment 1 and experiment 2) were injected with the same cancer cell line (MC38) in the opposite flank 7 weeks later (Figure 2A). The control cage group was challenged in the same manner. The rechallenged surviving mice and the challenged control cage group were maintained on a conventional diet without UroA for 1 week prior to tumor injection. Figure 2B shows that mice fed the UroA diet (open circles) as described above (Figure 1b) developed smaller tumors (Figure 3, average tumor size of 100 mm3) at the time of rechallenge compared to the newly challenged controls (DMSO diet, filled circles, average tumor size of 600 mm3). Figure 2C shows the predicted survival rate, indicating that the UroA diet (open circles) improved overall survival compared to the controls (DMSO diet, filled circles) at the time of rechallenge. [Diagram 3] Analysis of tumor growth in tumor-challenged mice fed a UroA-enriched diet in the B16 model (see FIG. 3, top panel: mean values, bottom panel: individual data curves). In this experiment, five mice (B57BL / 6) were fed a DMSO diet ad libitum and five mice were fed a Urolithin A-enriched diet ad libitum for four weeks prior to tumor injection. The UroA diet-fed mice described above (FIG. 1b) developed smaller tumors compared to the control group (FIG. 3, top panel). Mice fed a DMSO diet showed an average tumor size of 180 mm3, whereas mice fed a Urolithin A showed an average tumor size of 70 mm3. Thus, the top panel of FIG. 3 shows improved tumor control by the UroA diet of the invention in the less immunogenic B16 tumor model. [Figure 4] Figure 2 shows that Urolithin A supplementation following subcutaneous injection of 5x10 MC38 cells into the right bilateral flank of immunodeficient mice (NSG) does not result in an enhanced adaptive immune response. There is no change in tumor growth rate and volume in both DMSO control and Urolithin A-fed mice. [Diagram 5] The preventive effect of feeding Urolithin A boosts the immune system. Figure 5 shows that mice fed DMSO or DMSO on / off groups showed similar tumor volumes, reaching average tumor sizes of 350mm3 and 430mm3 on day 17, whereas mice in the UroA and Urolithin A on / off groups showed reduced tumor growth, reaching average tumor sizes of 200mm3 on day 17. These results indicate that a 4-week Urolithin A diet has a preventive effect and produces a stronger immune response against cancer cells. This effect was maintained even after the Urolithin A diet was discontinued, suggesting that Urolithin A may have a mechanism of imprinting on the immune system.

[0037] [Mode for carrying out the invention] definition Some definitions are provided below. However, definitions may be found in the "Embodiments" section below, and the heading "Definitions" above does not imply that such disclosure in the "Embodiments" section is not a definition.

[0038] All percentages set forth herein are by weight of the total composition unless otherwise indicated. As used herein, "about," "approximately," and "substantially" are understood to refer to numbers within a range of numerical values, e.g., within -10% to +10% of the referenced number, preferably within -5% to +5% of the referenced number, more preferably within -1% to +1% of the referenced number, and most preferably within -0.1% to +0.1% of the referenced number. All numerical ranges herein should be understood to include all integers or fractions within the range. Furthermore, these numerical ranges should be construed to support claims directed to any number or subset of numbers within the range. For example, a disclosure of 1 to 10 should be construed to correspond to ranges of 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc. Endpoints are expressly included in such ranges.

[0039] As used in this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to "a component" or "the component" includes two or more components.

[0040] The terms "comprise", "comprises", and "comprising" should be construed as inclusive rather than exclusive. Similarly, the terms "include", "including", and "or" should all be construed as inclusive unless such interpretation is clearly prevented by the context. However, the compositions disclosed herein may not include elements not specifically disclosed herein. Thus, disclosure of an embodiment using the term "comprising" includes disclosure of embodiments "consisting essentially of" and "consisting of" the specified components. A composition or unit dosage form "consisting essentially of" means that the referenced component comprises at least 50% by weight, preferably at least 75% by weight, more preferably at least 85% by weight, and most preferably at least 95% by weight of the referenced component.

[0041] The term "and / or" used in the context of "X and / or Y" should be interpreted as "X" or "Y" or "X and Y." Similarly, "at least one of X or Y" should be interpreted as "X" or "Y" or "both X and Y."

[0042] As used herein, the terms "examples" and "such as," especially when followed by a list of terms, are merely exemplary and illustrative and should not be considered as exclusive or inclusive. As used herein, a condition "associated with" or "linked with" another condition means that the conditions occur simultaneously, preferably that the conditions are caused by the same underlying condition, and most preferably that one of the specified conditions is caused by the other specified condition.

[0043] "Prevention" includes reducing the risk and / or severity of a condition or disease. The terms "treatment", "treat" and "to alleviate" include both prophylactic or preventive treatments (which prevent and / or delay the onset of the targeted condition or disorder) and curative, therapeutic or disease-modifying treatments, including therapeutic measures that cure, delay, attenuate the symptoms and / or halt the progression of a diagnosed condition or disease; as well as treatment of patients who are ill or diagnosed as suffering from a disease or medical condition, in addition to treatment of patients at risk of or suspected of having a disease. The terms do not necessarily imply that a subject is treated until cured. The terms "treatment" and "treat" also refer to maintaining and / or promoting the health of individuals who are not afflicted with a disease but who may be susceptible to an unhealthy condition. The terms "treatment / therapy", "treat / treat" and "alleviating" are also intended to include the synergistic or otherwise potentiating action of one or more primary preventative or therapeutic measures. The terms "treatment / therapy", "treat / treat" and "alleviating" are further intended to include the dietary management of a disease or condition, or dietary management for the prophylaxis or prevention of a disease or condition. Treatment may be patient-related or physician-related.

[0044] A "subject" or "individual" or "patient" is preferably a mammal, more preferably a human. Alternatively, a "subject" or "individual" or "patient" may be a pet, such as a dog or cat.

[0045] As used herein, an "effective amount," preferably a "therapeutically effective amount," is an amount that prevents a deficiency, treats a disease or medical condition in an individual, or, more generally, alleviates symptoms, manages the progression of a disease, or provides a nutritional, physiological or medical benefit to the individual. The relative terms "improved," "increased," "enhanced," and the like refer to the effect of the compositions disclosed herein, i.e., compositions comprising a urolithin or a urolithin or a pharmacologically acceptable salt thereof.

[0046] The terms "food", "food product", and "food composition" refer to a product or composition intended for consumption by an individual, such as a human, and providing at least one nutrient to such an individual. "Food", "food product", and "food composition" typically contain at least one of protein, lipid, carbohydrate, and optionally one or more vitamins and minerals. "Food", "food product", and "food composition" may further contain acidulants, thickeners, buffering or pH adjusting agents, chelating agents, colorants, emulsifiers, excipients, flavoring agents, minerals, osmotic agents, pharmacologically acceptable carriers, preservatives, stabilizers, sugars, sweeteners, texture modifiers, and / or vitamins. Optional ingredients may be added in any suitable amount. The compositions of the present disclosure, including the many embodiments described herein, may comprise, consist of, or essentially comprise the elements disclosed herein, as well as any additional or optional ingredients, components, or elements useful in the diet, whether described herein or not.

[0047] As used herein, the term "unit dosage form" refers to physically discrete units suitable as dosage units for human and animal subjects, each unit containing a predetermined amount of a composition disclosed herein, in an amount sufficient to produce the desired effect, together with a pharmacologically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage form depend on the particular compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0048] [Problem to be solved by the invention] The present invention will be described in more detail below based on the accompanying embodiments. All aspects described in this context of the accompanying embodiments may be combined with the embodiments as appropriate, either alone or together with other aspects. Moreover, different embodiments and their aspects as detailed below may be combined with each other as appropriate.

[0049] Pharmaceutical and nutritional compositions A first embodiment of the invention relates to a composition comprising a therapeutically effective amount of a urolithin or a precursor thereof, preferably a composition suitable for use in reducing the risk of recurrence of cancer or tumorigenesis in a patient in need thereof when the patient is in remission following a prior cancer treatment.

[0050] Further aspects of the first embodiment, which may be combined with the first embodiment either alone or in combination, are defined below.

[0051] According to a first embodiment, the compositions of the invention comprise urolithins, which are metabolic products of food-derived ellagic acid derivatives such as ellagitannins and are produced in the human gut by gut bacteria.

[0052] Ellagitannins are a class of antioxidant polyphenols present in several fruits, especially pomegranates, strawberries, raspberries, and walnuts. Ellagitannins are very poorly absorbed, but are rapidly metabolized to urolithins by the gut microbiota in the large intestine.

[0053] Due to their superior absorption, urolithins are believed to be bioactive molecules that mediate the effects of ellagitannins. For example, urolithins have previously been shown to have anti-proliferative, antioxidant and anti-inflammatory properties.

[0054] Examples of urolithins relevant to the present invention include ellagic acid, urolithin A (3,8-dihydroxyurolithin), urolithin B (3-hydroxyurolithin), urolithin C (3,8,9-trihydroxyurolithin), urolithin D (3,4,8,9-tetrahydroxyurolithin), urolithin A glucuronide, and urolithin B glucuronide. Ellagic acid, as well as urolithin A, urolithin B, urolithin C, and urolithin D have the following structures:

[0055] [Table 1]

[0056] According to a particular embodiment of the invention, the urolithin or precursor thereof contained in the composition of the invention is selected from the group consisting of urolithin, ellagic acid and ellagitannin, more preferably selected from urolithin A, urolithin B, urolithin C, urolithin D, urolithin A glucuronide and urolithin B glucuronide, even more preferably selected from urolithin A, urolithin B, urolithin C or urolithin D, or a combination thereof. According to a preferred embodiment, the urolithin is urolithin A or a combination of urolithin A with at least one of urolithin B, urolithin C or urolithin D, preferably with urolithin B. According to an even more preferred embodiment, the urolithin is urolithin A.

[0057] The compositions of the invention may comprise urolithins as defined above extracted from or contained in several fruits, such as pomegranate extract, tamarind extract or shilajit extract, strawberry, raspberry and walnut, which typically provide at least one urolithin or at least a portion of its precursors. In general, the compositions of the invention may comprise any of such pomegranate extract, tamarind extract or shilajit extract, strawberry, raspberry and walnut, or more preferably, urolithins extracted from such pomegranate extract, tamarind extract or shilajit extract, strawberry, raspberry and walnut. Alternatively, or in addition, the compositions of the invention may comprise any of the urolithins defined herein in isolated form. The isolated form may be prepared based on natural sources, such as those identified above, or may be provided by chemical synthesis.

[0058] The urolithins in the compositions of the invention may be present as salts or esters, particularly pharmacologically acceptable salts or esters. Pharmacologically acceptable salts of the agents of the invention, particularly urolithins, preferably include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts can be found in Berge et al. (1977) J Pharm Sci 66:1-19. The invention also includes all enantiomers and tautomers of such agents, where appropriate. The skilled artisan will recognize compounds that have optical properties (e.g., one or more chiral carbon atoms) or tautomeric properties. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art.

[0059] According to one aspect of the invention, the urolithin contained in the composition of the invention may be present in a therapeutically effective amount, preferably in an amount of about 500-2000 mg / day, more preferably in an amount of 750-1500 mg / day, such as about 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800 or 2000 mg / day, or any combination of such values, whereby each value is suitable as an upper or lower limit, and most preferably about 1000 mg / day. The composition may be provided via a single daily dose or in two or more separate daily doses, for example, in two, three, four or more separate doses per day, preferably either as a single dose or in two, three or four separate doses per day.

[0060] According to one aspect, compositions of the invention comprising urolithins may be provided as oral or enteral compositions, preferably as oral compositions.

[0061] According to another embodiment, the composition of the invention may be in any suitable form, preferably in unit dosage form, or in any other suitable form. Preferably, such a composition, for example as unit dosage form, is in the form of a pharmaceutical or nutritional composition, optionally in the form of a food product, a dietary supplement or additive, a nutraceutical, a functional food, a food for a specific medical purpose (FSMP), a nutritional supplement, a dietary supplement, a beverage product, a dairy drink, a small volume liquid nutritional supplement, a meal replacement drink, a vegetable drink, a gummy, or a combination thereof, including a milk powder-based product; an instant drink; a ready-to-drink formulation; a nutritional powder; a nutritional liquid; a dairy product, in particular yogurt or ice cream; a cereal product; a beverage; water; coffee; a cappuccino; a malt drink; a chocolate-flavored drink; a cooking product; a soup; a tablet; and / or a syrup. In a particularly preferred embodiment, the composition of the invention comprising a therapeutically effective amount of a urolithin according to the above definition is in the form of a dietary supplement, a food additive or a medicine, for example a nutraceutical. The food additive or medicine may be in the form of, for example, a tablet, a capsule, a lozenge, or a liquid. The food additive or pharmaceutical is preferably provided as a sustained release formulation, allowing for a constant supply of urolithin or its precursors over an extended period of time. All suitable forms are encompassed herein.

[0062] The compositions of the present invention may further contain protective hydrocolloids (gums, proteins, modified starches, etc.), binders, film formers, encapsulants / encapsulants, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithin, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, flavoring agents, bulking agents, jellifying agents, gel forming agents, antioxidants, and antimicrobial agents.

[0063] Additionally, the compositions may contain vitamins, minerals, trace elements and other micronutrients as recommended by government agencies such as the USRDA, in addition to organic or inorganic carrier materials suitable for oral or enteral administration.

[0064] The compositions of the present invention may contain a protein source, a carbohydrate source and / or a lipid source.

[0065] Thus, according to one aspect, the composition of the present invention may optionally include at least one protein.The at least one protein may be a milk protein, a vegetable protein, or an animal protein, or any combination thereof.The milk protein may include, for example, casein, caseinate (e.g., all forms including sodium caseinate, calcium caseinate, potassium caseinate), casein hydrolysate, whey (e.g., all forms including concentrate, isolate, demineralized), whey hydrolysate, milk protein concentrate, and milk protein isolate. Vegetable proteins include, for example, soy protein (e.g., all forms including concentrates and isolates), pea protein (e.g., all forms including concentrates and isolates), canola protein (e.g., all forms including concentrates and isolates), and other suitable commercially available vegetable proteins are wheat and fractionated wheat protein, corn and its fractions including zein, rice, oats, potatoes, peanuts, green pea flour, green bean flour, and kidney beans, lentils, and pulses. Animal proteins can be selected from the group consisting of beef, chicken, fish, lamb, seafood, or combinations thereof.

[0066] According to a further aspect, the composition of the present invention may optionally include a fat source. The fat source may include vegetable fats (e.g., olive oil, corn oil, sunflower oil, rapeseed oil, hazelnut oil, soybean oil, palm oil, coconut oil, canola oil, lecithin, etc.), animal fats (e.g., dairy fat), or combinations thereof. When the composition of the present invention includes a fat source, the fat source preferably provides 5% to 40% of the energy of the formula; for example, 20% to 30% of the energy of the formula. In one aspect, the composition of the present invention preferably includes a fatty acid component, preferably selected from the group consisting of docosahexaenoic acid ("DHA"), eicosapentaenoic acid ("EPA"), and combinations thereof. DHA and EPA may also be derived from krill, plant raw materials containing omega-3 fatty acids, flaxseed, walnuts, algae, and combinations thereof. Some fatty acids (e.g., 18:4 fatty acids) may be rapidly converted to DHA and / or EPA. The composition of the present invention may also contain alpha-linolenic acid. A suitable fat profile can be obtained using a blend of canola oil, corn oil, and high oleic sunflower oil. Alternatively or additionally, preferably fish oil or its components may be used.

[0067] In a further aspect of the present invention, the composition of the present invention optionally comprises a fiber or fiber blend. The fiber blend may contain a mixture of soluble and insoluble fibers. Soluble fibers may include, for example, fructooligosaccharides, acacia gum, inulin, etc. Insoluble fibers may include, for example, pea husk fiber.

[0068] In a further embodiment of the present invention, the composition of the present invention may optionally include a carbohydrate source. The carbohydrate source for the composition of the present invention may more preferably provide 40% to 80% of the energy of the composition. The carbohydrate source may include sucrose, lactose, glucose, fructose, corn syrup solids, maltodextrin, modified starch, amylose starch, tapioca starch, maize starch, or combinations thereof. The incorporation of carbohydrates is advantageous for simplifying the preparation of nutritional products, especially in the form of, for example, a powder dispersion.

[0069] In a further embodiment, the composition of the present invention comprises an amino acid, which may preferably be selected from the group consisting of alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, glutamate, glutamine, glycine, histidine, hydroxyproline, hydroxyserine, hydroxytyrosine, hydroxylysine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, taurine, threonine, tryptophan, tyrosine, valine, and combinations thereof.

[0070] In a further embodiment, the composition of the present invention may optionally comprise at least one prebiotic, preferably at least one of the following prebiotics: fructooligosaccharides, fucosyllactose, galactooligosaccharides, galactomannans, gentiooligosaccharides, glucooligosaccharides, guar gum, inulin, isomaltooligosaccharides, lactoneotetraose, lactosucrose, lactulose, levan, maltodextrin, milk oligosaccharides, partially hydrolyzed guar gum, pectin oligosaccharides, resistant starch, retrograded starch, sialooligosaccharides, sialyllactose, soybean oligosaccharides, sugar alcohols, xylooligosaccharides, or hydrolysates thereof, or combinations thereof, or any combination thereof. Prebiotics are food substances that selectively promote the growth of beneficial bacteria in the intestine or inhibit the growth or mucosal adhesion of pathogenic bacteria. Prebiotics are not inactivated in the stomach and / or upper intestinal tract or absorbed in the gastrointestinal tract of the individual who ingests them, but are fermented by the microflora and / or probiotics in the gastrointestinal tract. Prebiotics are defined, for example, by Glenn R. Gibson and Marcel B. Roberfroid, Dietary Modulation of the Human Colonic Microbiota: Introducing the Concept of Prebiotics, J. Nutr. 1995 125: 1401-1412.

[0071] In a further embodiment, the composition of the present invention may optionally include at least one probiotic. Probiotics are food-grade microorganisms (including live, semi-viable or attenuated and / or non-replicating microorganisms), metabolites, microbial cell preparations or microbial cell components that can confer a health benefit to the host when administered, more specifically, probiotics act beneficially on the host by improving the intestinal microbial balance and providing an effect on the health or well-being of the host. See Salminen S, Ouwehand A. Benno Y. et al., Probiotics: how should they be defined?, Trends Food Sci.Technol.1999:10,107-10. In general, these probiotics are believed to inhibit or affect the growth and / or metabolism of pathogenic bacteria in the intestinal tract. Probiotics may also activate the immune function of the host.The probiotics are preferably selected from the group consisting of Aerococcus, Aspergillus, Bacteroides, Bifidobacterium, Candida, Clostridium, Debaromyces, Enterococcus, Fusobacterium, Lactobacillus, Lactococcus, Leuconostoc, Melissococcus, Micrococcus, Mucor, Mucor, Oenococcus, Pediococcus, Penicillium, Peptostrepococcus, Pichia, Propionibacterium, Pseudocatenulatum, Rhizopus, Saccharomyces, Staphylococcus, Streptococcus, Torulopsis, Weissella, and combinations thereof.

[0072] The compositions of the present invention may optionally include a synbiotic, which is a supplement that includes both a prebiotic (at least one of those mentioned above) and a probiotic (at least one of those mentioned above) that act in concert to improve the gut microbiome.

[0073] In a further aspect, the compositions of the invention comprise further phytonutrients in addition to the urolithins. Such further phytonutrients may preferably be selected from the group consisting of flavonoids, combined phenolic compounds, polyphenolic compounds, terpenoids, alkaloids, sulfur-containing compounds, and combinations thereof, in particular carotenoids, phytosterols, quercetin, curcumin, limonin, and combinations thereof.

[0074] In a further aspect, the compositions of the present invention may optionally include minerals, such as boron, calcium, chromium, copper, iodine, iron, magnesium, manganese, molybdenum, nickel, phosphorus, potassium, selenium, silicon, tin, vanadium, zinc, or any combination thereof.

[0075] In another embodiment, the composition of the present invention comprises an antioxidant, which may preferably be selected from the group consisting of astaxanthin, carotenoids, coenzyme Q10 ("CoQ1O"), flavonoids, glutathione, goji (wolfberry), hesperidin, lacto-wolfberry, lignans, lutein, lycopene, polyphenols, selenium, vitamin A, vitamin C, vitamin E, zeaxanthin, and combinations thereof.

[0076] In further embodiments, the composition of the present invention may contain vitamins. As used herein, the term "vitamin" refers to any of a variety of organic substances that are essential in trace amounts for most animal nutrition and function as coenzymes and coenzyme precursors, especially in the control of metabolic processes. Vitamins have various biochemical functions, such as hormones (e.g., vitamin D), antioxidants (e.g., vitamin C and vitamin E), and mediators of cell signaling, cell proliferation control, tissue growth and differentiation (e.g., vitamin A). The most numerous vitamin B complex functions as precursors of enzyme cofactors (coenzymes) of biomolecules that help function as catalysts and substrates in metabolism. Therefore, the optional ingredients in the composition of the present invention may also include vitamins, such as vitamin A, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin or niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B7 (biotin), vitamin B9 (folic acid), and vitamin B12 (various cobalamins; in vitamin supplements, usually cyanocobalamin), vitamin C, vitamin D, vitamin E, vitamin K, folic acid, and biotin), preferably in the amounts prescribed by the FDA as the recommended daily intake. Particularly preferred are vitamin B and vitamins E and C, and even more preferred is vitamin B12.

[0077] In one embodiment, the compositions of the invention may comprise, in addition to a urolithin, an additional phytonutrient, which is at least one of a flavonoid, a phenol-related compound, a polyphenolic compound, a terpenoid, an alkaloid, and a sulfur-containing compound.

[0078] Phytonutrients are non-nutritional compounds found in many foods. Phytonutrients are functional foods that have health benefits other than basic nutrition, and are health-promoting compounds obtained from plant raw materials. Phytonutrients refer to any chemical produced by plants that confers one or more health benefits to the user. Non-limiting examples of phytonutrients include: i) monophenols (e.g., apiol, carnosol, carvacrol, dillapiol, rosemarinol); flavonols (e.g., quercetin, fingerol, kaempferol, myricetin, rutin, isorhamnetin, etc.), flavanones (e.g., fesperidin, naringenin, silybin, eriodictyol, etc.), flavones (e.g., apigenin, tangeretin, luteol, etc.), flavan-3-ols (e.g., catechin, (+)-catechin, (+)-gallocatechin, (-)-epicatechin, (-)-epigallocatechin, (-)-epigallocatechin gallate (EGCG), (-)-epicatechin 3-gallate, theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate, theaflavin-3,3'-digallate, thearubigin, etc.), anthocyanins (flavonals) and anthocyanidins ( Flavonoids (polyphenols), including, for example, pelargonidin, peonidin, cyanidin, delphinidin, malvidin, petunidin, etc.; isoflavones (phytoestrogens) (e.g., daidzein (formononetin), genistein (biochanin A), glycitein, etc.); dihydroflavonols, chalcones, coumestrol (phytoestrogens), and coumestrol; phenolic acids (e.g., gallic acid, tannic acid, vanillin, curcumin, etc.); hydrophobic acids (e.g., oleic acid, oleaginous ... phenolic compounds, including hydroxycinnamic acids (e.g., caffeic acid, chlorogenic acid, cinnamic acid, ferulic acid, coumarin, etc.); lignans (phytoestrogens), silymarin, secoisolariciresinol, pinoresinol, and lariciresinol; tyrosol esters (e.g., tyrosol, hydroxytyrosol, oleocanthal, oleuropein, etc.); stilbenoids (e.g., resveratrol, pterostilbene, piceatannol, etc.) and punicalagins; ii) carotenoids (tetraterpenoids), including carotenes (e.g., α-carotene, β-carotene, γ-carotene, δ-carotene, lycopene, neurosporene, phytofluene, phytoene) and xanthophylls (e.g., canthaxanthin, cryptoxanthin, zeaxanthin, astaxanthin, lutein, rubixanthin); monoterpenes (e.g., limonene, perillyl alcohol, etc.); saponins; lipids, such as phytosterols (e.g., campesterol, β-sitosterol, γ-sitosterol, stigmasterol), tocopherols (vitamin E), and gamma-3, gamma-6, and gamma-9 fatty acids (e.g., gamma-linolenic acid); terpenes (isoprenoids), including triterpenoids (e.g., oleanolic acid, ursolic acid, betulinic acid, moronic acid, etc.); iii) Betalains, including betacyanins (e.g., betanin, isobetanin, probetanin, neobetanin, etc.); and β-xanthins (non-glycosylated) (e.g., indicaxanthin, vulgaxanthin, etc.). iv) organosulfides, including, for example, dithiolthiones (isothiocyanates) (e.g., sulforaphane); and thiosulfonates (allyl compounds) (e.g., allyl methyl trisulfide, and diallyl sulfide), indoles, glucosinolates such as those containing indole-3-carbinol; sulforaphane; 3,3'-diindolylmethane; sinigrin; allicin; alliin; allyl isothiocyanate; piperine; syn-propanethial-S-oxide. v) protein inhibitors, including, for example, protease inhibitors; vi) Other organic acids, including oxalic acid, phytic acid (inositol hexaphosphate); tartaric acid; and anacardic acid. Examples include:

[0079] In one aspect, the compositions of the invention may further comprise, in addition to urolithins, at least one of proteins, lipids and carbohydrates, fiber, antioxidants, vitamins, amino acids, additional phytonutrients, prebiotics and / or probiotics, or any combination thereof. For example, the compositions of the invention may comprise 15-50% protein, 10-15% lipid, 25-50% carbohydrate and / or 5-10% fiber by weight of the total dry weight of the nutritional composition.

[0080] Those skilled in the art can determine the appropriate amount of such additional raw materials of the composition of the present invention according to the above definition according to the desired dosage of the component.The dosage can vary according to factors such as age, size, and health condition, lifestyle, and genetic heritage of the subject to be administered.The dosage can be in line with the Recommended Daily Allowance (RDA) developed by organizations such as Food and Nutrition Board of the National Academy of Sciences.

[0081] In further aspects, compositions of the invention include a combination of a urolithin and an NAD+ precursor and / or vitamin B12, i.e., a combination of a urolithin and an NAD+ precursor, a combination of a urolithin and vitamin B12, or a combination of a urolithin and an NAD+ precursor and vitamin B12.

[0082] The NAD of the present invention +The precursor is preferably selected from the group consisting of nicotinic acid (niacin), nicotinamide (niacinamide), nicotinamide riboside (NR), reduced nicotinamide riboside (NRH), β-nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide, nicotinic acid riboside, food extracts enriched in at least one of these compounds, such as food extracts enriched in nicotinamide adenine dinucleotide (NAD), and mixtures thereof. As used herein, "nicotinamide riboside" includes the L-valine and L-phenylalanine esters of nicotinamide riboside.

[0083] In a preferred embodiment, the NAD+ precursor is nicotinamide riboside.

[0084] Nicotinamide Riboside Nicotinamide riboside (NR) is the pyridine-nucleoside form of vitamin B3, the precursor of nicotinamide adenine dinucleotide (NAD).

[0085] Nicotinamide riboside has the following structure:

[0086] [ka]

[0087] Nicotinamide riboside or NAD+ precursor can be administered in an amount of about 0.001 mg / day to about 2000 mg / day, preferably about 0.001 mg / day to about 1000 mg / day, more preferably about 0.001 mg / day to about 750 mg / day, even more preferably about 0.001 mg / day to about 500 mg / day, and most preferably about 0.001 mg / day to about 250 mg / day, such as about 0.001 mg / day to about 100 mg / day, about 0.001 mg / day to about 75 mg / day, about 0.001 mg / day to about 50 mg / day, about 0.001 mg / day to about 25 mg / day, about 0.001 mg / day to about 10 mg / day, or about 0.001 mg / day to about 1 mg / day. Of course, the daily dose can be administered in small doses at various times throughout the day. In any case, however, the amount of compound administered will vary depending on factors such as the solubility of the active ingredient, the formulation used, the condition of the subject (e.g., body weight), and / or the route of administration. For example, the daily doses of nicotinamide riboside disclosed above are non-limiting and may vary in some embodiments, in particular, the compositions disclosed herein may be utilized as foods for acute specific medical purposes (FSMPs) and contain up to about 2.0 mg / day of nicotinamide riboside.

[0088] Vitamin B12 (also known as cobalamin) is a group of cobalt-containing water-soluble vitamins that cannot be synthesised by the human body and therefore must be obtained from the diet or by synthesis by the intestinal microflora.

[0089] The pool of vitamin B12 in the human body is composed of several forms of cyanocobalamin, which is inactive and requires conversion to become active, and the metabolically active forms of vitamin B12, methylcobalamin and adenosylcobalamin.

[0090] Two enzymes, methionine synthase and methylmalonyl-CoA mutase, are known to utilize vitamin B12 as a cofactor. Methionine synthase is an intracellular enzyme that utilizes methylcobalamin to convert homocysteine ​​to methionine. This conversion provides S-adenosylmethionine (SAM) as a methylation donor, playing an important role in preventing the toxic accumulation of homocysteine. Low SAM and high homocysteine ​​levels observed with severe vitamin B12 deficiency impair myelination of peripheral nerves and the spinal cord. Methionine synthase also catalyzes the activation of 5-methyl-tetrahydrofolate to the biologically active tetrahydrofolate, which is required for one-carbon metabolism and DNA synthesis, thus contributing to the increase in red blood cells. Methylmalonyl-CoA mutase is a mitochondrial enzyme that utilizes adenosylcobalamin to convert methyl-malonyl-CoA to succinyl-CoA, which is subsequently incorporated into the TCA cycle. It is essential for regulating neurodevelopment during embryonic life, but not in adulthood, as evidenced by the degradation of branched-chain amino acids and odd-chain fatty acids.

[0091] Vitamin B12 of the present invention may be in the form of, for example, vitamin B12 itself, the semi-synthetic derivatives cyanocobalamin, hydroxocobalamin, methylcobalamin, and / or adenosylcobalamin. Methylcobalamin may be particularly effective.

[0092] In some embodiments, vitamin B12 is administered to a subject at 0.1 to 40 times the recommended daily allowance (RDA) of vitamin B12 per day, e.g., 1 to 10 times the recommended daily allowance (RDA) of vitamin B12 per day.

[0093] Thus, vitamin B12 can be administered in a daily amount of about 10, 20, 30, or 40 times the daily RDA for vitamin B12. Preferably, the daily dose provides 10-40 times, more preferably 10-30 times, or even more preferably 10-25 times, and most preferably about 12-21 times the daily RDA for vitamin B12.

[0094] In the United States, the RDA for vitamin B12 is 2.4 μg per day for humans aged 14 years or older, so that such individuals may be administered a daily amount providing from about 0.002 mg to about 0.4 mg of vitamin B12 per day, preferably from 0.02 mg to 0.07 mg of vitamin B12 per day, and more preferably from 0.03 mg to 0.05 mg of vitamin B12 per day.

[0095] therapeutic use A second embodiment of the invention relates to a therapeutic or second medical use of a composition as defined above comprising a therapeutically effective amount of a urolithin or a precursor thereof, in particular for reducing the risk of recurrence of cancer or tumor formation in a patient in need thereof during remission after a prior cancer treatment in said patient. Thus, the invention preferably relates to preventing recurrence of cancer or tumor formation in a patient in need thereof during remission after (completion of) said patient's prior cancer treatment. Whether or not said patient has completed a prior cancer treatment and is in remission is generally well known to the skilled artisan and is typically determined by the skilled artisan, e.g. a physician, based on clinical criteria or other well known criteria in this particular cancer treatment field.

[0096] Further aspects of the second embodiment, which may be combined with the therapeutic use of the invention, either alone or in combination, are defined below. Furthermore, the second embodiment may be combined with the first embodiment and its aspects as defined above in any combination.

[0097] According to one aspect of the invention, the patient treated in the therapeutic use is a human or non-human mammal, preferably a human, optionally a human adult, child or infant. According to a further aspect, the patient is an immunocompromised patient. According to another preferred aspect, the patient is an immunocompromised human or an immunocompromised non-human mammal, preferably an immunocompromised human, optionally an immunocompromised human adult, child or infant. An infant in this context is typically a human infant, preferably aged 1-12 months, a child is typically considered to be a human aged 12 months to 18 years, and an adult is typically considered to be a human aged over 18 years. Alternatively, the patient treated by the therapeutic use may be a pet, such as a dog or cat.

[0098] According to one aspect of the invention, the urolithin contained in the composition of the invention may be administered in therapeutic use in a therapeutically effective amount, preferably in an amount of about 500-2000 mg / day, more preferably in an amount of 750-1500 mg / day, such as about 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800 or 2000 mg / day, or any combination of such values, each value therefore being suitable as an upper or lower limit. Administration may be via a single daily dose or in two or more separate daily doses, for example two, three, four or more separate doses per day, preferably either as a single dose or in two, three or four separate doses per day.

[0099] According to another aspect of the invention, administration of the composition of the invention comprising a urolithin in therapeutic use is preferably initiated in the remission phase following a prior cancer treatment in said patient, i.e., after completion of the prior intervention as described above. Preferably, administration of the composition comprising a urolithin is initiated in said patient on day 0 of the remission phase or at a later stage, e.g., about 1, 2, 3, 4, 5, 6, or 7 days after the onset of the remission phase, or 1-2 or 2-3 weeks after the onset of the remission phase, e.g., administration is initiated from day 0 (or day 1, 2, 3, 4, 5, 6, or 7) of the remission phase to about 2 months after the onset of the remission phase, preferably in a time frame of about 1-2 weeks to 2 months, more preferably about 2 weeks to 2 months, more preferably about 3 weeks to 6 weeks, and most preferably about 4-5 weeks or 1 month after the onset of the remission phase, after completion of the prior cancer treatment. As a result, the first day of the remission phase, and thus the "onset of the remission phase", is preferably calculated as "day 0" of the remission phase. Administration during the remission phase is preferably continuous.

[0100] According to a further aspect of the invention, administration of a composition comprising a urolithin is preferably carried out in therapeutic use for at least about 1 month, at least about 2 months, at least about 2 or about 3 months, preferably at least about 4 or about 5 months, more preferably at least about 6 or about 7 months, for example, about 1 to about 60 months, for example, about 1 to about 48 months, about 1 to about 36 months, about 1 to about 24 months, or about 1 to about 12 months, preferably for example, about 2 to about 60 months, for example, about 2 to about 48 months, about 2 to about 36 months, about 2 to about 24 months, or about 2 to about 12 months, even more preferably for example, about 4 to about 60 months, for example, about 4 to about 48 months, about 4 to about 36 months, about 4 to about 24 months, or about 4 to about 12 months, etc. during the remission phase.

[0101] According to certain aspects of the invention, administration of the composition of the invention comprising a urolithin is preferably initiated in said patient on day 0 of the remission phase or at a later stage, such as about 1, 2, 3, 4, 5, 6, or 7 days after the onset of the remission phase, or 1-2 or 2-3 weeks after the onset of the remission phase, for example from day 0 (or day 1, 2, 3, 4, 5, 6, or 7) of the remission phase to about 2 months after the onset of the remission phase, preferably in a time frame of about 1-2 weeks to 2 months, more preferably about 2 weeks to 2 months, more preferably about 3 weeks to 6 weeks, and most preferably about 4-5 weeks or 1 month after the onset of the remission phase, i.e., after the completion of the prior cancer treatment, and The administration is preferably carried out for at least about 1 month, at least about 2 months, at least about 2 or about 3 months, preferably at least about 4 or about 5 months, more preferably at least about 6 or about 7 months, for example, about 1 to about 60 months, for example, about 1 to about 48 months, about 1 to about 36 months, about 1 to about 24 months, or about 1 to about 12 months, preferably, for example, about 2 to about 60 months, for example, about 2 to about 48 months, about 2 to about 36 months, about 2 to about 24 months, or about 2 to about 12 months, more preferably, for example, about 4 to about 60 months, for example, about 4 to about 48 months, about 4 to about 36 months, about 4 to about 24 months, or about 4 to about 12 months.

[0102] According to another aspect of the invention, the prior cancer treatment may be cancer surgery, radiotherapy, chemotherapy, targeted cancer therapy, immunotherapy, hormonal therapy, or phytochemical-based cancer therapy. Such cancer treatment is preferably directed to one of the cancers as defined above. According to one aspect, the prior cancer treatment may comprise the use of a urolithin as defined herein, preferably urolithin A, or chemotherapy.

[0103] Such cancer may, according to further aspects of the invention, be a solid or liquid tumor, preferably a solid tumor, more preferably a lymphoma, carcinoma or sarcoma, even more preferably breast cancer, prostate cancer, uterine cancer, hepatocellular carcinoma, pancreatic cancer, cervical cancer, colon cancer, colorectal cancer, gastric cancer, bladder cancer, skin cancer, lung cancer or head and neck cancer, most preferably pancreatic cancer, colorectal cancer, skin cancer or breast cancer. In some aspects, the cancer may be a blood cancer, leukemia, lymphoma or myeloma.

[0104] According to one aspect, the compositions of the invention comprising urolithins may, in therapeutic use, be administered enterally or orally, preferably orally. Accordingly, the compositions of the invention are preferably provided as oral or enteral compositions, preferably as oral compositions.

[0105] According to one other aspect, the compositions of the invention to be administered in therapeutic use may be in any suitable form, preferably in unit dosage form or any other suitable form, preferably as defined above.

[0106] Methods for preparing the compositions of the present invention A third embodiment of the invention relates to a method of making a nutritional composition comprising the step of incorporating a therapeutically effective amount of a urolithin as defined herein into a composition as defined above, preferably a pharmaceutical or nutritional composition as defined above. All ingredients defined for the composition can be added before, in parallel with or after the step of incorporating a therapeutically effective amount of a urolithin as defined herein above. All specific aspects of the composition defined herein are applicable.

[0107] Treatment method A fourth embodiment of the present invention relates to a method of treating a patient in need of treatment, comprising reducing the risk of recurrence of cancer or tumor formation in a patient in need thereof during remission following a prior cancer treatment, the method comprising: a) providing a composition comprising a therapeutically effective amount of a urolithin or a precursor thereof, the composition being preferably as defined herein above; b) administering to a patient in need thereof a therapeutically effective amount of a composition comprising a urolithin or a precursor thereof; c) optionally following up the patient periodically, preferably at predetermined intervals, preferably simultaneously with administration of the composition according to step b), for possible recurrence of the cancer treated in the prior cancer treatment, preferably by using cancer-specific biomarkers; The present invention relates to a method comprising the steps of:

[0108] The therapeutic methods described herein aim to prevent recurrence of cancer or tumor formation in a patient in need thereof during remission of the patient's prior cancer treatment (after completion). Whether or not the patient has completed the prior cancer treatment and is in remission is generally well known to those of skill in the art and is typically determined by the skilled artisan, e.g., a physician, based on clinical criteria or other well-known criteria known in the field of this particular cancer treatment.

[0109] Further aspects of the fourth embodiment, which may be combined with the method of the invention either alone or in combination, are defined below. Furthermore, the fourth embodiment and its aspects may be combined with the first embodiment and any of its aspects as defined above.

[0110] According to one aspect, the composition administered in step b) of the treatment method of the present invention is preferably a composition as defined according to the first embodiment herein.Preferably, such composition is in the form of a pharmaceutical or nutritional composition, optionally in the form of a food product, a dietary supplement, a nutraceutical, a food for specific medical purposes (FSMP), a nutritional supplement, a dairy drink, a small volume liquid nutritional supplement or meal replacement drink, a botanical drink, a gummy, or a combination thereof.

[0111] According to a further aspect, the patient treated in the therapeutic method of the invention is a human or a non-human mammal, preferably a human, optionally a human adult, child or infant. According to a further aspect, the patient is an immunocompromised patient. According to another preferred aspect, the patient is an immunocompromised human or an immunocompromised non-human mammal, preferably an immunocompromised human, optionally an immunocompromised human adult, child or infant. An infant in this context is typically a human infant, preferably aged 1-12 months, a child is typically considered to be a human aged 12 months to 18 years, and an adult is typically considered to be a human aged over 18 years. Alternatively, the patient treated by the therapeutic use may be a pet, such as a dog or a cat.

[0112] According to another aspect of the invention, a urolithin as defined herein may be administered in step b) of the treatment method of the invention in a therapeutically effective amount, preferably in an amount of about 500-2000 mg / day, more preferably in an amount of 750-1500 mg / day, such as about 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800 or 2000 mg / day, or any combination of such values, each value therefore being suitable as an upper or lower limit. Administration may be via a single daily dose or in two or more separate daily doses, such as two, three, four or more separate doses per day, preferably either as a single dose or in two, three or four separate doses per day.

[0113] The administered composition may further comprise additional compounds as defined herein, such as vitamins, additional phytonutrients, minerals, probiotics, prebiotics, etc. It should be noted here that a person skilled in the art can easily determine the appropriate dose of such additional compounds without undue experimentation. Typically, a physician will determine the actual dose that is most suitable for an individual patient based on a variety of factors, including the activity of the specific active ingredient used, the metabolic stability and duration of action of the agent, age, weight, general health, sex, diet, method and time of administration, excretion rate, drug combination, severity of the particular condition, and the individual being treated. Of course, there may be individual cases where higher or lower dosage ranges are merited, and such cases are within the scope of the present invention.

[0114] According to another aspect of the invention, administration of the composition of the invention comprising a urolithin in step b) of the treatment method of the invention is preferably initiated after the prior cancer treatment in said patient, i.e., after completion of the prior intervention as described above. Preferably, administration of the composition comprising a urolithin is initiated in said patient on day 0 of the remission phase or at a later stage, such as about 1, 2, 3, 4, 5, 6, or 7 days after the onset of the remission phase, or about 1-2 or about 2-3 weeks after the onset of the remission phase, such as from day 0 (or day 1, 2, 3, 4, 5, 6, or 7) of the remission phase to about 2 months after the onset of the remission phase, preferably in a time frame of about 1-2 weeks to about 2 months, more preferably about 2 weeks to about 2 months, more preferably about 3 weeks to about 6 weeks, and most preferably about 4-5 weeks or 1 month after the onset of the remission phase, i.e., after completion of the prior cancer treatment.

[0115] According to a further aspect of the invention, administration of a composition comprising a urolithin is preferably carried out in step b) of the treatment method of the invention for at least about 1 month, at least about 2 months, at least about 2 or about 3 months, preferably at least about 4 or about 5 months, more preferably at least about 6 or about 7 months, for example, about 1 to about 60 months, about 1 to about 48 months, about 1 to about 36 months, about 1 to about 24 months, or about 1 to about 12 months, preferably for example, about 2 to about 60 months, for example, about 2 to about 48 months, about 2 to about 36 months, about 2 to about 24 months, or about 2 to about 12 months, more preferably for example, about 4 to about 60 months, about 4 to about 48 months, about 4 to about 36 months, about 4 to about 24 months, or about 4 to about 12 months, etc. during the remission phase.

[0116] According to a particular aspect of the invention, administration of the composition of the invention comprising a urolithin is preferably initiated in said patient on day 0 of the remission phase in step b) of the treatment method of the invention or at a later stage, such as about 1, 2, 3, 4, 5, 6, or 7 days after the onset of the remission phase, or 1-2 or 2-3 weeks after the onset of the remission phase, for example from day 0 (or day 1, 2, 3, 4, 5, 6, or 7) of the remission phase to about 2 months after the onset of the remission phase, preferably about 1-2 weeks to 2 months, more preferably about 2 weeks to 2 months, more preferably about 3 weeks to 6 weeks, and most preferably about 4-5 weeks or 1 month after the onset of the remission phase, i.e., after the completion of the preceding cancer treatment. The administration of the composition comprising a urolithin is preferably carried out for at least about 2 or 3 months, preferably at least about 4 or 5 months, more preferably at least about 6 or 7 months, for example, about 1 to about 60 months, for example, about 1 to about 48 months, about 1 to about 36 months, about 1 to about 24 months, or about 1 to about 12 months, preferably for example, about 2 to about 60 months, for example, about 2 to about 48 months, about 2 to about 36 months, about 2 to about 24 months, or about 2 to about 12 months, more preferably for example, about 4 to about 60 months, for example, about 4 to about 48 months, about 4 to about 36 months, about 4 to about 24 months, or about 4 to about 12 months, during the remission phase.

[0117] According to another aspect of the invention, the prior cancer treatment may be cancer surgery, radiation therapy, chemotherapy, targeted cancer therapy, immunotherapy, hormonal therapy, or phytochemical-based cancer treatment. Such cancer treatment is preferably directed to one of the cancers defined above. According to one aspect, the prior cancer treatment may comprise the use of a urolithin as defined herein, preferably urolithin A, or chemotherapy.

[0118] Such cancer may, according to further aspects of the invention, be a solid or liquid tumor, preferably a solid tumor, more preferably a lymphoma, carcinoma or sarcoma, even more preferably breast cancer, prostate cancer, uterine cancer, hepatocellular carcinoma, pancreatic cancer, cervical cancer, colon cancer, colorectal cancer, gastric cancer, bladder cancer, skin cancer, or head and neck cancer, most preferably pancreatic cancer, colorectal cancer, skin cancer, lung cancer or breast cancer. In some aspects, the cancer may also be a blood cancer, leukemia, lymphoma or myeloma.

[0119] According to one aspect of the treatment method of the invention, the composition of the invention comprising a urolithin may be administered orally or enterally, preferably orally. Thus, the composition of the invention is preferably provided as an oral or enteral composition, preferably as an oral composition. According to another aspect, the composition of the invention administered in step b) of the treatment method of the invention may be in any suitable form, preferably in unit dosage form, or any other suitable form, preferably as defined above.

[0120] It will be understood that all references herein to methods of treatment include curative, palliative and prophylactic treatment. The treatment of mammals, particularly humans, is preferred. Both human and veterinary treatments are within the scope of the present invention.

[0121] The compositions used in the present invention may be administered alone but, particularly in human therapy, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent.

[0122] kit In another aspect, the invention also provides a kit containing a composition of the invention comprising a therapeutically effective amount of a urolithin as defined herein. The composition of the invention comprising a therapeutically effective amount of a urolithin may be provided in a suitable container. The kit may also include instructions for use.

[0123] It is understood that a person skilled in the art can combine all features of the invention disclosed herein without departing from the scope of the invention disclosed.

[0124] Preferred features and embodiments of the present invention will now be described by way of non-limiting examples.

[0125] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of chemistry, biochemistry, molecular biology, microbiology, and immunology which are within the capabilities of those skilled in the art and are explained in the literature. For example, Sambrook, J., Fritsch, EFand Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory Press; Ausubel, FMet al. (1995 and periodic supplements) Current Protocols in Molecular Biology, Ch. 9, 13 and 16, John Wiley & Sons; Kahn, A. (1996) DNA Isolation and Sequencing: Essential Techniques, John Wiley & Sons; Polak, JMand McGee, J.O'D. (1990) In Situ Hybridization: Principles and Practice, Oxford University Press; Gait, MJ (1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press and Lilley, DMand. Dahlberg, J.E. (1992) Methods in Enzymology: DNA Structures. See Part A: Synthesis and Physical Analysis of DNA, Academic Press. Each of these general texts is incorporated herein by reference.

[0126] [Example] Example 1 Materials and Methods Cell lines and in vitro culture: MC38 colorectal cancer cell line and B16 cell line were used. MC38 colorectal cancer cell line (Corbett et al., Can Res, 1975) is a murine colon adenocarcinoma cell line derived from C57BL / 6 mice. The cells are adherent and have a fibroblastic morphology. MC38 cells form tumors and metastases after transplantation into syngeneic C57BL / 6 or immunodeficient mice. B16 melanoma is a murine tumor cell line used in research as a model for human skin cancer. Both MC38 and B16 cancer cell lines are commercially available.

[0127] The MC38 colorectal cancer cell line was maintained in RPMI 1640 medium (Thermofisher) supplemented with 10% FBS (Gibco), 50 μM β-mercaptoethanol (Thermofisher), 100 U / mL penicillin / streptomycin (Thermofisher), and 1 mM sodium pyruvate (Thermofisher).

[0128] The B16 cell line was maintained in DMEM+GlutaMAX (Thermofisher) supplemented with 10% FBS (Gibco) and 100 U / mL penicillin / streptomycin (Thermofisher).

[0129] Tumor engraftment, dietary treatment and rechallenge experiments: B57BL / 6 mice were purchased from ENVIGO and housed in the animal facility of the University of Lausanne. One week after arrival, mice were fed ad libitum with a Urolithin A-enriched diet. The Urolithin A diet was prepared as follows: 300 mg of Urolithin A (Novalix) was dissolved in DMSO (Applichem) and mixed with 1 kg of “2016 Irradiated Global 16% Rodent diet ground” (ENVIGO), corresponding to a dose of 50 mg / kg / day. For the control diet (hereafter referred to as DMSO diet), DMSO (Applichem) was mixed with 1 kg of “2016 Irradiated Global 16% Rodent diet ground” (ENVIGO). The diet was aliquoted into small pellets and dried under sterile conditions. Mice were fed ad libitum with the DMSO diet or the Urolithin A diet for 4 weeks before tumor engraftment.

[0130] For tumor engraftment, 5 × 10 5 MC38 cancer cells or 1 × 10 5 B16 cancer cells were injected subcutaneously into the right flank of each mouse.

[0131] For the MC38 and B16 experiments, five mice were fed a DMSO diet ad libitum and five mice were fed a Urolithin A-enriched diet ad libitum for four weeks prior to tumor injection. Mice were sacrificed at humane endpoints established by Swiss federal regulations and approved by national authorities. Examples of humane endpoints include: 1000m 3 The following symptoms were observed: tumor size exceeding 100%, weight loss (15% from the previous time point) and signs of distress. In the case of MC38, four out of five mice fed the Urolithin A diet did not develop tumors. These mice were designated survivors.

[0132] For the rechallenge experiment, surviving mice were removed from the UroA diet and placed on a conventional diet (provided by the animal facility of the University of Lausanne) for 1 week. During this week, one mouse developed a tumor and was removed from the experiment. The remaining three mice were immunized with 5 × 10 5MC38 cancer cells were subcutaneously injected into five mice (designated the control cage) at the same time. 5 MC38 cancer cells were subcutaneously injected into the left flank of the mice, and this second tumor injection was performed to distinguish between tumors arising from the first injection and those arising from the second rechallenge injection.

[0133] All experiments were performed in accordance with Swiss federal regulations and approved by the veterinary authorities of Canton Vaud.

[0134] Statistical analysis: Data points represent biological replicates and are shown as mean ± SEM. Statistical significance was determined by Student's T-test or long-rank (Mantel-Cox) test.

[0135] result Initial studies showed that mice fed a UroA-supplemented diet increased / improved splenocyte numbers and overall quality of HSCs, in addition to potential applications in in vitro or ex vivo conditions. Following this result, we tested whether a UroA-enriched diet could improve the host immune system's ability to control tumor growth. To test this hypothesis, mice were fed ad libitum with a UroA diet (see above, Urolithin A diet) and a control diet (DMSO, see above) for 4 weeks. Mice were injected subcutaneously with colorectal cancer cells MC38 in the right flank (Figure 1A). Tumor volume was estimated using the formula: tumor volume = (length x width x width) / 2. In two separate experiments (Figure 1B: experiment 1 and Figure 1B: experiment 2), tumor engraftment and growth were significantly reduced in mice exposed ad libitum to a UroA-enriched diet (Figure 1B, Figure 1C).

[0136] In experiment 1, five mice fed the DMSO diet (see above) were 3 The five mice fed the Urolithin A-enriched diet showed an average tumor size of 50 mm 3 The mean tumor size of each group is shown in the left panel of Fig. 1B. The right panel of Fig. 1B shows the single curves (the UroA curve is overlaid, and the DMSO curve at the bottom is a single curve).

[0137] In experiment 2, three mice were fed the DMSO diet (see above), and two of the three mice had a 100 mm 3 Of the three mice fed the Urolithin A-enriched diet, only one developed larger tumors measuring 100 mm 3 In addition, the UroA diet improved overall survival (Figure 1D).

[0138] We then tested whether tumor control mediated by UroA acts through adaptive immune responses. We hypothesized the working hypothesis that memory T cells with antitumor activity are generated in surviving hosts, which rapidly respond to a second tumor graft. To test this hypothesis, the same cancer cell line (MC38) was injected into the opposite flank of the surviving mice in the UroA group after 7 weeks (Figure 2A). To exclude the possibility of UroA involvement in tumor growth, the survivor mice and the control cage group were maintained on a conventional diet without UroA for 1 week before tumor injection. Notably, the survivor mice showed better tumor control ability and survival rate compared to the control group (Figures 2B and 2C). The DMSO diet-fed mice were fed a 600 mm 3 The Urolithin A-fed mice had an average tumor size of 100 mm 3 The mean tumor size was shown.

[0139] Overall, the current data convincingly demonstrate that dietary UroA supplementation impedes tumor growth through the establishment of an enhanced adaptive immune response.

[0140] Example 2 Improved tumor control in poorly immunogenic tumor models Next, we also tested whether the UroA diet of the present invention could improve tumor control in poorly immunogenic tumor models such as B16 melanoma (see Lechner, MG, et al., Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy. J Immunother, 2013.36(9):p.477-89). In this experiment, five mice (B57BL / 6) were fed a DMSO diet ad libitum and five mice were fed a Urolithin A-enriched diet ad libitum for four weeks prior to tumor injection. As described above, mice fed the UroA diet (Figure 1b) developed smaller tumors compared to the control group (Figure 3). DMSO diet-fed mice developed tumors measuring 180 mm 3 The Urolithin A-fed mice showed an average tumor size of 70 mm 3 The mean tumor size was shown.

[0141] Tumor engraftment, dietary treatment and re-challenge experiments were as originally described in Example 1.

[0142] Example 3 Effects on adaptive immune responses To verify that urolithin A supplementation enhances adaptive immune responses, immunodeficient mice (NSG mice, NOD.Cg-Prkdc) were fed a urolithin A-enriched diet for 4 weeks. scid Il2rg tm1Wjl / SzJ) on the right double side 5×10 5 MC38 cells were injected subcutaneously. Tumor volume was estimated using the formula: tumor volume = (length x width x width) / 2. Five mice were fed the DMSO diet and five mice were fed the Urolithin A-enriched diet. Both the five mice fed the DMSO diet and the five mice fed the Urolithin A-enriched diet developed tumors. Tumors grew at the same rate and at the end time point (day 18), the DMSO control and Urolithin A-fed mice showed comparable tumor sizes (1000 mm 3) Thus, as can be seen in Figure 4, administration of UroA does not affect tumor size in immunodeficient mice, as evidenced by the same rate of tumor growth.

[0143] Example 4 Boosting the immune system helps prevent tumor growth To test whether Urolithin A feeding has a preventive effect by boosting the immune system, we carried out the following experiment. The poorly immunogenic tumor model B16 melanoma was selected for this experiment. For 4 weeks, 10 mice were fed ad libitum with a DMSO diet (see above) and 10 mice were fed ad libitum with a Urolithin A-enriched diet (see above). Then, 5 mice from the DMSO diet were placed under a conventional diet (provided by the animal facility), and this group was called DMSO on / off. The remaining 5 mice continued on the DMSO diet and were named the DMSO group. Five mice from the Urolithin diet were placed under a conventional diet (provided by the animal facility), and this group was called UroA on / off. The remaining 5 mice continued on the DMSO diet and were named the UroA group. After 1 week, 5×10 5 B16 cells were injected subcutaneously into the right flank of B57BL / 6 mice.

[0144] Tumor engraftment, dietary treatment and re-challenge experiments were as originally described in Example 1.

[0145] Mice fed DMSO or DMSO on / off groups showed similar tumor volumes, reaching 350 mm on day 17. 3 and 430mm 3 While mice in the UroA and UroA on / off groups showed reduced tumor growth, reaching an average tumor size of 200 mm on day 17. 3 "The results suggest that a 4-week dietary intake of Urolithin A has a preventative effect, resulting in a stronger immune response against cancer cells. This effect was maintained even after the dietary intake was discontinued, suggesting that Urolithin A may have a mechanism of imprinting on the immune system."

[0146] summary Based on our observations, urolithin dietary supplementation can reduce tumor growth in two different tumor models (Figures 1 and 3). Both of these preclinical models are used to investigate the involvement of immune cells, especially adaptive immune cells, in tumor control and tumor regression events. Under experimental conditions, urolithin A supplementation was able to generate a strong immune response, thereby capable of a) preventing cancer cell proliferation (Figure 1), and b) forming an appropriate and strong immune memory against cancer cells upon re-exposure to cancer development (Figure 2). The formation of immune memory is the aim of all established cell-based immunotherapies (e.g. vaccines). In the presence of immune memory, the immune system can rapidly respond to re-exposure to pathogens or possible tumor recurrence. Immune memory is ensured by the generation of a specific set of T cells. To demonstrate that urolithin A supplementation boosted T cell function, we performed the same set of experiments in immunocompromised hosts lacking adaptive immune cells, including T cells (Figure 4). Under these experimental conditions, Urolithin A supplementation did not affect tumor growth, demonstrating that a) Urolithin A does not affect cancer cell proliferation in an immunodeficiency model, and b) Urolithin A supplementation in the absence of adaptive immune cells does not reduce tumor growth. These results indicate that Urolithin A effectively boosts the adaptive immune response against cancer cells under the experimental conditions. Therefore, the use of Urolithin A may be particularly effective when used during the remission phase of prior cancer treatment.

[0147] All publications mentioned in the above specification are incorporated herein by reference.Various modifications and alterations of the compositions, uses and methods disclosed in the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention.Although the present invention has been disclosed in connection with certain preferred embodiments, it should be understood that the invention claimed should not be unduly limited to such specific embodiments.Indeed, various modifications of the disclosed modes for carrying out the invention will be apparent to those skilled in the art and are intended to be within the scope of the following claims.

Claims

1. 1. A composition comprising a therapeutically effective amount of a urolithin or a precursor thereof, for use in reducing the risk of recurrence of cancer or tumorigenesis in a patient in need thereof when the patient is in remission from a prior cancer treatment.

2. The composition for use according to claim 1, wherein the patient is a human or non-human mammal, preferably a human, optionally a human adult, child or infant.

3. The composition for use according to claim 1 or 2, wherein the patient is an immunocompromised patient.

4. 4. The composition for use according to any one of claims 1 to 3, wherein the urolithin or precursor thereof is selected from the group consisting of urolithin, ellagic acid and ellagitannin, more preferably selected from urolithin A, urolithin B, urolithin C, or urolithin D, or a combination thereof.

5. The composition for use according to any one of claims 1 to 4, wherein the urolithin is urolithin A, or a combination of urolithin A and at least one of urolithin B, urolithin C, or urolithin D.

6. The composition for use according to any one of claims 1 to 5, wherein the urolithin is urolithin A.

7. 7. The composition for use according to any one of claims 1 to 6, wherein the urolithin is administered in an amount of about 500 to 2000 mg / day, preferably in an amount of 750 to 1500 mg / day.

8. The composition for use according to any one of claims 1 to 7, wherein the administration of the composition comprising a urolithin is initiated on day 0 of the remission phase or a subsequent stage, such as about 1, 2, 3, 4, 5, 6, or 7 days after the onset of the remission phase, or 1-2 or 2-3 weeks after the onset of the remission phase, such as from day 0 (or day 1, 2, 3, 4, 5, 6, or 7) of the remission phase to about 2 months after the onset of the remission phase, preferably in a time frame of about 1-2 weeks to 2 months after the onset of the remission phase, and preferably is carried out for at least about 1 month.

9. The composition for use according to any one of claims 1 to 8, wherein the cancer is a solid or liquid tumor, preferably a lymphoma, carcinoma or sarcoma, more preferably breast cancer, prostate cancer, uterine cancer, hepatocellular carcinoma, pancreatic cancer, cervical cancer, colon cancer, colorectal cancer, gastric cancer, bladder cancer, skin cancer, or lung cancer, or head and neck cancer, most preferably pancreatic cancer, colorectal cancer, skin cancer, breast cancer, blood cancer, leukemia, lymphoma or myeloma.

10. 10. The composition for use according to any one of claims 1 to 9, wherein said prior cancer treatment is cancer surgery, radiotherapy, chemotherapy, targeted cancer therapy, immunotherapy, hormonal therapy, or phytochemical-based cancer treatment.

11. 11. The composition for use according to any one of claims 1 to 10, wherein the prior cancer treatment comprises the use of a urolithin, preferably urolithin A, or chemotherapy.

12. The composition for use according to any one of claims 1 to 11, wherein the composition is administered orally.

13. 13. The composition for use according to any one of claims 1 to 12, wherein the composition is in the form of a pharmaceutical or nutritional composition, optionally in the form of a food product, a dietary supplement, a nutraceutical, a food for specific medical purposes (FSMP), a nutritional supplement, a dairy drink, a small volume liquid nutritional supplement or meal replacement drink, a botanical drink, a gummy, or a combination thereof.

14. 14. The composition of claim 13, wherein the composition comprises a pomegranate extract, a tamarind extract, or a shilajit extract, which provides at least a portion of at least one urolithin or a precursor thereof.

15. The composition of claim 14, wherein the composition comprises a urolithin in an isolated form.

16. 16. The composition for use according to any one of claims 1 to 15, wherein the composition further comprises an NAD+ precursor and / or a vitamin B, wherein the NAD+ precursor is preferably selected from the group consisting of nicotinic acid, nicotinamide, nicotinamide riboside (NR), reduced nicotinamide riboside (NRH), nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide, nicotinic acid riboside, and mixtures thereof, and wherein the vitamin B is preferably selected from vitamin B6, vitamin B9 or vitamin B12, preferably vitamin B12.

17. 17. The composition for use according to any one of claims 1 to 16, wherein the composition further comprises nicotinamide riboside and vitamin B12.

18. 1. A method of reducing a risk of recurrence of cancer or tumor formation in a patient in need thereof when said patient is in remission following a prior cancer treatment, comprising: a) providing a composition comprising a therapeutically effective amount of a urolithin or a precursor thereof, said composition being preferably a composition as defined in any one of claims 1 to 17; b) administering the therapeutically effective amount of the composition comprising a urolithin or a precursor thereof to the patient in need thereof, wherein the patient is in remission following a prior cancer treatment; and c) optionally following up said patient periodically, preferably at predetermined intervals, preferably simultaneously with administration of said composition according to step b), for possible recurrence of the cancer treated in said prior cancer treatment, preferably by using cancer specific biomarkers; A method comprising:

19. The method of claim 18, wherein the composition administered is a composition according to any one of claims 1 to 17.

20. A kit comprising a composition as defined in any one of claims 1 to 17 and instructions for use.

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