Low tryptophan diet for adjuvant cancer treatment

Abstract

Provided herein are dietary compositions to minimize tryptophan intake in diet. The dietary compositions provided are beneficial for patients suffering from cancer and / or neurological diseases.

Description

Attorney Docket No. UTSDP4183WO-1001375084TITLE LOW TRYPTOPHAN DIET FOR ADJUVANT CANCER TREATMENT CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Patent Application Serial No.63 / 747,848 filed January 21, 2025, and U. S. Provisional Patent Application Serial No.63 / 809,176 filed May 20, 2025, each of which are incorporated by reference herein in their entirety.ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under Grant No. CA245548 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND1. Field

[0003] The present disclosure relates to low or no tryptophan formulations and methods for using the formulations in the treatment of cancer.2. Discussion of Related Art

[0004] Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Despite therapeutic efforts, liver cancer is a highly refractory disease with a five-year survival rate of 30%. There is a need for developing additional approaches to tackle the disease.

[0005] Cancer cells develop an increased ability to obtain nutrients and efficiently utilize them for biomass production and cell growth. Recent studies have explored the efficacy of limiting single dietary components in cancer treatment. For example, methionine deprivation reduces the growth of colon cancer cells, and asparagine deprivation prevents the growth of cancer cells by altering mitochondrial function. Furthermore, diets restricted in serine and glycine reduce cancer cell growth through the accumulation of deoxysphingolipids. Because the different types of cancer vary in their metabolic activity, preferred energy source, and nutritional dependencies, this approach is not a one-size-fits-all approach. Characterization of nutrient demands by individual tumor types has the potential to identify their specific vulnerabilities that can be safely manipulated through dietary or pharmacologic interventions to target the destruction of cancer cells, for example tumor cell, while minimally affecting healthy tissues.301415446 - 1 -Attorney Docket No. UTSDP4183WO-1001375084SUMMARY

[0006] In some aspects, the current disclosure encompasses a dietary product for treating or reducing the symptoms of cancer in a subject in need thereof, the dietary product comprising at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; wherein the dietary product is substantially devoid of tryptophan. Also disclosed herein is a method of treating or reducing the symptoms of cancer in a subject in need thereof, the method comprising administering a controlled diet to the subject, wherein the controlled diet is substantially devoid of tryptophan.

[0007] In some aspects, the subject obtains at least about 25% to 50% of the daily calories from fat. In some aspects, the subject is on a ketogenic diet.

[0008] In some aspects, the dietary product as disclosed provides about 50% to about 80% of its total calorie amount from fat. In some aspects, the dietary product comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of the dietary product. In some aspects, the dietary product comprises no tryptophan. In some aspects, the dietary product is part of a controlled diet for a subject in need thereof; wherein the controlled diet comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food intake. In some aspects, the product comprises at least 4, at least 5, at least 6, at least 7, or 8 of the essential amino acids (excluding tryptophan). In some aspects, each of the at least 4, at least 5, at least 6, at least 7, or 8 of the essential amino acids are in an amount of 0.01 mg to 10 mg per 100 grams of the dietary product. In some aspects, the dietary product further comprises one or more non-essential amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine. In some aspects, the dietary product comprises at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or all of the non-essential amino acids. In some aspects, the dietary product may also comprise one or more macronutrient and / or one or more micronutrient source, or any combination thereof. Non-limiting examples of suitable micronutrient include one or more vitamins, one or more macro minerals, or one or more trace minerals.

[0009] In some aspects of the disclosed composition or methods, the subject is a mammal. In some aspects, the subject is a human.

[0010] In some exemplary aspects, the dietary product comprises about 7-10 g of leucine, 4-6 g of isoleucine, 4-5 g of valine, 6-8 g of lysine, 1-3 g of methionine, 2-3 g of phenylalanine, 5-7 g of threonine, 1-2 g of histidine, 4-5 g of alanine, 2-3 g of arginine, 9-13 g of aspartic acid, 14-16 g of glutamic acid, 1-2 g of glycine, 4-5 g of proline, 3-5 g of serine, or 2-3 g of tyrosine, or any combination thereof, per 100 g of protein. In some aspects, the dietary product301415446 - 2 -Attorney Docket No. UTSDP4183WO-1001375084comprises about 7-10 g of leucine, 4-6 g of isoleucine, 4-5 g of valine, 6-8 g of lysine, 1-3 g of methionine, 2-3 g of phenylalanine, 5-7 g of threonine, 1-2 g of histidine, 3-5 g of alanine, 2-3 g of arginine, 9-13 g of aspartic acid, 14-16 g of glutamic acid, 1-2 g of glycine, 4-5 g of proline, 3-5 g of serine, and 2-3 g of tyrosine per 100 g of protein. In some aspects, the dietary product comprises, per kilogram of the dietary product, about 9-13 g of leucine, 6-10 g of isoleucine, 6-10 g of valine, 16-20 g of lysine, 6-10 g of methionine, 6-10 g of phenylalanine, 6-10 g of threonine, 3-6 g of histidine, 2-6 g of alanine, 10-14 g of arginine, 2-6 g of aspartic acid, 38-42 g of glutamic acid, 21-25 g of glycine, 2-6 g of proline, 2-6 g of serine, or 3-7 g of tyrosine, or any combination thereof. In some aspects, the dietary product may also comprise serotonin supplement to address symptoms associated with serotonin deficiency. Non-limiting examples include one or more of 5-hydroxytryptophan (5-HTP), St. John’s Wort, S-adenosylmethionine (SAMe), vitamin B6, L-methylfolate, magnesium, omega-3 fatty acids, or vitamin D. In some aspects, the dietary product is in the form of a powder, a gel, a solution, a suspension, a paste, a solid, a pellet, a liquid, a liquid concentrate, a powder which may be reconstituted, a shake, a concentrate, a pill, a bar, a tablet, a capsule, injectable solution, or a ready-to-use product.

[0011] Also disclosed herein is a method of treating or preventing a cancer in a subject in need thereof, the method comprising administering to the subject a controlled diet, wherein the controlled diet comprises administering to the subject any one of the disclosed dietary product. In some aspects, the cancer is a MYC-related cancer. In some aspects, the cancer is Burkitt lymphoma, diffuse large B-cell lymphoma, multiple myeloma, medulloblastoma, neuroblastoma, small cell lung cancer, colorectal cancer, breast cancer, prostate cancer, hepatocellular carcinoma (HCC), ovarian cancer, pancreatic cancer, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, esophageal cancer, gastric cancer. In some aspects, the cancer is HCC.

[0012] In some aspects, the controlled diet comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food intake. In some aspects, controlled diet comprises no tryptophan. In some aspects, the dietary product comprises at least about 50% - 100% of the subjects diet. In some aspects, the controlled diet changes the overall calorie intake by less than 1%-25%. In some aspects, the method further comprises additional cancer therapies comprising chemotherapy, radiation therapy, surgery, immunotherapy, cell therapy, theragnostic, or any combination thereof. In some aspects, the method further comprises administering to the subject a serotonin supplement. Non-limiting examples of serotonin supplements or supplements that counter serotonin deficiency symptomatically include but are not limited to comprising one or more of 5-hydroxytryptophan (5-HTP), St. John’s Wort, S-adenosylmethionine (SAMe), vitamin B6, L-methylfolate,301415446 - 3 -Attorney Docket No. UTSDP4183WO-1001375084magnesium, omega-3 fatty acids, or vitamin D. In some aspects of the disclosed method, the controlled diet is for less than 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 3 weeks, or 2 weeks.

[0013] Disclosed herein is a method of treating or preventing a neurological disease in a subject in need thereof, the method comprising administering to the subject a controlled diet, wherein the controlled diet is substantially devoid of tryptophan. In some aspects, the neurological disease is depression, anxiety disorders, obsessive-compulsive disorder (OCD), bipolar disorder, schizophrenia, migraine, fibromyalgia, autism spectrum disorder (ASD), and irritable bowel syndrome (IBS).

[0014] Disclosed herein is a dietary regimen kit for treating or reducing the symptoms of cancer, the regimen kit comprising meals for a controlled diet, wherein the controlled diet is substantially devoid of tryptophan. In some aspects, the meals provide about 25%-60% of calories in fat. In some aspects, the meals comprise a dietary composition disclosed herein. In some aspects, the meals comprise pre-packaged meals, each comprising less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food. In some aspects, the dietary regimen kit further comprises instructions for using the kit. In some aspects, the dietary regimen kit if for use for treating or reducing the symptoms of cancer.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. Aspects of the present disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific aspects presented herein.

[0016] FIGS. 1A-1Q show that MYC-driven liver tumors exhibit an increase in Trp uptake.FIG. 1A shows the Kyn pathway and its enzymes, kynurenic acid (KA), xanthurenic acid (XA).FIG. 1B provides a relative size comparison of WT and MYC-expressing livers and Western blots of liver protein lysates from WT liver and liver in which MYC was turned on for 45 days.FIG. 1C shows the relative mRNA expression of Trp transporters and Trp-metabolizing enzymes plotted from RNA-seq of WT liver (n = 2) and liver in which MYC was turned on for 45 days (n = 3). Plots show LOG2 fold change and error bars calculated by LOG2 FC SE.FIG. 1D shows relative mRNA expression for Trp transporters; data extracted from previously published dataset30, comparing WT and a mouse model of liver carcinoma driven by an inducible Tet-MYC transgene. Plots show RPKM values (n = 1). FIG. 1E provides an LC-MS / MS quantification of Trp, FIG. 1F provides an LC-MS / MS quantification of Kyn, FIG. 1G provides LC-MS / MS quantification of KA, FIG. 1H provides LC-MS / MS quantification of301415446 - 4 -Attorney Docket No. UTSDP4183WO-1001375084cinnabarinic acid (CA), FIG. 1I provides LC-MS / MS quantification of and serotonin (Ser, i) in WT (n = 3) and MYC-ON livers (n = 3). Plots show mean + / - SEM and P-value was calculated by unpaired t-test *P< 0.05. FIG. 1J is a schematic representation of 13C-Trp infusion in WT and MYC-expressing livers. FIGS. 1K-1M show quantification of 13C-Trp (FIG. 1K), 13C-Kyn (FIG. 1L), and 13C-KA (FIG. 1M) in WT (N = 3) and MYC-ON livers (n = 3). Plots show mean + / - SEM and P-value was calculated by unpaired t-test *P < 0.05. FIG. 1 N shows NAD+, NADH, and NADP+ measured by LC-MS-MS in WT (n = 2) and MYC-expressing livers (n = 4) MYC-ON. Plots show mean + / - SEM and P-value was calculated by unpaired test *P < 0.05.FIG. 10 shows quantification of 13C-NAD+ in WT (n = 3), normal looking regions of MYC-overexpressing livers (n = 3), and tumors of MYC-overexpressing livers (n = 6) after 13 C-Trp infusion. Plots show mean + / - SEM and P-value was calculated by unpaired t-test. *P < 0.05.FIG. 1P shows relative mRNA expression of transporters and enzymes that generate NAD by the salvage pathway plotted from RNA-seq of WT liver (n = 2) and liver in which MYC was turned on for 45 days (n = 3). Plots show LOG2 fold change, and error bars calculated by LOG2 FC SE. FIG. 1Q is a Western blot analysis for SLC1A5, S6, and S6K and Trp-metabolizing enzymes of WT and MYC-expressing livers (n = 3).

[0017] FIGS. 2A-2S show effects of Trp depletion in normal mice. FIG. 2A is a table providing Trp content in diets. FIGS. 2B-2D show Trp (FIG. 2B), Kyn (FIG. 2C), and serotonin (FIG. 2D) in control (n = 3), Low-Trp (n = 4), and No-Trp diets (n = 4) in the WT liver. Each dot represents one mouse. Plot shows mean + / - SEM and P-value was calculated by unpaired t-test. *P<0.05. FIGS. 2E-2G show Trp (FIG. 2E) Kyn (FIG. 2F), and serotonin (FIG. 2G) in serum of mice fed the indicated diets for 21 days (n = 3). Each dot represents one mouse. Plot shows mean + / - SEM and P-value was calculated by unpaired t-test. *P<0.05. FIGS. 2H-2I show data for the amount of amino acid in liver (FIG. 2H) and serum (FIG. 2I) after 21 days in the indicated diets (n = 3). Each dot represents one mouse. Plot shows mean + / - SEM and P-value was calculated by unpaired t-test. *P<0.05. FIG. 2J shows weight of mice fed control or No-Trp diet (n = 6). The plots show mean with SEM and the P-value was calculated by unpaired t-test. *P<0.05. FIGS. 2K-2M show daily food consumption (FIG. 2K), cumulative (FIG. 2L), and per weight (FIG. 2M) in control or No-Trp diets day 18-21 (n = 6). The plots show mean with SEM and the P-value was calculated by unpaired t-test *P < 0.05. FIGS. 2N-20 show fat mass (FIG. 2N) and percentage (FIG. 20) measured by ECO MRI after 21 days on the diets (n = 6). The plots show mean with SEM and the P-value was calculated by unpaired t-test. *P<0.05. FIGS. 2P-2Q show lean mass (FIG. 2P) and percentage (FIG. 2Q) measured by ECO MRI after 21 days in the diets (n = 6 mice). The plots show mean with SEM and the P-value was calculated by unpaired t-test. *P<0.05. FIG. 2R shows the weight of animals fed No-Trp and re-fed complete diet (n = 4). Each dot represents one mouse. Plot301415446 - 5 -Attorney Docket No. UTSDP4183WO-1001375084shows mean + / - SEM and P-value was calculated by unpaired t-test. *P < 0.05. FIG. 2S shows 02 consumption (VO2), CO2 production (VCO2), respiration rate (RER) and heat production (Heat) in mice fed the control or No-Trp diet on day 18-21 (n = 4). Plot shows mean + / - SEM. Area under the curve with mean with SD and the P-value calculated by unpaired t-test. *P<0.05.

[0018] FIGS. 3A-3O show that T rp deprivation reduces the growth of MYC-driven liver tumors. FIG. 3A provides schematic of survival study. FIG. 3B shows survival curves of mice assigned in control, Low-T rp, or No-T rp diets (n = 8 mice per each group). FIG. 3C shows liver of animals assigned to control and No-Trp diet in FIG. 3B. FIG. 3D provides the ratio of liver to body weight of MYC-ON and WT mice fed either the control or No-Trp diet. MYC-ON control diet (n = 8), MYC-ON No-Trp diet (n = 8), WT control (n = 8), WT No-Trp diet (n = 7). Each dot represents one mouse. Plot shows mean + / - SEM and P-value was calculated by unpaired t-test. *P<0.05. FIGS. 3E-3F provide Trp and Kyn in the MYC-ON mice fed the control, Low-Trp, or No-Trp diets at day 67 of age (n = 6 mice per group). Each dot represents one mouse. Plot shows mean + / - SEM and P-value was calculated by unpaired t-test. *P < 0.05. FIG. 3G shows the MYC-ON mice assigned to the control diet or No-Trp diet for 21 days. FIG. 3H provides weight of the liver of MYC-ON mice fed either the control (n = 3) or No-T rp diet (n = 4) for 21 days. SEM and P-value was calculated by unpaired t-test. *P < 0.05. FIG. 3I provides a ratio of liver weight to body weight of MYC-ON mice after being fed either the control (n = 3) or No-Trp diet (n = 4) for 21 days. SEM and P-value was calculated by unpaired t-test. *P<0.05. FIGS. 3J-3K are representative H & E, Ki-67, and MYC staining of livers obtained from mice fed either the control or No-Trp diet for 21 days (as described in g) at 0.75X ( FIG.3J) or 20X (FIG. 3K) magnification. FIG. 3L provides a schematic of the survival study. MYC-ON mice were randomly assigned to either the control or No-T rp diet, and survival of mice was determined. FIG. 3M provides a survival curve denoting mice assigned to the control (n = 8) and the No-Trp diet (n = 4). FIG. 3N provides a schematic of the survival study. MYC-ON mice were assigned to the No-Trp diet and changed back to the control diet after 21 days, and survival of mice was measured. FIG. 30 provides a survival curve of mice that were fed for 21 days on No-Trp diet and switched back to the control diet (n = 4). The survival was compared animals fed control diet (n = 8).

[0019] FIGS. 4A-4M show that Trp deprivation rescues normal transcriptional programs in MYC-ON livers. FIG. 4A provides gene ontology (GO) of genes upregulated by the expression of MYC in the liver measured by RNA-seq comparing WT livers (n = 2) and livers that had MYC-ON for 45 days (n = 3). FIG. 4B provides GO of genes downregulated by the expression of MYC in the liver measured by RNA-seq comparing WT livers (n = 2) and livers that had MYC-ON for 45 days (n = 3). FIG. 4C provides GO analysis of the genes upregulated in the301415446 - 6 -Attorney Docket No. UTSDP4183WO-1001375084liver upon Trp starvation in MYC-ON mice fed either the control or No-Trp diet for 21 days (n = 3 mice per sample), showing the top 10 significant pathways. FIG. 4D provides GO analysis of the genes downregulated in the liver upon Trp starvation in MYC-ON mice fed either the control or No-Trp diet for 21 days (n = 3 mice per sample), showing the top 10 significant pathways. FIG. 4E provides a Venn diagram showing the overlap and GO of genes upregulated by MYC and downregulated by 21-day Trp starvation in the liver of mice. GO analysis of the genes upregulated upon Trp starvation in MYC-ON livers, showing the top 10 significant pathways affected. FIG. 4F provides a Venn diagram showing the overlap and GO of genes downregulated by MYC and unregulated by 21-day Trp starvation in the liver of mice. GO analysis of the genes upregulated upon Trp starvation in MYC-ON livers, showing the top 10 significant pathways affected. FIG. 4G provides a heatmap of genes regulated by Trp starvation and compared with WT, and MYC-ON liver transcriptional signatures. FIGS. 4H-4K show the relative mRNA levels of genes involved DNA replication (FIG. 4H) ribosome biogenesis (FIG. 4I), cyclin genes (FIG. 4J), and RNA polymerase genes (FIG. 4K) that are differentially expressed between the control (n = 3 mice) and No-Trp diet (n = 3 mice) in MYC-ON livers. Plots show LOG2 fold change, and error bars calculated by LOG2 FC SE. FIG. 4L provides upstream promoter analysis of the genes regulated by Trp starvation for 21 days the livers of MYC-ON mice. FIG. 4M provides the levels of MYC transgene measured in livers of mice after Trp starvation for 21 days (n = 3 mice for each group shown).

[0020] FIGS. 5A-5N provide data to confirm that mouse and human liver cancer cells are sensitive to Trp starvation. FIG. 5A shows expression of indicated genes in hepatocellular carcinoma (HCC) patients comparing normal and tumor tissues from the same patient. Upregulation > 1,3X. Downregulation < 0.7X. No change is between 0.7X and 1,3X. FIGS. 5B-5E provide plots depicting levels of Trp (FIG. 5B) Kyn (FIG. 5C) and KA (FIG. 5D) and serotonin (FIG. 5E) in benign tissue or tumor from HCC patients (n = 10). Each plot represents one patient sample. Plot shows mean + / - SEM and P-value was calculated by unpaired f-test. *P< 0.05. FIG. 5F provides viability data of HUH7 cells transfected with control, MYC, SLC1A5, and SLC7A5 siRNA measured by crystal violet, (n = 4). Plot shows mean + / - SEM and P-value was calculated by unpaired t-test. *P<0.05. FIG. 5G provides RT-qPCR data for MYC, SLC1A5, and SLC7A5 in HUH7 cells transfected with control or MYC siRNA. mRNA levels are shown as relative fold change to control siRNA and (n = 3). Plot shows mean + / - SEM and P-value was calculated by unpaired f-test. *P< 0.05. FIG. 5H shows viability of HCC53N cells 3 days after transfection of control or MYC, SLC1A5, and SLC7A5 siRNA measured by crystal violet (n = 3 per sample). Plot shows mean + / - SEM and P-value was calculated by unpaired t-test. *P<0.05. FIG. 5I shows RT-qPCR for expression of MYC, SLC1 A5, and SLC7A5 mRNA in HCC53N cells transfected with control or MYC siRNA (n = 3).301415446 - 7 -Attorney Docket No. UTSDP4183WO-1001375084mRNA levels are shown as relative fold change to control siRNA. Plot shows mean + / - SEM and P-value was calculated by unpaired f-test. *P<0.05. FIG. 5J Western blot for MYC in HCC53N and HUH7 cells compared to WT or MYC-ON liver, repeated 3X. FIGS. 5K-5L show tumors of xenographs of HUH7 (FIG. 5K) and (HCC53N) (FIG. 5L) of cells grown in mice fed either the control (n = 3) or No-Trp diet for 21 days (n = 4). Plot shows mean + / - SEM and P- value was calculated by unpaired f-test. *P< 0.05. FIGS. 5M-5N provide western blot of lysates from HUH7 (FIG. 5M) of HCC53N (FIG. 5N) xenografts grown in NOD SCID mice fed either the control or No-Trp diet for 21 days (n = 3).

[0021] FIGS. 6A-6J provide data to show that trp deprivation does not affect protein synthesis in liver cancer. FIG. 6A shows incorporation of13C-T rp into peptides in WT and MYC-ON livers (n = 3). Each dot represents one mouse. Plots show mean + / - SD and P-value was calculated by f-test. FIG. 6B shows peak intensities of peptides containing13C-glutamine normalized by total amount of peptides detected by proteomics in livers from mice fed either the control or No-Trp diet 3 h after tail vein injection of13C-glutamine (n = 3). Each dot represents one mouse. Plots show mean + / - SD and P-value was calculated by f-test. FIG. 6C shows peak intensities of peptides containing13C-glutamine normalized by all glutamine-containing peptides detected by proteomics in livers from mice fed either the control or No-Trp e diet. P-value indicated above bar. (n = 3) Each dot represents one mouse. Plots show mean + / - SD and P-value was calculated by f-test. FIG. 6D provides protein synthesis levels measured in cells grown in the presence or absence of Trp. Puromycyn with or without cycloheximide (CHX) was added during the final 1 h of the experiment, repeated 3X. FIG. 6E provides protein synthesis levels measured by Click-IT™ AHA in cells grown in the absence or presence of Trp, repeated 3X. FIG. 6F Percentage of Trp in proteins whose abundance increased (UP) or decreased (DOWN) upon Trp starvation in MYC-ON livers. Each dot represents one protein. Plots show mean + / - SD and P-value was calculated by f-test. FIG. 6G shows peak intensities of peptides containing Trp substituted by tyrosine, phenylalanine, leucine, or isoleucine normalized by total peptides detected by proteomics in livers from MYC-ON mice fed either the control or No-T rp diet (n = 3). Each dot represents the ratio using the average of 3 replicates. FIG. 6H shows peak intensities of peptides containing Trp substituted by tyrosine, phenylalanine, leucine, or isoleucine normalized by total peptides detected by proteomics in HCC53N xenografts from mice fed the control or No-Trp diet (n = 3). Each dot represents the ratio using the average of 3 replicates. FIG. 6I provides a western blot of HCC53N lysates grown overnight in the indicated media, repeated 3X. FIG. 6J provides a western blot of MYC-ON liver lysates from mice fed either the control (n = 3) or No-Trp (n = 3). *P<0.05.

[0022] FIGS. 7A-7Q provide data to show that I3P increases the growth of Trp-starved tumors. FIG. 7A shows a schematic of Trp metabolism. ILA lndole-3-lactic acid, I3A lndole-3-301415446 - 8 -Attorney Docket No. UTSDP4183WO-1001375084carboxaldehyde. FIG. 7B shows plots of HUH7 in No-Trp with Trp (75 pM), Kyn (20 pM), nicotinic acid (NA) (25 pM), or nicotinamide (NMN) (25 pM) (n = 3). Plot shows mean + / - SEM and P-value calculated by one-way ANOVA. *P<0.05. FIG. 7C provides viability of HUH7 in No-Trp with 25 pM of Trp (n = 16), Kyn (n = 8), 5HTP (n = 8), or I3P (n = 8). Plot shows mean + / - SEM and P-value calculated by one-way ANOVA. *P<0.05. FIG. 7D show plot of HUH7 in No-Trp with Trp (n = 8), or I3P (n = 8). Plot shows mean + / - SEM and P-value calculated by one-way ANOVA. *P < 0.05. FIG. 7E is a plot of HUH7 with Trp (n = 8) with and without I3P (n = 8). Plot shows mean + / - SEM and P-value calculated by one-way ANOVA. *P < 0.05. FIG. 7F is a plot of HUH7 in No-Trp with DMSO (n = 8), ISP (n = 7), or ILA (n = 8). Plots show mean + / - SEM and P-value calculated by one-way ANOVA. *P<0.05. FIG. 7G shows plot of HCC53N in No-Trp, with Trp (75 pM (n = 16), Kyn (20 pM) (n = 8), 5HTP (25 pM) (n = 8), or I3P (25 pM) (n = 8). Plot shows mean + / - SEM and P-value calculated by one-way ANOVA. *P<0.05. FIG. 7H shows plot of HCC53N in No-Trp with Trp or I3P (n = 8). Plot shows mean + / - SEM and P-value calculated by one-way ANOVA. *P<0.05. FIG. 7I shows plot of HCC53N in Trp (25 pM) with and without I3P (25 pM) (n = 8). Plot shows mean + / - SEM and P-value calculated by one-way ANOVA. *P<0.05. FIG. 7 J HCC53N in No-Trp with DMSO, I3P, or ILA (n = 8). Plots shows mean + / - SEM and P-value calculated by one-way ANOVA. (*) P < 0.05. FIG. 7K shows plot of I3P in HCC53N in the absence or presence of ISP (25 pM) (n = 3) for 1 h. Plot shows mean + / - SEM and P-value calculated by one-way ANOVA. *P<0.05. FIG. 7L shows plots of Trp, I3P, and ILA in HCC53N cultured for 24 h in control or No-Trp (n = 3). Plot shows mean + / - SEM and P-value calculated by two-way ANOVA. *P<0.05. FIG. 7M shows a schematic of experiments in xenografts. FIG. 7N provides HCC53N xenografts images in the No-Trp diet plus daily injections of vehicle or I3P (75 pM).FIGS. 7O-7P provide weight of HCC53N xenografts (FIG. 70) and of NOD SCID (FIG. 7P) mice fed the No-Trp diet plus vehicle (n = 4) or I3P injections (n = 3). Each dot represents one mouse. Plots show mean + / - SEM and P-value calculated by t-test. *P < 0.05. FIG. 7Q shows levels of I3P, I3A, and ILA in xenografts of mice fed the No-Trp diet plus vehicle (n = 3) or I3P injections (n = 3). Each dot represents one mouse. Plots show mean + / - SEM and P-value calculated by unpaired t-test. *P < 0.05.

[0023] FIGS. 8A-8N show that I3P levels are elevated in MYC-ON liver tumors and its supplementation rescues the growth of Trp-starved MYC-ON liver tumors. FIG. 8A shows levels of I3P, I3A, ILA in WT (n = 3) or MYC-ON (n = 3) livers. Each dot represents one mouse. Plots show mean + / - SEM and P-value was calculated by unpaired t-test. *P < 0.05. FIG. 8B shows that T rp starvation reduces T rp metabolites in the liver. FIG. 8C provides levels of IL4I1 in lysates of WT (n = 2) or MYC-ON (n = 3) livers. FIG. 8D provides survival data for patients with top 30% (red) and bottom 30% (blue) expression of IL41A. FIG. 8E provides IL41A mRNA301415446 - 9 -Attorney Docket No. UTSDP4183WO-1001375084levels in tumors and normal liver from TCGA. (Tumor n = 369, Normal n = 50) Each dot represents one sample. FIG. 8F provides a schematic of experiments with MYC-driven liver tumors fed the No-Trp diet supplemented with I3P. FIG. 8G shows livers from MYC-ON mice fed the No-Trp diet supplemented with daily injections of either vehicle or I3P. FIG. 8H provides weight of livers of MYC-ON mice fed the No-Trp diet supplemented with daily injections of either vehicle (n = 3) or (75 pM) of I3P (n = 3). Each dot represents one mouse. Plots show mean + / - SEM and P-value was calculated by unpaired t-test. *P<0.05. FIG. 8I provides whole-body weight of mice in (FIG. 8H). FIG. 8J shows T rp and I3P in MYC-ON livers of animals fed the No-Trp diet supplemented with daily IP injections of either vehicle or ISP (75 pM). FIG. 8K shows T rp in HCC53N cells incubated for 1 h or 24 h with I3P in the presence (n = 3) or absence (n = 3) of Trp measured by LC-MS / MS. Plot shows mean + / - SEM and P-value was calculated by one-way ANOVA. *P<0.05. FIG. 8L shows viability of HCC53N transfected with control siRNA (siCont) (n = 8) or siRNA for AHR (siAHR) (n = 8) cultured in No- Trp with 20 pM of I3P. Plot shows mean + / - SEM and P-value was calculated by one-way ANOVA. *P<0.05. FIG. 8M provides western blots of nuclear and cytoplasmic fractionations of HCC53N in the presence or absence of Trp for 1 h supplemented with I3P (25 pM) or DMSO, 3 repeats performed. FIG. 8N provides western blots of lysates of HCC53N grown in the presence or absence of Trp with I3P (25 pM) or DMSO, 3 repeats performed.

[0024] FIG. 9 provides a summary of the findings on Trp dependency and vulnerability in MYC-driven tumors. MYC upregulation, frequently found in tumors, drives the expression of the Trp transporters SLC1A5 and SLC7A5, which in turn promotes the uptake of Trp. Trp is used to generate the oncometabolite I3P, which activates liver cancer cell growth.

[0025] FIGS. 10A-10E depict comprehensive mapping of Trp metabolites across ages, sexes and tissues. FIG. 10A is a summary of Trp metabolism pathway and the Trp metabolites quantified by LC-MS / MS. FIG. 10B is a schematic for the experiment. Tissues were harvested from 3-, 53-, and 74-week-old male and female mice. Tissues were flash frozen for later processing through LC-MS / MS. FIG. 10C is a heatmap of all metabolites in the tissues after being normalized by metabolite. FIG. 10D is a schematic for experiment for the collection of the brain areas. Tissues were harvested from 3-, 53-, and 74-week-old male and female mice and then processed through LC-MS / MS. FIG. 10E is a heatmap of all metabolites in the brain areas.

[0026] FIGS. 11A-11E provide abundance of Trp metabolites across different organs in adult tissues. FIG. 11A provides amounts (ng / g) measured by LC-MS / MS of Trp across all tissues. FIG. 11B provides abundance (ng / g) of metabolites of the I3P pathway by LC-MS / MS across different tissues. FIG. 11C provides abundance (ng / g) of metabolites of the kynurenine pathway by LC-MS / MS across different tissues. FIG. 11D provides abundance (ng / g) of301415446 - 10 -Attorney Docket No. UTSDP4183WO-1001375084metabolites of the serotonin pathway by LC-MS / MS across different tissues. FIG. 11E provides abundance (ng / g) of tryptamine by LC-MS / MS across different tissues.

[0027] FIGS. 12A-12C show variation of Trp metabolite levels based on sex. FIG. 12A shows a heatmap highlighting male and female difference of Trp metabolite abundance across different tissues in 3-week-old mice. FIG. 12B shows a heatmap highlighting male and female difference of Trp metabolite abundance across different tissues in 53-week-old mice. FIG. 12C shows a heatmap highlighting male and female difference of Trp metabolite abundance across different tissues in 74-week-old mice.

[0028] FIGS. 13A-13F provide Trp metabolites level changes with aging. FIG. 13A provides Principal Component Analysis (PCA) plots of all metabolites across all ages done through MetaboAnalyst 6.0 after Log transformation. FIG. 13B shows significant changes in abundance for Trp (Tryptamine, Kyn, I3P, ILA) metabolites across aging in the male liver. FIG.13C shows significant changes in abundance of Trp (Trp, Kyn, I3P, ILA, I3A) metabolites across aging in the colon. FIG. 13D shows significant changes in abundance of Trp (Tryptamine, Kyn, I3P, I3A) metabolites across aging in the heart. FIG. 13E shows significant changes in abundance of Trp (Tryp, Kyn, CA, I3P, ILA) metabolites across aging in the ingWAT. FIG. 13F shows significant changes in abundance of Trp (Tryp, Kyn, CA, NFK, I3A) metabolites across aging in the BAT.

[0029] FIGS. 14A-14M show Trp metabolite levels in the brain across different ages and sexes. FIG. 14A provides amounts (ng / g) measured by LC-MS / MS of Trp across different brain regions. FIG. 14B provides abundance (ng / g) of metabolites of NFK by LC-MS / MS across different brain regions. FIG. 14C provides abundance (ng / g) of metabolites of Kyn by LC-MS / MS across different brain regions. FIG. 14D provides abundance (ng / g) of metabolites of KA by LC-MS / MS across different brain regions. FIG. 14E provides abundance (ng / g) of metabolites of CA by LC-MS / MS across different brain regions FIG. 14F provides abundance (ng / g) of metabolites of XA by LC-MS / MS across different brain regions. FIG. 14G provides abundance (ng / g) of metabolites of 5HIAA by LC-MS / MS across different brain regions. FIG.14H provides abundance (ng / g) of metabolites of I3P by LC-MS / MS across different brain regions. FIG. 141 provides abundance (ng / g) of metabolites of I3A by LC-MS / MS across different brain regions. FIG. 14J provides a heatmap highlighting male and female difference of Trp metabolite abundance across different brain regions in 3-week-old mice. FIG. 14K provides a heatmap highlighting male and female difference of Trp metabolite abundance across different brain regions in 53-week-old mice. FIG. 14L provides a heatmap highlighting male and female difference of Trp metabolite abundance across different brain regions in 74-week-old mice. FIG. 14M provides PCA plots of all metabolites across all ages done through MetaboAnalyst 6.0 after Log transformation.301415446 - 11 -Attorney Docket No. UTSDP4183WO-1001375084

[0030] FIGS. 15A-15B show a summary of Trp metabolism in adult mice. FIG. 15A provides a summary of Trp metabolite abundance in 53-week-old mice Highlighting the organ with highest expression levels. FIG. 15B provides a summary of Trp metabolite abundance in 53-week-old mice Highlighting the brain region with highest expression levels.

[0031] FIGS. 16A-16C show the synergistic impact of the Trypt-out diet combined with a high fat diet (HFD) on tumor size and nodules. FIG. 16A is a graph showing liver weight of HCC mice after three weeks on Control, High-Fat Diet (HFD), Trypt-out, or HFD Trypt-out diets, showing reduced liver mass with Trypt-out and a further reduction with HFD Trypt-out, while HFD alone shows no benefit relative to Control. FIG. 16B is a graph showing the weight of mice minus the liver, showing that the dietary intervention does not impact the overall weight of the mice. FIG. 16C. is a graph showing liver tumor nodule counts under the same dietary conditions, showing fewer nodules with Trypt-out and an additional decrease with HFD Trypt-out, with HFD alone comparable to Control.DETAILED DESCRIPTION

[0032] The following detailed description references the accompanying drawings that illustrate various aspects of the present disclosure. The drawings and description are intended to describe aspects of the present disclosure in sufficient detail to enable those skilled in the art to practice the present disclosure. Other components can be utilized and changes can be made without departing from the scope of the present disclosure. The following description is, therefore, not to be taken in a limiting sense.

[0033] Tryptophan (Trp), one of the nine essential amino acids, is distinguished by its large size and unique chemical structure, featuring the highest carbon count among essential amino acids and an indole ring. This ring grants Trp hydrophobic properties that are critical in protein structure and protein interactions. Trp is the least abundant amino acid in the proteome representing only an average of 1.3% of the protein content. Therefore, the majority of Trp molecules serve as precursors for a wide range of downstream catabolites that can carry specific biological activities including immunoregulation and neuronal signaling.

[0034] In some aspects, the current disclosure is based on the surprising discovery that MYC-driven liver tumors display enhanced Trp uptake compared to normal livers, yet downregulate metabolism along the Kyn pathway. This is opposite to many cancers such as cancers of the colon, pancreas, breast, and brain in which noncancerous tissue display a significantly lower expression of Kyn pathway enzymes than tumor tissue. Instead, unexpectedly, it was found that MYC-driven liver oncogenesis requires the amino acid Trp, suggesting temporary Trp deprivation as a method of combating cancer. Additionally, temporary lack of Trp did not adversely affect translation of protein in the subject.301415446 - 12 -Attorney Docket No. UTSDP4183WO-1001375084I. Terminology

[0035] The phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting. For example, the use of a singular term, such as, “a” is not intended as limiting of the number of items. Also, the use of relational terms such as, but not limited to, “top,” “bottom,” “left,” “right,” “upper,” “lower,” “down,” “up,” and “side,” are used in the description for clarity in specific reference to the figures and are not intended to limit the scope of the present disclosure or the appended claims.

[0036] Any term of degree such as, but not limited to, “substantially” as used in the description and the appended claims, should be understood to include an exact, or a similar, but not exact configuration. For example, “a substantially planar surface” means having an exact planar surface or a similar, but not exact planar surface. Similarly, the terms “about” or “approximately,” as used in the description and the appended claims, should be understood to include the recited values or a value that is three times greater or one third of the recited values. For example, about 3 mm includes all values from 1 mm to 9 mm, and approximately 50 degrees includes all values from 16.6 degrees to 150 degrees. For example, they can refer to less than or equal to ± 5%, such as less than or equal to ± 2%, such as less than or equal to ± 1%, such as less than or equal to ± 0.5%, such as less than or equal to ± 0.2%, such as less than or equal to ± 0.1%, such as less than or equal to ± 0.05%.

[0037] The terms “comprising,” “including,” and “having” are used interchangeably in this disclosure. The terms “comprising,” “including,” and “having” mean to include, but not necessarily be limited to the things so described.

[0038] The terms “or” and “and / or,” as used herein, are to be interpreted as inclusive or meaning any one or any combination. Therefore, “A, B, or C” or “A, B, and / or C” mean any of the following: “A,” “B,” or “C”; “A, and B”; “A, and C”; “B and C”; “A, B, and C.” An exception to this definition will occur only when a combination of elements, functions, steps, or acts are in some way inherently mutually exclusive.

[0039] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (3rd ed. 2006); The Cambridge Dictionary of Science and Technology (Walker ed., 1990); The Glossary of Genetics, 5th Ed., R. Rieger et al. (2008), The HarperCollins Dictionary of Biology (1991), all of which are incorporated by reference herein. As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.301415446 - 13 -Attorney Docket No. UTSDP4183WO-1001375084

[0040] The phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting. When introducing elements of the present disclosure or the preferred aspects(s) thereof, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements. Wherever the terms “comprising” or “including” are used, it should be understood the disclosure also expressly contemplates and encompasses additional aspects “consisting of” the disclosed elements, in which additional elements other than the listed elements are not included.

[0041] The term “about” or “approximately,” as used herein, can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the given value. Where particular values are described in the application and claims, unless otherwise stated the term “about” can mean an acceptable error range for the particular value, such as 10% of the value modified by the term “about.” As used herein, the term “about,” can mean relative to the recited value, e.g., amount, dose, temperature, time, percentage, etc., ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%.

[0042] As used herein, “treatment,” “therapy,” and / or “therapy regimen” refer to the clinical intervention made in response to a disease, disorder or physiological condition manifested by a patient or to which a patient may be susceptible. The aim of treatment includes the alleviation or prevention of symptoms, slowing or stopping the progression or worsening of a disease, disorder, or condition and / or the remission of the disease, disorder or condition.

[0043] As used herein, “prevent” or “prevention” refers to eliminating or delaying the onset of a particular disease, disorder or physiological condition, or to the reduction of the degree of severity of a particular disease, disorder or physiological condition, relative to the time and / or degree of onset or severity in the absence of intervention.

[0044] The term “effective amount” or “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desirable biological and / or clinical results. The term “therapeutically effective amount,” as used herein, means an amount of a compound or combination of compounds that ameliorates, attenuates, or eliminates one or more symptoms of cancer or prevents or delays the onset of one or more symptoms of cancer as defined herein.301415446 - 14 -Attorney Docket No. UTSDP4183WO-1001375084

[0045] As used herein, “individual,” “subject,” “host,” and “patient” can be used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, prophylaxis or therapy is desired, for example, humans, pets, livestock, horses or other animals. As used herein, the term “subject” and “patient” are used interchangeably herein and refer to both human and nonhuman animals. The term “nonhuman animals” of the disclosure includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dog, cat, horse, cow, chickens, amphibians, reptiles, and the like. In some aspects, the subject can be a human. In other aspects, the subject can be a human in need of treating a cancer.

[0046] A dietary product as used herein is a consumable item designed to supplement the diet by providing essential nutrients, bioactive compounds, or other substances that may not be adequately obtained from regular food intake, or to exclude from the diet a particular component. These products aim to support overall health, enhance specific bodily functions, or address nutritional needs. Dietary products can include vitamins, minerals, proteins, amino acids, fatty acids, fiber, probiotics, and herbal extracts, and they are commonly available in various forms such as a powder, a gel, a solution, a suspension, a paste, a solid, a pellet, a liquid, a liquid concentrate, a powder which may be reconstituted, a shake, a concentrate, a pill, a bar, a tablet, a capsule, injectable solution, or a ready-to-use product. In some aspects, the dietary product is not intended to replace a diet but to complement it, and their use is often guided by individual health needs, lifestyle, or specific wellness goals. In some aspects, the dietary product is intended to partially or fully replace an individual’s diet. A dietary product for therapeutic use is a specialized formulation designed to provide or exclude specific nutrients or bioactive compounds aimed at managing or improving health conditions. These products are typically used under medical supervision and are tailored to address deficiencies, support metabolic processes, or alleviate symptoms associated with diseases, recovery from illness, or specific health challenges. They may include macronutrients (proteins, fats, carbohydrates), micronutrients (vitamins, minerals), amino acids, fiber, probiotics, or plant-based extracts, depending on the intended therapeutic effect. Regulatory standards for these products ensure their safety, efficacy, and alignment with medical guidelines.

[0047] Further, as the present disclosure is susceptible to aspects of many different forms, it is intended that the present disclosure be considered as an example of the principles of the present disclosure and not intended to limit the present disclosure to the specific aspects shown and described. Any one of the features of the present disclosure may be used separately or in combination with any other feature. References to the terms “aspect,” “aspects,” and / or the like in the description mean that the feature and / or features being referred to are included in, at least, one aspect of the description. Separate references to the301415446 - 15 -Attorney Docket No. UTSDP4183WO-1001375084terms “aspect,” “aspects,” and / or the like in the description do not necessarily refer to the same aspect and are also not mutually exclusive unless so stated and / or except as will be readily apparent to those skilled in the art from the description. For example, a feature, structure, process, step, action, or the like described in one aspect may also be included in other aspects but is not necessarily included. Thus, the present disclosure may include a variety of combinations and / or integrations of the aspects described herein. Additionally, all aspects of the present disclosure, as described herein, are not essential for its practice. Likewise, other systems, methods, features, and advantages of the present disclosure will be, or become, apparent to one with skill in the art upon examination of the figures and the description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be encompassed by the claims.II. Dietary products

[0048] In some aspects, disclosed herein are dietary products. In some aspects, the dietary products disclosed herein are for intake as replacement, or partial replacement, diets to reduce the intake of tryptophan in the diet. In some aspects, the dietary product comprises one or more amino acids, or amino acid source like proteins and peptides, carbohydrates, lipids, and / or additional components typically present in food products.A. Amino acids and proteins

[0049] In some aspects, the current disclosure encompasses dietary products comprising at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; wherein the dietary product is substantially devoid of tryptophan. In some aspects, the current disclosure encompasses dietary products for nutritional therapy of a disease or disorder in a subject in need thereof, wherein the dietary product comprises at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; and wherein the dietary product is substantially devoid of tryptophan. In some aspects, the current disclosure encompasses dietary products for nutritional therapy of cancer and / or a neurological disease or disorder, wherein the dietary product comprises at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; and wherein the dietary product is substantially devoid of tryptophan. The term “dietary product” as used herein encompasses consumable items, including foods, beverages, and supplements, formulated to provide specific nutritional benefits beyond basic sustenance. These products may be designed to enhance overall health, address nutritional deficiencies and / or dietary excesses, and support301415446 - 16 -Attorney Docket No. UTSDP4183WO-1001375084targeted physiological functions such as metabolism, cognitive performance, immune response, or recovery from physical activity. In some aspects, the dietary product may provide therapeutic benefits to treat, reduce, or reduce the likelihood of occurrence of a cancer. In some aspects, the dietary product may provide therapeutic benefits to treat, reduce, or reduce the likelihood of occurrence of a neurological disease or disorder. A dietary supplement may comprise, consist essentially of, consist of, or exclude one or more macronutrients, micronutrients, bioactive compounds, and other functional ingredients intended to optimize health and well-being when consumed as part of a diet.

[0050] As used herein, the term “substantially devoid of tryptophan” as used herein may refer to a product with no tryptophan, or low amounts of tryptophan. In some aspects, the dietary product disclosed herein has no tryptophan. In some aspects, the dietary product may include less than, equal to, or about 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.09 mg, 0.08 mg, 0.07 mg, 0.06 mg, 0.04 mg, 0.03 mg, 0.02 mg, 0.01 mg, 0.009 mg, 0.008 mg, 0.007 mg, 0.006 mg, 0.004 mg, 0.003 mg, 0.002 mg, or 0.001 mg of tryptophan per 100 grams of the dietary product. In some aspects, the dietary product contributes less than about 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, or less of the daily dietary requirement for tryptophan.

[0051] In some aspects, the dietary product comprises, consists essentially of, consists of, or excludes one or more of the essential amino acids selected form histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine, or any combination thereof; wherein the dietary product is substantially devoid of tryptophan. In some aspects, the dietary product may further comprise or exclude one or more non-essential amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine, or any combination thereof. In some aspects, the dietary product may comprise, or exclude one or more amino acids selected from histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, valine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine, or any combination thereof. In some aspects, the dietary product may comprise all of the amino acids histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, valine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine.

[0052] In some aspects, each of the essential amino acids which is present in the dietary product is present in an amount of less than, equal to, or more than 0.01 mg to 20 mg per 100 grams of the product.301415446 - 17 -Attorney Docket No. UTSDP4183WO-1001375084

[0053] In some aspects, each of the essential amino acids which is present in the dietary product is present in an amount of at least, equal to, at most 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.55, 2.60, 2.65, 2.70, 2.75, 2.80, 2.85, 2.90, 2.95, 3.00, 3.05, 3.10, 3.15, 3.20, 3.25, 3.30, 3.35, 3.40, 3.45, 3.50, 3.55, 3.60, 3.65, 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4.95, 5.00, 5.05, 5.10, 5.15, 5.20, 5.25, 5.30, 5.35, 5.40, 5.45, 5.50, 5.55, 5.60, 5.65, 5.70, 5.75, 5.80, 5.85, 5.90, 5.95, 6.00, 6.05, 6.10, 6.15, 6.20, 6.25, 6.30, 6.35, 6.40, 6.45, 6.50, 6.55, 6.60, 6.65, 6.70, 6.75, 6.80, 6.85, 6.90, 6.95, 7.00, 7.05, 7.10, 7.15, 7.20, 7.25, 7.30, 7.35, 7.40, 7.45, 7.50, 7.55, 7.60, 7.65, 7.70, 7.75, 7.80, 7.85, 7.90, 7.95, 8.00, 8.05, 8.10, 8.15, 8.20, 8.25, 8.30, 8.35, 8.40, 8.45, 8.50, 8.55, 8.60, 8.65, 8.70, 8.75, 8.80, 8.85, 8.90, 8.95, 9.00, 9.05, 9.10, 9.15, 9.20, 9.25, 9.30, 9.35, 9.40, 9.45, 9.50, 9.55, 9.60, 9.65, 9.70, 9.75, 9.80, 9.85, 9.90, 9.95, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg (or any range derivable therein) per 100 grams of the product.

[0054] In some aspects, each of the non-essential amino acids which is present in the dietary product is present in an amount of at least, equal to, at most 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.55, 2.60, 2.65, 2.70, 2.75, 2.80, 2.85, 2.90, 2.95, 3.00, 3.05, 3.10, 3.15, 3.20, 3.25, 3.30, 3.35, 3.40, 3.45, 3.50, 3.55, 3.60, 3.65, 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4.95, 5.00, 5.05, 5.10, 5.15, 5.20, 5.25, 5.30, 5.35, 5.40, 5.45, 5.50, 5.55, 5.60, 5.65, 5.70, 5.75, 5.80, 5.85, 5.90, 5.95, 6.00, 6.05, 6.10, 6.15, 6.20, 6.25, 6.30, 6.35, 6.40, 6.45, 6.50, 6.55, 6.60, 6.65, 6.70, 6.75, 6.80, 6.85, 6.90, 6.95, 7.00, 7.05, 7.10, 7.15, 7.20, 7.25, 7.30, 7.35, 7.40, 7.45, 7.50, 7.55, 7.60, 7.65, 7.70, 7.75, 7.80, 7.85, 7.90, 7.95, 8.00, 8.05, 8.10, 8.15, 8.20, 8.25, 8.30, 8.35, 8.40, 8.45, 8.50, 8.55, 8.60, 8.65, 8.70, 8.75, 8.80, 8.85, 8.90, 8.95, 9.00, 9.05, 9.10, 9.15, 9.20, 9.25, 9.30, 9.35, 9.40, 9.45, 9.50, 9.55, 9.60, 9.65, 9.70, 9.75, 9.80, 9.85, 9.90, 9.95, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg (or any range derivable therein) per 100 grams of the product.

[0055] In some aspects, the dietary product comprises at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; wherein the dietary product is substantially devoid of tryptophan. In some aspects, the dietary product comprises at least 3, at least 4, at least 5, at301415446 - 18 -Attorney Docket No. UTSDP4183WO-1001375084least 6, at least 7, at least 8 essential amino acids, and is substantially devoid of tryptophan. In some aspects, the dietary product comprises about 7-10 g (or any range derivable therein) of leucine, 4-6 g (or any range derivable therein) of isoleucine, 4-5 g (or any range derivable therein) of valine, 6-8 g (or any range derivable therein) of lysine, 1-3 g (or any range derivable therein) of methionine, 2-3 g of phenylalanine, 5-7 g (or any range derivable therein) of threonine, or 1-2 g (or any range derivable therein) of histidine or any combination thereof, per 100 g of protein. In some aspects, the ratio of branched-chain amino acids (leucine:isoleucine:valine) is approximately 2:1:1, which supports muscle protein synthesis and recovery.

[0056] In some aspects, the dietary product comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 or all non-essential amino acids. In some aspects, the dietary product comprises one or more of about 4-5 (or any range derivable therein) g of alanine, 2-3 g (or any range derivable therein) of arginine, 9-11 g (or any range derivable therein) of aspartic acid, 14-16 g (or any range derivable therein) of glutamic acid, 1-2 g (or any range derivable therein) of glycine, 4-5 g (or any range derivable therein) of proline, 3-5 g (or any range derivable therein) of serine, or 2-3 g (or any range derivable therein) of tyrosine, or any combination thereof, per 100 g of protein, while being substantially devoid of tryptophan.

[0057] In some aspects, the dietary product comprises, per kilogram of the dietary product, about 9–13 g (or any range derivable therein) of leucine, 6–10 g (or any range derivable therein) of isoleucine, 6–10 g (or any range derivable therein) of valine, 16–20 g (or any range derivable therein) of lysine, 6–10 g (or any range derivable therein) of methionine, 6–10 g (or any range derivable therein) of phenylalanine, 6–10 g (or any range derivable therein) of threonine, 3–6 g (or any range derivable therein) of histidine, 2–6 g (or any range derivable therein) of alanine, 10–14 g (or any range derivable therein) of arginine, 2–6 g (or any range derivable therein) of aspartic acid, 38–42 g (or any range derivable therein) of glutamic acid, 21–25 g (or any range derivable therein) of glycine, 2–6 g (or any range derivable therein) of proline, 2–6 g (or any range derivable therein) of serine, or 3–7 g (or any range derivable therein) of tyrosine, or any combination thereof.

[0058] In some aspects, the dietary product disclosed herein comprises each of the one or more essential and / or non-essential amino acids in amounts similar to those found in commonly known protein supplements, for example, whey protein, soy protein, collagen protein, or plant-based protein, but substantially devoid of tryptophan.

[0059] In some aspects, the dietary product may further comprise one or more amino acid derivatives. Non-limiting examples include creatine, L-carnitine, N-acetyl cysteine (NAC), S-301415446 - 19 -Attorney Docket No. UTSDP4183WO-1001375084adenosylmethionine (SAMe), beta-alanine, taurine, glutathione, L-theanine, citrulline malate, ornithine, GABA, 5-HTP, acetyl-L-carnitine (ALCAR), arginine alpha-ketoglutarate (AAKG), or any combination thereof.

[0060] In some aspects, the dietary product may comprise isolated amino acids, synthesized amino acids, amino acid derivatives, or sources of amino acids, for example, small peptides or proteins. In some aspects, the peptides or proteins may be isolated or produced using recombinant protein production. In some aspects, the proteins for use in the dietary product are substantially devoid of tryptophan. In some aspects, the proteins may be engineered to be substantially devoid of tryptophan. Methods of recombinant protein production are well known in the art. In some aspects, the recombinant protein is expressed in a yeast, bacterium, animal, or plant cell. In some aspects, the expression cell may be engineered to have a orthologous translation system, such that the expressed protein is substantially devoid of tryptophan.

[0061] In some aspects, the recombinant proteins described herein may be produced in a microorganism such as yeast and bacteria. Recombinant protein may be expressed in bacteria such as Escherichia coli, Caulobacter crescentus, Rodhobacter sphaeroides, Pseudoalteromonas haloplanktis, Shewanella sp., Pseudomonas putida, P. aeruginosa, P. fluorescens, Halomonas elongate, Chromohalobacter salexigens, Streptomyces lividans, S. griseus, Nocardia lactamdurans, Mycobacterium smegmatis, Corynebacterium glutamicum, C. ammoniagenes, Brevibacterium lactofermentum, Bacillus subtilis, B. brevis, B. megaterium, B. licheniformis, B. amyloliquefaciens, Lactococcus lactis, L. plantarum, L. casei, L. reuteri, or L. gasseri. In some aspects, the recombinant protein is expressed in a eukaryotic microorganism, such as Saccharomyces spp., Kluyveromyces spp., Pichia spp., Aspergillus spp., Tetrahymena spp., Yarrowla spp., Hansenula spp., Blastobotrys spp., Candida spp., Zygosaccharomyces spp., Debrayomyces spp., Fusarium spp., and Trichoderma spp.

[0062] In some aspects, the recombinant proteins are expressed in yeast.

[0063] The recombinant protein may be expressed in one or more cells using genetic sequences (e.g., DNA or RNA sequences) isolated or derived from cow (Bos taurus), goat (Capra hircus), sheep (Ovis aries), water buffalo (Bubalus bubalis), dromedary camel (Camelus dromedaries), bactrian camel (Camel us bactrianus), wild yak (Bos mutus), horse (Equus caballus), donkey (Equus asinus), reindeer (Rangifer tarandus), Eurasian elk (Alces alces), alpaca (Vicugna pacos), zebu (Bos indicus), llama (Lama glama), or human (Homo sapiens).

[0064] In some aspects, a genetic sequence used to encode the recombinant protein has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%,301415446 - 20 -Attorney Docket No. UTSDP4183WO-1001375084or at least 99% identity with the genetic sequence encoding a protein in one or more of cow (Bos taurus), goat (Capra hi reus), sheep (Ovis aries), water buffalo (Bubalus bubalis), dromedary camel (Camelus dromedaries), bactrian camel (Camelus bactrianus), wild yak (Bos mutus), horse (Equus caballus), donkey (Equus asinus), reindeer (Rangifer tarandus), Eurasian elk (Alces aloes), alpaca (Vicugna pacos), zebu (Bos indicus), llama (Lama glama), or human (Homo sapiens). In some aspects, the recombinant protein expressed in a nonmammalian cell has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with a protein from one or more of cow (Bos taurus), goat (Capra hircus), sheep (Ovis aries), water buffalo (Bubalus bubalis), dromedary camel (Camelus dromedaries), bactrian camel (Camelus bactrianus), wild yak (Bos mutus), horse (Equus caballus), donkey (Equus asinus), reindeer (Rangifer tarandus), Eurasian elk (Alces alces), alpaca (Vicugna pacos), zebu (Bos indicus), llama (Lama glama), or human (Homo sapiens). The recombinant protein may be extracted using standard methods known in the art. For example, the proteins may be extracted using solvent or aqueous extraction or using phenol extraction. Once extracted, the proteins may be maintained in a buffered environment (e.g., Tris, MOPS, HEPES), in order to avoid sudden changes in the pH. The proteins may also be maintained at a particular temperature, such as 4 °C. One or more additives may be used to aid the extraction process (e.g., salts, protease / peptidase inhibitors, osmolytes, reducing agents, etc.)

[0065] In some aspects the protein content of the dietary product comprises less than, more than, or equal to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% amino acids, peptides, or proteins, or derivatives thereof.B. Lipids

[0066] In some aspects, the dietary products provided herein further comprises lipids. Lipids may be critical for sensory characteristics such as mouthfeel and consistency. In addition, lipids provide nutrition and health benefits. Additionally, lipids can influence the flavors and / or aroma of dietary products.

[0067] In some aspects, the dietary products provided herein comprise one or more lipids selected from the group consisting of fats, oils, monoglycerides, diglycerides, triglycerides, phospholipids, and free fatty acids. In some aspects, the dietary products may comprise, consist essentially of, consist of, exclude lipids from an animal source. In some aspects, the dietary products may comprise, consist essentially of, consist of, exclude lipids from an plant source. In some aspects, the dietary products comprise only saturated lipids. In some aspects,301415446 - 21 -Attorney Docket No. UTSDP4183WO-1001375084the dietary products comprise only unsaturated lipids. In some aspects, the dietary products comprise saturated lipids and unsaturated lipids.

[0068] Non-limiting examples of oils / fats that may be incorporated into the dietary product include, but are not limited to: oils (e.g., sunflower oil, coconut oil, mustard oil, peanut oil, canola oil, corn oil, cottonseed oil, flax seed oil, olive oil, palm oil, rapeseed oil, safflower oil, sesame oil, soybean oil, almond oil, beech nut oil, Brazil nut oil, cashew oil, hazelnut oil, macadamia nut oil, mongongo nut oil, pecan oil, pine nut oil, pistachio nut oil, walnut oil, avocado oil, grape oil), microbe-derived oils, algae-derived oils, fungus-derived oils, marine animal oils (e.g., Atlantic fish oil, pacific fish oil, mediterranean fish oil, light pressed fish oil, alkaline treated fish oil, heat treated fish oil, light and heavy brown fish oil, bonito oil, pilchard oil, tuna oil, sea bass oil, halibut oil, spearfish oil, barracuda oil, cod oil, menhaden oil, sardine oil, anchovy oil, capelin oil, Atlantic cod oil, Atlantic herring oil, Atlantic mackerel oil, Atlantic menhaden oil, salmonid oil, and shark oil, squid oil, cuttlefish oil, octopus oil, krill oil, seal oil, whale oil), non-essential oils, essential oils, natural oils, non-hydrogenated oils, partially hydrogenated oils, hydrogenated oils (e.g., hydrogenated coconut oil), crude oils, semi-refined (also called alkaline refined) oils, and refined oils. In some aspects, longer chain oils (e.g., sunflower oil, corn oil, olive oil, soy oil, peanut oil, walnut oil, almond oil, sesame oil, cottonseed oil, canola oil, safflower oil, flax seed oil, palm oil, palm kernel oil, palm fruit oil, coconut oil, babassu oil, shea butter, mango butter, cocoa butter, wheat germ oil, rice bran oil, engineered sunflower oil that overexpresses oleic acid by 400% combined with short-chain triglycerides to produce transesterified fatty acid esters, tallow, lard, butterfat, chicken fat, duck fat, lecithin, sphingomyelin, sterols, waxes (for example lanolin), essential fatty acids (for example, arachidonic acid, omega-3 fatty acids), and milk lipids. Various combinations of triglycerides and longer chain oils can be incorporated to create a number of different flavor and nutrient profiles.

[0069] Non-limiting examples of monoglycerides and diglycerides include plant-derived monoglycerides and diglycerides (e.g., monoglycerides and diglycerides derived from sunflower, coconut, peanut, cottonseed, olive, palm, rapeseed, safflower, sesame seed, soybean, almond, beech nut, Brazil nut, cashew, hazelnut, macadamia nut, mongongo nut, pecan, pine nut, pistachio, walnut, and avocado). The monoglycerides and diglycerides can include the acyl chain of any of the free fatty acids listed herein. Additional examples of monoglycerides and diglycerides are known in the art.

[0070] Non-limiting examples of free fatty acids include butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, pamitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid,301415446 - 22 -Attorney Docket No. UTSDP4183WO-1001375084eicosapentaenoic acid, erucic acid, docosahexaenoic acid, omega-fatty acids (e.g., arachidonic acid, omega-3-fatty acids, omega-6-fatty acids, omega-7-fatty acids, omega-9-fatty acids), fatty acids with even number of carbons of 4-16 carbons in length, monosaturated acids (particularly with 18 carbons), fatty acids with low interfacial tension (e.g., less than 20, less than 15, less than 11, less than 9, less than 7, less than 5, less than 3, less than 2, less than 1, or less than 0.5 dynes / cm, from 0.1 to 20, from 1 to 15, from 2 to 9, from 3 to 9, from 4 to 9, from 5 to 9, from 2 to 7, from 0.1 to 5, from 0.3 to 2, or from 0.5 to 1 dynes / cm, 0.1, 0.5, I.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, II.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, or 20.0), butyric (4:0) acid or caproic (6:0) acid that is esterified at sn-3, mediumchain fatty acids (8:0-14:0) as well as 16:0 that are esterified at positions sn-1 and sn-2, fatty acids in which stearic acid (18:0) is placed at position sn-1, fatty acids in which oleic acid (18:1) is placed at positions sn-1 and sn-3, fatty acids that have a range of carbon atoms (e.g., from 8 to 40, from 10 to 38, from 12 to 36, from 14 to 34, from 16 to 32, from 18 to 30, or from 20 to 28 carbon atoms), fatty acids that comprise at least one unsaturated bond (i.e., a carboncarbon double or triple bond; e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 carbon-carbon double bonds and / or triple bonds), fatty acids with conjugated unsaturated bonds (i.e., at least one pair of carbon-carbon double and / or triple bonds are bonded together, without a methylene (CH2) group between them, and derivatives of the above named fatty acids (e.g., esters (e.g., methyl and ethyl esters), salts (e.g., sodium and potassium salts), triglyceride derivatives, diglycerides derivatives, monoglyceride derivatives). The free fatty acids can be saturated on unsaturated. In some aspects, the free fatty acids are not derived from or produced by a mammal. Additional examples of free fatty acids are known in the art.

[0071] Non-limiting examples of phospholipids include lecithin phospholipids (e.g., soy lecithin phospholipids, sunflower lecithin phospholipids, cotton lecithin phospholipids, rapeseed lecithin phospholipids, rice bran lecithin phospholipids, and corn lecithin phospholipids), cardiolipin, ceramide phosphocholines, ceramide phosphoethanolamines, glycerophospholipids, phasphatidicacid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphospingolipids, and phsophatidylserine. In some aspects, the phospholipids are not derived from or produced by a mammal. Additional aspects of phospholipids are known in the art.

[0072] Non-limiting examples of triglycerides include tributyrin, short-chain triglycerides, short-chain triglycerides comprising three oleic acids; short-chain triglycerides comprising hexanoic acid; short-chain triglycerides comprising hexanoic acid and butyric acid; short-chain triglycerides comprising hexanoic acid and decanoic acid; and short-chain triglycerides301415446 - 23 -Attorney Docket No. UTSDP4183WO-1001375084comprising one butyric, one hexanoic, and one octanoic acid. In some aspects, the flavor profiles of the compositions provided herein are modulated by incorporating synthetic shortchain triglycerides combined with plant-based oils (e.g., sunflower oil) in desired combinations. For example, a mixture of (C18 C18 C6) and (C18 C6 C18) provides a different flavor profile than a mixture of (C18 C4 C4) and (C18 C10 C10).

[0073] In some aspects, the dietary products provided herein comprise between 0% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%; between 0.1% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, or 0.2%; between 0.2% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, or 0.3%; between 0.3% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.4%; between 0.4% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%; between 0.5% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%; between 1% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2%; between 2% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, or 3%; between 3% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, or 4%; between 4% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, or 5%; between 5% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, or 6%; between 6% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, or 7%; between 7% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, or 8%; between 8% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 9%; between 9% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%; between 10% and 50%, 45%, 40%, 35%, 30%, 25%, 20%, or 15%; between 15% and 50%, 45%, 40%, 35%, 30%, 25%, or 20%; between 20% and 50%, 45%, 40%, 35%, 30%, or 25%; between 25% and 50%, 45%, 40%, 35%, or 30%; between 30% and 50%, 45%, 40%, or 35%; between 35% and 50%, 45%, or 40%; between 40% and 50%, or 45%; or between 45% and 50% by weight of lipid.i-fat and

[0074] In certain aspects, the lipid component of the disclosed dietary products is configured to provide a high-fat or ketogenic macronutrient profile in combination with tryptophan depletion, thereby further suppressing tumor growth relative to tryptophan depletion alone. Without being bound by theory, increasing dietary fat (while maintaining substantially no tryptophan) is exemplified here to (i) shift whole-body substrate utilization toward fatty acid oxidation and ketone body production, (ii) reduce glucose availability and insulin signaling that301415446 - 24 -Attorney Docket No. UTSDP4183WO-1001375084support tumor anabolism, and (iii) modulate tumor-promoting immune and inflammatory cues, collectively potentiating the anti-tumor effect achieved by restricting tryptophan and its oncometabolites (e.g., I3P) in the tumor microenvironment.1. Suitable lipid classes and sources.

[0075] Any of the lipid classes described herein (fats, oils, mono- / di- / triglycerides, phospholipids, and free fatty acids) may be used to formulate the high-fat or ketogenic aspects, including plant, algal, microbial, and marine sources. Non-limiting examples include olive, avocado, high-oleic sunflower / safflower, canola, coconut / MCT oils, cocoa butter, ghee, butterfat, tallow, lard, milk lipids, lecithins, structured triglycerides, omega-3-containing fish or algal oils, and combinations thereof. The lipid fraction may include medium-chain triglycerides (MCTs) to facilitate ketosis at lower total fat loads, or high-oleic MUFA-rich oils to improve palatability and oxidative stability for ready-to-use formats.

[0076] In some aspects, the fat fraction comprises 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% (or any range derivable therein) Monounsaturated Fatty Acids (MUFA); 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% (or any range derivable therein) Polyunsaturated Fatty Acids (PLIFA) (optionally including EPA / DHA); and 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% (or any range derivable therein) Saturated Fatty Acids (SFA), with the precise distribution selected to meet sensory, stability, and clinical goals. Non-limiting examples of sources of MUFA include olive oil, avocado oil, avocados, high-oleic sunflower oil, high-oleic safflower oil, and macadamia nut oil; of PUFA include flaxseed oil, flaxseeds, chia seeds, walnuts, walnut oil, soybean oil, corn oil, sunflower oil (non-high-oleic), safflower oil (non-high-oleic), fish oil, salmon oil, sardine oil, hemp seed oil; and of SFA include butter, ghee, coconut oil, MCT oil, lard, tallow, palm oil, palm kernel oil, cream, cheese, and cocoa butter. For medical-food or kit formats, lipids may be supplied as (i) liquid emulsions / shakes, (ii) powdered lipid microencapsulates blended with the amino-acid base, or (iii) bars / RTD products engineered for portion-controlled dosing. Electrolytes, vitamins (including fat-soluble A, D, E, K), choline, and carnitine may be included to support fat metabolism during prolonged high-fat administration.2. Macronutrient ranges for high-fat / ketogenic formulations.

[0077] In some aspects, the dietary product provides about 40%-85% of total calories from fat (i.e., 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%); in particular aspects >50% (i.e., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%), >60% (i.e., 60%, 65%, 70%, 75%, 80%, 85%), >70% (i.e., 70%, 75%, 80%, 85%), or about 75%-80% (i.e., 75%, 80%) of total calories are provided by fat. Ketogenic formulations may be expressed as a fat:(protein+carbohydrate)301415446 - 25 -Attorney Docket No. UTSDP4183WO-1001375084ratio (w / w), e.g., 2:1, 3:1, or 4:1, while maintaining substantially no tryptophan in the amino acid fraction. Carbohydrates may be limited to <10% of total calories (e.g., <5%) and protein provided by an essential amino acid blend substantially devoid of tryptophan as disclosed herein. These ranges enable induction or maintenance of nutritional ketosis while simultaneously constraining tryptophan flux to tumors.B. Carbohydrates

[0078] In some aspects, the dietary products provided herein further comprise one or more carbohydrates. Carbohydrates, for example sugars, starches and fibers, provide sweetness to the taste profiles and / or serve as fast-acting energy and nutrition sources.

[0079] In some aspects, the dietary products provided herein comprise one or more saccharides (e.g., monosaccharides, disaccharides, polysaccharides). Non-limiting examples of saccharides include glucose, mannose, maltose, fructose, galactose, lactose, sucrose, and tagatose. In some aspects, the dietary products comprise less than 4.5%, less than 4.25%, less than 4%, less than 3.75%, less than 3.5%, less than 3.25%, less than 3%, less than 2.75%, or less than 2.5% by weight of monosaccharides and / or disaccharides.

[0080] In some aspects, the dietary product may comprise one or more starches and / or fibers. Non-limiting examples of starches include com, potato, rice, wheat, arrowroot, guar gum, locust bean, tapioca, arracacha, buckwheat, banana, barley, cassava, konjac, kudzu, oca, sago, sorghum, sweet potato, taro, yams, fruit, vegetable, tuber, legume, cereal grain, pseudograin starch, or any derivative thereof, or any combinations thereof. Non-limiting examples of suitable fiber sources are pea fiber, oat fiber, bamboo fiber, rice bran, waxy maize, bean fiber, beet fiber, guar gum, pectin, carrageenan, apple fiber, citrus fiber, carrot fiber, barley fiber, psyllium husk, soy fiber, sesame flour, flaxseed fiber, nuts, garcinia fiber, chicory fiber, fenugreek fiber, or any derivative thereof, or any combinations thereof. In some aspects, the one or more starches and / or fibers incorporated into the dietary product are substantially devoid of, and or are processed to be substantially devoid of tryptophan.

[0081] In some aspects, the dietary products comprise between 0.001% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.01%; between 0.001% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1%; between 0.1% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%; between 0.5% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%; between 1% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2%; between 2% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, or 3%; between 3% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, or 4%; between 4% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, or 5%; between 5% and 25%, 20%, 15%, 10%, 9%, 8%, 7%, or 6%; between 6% and 25%, 20%, 15%, 10%,301415446 - 26 -Attorney Docket No. UTSDP4183WO-10013750849%, 8%, or 7%; between 7% and 25%, 20%, 15%, 10%, 9%, or 8%; between 8% and 25%, 20%, 15%, 10%, or 9%; between 9% and 25%, 20%, 15%, or 10%; between 10% and 25%, 20%, or 15%; between 15% and 25%, or 20%; or between 20% and 25% by weight of carbohydrate.

[0082] In some aspects, the dietary products comprise carbohydrates derived essentially from plants. In some aspects, the dietary product comprises carbohydrates derived from both animals and plants.C. Other components

[0083] The dietary products provided herein may comprise one or more other components, for example one or more vitamins, one or more of minerals, hydrocolloids, fibers, salts, binder, flavor enhancer, aromatic elements, starch, gelling agents, thickeners, emulsifiers, or any combination thereof.

[0084] Non-limiting examples of other components include minerals (e.g., fat soluble minerals, water soluble minerals, calcium, phosphorous, potassium, sodium, citrate, chloride, phosphate, magnesium, potassium, zinc, iron, molybdenum, manganese, copper). Minerals can contribute to the structure and stability of the dietary products provided herein by interacting with fat globules and micelles to maintain an emulsified mixture. Minerals can also affect sensory characteristics such as mouthfeel, consistency, and to a certain extent, flavor of the dietary products. Minerals can also improve the nutritional profile of the dietary products.

[0085] Further non-limiting examples of other components include vitamins. Examples of nonlimiting vitamins include lipid soluble vitamins, water soluble vitamins, thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), vitamin B6 (pyridoxine), vitamin B12 (cobalamin), vitamin C, folate, vitamins A, vitamin D, vitamin E, and vitamin K).

[0086] Further non-limiting examples of other components include coloring agents, color enhancers, and color stabilizers (e.g., titanium oxide).

[0087] Further non-limiting examples of other components include taste agents, taste enhancers, and taste stabilizers (e.g., b-decalactone, ethyl butyrate, 2-furyl methyl ketone, 2,3-pentanedione, y-undecalactone, b-undecalactone, natural favors, artificial flavors, triglycerides, hydrolyzed casein, and / or whey protein).

[0088] Further non-limiting examples of other components include sweetening agents (e.g., stevia, aspartame, cyclamate, saccharin, sucralose, mogrosides, brazzein, curculin, erythritol, glycyrrhizin, inulin, isomalt, lacititol, mabinlin, malititol, mannitol, miraculin, monatin, monelin, osladin, pentadin, sorbitol, thaumatin, xylitol, acesulfame potassium, advantame, alitame,301415446 - 27 -Attorney Docket No. UTSDP4183WO-1001375084aspartame-acesulfame, sodium cyclamate, dulcin, glucin, neohesperidin dihyrdochalcone, neotame, and / or P-4000). In some aspects, the sweetening agents do not comprise carbohydrates.

[0089] Further non-limiting examples of other components include aroma agents, aroma stabilizers, and aroma enhancers (e.g., propylene glycol, glycerol, ethyl alcohol, salt, sugars).

[0090] Further non-limiting examples of other components include shelf life extending agents (e.g., carbon monoxide, nitrites, sodium metabisulfite, Bombal, vitamin E, rosemary extract, greet tea extract, catechins, antioxidants).

[0091] Further non-limiting examples of other components include supramolecules (i.e., complexes of linked molecules (e.g., linked proteins) other than micelles.

[0092] The dietary product may comprise a hydrocolloid. The hydrocolloid may comprise konjac gum, gum Arabic, carrageenan, agar-agar, pectin, alginate, gellan, konjac glucomannan, xanthan, modified starch, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, guar gum, locust bean gum, tara gum, gum tragacanth, gum ghatt, their derivatives, or any combination thereof. The hydrocolloid may comprise konjac flour, methyl cellulose, gum Arabic, carrageenan, or any combination thereof. The hydrocolloid may be about 1 wt % to about 5 wt % of the dietary product.

[0093] The dietary product may comprise a fiber. The fiber may comprise konjac flour, guar gum, xantham gum, psyllium, chitin, inulin, pectin, dextrin, a starch, a cellulose, a hemicellulose, a starch, a lignin, a citrus fiber extract, or any combination thereof. The plantbased fiber may comprise inulin, gum Arabic, citrus fiber, maltodextrin, or any combination thereof. The fiber may be at least 5 wt %, or about 0.5 wt % to about 8.0 wt % of the product.

[0094] The dietary product may comprise a binder. The binder may comprise starch, gum, methyl cellulose, lecithin, or any combination thereof. The binder may be about 0.25 wt % to about 1.5 wt % of the product.

[0095] In some aspects, the dietary product comprises a buffering agent. In some aspects, the buffering agent maintains the pH of the dietary product. In some aspects, the dietary product has a pH of about 5 to about 8. In some aspects, the dietary product has a pH of less than 8.0, less than 7.5, less than 7, less than 6.5, less than 6, less than 5.5, less than 5, less than 4.9, less than 4.8, less than 4.7, less than 4.6, or less than 4.5; between 3.8 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4, or 3.9; between 3.9 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4; between 4 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1; between 4.1 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2; between 4.2 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3; between301415446 - 28 -Attorney Docket No. UTSDP4183WO-10013750844.3 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4; between 4.4 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5; between 4.5 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6; between 4.6 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7; between 4.7 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, or 4.8; between 4.8 and 7.5, 7, 6.5, 6, 5.5, 5, 4.9, or 4.8; between 4.9 and 7.5, 7, 6.5, 6, 5.5, or 5; between 5 and 7.5, 7, 6.5, 6, or 5.5; between 5.5 and 7.5, 7, 6.5, or 6; between 6 and 7.5, 7, or 6.5; between 6.5 and 7.5, or 7; or between 7 and 7.5.

[0096] In some aspects, the dietary product disclosed herein may comprise one or more probiotics. In some aspects, the added probiotics may provide health additional health benefits. In some aspects, the amount and / or the type of probiotics added to the dietary composition disclosed herein is such that it does not contribute substantially to the tryptophan content of the composition. Non-limiting examples of suitable probiotics include Aerococcus, Aspergillus, Bacillus, Bacteroides, Bifidobacterium, Candida, Clostridium, Debaromyces, Enterococcus, Fusobacterium, Lactobacillus, Lactococcus, Leuconostoc, Melissococcus, Micrococcus, Mucor, Oenococcus, Pediococcus, Penicillium, Peptostrepococcus, Pichia, Propionibacterium, Pseudocatenulatum, Rhizopus, Saccharomyces, Staphylococcus, Streptococcus, Torulopsis, Weissella, or a combination thereof. Some specific examples include but are not limited to Lactobacillus acidophilus, Lactobacillus klebsiella, Lactobacillus leuconostoc, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus plantarum, Lactobacillus caret, Lactobacillus pentoaceticus, Lactobacillus brevis, Lactobacillus thermophilus, and other members of the genera Lactobacillus, Leuconostoc, Pediococcus, Lactococcus, and Streptococcus, as well as the more peripheral Aerococcus, Carnobacterium, Enterococcus, Oenococcus, Sporolactobacillus, Tetragenococcus, Vagococcus, and Weissella that are classified as safe for consumption by humans and / or other animals by a federal or local regulatory agency (e.g., the Federal Food and Drug Agency (FDA)).

[0097] Further non-limiting examples of other components include anti-caking agents, antifoaming agents, anti-inflammatory agents, anti-microbial agents, anti-oxidants, coenzymes, enzymes, essential nutrients, neuroactive compounds, neutraceuticals, nutritional supplements, buffering agents, salts, emulsifiers, stabilizers, and mixtures of any of the other components disclosed herein.

[0098] In certain aspects, the dietary product further comprises one or more serotonin-supporting supplements formulated to mitigate or prevent declines in serotonergic tone that may occur during tryptophan restriction. In some aspects, the dietary product includes 5- hydroxytryptophan (5-HTP) and / or cofactors that support monoamine synthesis and turnover, non-limiting examples of which include vitamin B6 (e.g., pyridoxal-5'-phosphate), L-methylfolate, S-adenosylmethionine (SAMe), magnesium, omega-3 fatty acids (e.g., EPA301415446 - 29 -Attorney Docket No. UTSDP4183WO-1001375084and / or DHA), and vitamin D, singly or in combination. The serotonin-supporting component can be provided as a premix blended into powdered or ready- to-drink formats, as a microencapsulated beadlet for stability and controlled release, or as a separately packaged sachet to be co-administered with the amino acid base. In some aspects, the composition delivers a unit dose configured for once- or twice-daily administration and may be titratable according to subject weight, clinical scores, or serum / plasma biomarker readouts, while maintaining the dietary product substantially devoid of tryptophan. In kit aspects, the serotonin-supporting component may be provided as a labeled module with use instructions synchronized to on-diet and maintenance phases.

[0099] In some aspects, the dietary product comprises between 0.001% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.005%; between 0.005% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%; between 0.01% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05%; between 0.05% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1%; between 0.1% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%; between 0.5% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%; between 1% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2%; between 2% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, or 3%; between 3% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, or 4%; between 4% and 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%; between 5% and 12%, 11%, 10%, 9%, 8%, 7%, or 6%; between 6% and 12%, 11%, 10%, 9%, 8%, or 7%; between 7% and 12%, 11%, 10%, 9%, or 8%; between 8% and 12%, 11%, 10%, or 9%; between 9% and 12%, 11%, or 10%; between 10% and 12%, or 11%; or between 11% and 12% by weight of any one of the other components disclosed herein.

[0100] In some aspects, the dietary products comprise between 0.001% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.005%; between 0.005% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%; between 0.01% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05%; between 0.05% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1%; between 0.1% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%; between 0.5% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%; between 1% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2%; between 2% and 10%, 9%, 8%, 7%, 6%, 5%, 4%, or 3%; between 3% and 10%, 9%, 8%, 7%, 6%, 5%, or 4%; between 4% and 10%, 9%, 8%, 7%, 6%, or 5%; between 5% and 10%, 9%, 8%, 7%, or 6%; between 6% and 10%, 9%, 8%, or 7%; between 7% and 10%, 9%, or 8%; between 8% and 10%, or 9%; or between 9% and 10% by weight of all other components.

[0101] In most aspects, the dietary products further comprise water. In some such aspects, the dietary products comprise between 2% and 95%, 85%, 75%, 65%, 55%, 45%, 35%, 25%,301415446 - 30 -Attorney Docket No. UTSDP4183WO-100137508415%, 10%, or 5%; between 5% and 95%, 85%, 75%, 65%, 55%, 45%, 35%, 25%, 15%, or 10%; between 10% and 95%, 85%, 75%, 65%, 55%, 45%, 35%, 25%, or 15%; between 15% and 95%, 85%, 75%, 65%, 55%, 45%, 35%, or 25%; between 25% and 95%, 85%, 75%, 65%, 55%, 45%, or 35%; between 35% and 95%, 85%, 75%, 65%, 55%, or 45%; between 45% and 95%, 85%, 75%, 65%, or 55%; between 55% and 95%, 85%, 75%, or 65%; between 65% and 95%, 85%, or 75%; between 75% and 95%, or 85%; or between 85% and 95% by weight of water.D. Attributes

[0102] The dietary products provided herein have one or more desirable attributes.

[0103] In some aspects, the desirable attributes are desirable colors. The color of a composition can be evaluated by a panel of expert human subjects. Alternatively, the color of a composition can be described, for example, by measuring its spectral absorption pattern using a spectrophotometer or colorimeter. Variables that can be titrated to modulate the color of the dietary products provided herein include but are not limited to amounts and / or types of coloring agents, amounts and / or types of color stabilizers, amounts and / or types of color modifiers, and micelle characteristics (e.g., compositions, sizes, densities). In some aspects, the dietary products have a L* color value of between 80 and 95, an a* color value of between -5 and 0.5, and a b* color value of between 4 and 10. In some aspects, the dietary products comprise fluorescent proteins selected from the group consisting of green fluorescent protein (GFP), blue fluorescent protein (BFP), cyan fluorescent protein (CFP), yellow fluorescent protein (YFP), orange fluorescent protein (OFP), red fluorescent protein (RFP), and derivatives thereof.

[0104] In some aspects, the desirable attributes are desirable tastes. The taste of a composition can be evaluated by a panel of expert human subjects. Alternatively, the taste of a composition can be described using automated devices (e.g., iNSENT TS-5000Z Taste Testing System (Higuchi USA Inc., Japan), Astree tongue system (Alpha MOS America, Hanover, Md.)). Variables that can be titrated to modulate the taste of the dietary products provided herein include but are not limited to amounts and / or types taste agents, amounts and / or types taste stabilizers, amounts and / or types taste modifiers, and amounts and / or types of taste blockers.

[0105] In some aspects, the desirable attributes are desirable textures (i.e., mechanical characteristics that are correlated with sensory perceptions; non-limiting examples are mouthfeel, fattiness, creaminess, viscosity, homogenization, richness, thickness, G' storage modules value). The texture of a composition can be evaluated by a panel of expert human subjects. Alternatively, the texture of a composition can be described by dynamic oscillation301415446 - 31 -Attorney Docket No. UTSDP4183WO-1001375084rheology, viscosity analysis, flow analysis, melt analysis, sheer stress analysis, storage modulus analysis, and texture profile analysis using a texture analyzer. Variables that can be titrated to modulate the texture of the dietary products provided herein include but are not limited to composition (e.g., types and amounts of amino acids and proteins, types and / or amounts of lipids, types and / or amounts of carbohydrates, types and / or amounts of micelles, types and / or amounts of hydrocolloids, types and / or amounts of stabilizers, types and / or amounts of emulsifiers), micelle characteristics (e.g., composition, size, density), pH, water activity, and production process conditions (e.g., temperature, hold time at temperature, pH, amount of shear applied, types of starter cultures, post fermentation treatments, and ion strengths).

[0106] In some aspects, the desirable attributes are desirable digestibility. The digestibility of a composition can be described by incubating the composition in the presence of digestive enzymes (e.g., porcine pepsin) and under conditions that prevail in the digestive tract (e.g., in presence of simulated gastric fluid with acidic pH). Variables that can be titrated to modulate the digestibility of the dietary products provided herein include but are not limited to the content of proteins comprising target sites for digestive enzymes, thermal treatment, and content of anti-nutritional factors.

[0107] In some aspects, the desirable attributes are desirable nutrient contents. In some aspects, the desirable nutrient contents are nutrient contents that are different from the nutrient contents of obtained from diet (e.g., better amino acid content, better mineral balance). Nutrient content can be defined by protein content, types and / or amounts of amino acids, types and / or amounts of lipids, types and / or amounts of carbohydrates, types and / or amounts of minerals, types and / or amounts of vitamins, types and / or amounts of bioactive compounds, types and / or amounts of micronutrients, types and / or amounts of macronutrients, types and / or amounts of lactic acid bacteria, PDCAAS score, etc. The nutrient content of a composition can be determined by analytical methods (e.g., AOAC International reference methods AOAC 990.03 and AOAC 992.15, electrophoresis (e.g., SDS-PAGE), liquid column chromatography, immunochemical tests, or on-chip electrophoresis (e.g., using the Agilent Protein 80 kit and the Agilent 2100 Bioanalyzer) for determination of type and / or content of proteins and amino acids; AOAC International reference method AOAC 954.02 for determination of type and / or content of lipids), or it can be derived from the nutrient contents of the ingredients of a dietary product. In some aspects, the dietary products provided herein comprise at least 0.5%, 0.6%, 0.7%, or 0.8%; between 0.5% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, or 0.6%; between 0.6% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, or 0.7%; between 0.7% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, or 0.8%; between 0.8% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, or 0.9%;301415446 - 32 -Attorney Docket No. UTSDP4183WO-1001375084between 0.9% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, or 1.0%; between 1.0% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, 1.2%, or 1.1%; between 1.1% and 2.5%, 2%, 1.5%, 1.4%, 1.3%, or 1.2%; between 1.2% and 2.5%, 2%, 1.5%, 1.4%, or 1.3%; between 1.3% and 2.5%, 2%, 1.5%, or 1.4%; between 1.4% and 2.5%, 2%, or 1.5%; between 1.5% and 2.5%, or 2%; or between 2% and 2.5% by weight of branched amino acids. In some aspects, the dietary products have PDCAAS scores of at least 80; at least 85; at least 90; at least 100; at least 105; at least 110; at least 115; at least 120; at least 125; between 80 and 150, 140, 130, 120, 110, 100, or 90; between 90 and 150, 140, 130, 120, 110, or 100; between 100 and 150, 140, 130, 120, or 110; between 110 and 150, 140, 130, or 120; between 120 and 150, 140, or 130; between 130 and 150, or 140; or between 140 and 150. In some aspects, the dietary products comprise less than 4% by weight of lactose. In some aspects, the dietary products comprise less than 2% by weight of monosaccharides. In some aspects, the dietary products comprise less than 2% by weight of disaccharides. In some aspects, the dietary products compared to dietary products have a higher content of at least one component selected from the group consisting of calcium, phosphate, B complex vitamins, vitamin A, vitamin D, vitamin E, and vitamin K.

[0108] In some aspects, the desirable attributes are desirable shelf-lives. The shelf life of a composition can be described by repeatedly measuring key attributes of the composition over the course of storage. Variables that can be titrated to modulate the shelf life of a composition include but are not limited to types and / or amounts of proteases, microbial load, solid concentration, water activity, redox potential, salt concentration, pH, natural preservative content, and humidity. In some aspects, the dietary products provided herein are stable at temperatures of 4 C or below for at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 15 days, at least 20 days, at least 30 days, at least 40 days at least 50 days, at least 60 days, at least 70 days, at least 80 days, at least 90 days, between 4 days and 25 days, between 8 days and 20 days, between 15 days and 30 days, or between 40 days and 90 days. In some aspects, the dietary products are stable at ambient temperature for at least 2 months; at least 3 months; at least 4 months; at least 5 months; at least 6 months; between 2 months and 12 months, 10 months, 8 months, 6 months, or 4 months; between 4 months and 12 months, 10 months, 8 months, or 6 months; between 6 months and 12 months, 10 months, or 8 months; between 8 months and 12 months, or 10 months; or between 10 months and 12 months.

[0109] In some aspects, the desirable attributes are desirable hunger and / or satiety regulation. The hunger and / or satiety regulation of a composition can be evaluated by a panel of expert human subjects. Variables that can be titrated to modulate the hunger and / or satiety regulation of the dietary products provided herein include but are not limited to nutrient content301415446 - 33 -Attorney Docket No. UTSDP4183WO-1001375084(e.g., types and / or amounts of protein, types and / or amounts of lipid, types and / or amounts of carbohydrate), digestibility, fiber content, and glycemic response.

[0110] In some aspects, the desirable attributes are desirable use versatility (i.e., ability to use the dietary products in a variety of manners and / or to derive a diversity of other compositions from the dietary product). Variables that can be titrated to modulate the use versatilities of a composition provided herein include but are not limited to types and / or amounts of proteins, types and / or amounts of carbohydrates, types and / or amounts of lipids, hydrocolloid contents, process conditions (e.g., temperature, hold time, pH, shear amount), membrane processing, and ion strengths.

[0111] In some aspects, the desirable attributes is texture (e.g., creaminess, richness, thickness, smoothness, hardness, crystallization, shape retention). The texture of a composition can be evaluated by panels of expert human subjects, melt tests, shape retention tests, ice crystal counting, altitude stability testing, and overrun capacity analysis. Variables that can be titrated to modulate the texture of the dietary products provided herein include but are not limited to amounts and / or types of protein, amounts and / or types of lipids, amounts and / or types of carbohydrates, moisture content, pH, amounts and / or types of high and low molecular weight components that can affect freezing points, hydrocolloid contents, emulsified contents, method of manufacture (e.g., temperature of pasteurization, hold time, homogenization conditions, cooling / aging rate, conditions and / or methods of freezing, hardening), and storage conditions.

[0112] In some such aspects, the desirable attributes are not requiring pasteurization or cold shipping (e.g., due to possibility of sterilizing components individually prior to combining). Variables that can be titrated to modulate the pasteurization or cold shipping requirement of dietary products provided herein include but are not limited to amounts and / or types of bacteria in the composition.

[0113] In some aspects, the desirable attributes persist over storing the dietary products provided herein at suitable storage conditions. In some such aspects, the suitable storage conditions include storage at temperatures of less than 15° C. In some aspects, the desirable attributes persist over one or more cycles of freezing and thawing. In some such aspects, the one or more cycles of freezing and thawing are 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, or more than 5 cycles of freezing and thawing.

[0114] In some aspects, the dietary product may be in any form suitable for consumption. In some aspects, the dietary product is in the form of a powder, a gel, a solution, an emulsion, a suspension, a paste, a solid, a pellet, a liquid, a liquid concentrate, a powder which may be301415446 - 34 -Attorney Docket No. UTSDP4183WO-1001375084reconstituted, a shake, a concentrate, a pill, a bar, a tablet, a capsule, injectable solution, or a ready-to-use product.III. Kits and dietary regimens

[0115] In some aspects, the current disclosure also encompasses dietary regimens or kits comprising prepackaged meals and instructions for use. Prepackaged meal regimens offer a convenient and structured way to manage daily nutrition, particularly for individuals with busy schedules, specific dietary goals (for example, intake of a diet essentially devoid of tryptophan, or low tryptophan diets) or health-related needs. These regimens typically include a variety of ready-to-eat or easy-to-prepare meals that are portion-controlled and balanced in terms of macronutrients (proteins, carbohydrates, and fats). In some aspects, these regimens may correspond to a particular type of diet, for example a high fat diet ketogenic diet. They are designed to simplify meal planning and help individuals adhere to specific dietary requirements, such as low-tryptophan and / or high fat diets as disclosed herein. In some aspects, a prepackaged meal regimen of the current disclosure may comprise one or more meals which are essentially devoid of tryptophan. In some aspects, the prepackaged meal regimen may comprise one or more daily meals, for example breakfast, lunch, dinner, one or more snacks, or any combination thereof. In some aspects, the prepackaged meal regimen may comprise uncooked, cooked, or partially cooked meals, with instructions to cook, heat, re-heat the meal. Many prepackaged meal regimens are available in different formats, including frozen, refrigerated, or shelf-stable options, and they often come with detailed nutritional information and calorie counts to help users stay on track with their goals.IV. Methods of treating

[0116] In some aspects, the current disclosure encompasses a method for treating or preventing a disease or disorder comprising a controlled diet intake by the subject, wherein the diet is substantially devoid of tryptophan. Tryptophan restriction may be implemented by providing the subject with dietary instructions on reducing or eliminating daily intake of tryptophan containing diets. Alternatively, the subject may be provided with meals (e.g., breakfast meals, lunch meals, dinner meals, or snacks) that do not contain or have low amounts of tryptophan. In certain aspects, the diet reduces the subject's daily intake of foods containing tryptophan by at least 20% to 100%, including any percent within this range, such as 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100%. Preferably, the diet provides other nutrients at levels in accordance with United States Recommended Daily Allowances (USRDA) guidelines. In some aspects, replacement or substantial replacement of consumption of usual sources of amino acids such as protein with the disclosed dietary product or diet regimen will yield a diet substantially devoid of tryptophan.301415446 - 35 -Attorney Docket No. UTSDP4183WO-1001375084In some aspects, the controlled diet may provide therapeutic benefits to a subject suffering from a disease or disorder. In some aspects, the disease or disorder is cancer. In some aspects, the disease or disorder is a neurological disease.

[0117] In some aspects, the subject is put on a protein-free or low-protein diet and further administered an amino acid-containing supplement comprising all of the essential amino acids (i.e., histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine), except tryptophan. The amino acid-containing supplement may further comprise one or more nonessential amino acids selected from the group consisting of alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, and tyrosine. In some aspects, the subject is administered a dietary product as disclosed herein, as the amino acid supplement. In some aspects, the subject may be provided a dietary product as disclosed herein to reduce the amount of tryptophan in the diet. In some aspects, the dietary product may account for at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more of the diet of the subject.

[0118] In some aspects, the subject is administered the controlled diet is for less than, more than or about 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 3 weeks, or 2 weeks.A. Cancer

[0119] In some aspects, the current disclosure encompasses a method of treating, preventing, reducing the symptoms of, or delaying the onset of a cancer in a subject in need thereof, the method comprising administering a controlled diet to the subject, such that the controlled diet is substantially devoid of tryptophan. In some aspects, the controlled diet comprises, consists of, or consists essentially of a dietary product disclosed herein.

[0120] “Subject” means any animal, but is preferably a mammal, such as, for example, a human, monkey, mouse, rabbit or rat. In some aspects, the subject is a mammal who has, or is suspected of having a cancer. In some aspects, the subject In some aspects, the subject has, or is suspected of having a lung tumor, primary brain tumors, stomach cancer, colon cancer, pancreatic cancer, carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, or prostate cancer. In some aspects, the cancer is a solid tumor. In some aspects, the cancer corresponds to a sarcoma selected from chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial301415446 - 36 -Attorney Docket No. UTSDP4183WO-1001375084sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma; a melanoma selected from acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, and superficial spreading melanoma; a carcinoma selected from acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidernoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, naspharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma viflosum; a leukemia301415446 - 37 -Attorney Docket No. UTSDP4183WO-1001375084acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia; or other cancers selected from Hodgkin's Disease, NonHodgkin's Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, or prostate cancer.

[0121] In some aspects, the cancer is a MYC-related cancer. In some aspects, the current disclosure is based on the surprising discovery that depriving MYC-driven tumors of tryptophan through a no-tryptophan diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite tryptophan starvation, protein synthesis remains unhindered in liver cancer cells. In some aspects, the method disclosed herein may be used for any Myc-driven tumor, non-limiting examples of which include Burkitt lymphoma, diffuse large B-cell lymphoma, multiple myeloma, medulloblastoma, neuroblastoma, small cell lung cancer, colorectal cancer, breast cancer, prostate cancer, hepatocellular carcinoma (HCC), ovarian cancer, pancreatic cancer, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, esophageal cancer, or gastric cancer. In some aspects, the cancer is HCC.

[0122] In some aspects, the dietary product may be used as an adjuvant cancer treatment. One or more additional cancer therapies may be administered simultaneously or staggered with the disclosed method.301415446 - 38 -Attorney Docket No. UTSDP4183WO-1001375084Additional Anti-Cancer

[0123] The methods may comprise or further comprise administration of an additional anticancer therapy or agent. The compositions may comprise or further comprise an additional anti-cancer therapy or agent. The methods and / or compositions may exclude an additional anti-cancer therapy.Immunostimulators

[0124] The anti-cancer therapy or agent may be an immunostimulator. The term “immunostimulator” as used herein refers to a compound that can stimulate an immune response in a subject and may include an adjuvant. In some aspects, an immunostimulator is an agent that does not constitute a specific antigen but can boost the strength and longevity of an immune response to an antigen. Such immunostimulators may include, but are not limited to stimulators of pattern recognition receptors, such as Toll-like receptors, RIG-1 and NOD-like receptors (NLR), mineral salts, such as alum, alum combined with monphosphoryl lipid (MPL) A of Enterobacteria, such as Escherihia coli, Salmonella minnesota, Salmonella typhimurium, or Shigella flexneri or specifically with MPL (ASO4), MPL A of above-mentioned bacteria separately, saponins, such as QS-21, Quil-A, ISCOMs, ISCOMATRIX, emulsions such as MF59, Montanide, ISA 51 and ISA 720, AS02 (QS21+squalene+MPL.), liposomes and liposomal formulations such as AS01, synthesized or specifically prepared microparticles and microcarriers such as bacteria-derived outer membrane vesicles (OMV) of N. gonorrheae, Chlamydia trachomatis and others, or chitosan particles, depot-forming agents, such as Pluronic block co-polymers, specifically modified or prepared peptides, such as muramyl dipeptide, aminoalkyl glucosaminide 4-phosphates, such as RC529, or proteins, such as bacterial toxoids or toxin fragments.

[0125] The additional anti-cancer therapy may comprise an agonist for pattern recognition receptors (PRR), including, but not limited to Toll-Like Receptors (TLRs), specifically TLRs 2, 3, 4, 5, 7, 8, 9 and / or combinations thereof. The additional anti-cancer therapy may comprise agonists for Toll-Like Receptors 3, agonists for Toll-Like Receptors 7 and 8, or agonists for Toll-Like Receptor 9; preferably the recited immunostimulators comprise imidazoquinolines; such as R848; adenine derivatives, such as those disclosed in U. S. Pat. No. 6,329,381, U. S. Published Patent Application 2010 / 0075995, or WO 2010 / 018132; immunostimulatory DNA; or immunostimulatory RNA. In some aspects, the additional anti-cancer therapies also may comprise immunostimulatory RNA molecules, such as but not limited to dsRNA, poly l: C or poly I: poly C12U (available as Ampligen. RTM., both poly l: C and poly l:polyC12U being known as TLR3 stimulants), and / or those disclosed in F. Heil et al., " Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8" Science 303(5663), 1526-1529 (2004);301415446 - 39 -Attorney Docket No. UTSDP4183WO-1001375084J. Vollmer et al., " Immune modulation by chemically modified ribonucleosides and oligoribonucleotides" WO 2008033432 A2; A. Forsbach et al., " Immunostimulatory oligoribonucleotides containing specific sequence motif(s) and targeting the Toll-like receptor 8 pathway" WO 2007062107 A2; E. Uhlmann et al., " Modified oligoribonucleotide analogs with enhanced immunostimulatory activity" U. S. Pat. Appl. Publ. US 2006241076; G. Lipford et al., " Immunostimulatory viral RNA oligonucleotides and use for treating cancer and infections" WO 2005097993 A2; G. Lipford et al., " Immunostimulatory G, U-containing oligoribonucleotides, compositions, and screening methods" WO 2003086280 A2. In some aspects, an additional anti-cancer therapy may be a TLR-4 agonist, such as bacterial lipopolysaccharide (LPS), VSV-G, and / or HMGB-1. In some aspects, additional therapies may comprise TLR-5 agonists, such as flagellin, or portions or derivatives thereof, including but not limited to those disclosed in U. S. Pat. Nos. 6,130,082, 6,585,980, and 7,192,725.

[0126] In some aspects, additional anti-cancer therapies may be proinflam matory stimuli released from necrotic cells (e.g., urate crystals). In some aspects, additional anti-cancer therapies may be activated components of the complement cascade (e.g., CD21, CD35, etc.). In some aspects, additional anti-cancer therapies may be activated components of immune complexes. Additional anti-cancer therapies also include complement receptor agonists, such as a molecule that binds to CD21 or CD35. In some aspects, the complement receptor agonist induces endogenous complement opsonization of the synthetic nanocarrier. In some aspects, immunostimulators are cytokines, which are small proteins or biological factors (in the range of 5 kD-20 kD) that are released by cells and have specific effects on cell-cell interaction, communication and behavior of other cells. In some aspects, the cytokine receptor agonist is a small molecule, antibody, fusion protein, or aptamer.

[0127] In some aspects, the additional anti-cancer therapy comprises a cancer immunotherapy. Cancer immunotherapy (sometimes called immuno-oncology, abbreviated IO) is the use of the immune system to treat cancer. Immunotherapies can be categorized as active, passive or hybrid (active and passive). These approaches exploit the fact that cancer cells often have molecules on their surface that can be detected by the immune system, known as tumor-associated antigens (TAAs); they are often proteins or other macromolecules (e.g. carbohydrates). Active immunotherapy directs the immune system to attack tumor cells by targeting TAAs. Passive immunotherapies enhance existing anti-tumor responses and include the use of monoclonal antibodies, lymphocytes and cytokines. Immunotherapies are known in the art, and some are described below.301415446 - 40 -Attorney Docket No. UTSDP4183WO-1001375084Inhibition of co-stimulatory molecules

[0128] In some aspects, the immunotherapy comprises an inhibitor of a co-stimulatory molecule. In some aspects, the inhibitor comprises an inhibitor of B7-1 (CD80), B7-2 (CD86), CD28, ICOS, 0X40 (TNFRSF4), 4-1 BB (CD137; TNFRSF9), CD40L (CD40LG), GITR (TNFRSF18), and combinations thereof. Inhibitors include inhibitory antibodies, polypeptides, compounds, and nucleic acids.Dendritic cell

[0129] The additional anti-cancer therapy may comprise dendritic cells. Dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. Dendritic cells are antigen presenting cells (APCs) in the mammalian immune system. In cancer treatment they aid cancer antigen targeting. One example of cellular cancer therapy based on dendritic cells is sipuleucel-T.

[0130] One method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates or short peptides (small parts of protein that correspond to the protein antigens on cancer cells). These peptides are often given in combination with adjuvants (highly immunogenic substances) to increase the immune and anti-tumor responses. Other adjuvants include proteins or other chemicals that attract and / or activate dendritic cells, such as granulocyte macrophage colony-stimulating factor (GM-CSF).

[0131] Dendritic cells can also be activated in vivo by making tumor cells express GM-CSF. This can be achieved by either genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF.

[0132] Another strategy is to remove dendritic cells from the blood of a patient and activate them outside the body. The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide / protein or a tumor cell lysate (i.e. a solution of broken down tumor cells). These cells (with optional adjuvants) are infused and provoke an immune response.

[0133] Dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such as TLR3, TLR7, TLR8 or CD40 have been used as antibody targets.301415446 - 41 -Attorney Docket No. UTSDP4183WO-1001375084CAR-T cell

[0134] The additional anti-cancer therapy may comprise a chimeric antigen receptor (CAR). CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are engineered receptors that combine a new specificity with an immune cell to target cancer cells. Typically, these receptors graft the specificity of a monoclonal antibody onto a T cell. The receptors are called chimeric because they are fused of parts from different sources. CAR-T cell therapy refers to a treatment that uses such transformed cells for cancer therapy.

[0135] The basic principle of CAR-T cell design involves recombinant receptors that combine antigen-binding and T-cell activating functions. The general premise of CAR-T cells is to artificially generate T-cells targeted to markers found on cancer cells. Scientists can remove T-cells from a person, genetically alter them, and put them back into the patient for them to attack the cancer cells. Once the T cell has been engineered to become a CAR-T cell, it acts as a “living drug”. CAR-T cells create a link between an extracellular ligand recognition domain to an intracellular signaling molecule which in turn activates T cells. The extracellular ligand recognition domain is usually a single-chain variable fragment (scFv). An important aspect of the safety of CAR-T cell therapy is how to ensure that only cancerous tumor cells are targeted, and not normal cells. The specificity of CAR-T cells is determined by the choice of molecule that is targeted.

[0136] The additional anti-cancer therapy may comprise cytokines. Cytokines are proteins produced by many types of cells present within a tumor. They can modulate immune responses. The tumor often employs them to allow it to grow and reduce the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response. Two commonly used cytokines are interferons and interleukins.

[0137] Interferons are produced by the immune system. They are usually involved in anti-viral response, but also have use for cancer. They fall in three groups: type I (IFNα and IFNβ), type II (IFNγ) and type III (IFNλ).

[0138] Interleukins have an array of immune system effects. IL-2 is an exemplary interleukin cytokine therapy.T-cell

[0139] The additional anti-cancer therapy may comprise adoptive T cell therapy. Adoptive T cell therapy is a form of passive immunization by the transfusion of T-cells (adoptive cell301415446 - 42 -Attorney Docket No. UTSDP4183WO-1001375084transfer). They are found in blood and tissue and usually activate when they find foreign pathogens. Specifically, they activate when the T-cell's surface receptors encounter cells that display parts of foreign proteins on their surface antigens. These can be either infected cells, or antigen presenting cells (APCs). They are found in normal tissue and in tumor tissue, where they are known as tumor infiltrating lymphocytes (TILs). They are activated by the presence of APCs such as dendritic cells that present tumor antigens. Although these cells can attack the tumor, the environment within the tumor is highly immunosuppressive, preventing immune-mediated tumor death.

[0140] Multiple ways of producing and obtaining tumor targeted T-cells have been developed. T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. Subsequent activation and culturing is performed ex vivo, with the results reinfused. Activation can take place through gene therapy, or by exposing the T cells to tumor antigens.Checkpoint Inhibitors and Combination Treatment

[0141] In some aspects, the additional anti-cancer immunotherapy comprises immune checkpoint inhibitors. Certain aspects are further described below.

[0142] PD-1 can act in the tumor microenvironment where T cells encounter an infection or tumor. Activated T cells upregulate PD-1 and continue to express it in the peripheral tissues. Cytokines such as IFN-gamma induce the expression of PDL1 on epithelial cells and tumor cells. PDL2 is expressed on macrophages and dendritic cells. The main role of PD-1 is to limit the activity of effector T cells in the periphery and prevent excessive damage to the tissues during an immune response. Additional anti-cancer therapies of the disclosure may block one or more functions of PD-1 and / or PDL1 activity.

[0143] Alternative names for “PD-1” include CD279 and SLEB2. Alternative names for “PDL1” include B7-H1, B7-4, CD274, and B7-H. Alternative names for “PDL2” include B7-DC, Btdc, and CD273. In some aspects, PD-1, PDL1, and PDL2 are human PD-1, PDL1 and PDL2.

[0144] In some aspects, the PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its ligand binding partners. In a specific aspect, the PD-1 ligand binding partners are PDL1 and / or PDL2. In another aspect, a PDL1 inhibitor is a molecule that inhibits the binding of PDL1 to its binding partners. In a specific aspect, PDL1 binding partners are PD-1 and / or B7-1. In another aspect, the PDL2 inhibitor is a molecule that inhibits the binding of PDL2 to its binding partners. In a specific aspect, a PDL2 binding partner is PD-1. The inhibitor may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide. Exemplary antibodies are described in U. S. Patent Nos. 8,735,553, 8,354,509, and 8,008,449, all incorporated herein by reference. Other PD-1 inhibitors for use in the301415446 - 43 -Attorney Docket No. UTSDP4183WO-1001375084methods and compositions provided herein are known in the art such as described in U. S. Patent Application Nos. US2014 / 0294898, US2014 / 022021, and US2011 / 0008369, all incorporated herein by reference.

[0145] In some aspects, the PD-1 inhibitor is an anti-PD-1 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody). In some aspects, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, and pidilizumab. In some aspects, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PDL1 or PDL2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some aspects, the PDL1 inhibitor comprises AMP-224. Nivolumab, also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®, is an anti-PD-1 antibody described in W02006 / 121168. Pembrolizumab, also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, is an anti-PD-1 antibody described in W02009 / 114335. Pidilizumab, also known as CT-011, hBAT, or hBAT-1, is an anti-PD-1 antibody described in W02009 / 101611. AMP-224, also known as B7-DCIg, is a PDL2-Fc fusion soluble receptor described in WO2010 / 027827 and WO2011 / 066342. Additional anti-cancer PD-1 inhibitors include MEDI0680, also known as AMP-514, and REGN2810.

[0146] In some aspects, the immune checkpoint inhibitor is a PDL1 inhibitor such as Durvalumab, also known as MEDI4736, atezolizumab, also known as MPDL3280A, avelumab, also known as MSB00010118C, MDX-1105, BMS-936559, or combinations thereof. In certain aspects, the immune checkpoint inhibitor is a PDL2 inhibitor such as rHlgM12B7.

[0147] In some aspects, the inhibitor comprises the heavy and light chain CDRs or VRs of nivolumab, pembrolizumab, or pidilizumab. Accordingly, in one aspect, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of nivolumab, pembrolizumab, or pidilizumab, and the CDR1, CDR2 and CDR3 domains of the VL region of nivolumab, pembrolizumab, or pidilizumab. In another aspect, the antibody competes for binding with and / or binds to the same epitope on PD-1, PDL1, or PDL2 as the above- mentioned antibodies. In another aspect, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) variable region amino acid sequence identity with the above-mentioned antibodies.

[0148] Another immune checkpoint that can be targeted in the methods provided herein as an additional anti-cancer therapy is the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152. The complete cDNA sequence of human CTI. A-4 has the Genbank accession number L15006. CTI. A-4 is found on the surface of T cells and acts as an “off”301415446 - 44 -Attorney Docket No. UTSDP4183WO-1001375084switch when bound to B7-1 (CD80) or B7-2 (CD86) on the surface of antigen-presenting cells. CTLA4 is a member of the immunoglobulin superfamily that is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells. CTLA4 is similar to the T-cell costimulatory protein, CD28, and both molecules bind to B7-1 and B7-2 on antigen-presenting cells. CTLA-4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. Intracellular CTLA-4 is also found in regulatory T cells and may be important to their function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4, an inhibitory receptor for B7 molecules. Inhibitors of the disclosure may block one or more functions of CTLA-4, B7-1, and / or B7-2 activity. In some aspects, the inhibitor blocks the CTLA-4 and B7-1 interaction. In some aspects, the inhibitor blocks the CTLA-4 and B7-2 interaction.

[0149] In some aspects, the immune checkpoint inhibitor is an anti-CTLA-4 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody), an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.

[0150] Anti-human-CTLA-4 antibodies (or VH and / or VL domains derived therefrom) suitable for use in the present methods can be generated using methods well known in the art. Alternatively, art recognized anti-CTLA-4 antibodies can be used. For example, the anti-CTLA-4 antibodies disclosed in: US 8,119,129, WO 01 / 14424, WO 98 / 42752; WO 00 / 37504 (CP675,206, also known as tremelimumab; formerly ticilimumab), U. S. Patent No. 6,207,156; Hurwitz et al., 1998; can be used in the methods disclosed herein. The teachings of each of the aforementioned publications are hereby incorporated by reference. Antibodies that compete with any of these art-recognized antibodies for binding to CTLA-4 also can be used. For example, a humanized CTLA-4 antibody is described in International Patent Application No. W02001 / 014424, W02000 / 037504, and U. S. Patent No. 8,017,114; all incorporated herein by reference.

[0151] A further anti-CTLA-4 antibody useful as a checkpoint inhibitor in the methods and compositions of the disclosure is ipilimumab (also known as 10D1, MDX- 010, MDX- 101, and Yervoy®) or antigen binding fragments and variants thereof (see, e.g., WOO 1 / 14424).

[0152] In some aspects, the inhibitor comprises the heavy and light chain CDRs or VRs of tremelimumab or ipilimumab. Accordingly, in one aspect, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of tremelimumab or ipilimumab, and the CDR1, CDR2 and CDR3 domains of the VL region of tremelimumab or ipilimumab. In another aspect, the antibody competes for binding with and / or binds to the same epitope on PD-1, B7-1, or B7-2 as the above- mentioned antibodies. In another aspect, the antibody has at least about301415446 - 45 -Attorney Docket No. UTSDP4183WO-100137508470, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) variable region amino acid sequence identity with the above-mentioned antibodies.virus

[0153] In some aspects, the additional anti-cancer therapy comprises an oncolytic virus. An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumor. Oncolytic viruses are thought not only to cause direct destruction of the tumor cells, but also to stimulate host anti-tumor immune responses for long-term immunotherapy.

[0154] In some aspects, the additional anti-cancer therapy comprises polysaccharides. Certain compounds found in mushrooms, primarily polysaccharides, can up-regulate the immune system and may have anti-cancer properties. For example, beta-glucans such as lentinan have been shown in laboratory studies to stimulate macrophage, NK cells, T cells and immune system cytokines and have been investigated in clinical trials as immunologic adjuvants.Neoantigens

[0155] In some aspects, the additional anti-cancer therapy comprises neoantigen administration. Many tumors express mutations. These mutations potentially create new targetable antigens (neoantigens) for use in T cell immunotherapy. The presence of CD8+ T cells in cancer lesions, as identified using RNA sequencing data, is higher in tumors with a high mutational burden. The level of transcripts associated with cytolytic activity of natural killer cells and T cells positively correlates with mutational load in many human tumors.

[0156] In some aspects, the additional anti-cancer therapy comprises a chemotherapy. Suitable classes of chemotherapeutic agents include (a) Alkylating Agents, such as nitrogen mustards (e.g., mechlorethamine, cylophosphamide, ifosfamide, melphalan, chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, chlorozoticin, streptozocin) and triazines (e.g., dicarbazine), (b) Antimetabolites, such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., 5-fluorouracil, floxuridine, cytarabine, azauridine) and purine analogs and related materials (e.g., 6-mercaptopurine, 6-thioguanine, pentostatin), (c) Natural Products, such as vinca alkaloids (e.g., vinblastine, vincristine), epipodophylotoxins301415446 - 46 -Attorney Docket No. UTSDP4183WO-1001375084(e.g., etoposide, teniposide), antibiotics (e.g., dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitoxanthrone), enzymes (e.g., L-asparaginase), and biological response modifiers (e.g., Interferon-a), and (d) Miscellaneous Agents, such as platinum coordination complexes (e.g., cisplatin, carboplatin), substituted ureas (e.g., hydroxyurea), methylhydiazine derivatives (e.g., procarbazine), and adrenocortical suppressants (e.g., taxol and mitotane). In some aspects, cisplatin is a particularly suitable chemotherapeutic agent.

[0157] Cisplatin has been widely used to treat cancers such as, for example, metastatic testicular or ovarian carcinoma, advanced bladder cancer, head or neck cancer, cervical cancer, lung cancer or other tumors. Cisplatin is not absorbed orally and must therefore be delivered via other routes such as, for example, intravenous, subcutaneous, intratumoral or intraperitoneal injection. Cisplatin can be used alone or in combination with other agents, with efficacious doses used in clinical applications including about 15 mg / m2 to about 20 mg / m2 for 5 days every three weeks for a total of three courses being contemplated in certain aspects. In some aspects, the amount of cisplatin delivered to the cell and / or subject in conjunction with the construct comprising an Egr-1 promoter operably linked to a polynucleotide encoding the therapeutic polypeptide is less than the amount that would be delivered when using cisplatin alone.

[0158] Other suitable chemotherapeutic agents include antimicrotubule agents, e.g., Paclitaxel (“Taxol”) and doxorubicin hydrochloride (“doxorubicin”). The combination of an Egr-1 promoter / TNFa construct delivered via an adenoviral vector and doxorubicin was determined to be effective in overcoming resistance to chemotherapy and / or TNF-a, which suggests that combination treatment with the construct and doxorubicin overcomes resistance to both doxorubicin and TNF-a.

[0159] Doxorubicin is absorbed poorly and is preferably administered intravenously. In certain aspects, appropriate intravenous doses for an adult include about 60 mg / m2 to about 75 mg / m2 at about 21-day intervals or about 25 mg / m2 to about 30 mg / m2 on each of 2 or 3 successive days repeated at about 3 week to about 4 week intervals or about 20 mg / m2 once a week. The lowest dose should be used in elderly patients, when there is prior bone-marrow depression caused by prior chemotherapy or neoplastic marrow invasion, or when the drug is combined with other myelopoietic suppressant drugs.

[0160] Nitrogen mustards are another suitable chemotherapeutic agent useful in the methods of the disclosure. A nitrogen mustard may include, but is not limited to, mechlorethamine (HN2), cyclophosphamide and / or ifosfamide, melphalan (L-sarcolysin), and chlorambucil. Cyclophosphamide (CYTOXAN®) is available from Mead Johnson and NEOSTAR® is available from Adria), is another suitable chemotherapeutic agent. Suitable oral doses for301415446 - 47 -Attorney Docket No. UTSDP4183WO-1001375084adults include, for example, about 1 mg / kg / day to about 5 mg / kg / day, intravenous doses include, for example, initially about 40 mg / kg to about 50 mg / kg in divided doses over a period of about 2 days to about 5 days or about 10 mg / kg to about 15 mg / kg about every 7 days to about 10 days or about 3 mg / kg to about 5 mg / kg twice a week or about 1.5 mg / kg / day to about 3 mg / kg / day. Because of adverse gastrointestinal effects, the intravenous route is preferred. The drug also sometimes is administered intramuscularly, by infiltration or into body cavities.

[0161] Additional suitable chemotherapeutic agents include pyrimidine analogs, such as cytarabine (cytosine arabinoside), 5-fluorouracil (fluouracil; 5-Fll) and floxuridine (fluorodeoxyuridine; FudR). 5-Fll may be administered to a subject in a dosage of anywhere between about 7.5 to about 1000 mg / m2. Further, 5-Fll dosing schedules may be for a variety of time periods, for example up to six weeks, or as determined by one of ordinary skill in the art to which this disclosure pertains.

[0162] Gemcitabine diphosphate (GEMZAR®, Eli Lilly & Co., “gemcitabine”), another suitable chemotherapeutic agent, is recommended for treatment of advanced and metastatic pancreatic cancer, and will therefore be useful in the present disclosure for these cancers as well.

[0163] The amount of the chemotherapeutic agent delivered to the patient may be variable. In one suitable aspect, the chemotherapeutic agent may be administered in an amount effective to cause arrest or regression of the cancer in a host, when the chemotherapy is administered with the construct. In other aspects, the chemotherapeutic agent may be administered in an amount that is anywhere between 2 to 10,000 fold less than the chemotherapeutic effective dose of the chemotherapeutic agent. For example, the chemotherapeutic agent may be administered in an amount that is about 20 fold less, about 500 fold less or even about 5000 fold less than the chemotherapeutic effective dose of the chemotherapeutic agent. The chemotherapeutics of the disclosure can be tested in vivo for the desired therapeutic activity in combination with the construct, as well as for determination of effective dosages. For example, such compounds can be tested in suitable animal model systems prior to testing in humans, including, but not limited to, rats, mice, chicken, cows, monkeys, rabbits, etc. In vitro testing may also be used to determine suitable combinations and dosages, as described in the examples.

[0164] In some aspects, the additional anti-cancer therapy comprises a targeted therapy. Targeted therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules (“molecular targets”) that are involved in the growth,301415446 - 48 -Attorney Docket No. UTSDP4183WO-1001375084progression, and / or spread of cancer. Targeted cancer therapies are sometimes called “molecularly targeted drugs,” “molecularly targeted therapies,” “precision medicines,” or similar names. Non-limiting examples of targeted therapies include hormone therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies, toxin delivery molecules, and the like. In particular aspects, the targeted therapy may be a poly ADP ribose polymerase (PARP) inhibitor (e.g., niraparib). PARP (e.g., PARP-1 and / or PARP-2) inhibitors are well known in the art (e.g., Olaparib, ABT- 888, BSI-201, BGP-15, INO-1001, PJ34, 3-aminobenzamide, 4-amino-1,8- naphthalimide, 6(5H)-phenanthridinone, benzamide, NU1025).Hormone

[0165] In some aspects, the additional anti-cancer therapy comprises hormone therapy. In some aspects, one or more anticancer therapies may be hormonal therapy, Hormonal therapeutic treatments can comprise, for example, hormonal agonists, hormonal antagonists (e.g., flutamide, bicalutamide, tamoxifen, raloxifene, leuprolide acetate (LUPRON), LH-RH antagonists), inhibitors of hormone biosynthesis and processing, and steroids (e.g., dexamethasone, retinoids, deltoids, betamethasone, cortisol, cortisone, prednisone, dehydrotestosterone, glucocorticoids, mineralocorticoids, estrogen, testosterone, progestins), vitamin A derivatives (e.g., all-trans retinoic acid (ATRA)); vitamin D3 analogs; antigestagens (e.g., mifepristone, onapristone), or antiandrogens (e.g., cyproterone acetate).

[0166] In some aspects, the additional anti-cancer therapy comprises radiation, such as ionizing radiation. As used herein, “ionizing radiation” means radiation comprising particles or photons that have sufficient energy or can produce sufficient energy via nuclear interactions to produce ionization (gain or loss of electrons). An exemplary and preferred ionizing radiation is an x-radiation. Means for delivering x-radiation to a target tissue or cell are well known in the art.

[0167] In some aspects, the amount of ionizing radiation is greater than 20 Gy and is administered in one dose. In some aspects, the amount of ionizing radiation is 18 Gy and is administered in three doses. In some aspects, the amount of ionizing radiation is at least, at most, or exactly 2, 4, 6, 8, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 18, 19, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 40 Gy (or any derivable range therein). In some aspects, the ionizing radiation is administered in at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 does (or any derivable range therein). When more than one dose is administered, the does may be about 1, 4, 8, 12, or 24 hours or 1, 2, 3, 4, 5, 6, 7,301415446 - 49 -Attorney Docket No. UTSDP4183WO-1001375084or 8 days or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, or 16 weeks apart, or any derivable range therein.

[0168] In some aspects, the amount of IR may be presented as a total dose of IR, which is then administered in fractionated doses. For example, in some aspects, the total dose is 50 Gy administered in 10 fractionated doses of 5 Gy each. In some aspects, the total dose is 50-90 Gy, administered in 20-60 fractionated doses of 2-3 Gy each. In some aspects, the total dose of I R is at least, at most, or about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 125, 130, 135, 140, or 150 (or any derivable range therein). In some aspects, the total dose is administered in fractionated doses of at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 20, 25, 30, 35, 40, 45, or 50 Gy (or any derivable range therein. In some aspects, at least, at most, or exactly 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 fractionated doses are administered (or any derivable range therein). In some aspects, at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 (or any derivable range therein) fractionated doses are administered per day. In some aspects, at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (or any derivable range therein) fractionated doses are administered per week. Surgery

[0169] The additional anti-cancer therapy may comprise surgery. Approximately 60% of persons with cancer will undergo surgery of some type, which includes preventative, diagnostic or staging, curative, and palliative surgery. Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and / or destroyed and may be used in conjunction with other therapies, such as the treatment of the present aspects, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy, and / or alternative therapies. Tumor resection refers to physical removal of at least part of a tumor. In addition to tumor resection, treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically-controlled surgery (Mohs’ surgery).

[0170] Upon excision of part or all of cancerous cells, tissue, or tumor, a cavity may be formed in the body. Treatment may be accomplished by perfusion, direct injection, or local application301415446 - 50 -Attorney Docket No. UTSDP4183WO-1001375084of the area with an additional anti-cancer therapy. Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. These treatments may be of varying dosages as well. Combination method with high-fat or ketogenic diet.

[0171] In some aspects, the method of treating, preventing, reducing the symptoms of, or delaying the onset of a cancer in a subject in need thereof comprises administering a controlled diet that is substantially devoid of tryptophan in combination with a high-fat and / or ketogenic macronutrient profile. The controlled diet may deliver about 40%-85% of total calories from fat (e.g., >50%, >60%, >70%) and <10% of total calories from carbohydrate, with protein supplied as an essential amino acid blend lacking tryptophan or from low tryptophan protein sources. In certain aspects, the diet follows a ketogenic 2:1, 3:1, or 4:1 (fat):(protein+carbohydrate) ratio. The regimen may be administered continuously or in cycles (e.g., 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days on-diet followed by 7-14 days on maintenance), for a total treatment window of about 2 weeks to about 6 months, with durations selected based on disease state, concomitant therapy, and clinical response.

[0172] In some aspects, subjects may receive pre-packaged meals or medical-nutrition products that: (a) meet daily caloric needs without changing total calories by more than about 1%-25% relative to baseline; (b) provide at least, about, or at most 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% of calories from fat (optionally including MCTs to facilitate ketosis); and (c) provide essential amino acids excluding tryptophan in the quantities disclosed herein. Blood p-hydroxybutyrate may be monitored to confirm ketosis, and lipid classes may be adjusted (e.g., MUFA-forward vs. MCT-forward) to optimize tolerability. The combination method may be administered as monotherapy or with additional anticancer therapies (e.g., chemotherapy, targeted therapy, radiotherapy, immunotherapy including PD-1 / PD-L1 or CTLA-4 inhibitors), given simultaneously or sequentially, in view of patient-specific considerations.

[0173] The combination method is applicable to cancers, for example MYC- related cancers and other solid or hematologic malignancies enumerated herein (e.g., HCC), particularly where tumor biology indicates enhanced tryptophan uptake and / or reliance on indole metabolites. The method may be used neoadjuvantly, adjuvantly, or for maintenance, and may be paused or transitioned to a lower-fat tryptophan-out maintenance plan following achievement of clinical objectives (e.g., radiographic response or surgical downstaging).301415446 - 51 -Attorney Docket No. UTSDP4183WO-1001375084B. Method of treating neurological diseases

[0174] Trp is a multifunctional essential amino acid that can be incorporated into new proteins, be converted into serotonin, and be metabolized by the Kyn pathway. In some aspects, the current disclosure is based on the discovery of interesting associations between Trp metabolite levels and neurological conditions. For example, low serotonin levels are linked to depression, and disruptions in metabolites like kynurenine (Kyn), xanthurenic acid (XA), cinnabarinic acid (CA), and kynurenic acid (KA) have been associated with various neurological disorders.

[0175] In some aspects, the current disclosure encompasses a method of treating, preventing, reducing the symptoms of, or delaying the onset of a neurological disease or disorder in a subject in need thereof, the method comprising administering a controlled diet to the subject, such that the controlled diet is substantially devoid of tryptophan. In some aspects, the controlled diet comprises, consists of, or consists essentially of a dietary product disclosed herein.

[0176] In some aspects, the subject is a mammal who has, or is suspected of having a neurological disease. Non-limiting examples include depression, anxiety disorders, obsessive-compulsive disorder (OCD), bipolar disorder, schizophrenia, migraine, fibromyalgia, autism spectrum disorder (ASD), and irritable bowel syndrome (IBS).EXAMPLES

[0177] The following examples are included to demonstrate preferred aspects of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of the present disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific aspects which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

[0178] Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. In some aspects, the current disclosure is based on the surprising finding that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. Is was found here that Trp-derived metabolite indole 3-pyruvate (I3P) plays a crucial role in liver tumor growth. I3P301415446 - 52 -Attorney Docket No. UTSDP4183WO-1001375084supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment.

[0179] Surprisingly it was also found that not only is a No-Trp diet effective in liver cancer treatment, it can also be used to treat other diseases. A metabolic screen in normal tissue was used to unravel tryptophan metabolism related new therapeutic avenues that selectively target aberrant pathways while preserving essential functions. Trp is a multifunctional essential amino acid that can be incorporated into new proteins, be converted into serotonin, and be metabolized by the Kyn pathway. The first step of the Kyn pathway is catabolized by 3 enzymes: indoleamine 2,3-dioxygenase 1 (IDO1), IDO2, and tryptophan 2,3-dioxygenase (TDO2). This produces the intermediate N-formyl kynurenine, which is converted into Kyn by arylformamidase (AFMID). Kyn can be further metabolized into kynurenic acid, cinnabarinic acid, xanthurenic acid, picolinic acid, quinolinic acid, and NAD+. The amounts and activity of different enzymes define the production rate and stability of specific Trp metabolites. Kyn levels are increased in colon cancer cells and in 90% of colon cancer tumors via increased Trp uptake and elevated expression of Trp-metabolizing enzymes. Kyn also causes T-cell inhibition and prevents cancer cell clearance. While IDO levels are elevated in certain tumors, several inhibitors that are designed to block the activity of IDO1 have failed in clinical trials, suggesting that a more complex and potentially tissue-specific role for Trp and its metabolites may be involved in tumor growth. In some aspects, the current disclosure provides extensive experimentation in this area to understand and use the complexity of these pathways.

[0180] Additionally, a No-Trp diet is effective in preventing and / or restoring obesity. This result was obtained after extensive experimentation using synthetic diets that each lack one of the nine essential amino acids. These diets were studied for their impact on food compunction, fat and lean mass in mice. It was observed that a diet lacking tryptophan, which was termed " Trypt-out," was the only diet that resulted in significant fat mass reduction while preserving lean mass without affecting food consumption. Remarkably, the Trypt-out diet prevented and reversed obesity, fatty liver and improved glucose clearance within a few weeks in hyperphagic Leptin knockout mice and in obese mice induced by high fat diet. Furthermore, the T rypt-out diet promoted weight loss even when combined with high dietary fat and sucrose. Respiratory exchange ratio (RER) measurements indicated a shift towards fat oxidation as an energy source. Metabolomic analyses revealed that Trp depletion led to decreased glutathione levels in both white and brown adipose tissues, triggering ferroptosis and subsequent fat reduction. This fat loss was attributed to the death of fat cells, making the effects of dietary Trp depletion long-lasting. It is proposed here that short-term administration301415446 - 53 -Attorney Docket No. UTSDP4183WO-1001375084of the T rypt-out diet represents a safe and effective intervention for achieving sustained weight loss and fatty liver clearance, even in the context of high-fat intake.Example 1: MYC-driven liver tumors exhibit an increase in Trp uptake

[0181] In the liver, Trp can be incorporated into proteins or other metabolites (FIG. 1A). Using RNA-seq to compare normal livers or liver tumors driven by the overexpression of MYC as a transgene (FIG. 1B), it was found that the expression of the Trp transporters SLC1A5 and SLC7A5, but not the Trp-metabolizing enzymes (TDO2, IDO2, AFMID, AADAT, KYNU, QPRT), were elevated in tumors (FIG. 1C). IDO1 expression was not measurable in this RNA-seq experiment. Examining a previously published dataset of MYC-induced liver tumors, it was confirmed that SLC1A5 and SLC7A5 were induced by MYC and that turning MYC off rapidly abrogated their expression (FIG. 1D), thus indicating that SLC1A5 and SLC7A5 are likely direct MYC targets in liver cancer as shown for colon cancer.

[0182] In line with the elevated expression of SLC1A5 and SLC7A5 in liver cancer, Trp levels were elevated in livers of mice upon MYC upregulation, as measured by tandem mass spectrometry (LC-MS / MS) (FIG. 1E, ). In the same samples, the Trp metabolites Kyn and kynurenic acid (KA) were decreased but Cinnabarinic acid (CA) and serotonin was not altered (FIGS. 1F-1I). To quantify Trp uptake by liver cells in vivo, control and mice carrying MYC-driven liver tumors were infused with Trp isotopically labeled in all carbons (13C-Trp) by intravenous injection using experimental conditions previously established for glutamine (FIG.1 J). The livers were dissected 1 h after injection and subjected to LC-MS / MS. This experiment revealed that 13C-Trp from the bloodstream made a larger contribution to the intracellular Trp pool in liver tumors than normal tissues, consistent with elevated uptake in tumors (FIG. 1K).Circulating 13C-T rp made a smaller contribution to the products of T rp, including Kyn, and KA, with serotonin levels below detection limit (FIGS. 1L, 1M). Other metabolites downstream were not measurable.

[0183] NAD+ and NADP+ were also reduced in MYC-driven liver tumors (FIGS. 1N, 10).NAD+ steady state levels (FIG. 1N) and levels generated from 13C-Trp (FIG. 10) were reduced in MYC-ON livers in agreement with the reduction in the expression of the enzymes necessary for their production (FIGS. 1P, 1Q). Enzymes involved in generating NAD+ via pathways that are independent of Trp were also downregulated in mouse liver tumors (FIGS.1P, 1Q). This finding supports the previous model of HCC driven by the prefoldin-like chaperone (URI), which displayed a reduction in Trp metabolites and Trp-metabolizing enzymes in parallel with the acquisition of growth-promoting pathways including phosphorylation of S6 kinase (also observed here, FIG. 1Q).301415446 - 54 -Attorney Docket No. UTSDP4183WO-1001375084Example 2: Characterizing physiological effects of synthetic diets containing low or no Trp

[0184] To test the importance of increased Trp for liver cancer growth, synthetic diets that contained established amounts of all nutrients but with Trp reduced or absent were used (FIG.2A, Table 1: for diet composition).

[0185] Table 1: Diet compositionComponent Control (g / Kg) Low Trp (g / Kg) No-Trp (g / Kg) L-T ryptophan 1.8 0.5 0L-Alanine 3.5 3.5 3.5L-Arginine HCI 12.1 12.1 12.1L-Asparagine 6 6 6L-Aspartic acid 3.5 3.5 3.5L-cystine 3.5 3.5 3.5L-Glutamic acid 40 40 40 Glycine 23.3 23.3 23.3L-Histidine HCI 4.5 4.5 4.5L-lsoleucine 8.2 8.2 8.2L-Leucine 11.1 11.1 11.1L-Lysine HCI 18 18 18L-Methionine 8.2 8.2 8.2L-Phenylalanine 7.5 7.5 7.5L- Proline 3.5 3.5 3.5L-serine 3.5 3.5 3.5L-Threonine 8.2 8.2 8.2L-Tyrosine 5 5 5L-Valine 8.2 8.2 8.2 Sucrose 351.68 351.68 351.68 Corn starch 150 150 150 Maltodextrin 150 150 150 Soybean oil 80 80 80 Cellulose 30 31.3 31.8 Mineral mix 35 35 35 Calcium phosphate 8.2 8.2 8.2 Vitamin mix 13 13 13 Choline bitartrate 2.5 2.5 2.5TBHQ, antioxidant 0.02 0.02 0.02

[0186] First, these diets were tested in normal mice. It took 21 days for the No-Trp diet to cause a significant reduction in Trp levels in the liver. In contrast, the reduced Trp diet did not affect Trp levels in the liver or in circulation (FIGS. 2B-2G). The No-Trp diet caused a 40% reduction of Trp levels in the liver (FIG. 2B) and a ~ 10-fold reduction in the serum (FIG. 2E).As expected, the levels of Kyn and serotonin were also reduced in the livers and circulation of mice fed a diet lacking Trp (FIGS. 2D-2G). Trp-reduced diets had more modest effects. Trp was the only amino acid that was significantly low in the livers (FIG. 2H) and circulation (FIG.2I) of mice fed the No-Trp diet. Interestingly and for reasons not yet determined, aspartate,301415446 - 55 -Attorney Docket No. UTSDP4183WO-1001375084glutamate, and serine in the livers (FIG. 2H) and methionine in the serum (FIG. 2I) were significantly higher in mice starved ofTrp. Trp starvation resulted in a reduction in body weight in the No-Trp mice compared to mice fed the control diet (FIG. 2J); however, similar amounts of food were consumed by both groups (FIGS. 2K-2M).

[0187] Interestingly, animals fed No-Trp diet lost predominantly fat mass (FIGS. 2N, 20) while preserving lean mass (FIGS. 2P, 2Q). The weight loss caused by Trp starvation was fully rescued by feeding the No-Trp mice the control diet (FIG. 2R), suggesting that no permanent effects on body weight were caused by transiently altering dietary levels of T rp. T rp starvation had modest effects on respiration rate, (FIG. 2S). These results also suggest that side effects of short-term Trp starvation are limited and reversible.Example 3: Trp deprivation reduces the growth of MYC-driven liver tumors

[0188] To test the importance of Trp for the initiation of MYC-driven liver cancer, mice overexpressing MYC in the liver that were fed with control, Low-Trp, or No-Trp diets for 21 days (FIG. 3A) were compared. The mice fed the control diet died between days 47-55 of age, and the mice fed Trp-reduced diet survived longer (FIG. 3B). Mice fed the No-Trp diet had no or small tumors and were all alive on day 67 (FIG. 3B). Per IACUC recommendation, all animals were sacrificed on day 67 due to >20% weight loss. Liver size and weight were lower in the mice fed the No-Trp diet than in the mice fed the control diet. The liver weight of mice with MYC-driven tumors reached 40% of the body weight. However, the liver weight of mice fed the No-Trp diet was around 10% of their body weight (FIGS. 3C, 3D). Moreover, the No-Trp diet did not affect the liver-body ratio in wild type (WT) mice (FIGS. 3D), indicating that Trp reduction has a more severe effect on cancer cells in the liver. The levels of Trp and Kyn (FIG. 3E, 3F) were lower with Trp starvation in the MYC-driven liver tumors.

[0189] To compare tumor burden, mice were fed either the control or No-Trp diets for only 21 days and all mice were sacrificed at day P50 (FIG. 3G). Mice that were Trp starved had dramatically lower liver weights (FIGS. 3H, 3I). Immunohistochemistry (IHC) showed that these livers had fewer and smaller tumors observed by the darker hematoxylin and eosin staining (H& E) (FIG. 3J). The small tumors present in livers of the mice starved of Trp were positive for Ki67 and MYC (FIGS. 3J, 3K), thus demonstrating a reduction in tumor burden, but not absence of tumors. H& E staining showed that T rp-starved tumors did not display gross cellular defects or nucleolar stress. Although provided a diet lacking T rp prevented liver tumors from forming, more modest effects on extending survival were observed when the No-Trp diet was provided to mice with advanced disease (FIGS. 3I-3M). Moreover, when Trp was reintroduced to the diet of Trp-starved MYC-ON mice, their tumors grew, but this growth was301415446 - 56 -Attorney Docket No. UTSDP4183WO-1001375084delayed (FIGS. 3N-3O). These data suggest that brief Trp starvation halted tumor growth but did not permanently impair it.Example 4: Trp starvation rescues a normal liver expression profile in MYC-ON tumors

[0190] To define the molecular changes induced by Trp starvation in liver tumors, RNA-seq of livers with tumors driven by MYC was performed. The mice were fed either the control or No-Trp diet for 21 days prior to harvesting RNA. The pattern of genes regulated by Trp starvation were compared with the genes regulated by the activation of MYC in the liver (FIG.4A-D). An overlap in the gene ontology (GO) of genes upregulated by MYC (FIG. 4A) and downregulated by Trp starvation (FIG. 4D) including cell cycle and DNA replication was found. Moreover, there was also an overlap between genes downregulated by the activation of MYC and genes upregulated by Trp starvation (FIGS. 4B, 4C). 1147 genes upregulated by MYC were downregulated upon Trp starvation and those genes were mostly related to cell growth (FIG. 4E). On the other hand, 1333 genes downregulated by activation of MYC were upregulated by Trp starvation and those genes were mostly related to lipid metabolism, a function performed by normal liver cells (FIG. 4F). A heatmap gated for the changes induced by Trp starvation confirm that starving MYC-ON livers of Trp rescues a transcriptional signature that resembles the gene signature present in WT livers (FIG. 4G). Genes involved in cell cycle, DNA replication, and ribosome biogenesis were among the pathways significantly downregulated (FIG. 4H-J). Expression was repressed upon Trp starvation for 25 genes involved in DNA replication machinery (FIG. 4H), 32 genes involved in multiple steps of ribosome biogenesis (FIG. 4I), and 8 cyclin genes (FIG. 4J). Expression was upregulated by Trp starvation for Ccnl2 and Ccni (FIG. 4J). RNA polymerase sub-units were also downregulated (FIG. 4K). On the basis of the transcripts downregulated upon Trp starvation and the motifs in their promoters, it was inferred that the activities of transcription factors are likely lower with Trp starvation. Interestingly, it was found that the most downregulated gene signature was downstream of MYC (FIG. 4I). The expression of MYC in the livers from mice fed the No-Trp diet was also lower than in livers from mice fed the control diet (FIG. 4M).Nevertheless, MYC was still expressed at significantly higher levels in the MYC-ON Trp-starved livers than in the WT livers (FIG. 4M), suggesting that there may be additional mechanism driving cell growth via the utilization of Trp in liver tumors.Example 5: Mouse and human liver cancer cell xenografts are sensitive to Trp starvation

[0191] Using RNA-seq from the TCGA data set for liver cancer, about 40% of patients with HCC had elevated SLC7A5, 50% had elevated SLC1 A5 (FIG. 5A) and 64% had either or both elevated. IDO1 was elevated in 50% of liver cancer samples while IDO2, TDO2, and AFMID301415446 - 57 -Attorney Docket No. UTSDP4183WO-1001375084were predominantly downregulated (FIG. 5A). Expression of SLC1A5, but not IDO1, TDO2, KYNU, and AFMID, was strongly associated with shortened survival of HCC patients. Trp levels were higher in the tumor than in morphologically normal liver tissue from the same patient (FIG. 5B); Kyn, KA, and serotonin were not significantly altered (FIGS. 5C-5E).Analysis of samples from individual patients with HCC revealed that 7 of the 10 patients had higher Trp levels in their tumor than in their benign tissue samples, and only 1 patient had a higher Kyn: Trp ratio in their tumor than in benign tissue samples. In summary, human liver tumors have variable levels of Kyn but higher Trp levels.

[0192] Human HCC cell lines HUH7, SNU449, and HepG2 expressed elevated levels of SLC1A5 and SLC7A5 in comparison to normal THLE2 liver cells. Silencing of MYC, SLC1A5, and SLC7A5 significantly stunted in vitro growth of HUH7 cells (FIG. 5F). Moreover, knocking MYC down by siRNA in HUH7 resulted in significantly less of the expression of SLC1A5 and SLC7A5 (FIG. 5G), thus indicating that MYC is necessary for the expression of these transporters in human cells. To determine whether tumors arising from different genetic alterations were also dependent on higher Trp levels and were sensitive to Trp starvation, a primary mouse liver cancer cell line HCC53N34 was generated from tumors driven by the combination of p53 KO and the overexpression of mutant N-Ras both found to occur in HCC. Like HUH7, knocking down MYC, SLC1A5, and SLC7A5 in these cells resulted in less cell proliferation (FIG. 5H) and the silencing of MYC resulted in less expression of SLC1A5 and SLC7A5 (FIG. 5I).

[0193] The time for in vivo growth of HCC53N and HUH7 cells as xenografts in NOD SCID mice was characterized and these 2 cell lines were used to study the importance of Trp for their growth. Both cell lines express higher levels of MYC than WT liver, thus supporting the importance of MYC in their growth (FIG. 5J). Trp starvation limited the growth of HUH7 cells xenotransplanted into NOD SCID mice (FIG. 5K. Similar growth limitations were seen in HCC53N cells xenotransplanted (FIG. 5I. Trp starvation also resulted in lower MYC levels in xenotransplanted HUH7 cells (FIG. 5M) but not in HCC53N (FIG. 5N), suggesting that Trp starvation limits tumor growth by mechanisms that do not require MYC repression. These results demonstrate that depletion of dietary T rp is efficient at limiting the growth of liver tumors arising from different genetic mutations and backgrounds. Trp starvation caused modest weigh loss in NOD SCID mice.Example 6: Trp starvation does not impair protein synthesis in liver cancer cells

[0194] Given that Trp is an essential amino acid, it was reasoned that elimination of Trp from the diet leads to a reduction in protein synthesis, thus limiting cell growth in vivo and in vitro. Indeed, incorporation of Trp into proteins is enhanced when MYC is turned on in the liver (FIG.301415446 - 58 -Attorney Docket No. UTSDP4183WO-10013750846A). These observations led us to compare protein synthesis in liver cancer cells grown in vitro and in vivo in the presence or absence of Trp. To determine whether Trp starvation in vivo affected protein synthesis in liver tumors, animals were fed with control diet or No-Trp diet for 3 weeks and infused these mice with 13C-glutamine. The incorporation of 13C-glutamine into proteins in the livers was measured by mass spectrometry 3 h after infusion. No difference in incorporation of 13C-glutamine was demonstrated between the livers from mice fed either the control or No-Trp diet (FIG. 6B, 6C).

[0195] To directly measure protein synthesis upon short-term Trp starvation, puromycylation in HUH7 and HCC53N was performed and it was found that puromycyn incorporation had no reduction between newly synthesized peptides without Trp (FIG. 6D). Translation by puromycylation was measured using culture media prepared with dialyzed serum to ensure that the T rp present in the serum was not compensating for the lack of T rp in the media. It was found that even using dialyzed serum, Trp starvation did not ablate translation rates in liver cancer cells and in some cases high levels of Trp-reduced translation. Overnight starvation of T rp prior to stimulation with increasing amounts of T rp also did not affect the overall translation of liver cancer cells. To increase the rigor of these experiments, translation initiation was measured via Click-IT chemistry with L-azidohomoalanine (AHA), which provides a fast, sensitive, non-radioactive technique to measure protein synthesis in liver cancer cells. It was found that Trp elimination had no effect on overall translation in cultured cells (FIG. 6E).Moreover, analyzing the results of mass spectrometry of the proteins expressed in MYC-ON livers in mice fed either the control or No-Trp diets for 3 weeks, no difference was found in the abundance of Trp in the up- or downregulated proteins, suggesting that the Trp content in expressed proteins is not affected by Trp starvation (FIG. 6F). Trp starvation was previously proposed to increase translational errors, leading to the incorporation of Phe, Tyr, lie or Leu instead of Trp for the Trp codon in cultured cells. Surprisingly, Trp starvation did not cause observable alterations in Trp> Phe / Tyr / lle / Leu substitutions in the livers of MYC-ON mice or xenografted HCC53N cells (FIG. 6G, 6H). 91 peptides were found with Trp substitutions in the MYC-ON livers of mice fed the control diet and 92 substitutions in livers of mice fed the No-Trp diet. The identity of these peptides varies, but the frequency of substitution at the Trp codon does not. Results show that Trp starvation does not cause amino acid substitutions in liver tumors.

[0196] The sustained protein synthesis found in Trp-starved cells can be explained by the low incidence of Trp in proteins. Importantly, this can also be explained by the increased expression of mRNAs encoding for the SLC family of transporters in livers of MYC-ON mice starved of Trp. Among these the expression levels of several amino acid transporters were also altered, suggesting an increase in nutrient transport activity into Trp-free cells. Strikingly,301415446 - 59 -Attorney Docket No. UTSDP4183WO-1001375084the expression of the Trp transporter, SLC1A5, was dramatically higher in cells and MYC-ON livers starved of Trp (FIG. 6I, 6J). Markers of autophagy and ATF4 were not affected. It was surmised that cells experiencing T rp starvation increase the expression of cellular transporters including the T rp transporter SLC1 A5 to maintain a rate of protein synthesis similar to the rate of the cells with Trp.Example 7: 13P rescues the growth of Trp-starved cells in vitro and in vivo

[0197] Given that Trp deprivation had no significant effect on protein synthesis within the experiments, whether the loss of Trp-derived metabolites is responsible for the growth restriction of liver tumors and cells in vitro and in vivo was investigated. It was examined the ability of the first downstream metabolite in each of the Trp metabolism pathways for their ability to rescue the growth of Trp-starved liver cancer cells: these are Kyn, 5HTP (a cell permeable intermediate of serotonin) and I3P, which is the first indole generated by IL4I1 (FIG.7A). Cell viability was reduced by 50% for HUH7 cells cultured in medium lacking Trp compared to HUH7 cells cultured with Trp medium. The addition of Kyn, nicotinic acid (NA) or nicotinamide (NMN) to the culture media, which reconstituted the pool of NAD+ by the salvage pathway, did not rescue the cells (FIG. 7B). Only I3P was capable of partially rescuing the growth of HUH7 cells (FIG. 7C). Increasing amounts of I3P led to further increases in the growth of Trp-starved HUH7 cells (FIG. 7D). Importantly, I3P did not increase the growth of Trp-fed cells, indicating that the growth advantage provided by I3P is the active metabolite downstream of Trp (FIG. 7E). Moreover, the I3P downstream product indole-3-aldehyde (I3A), indole-3-lacticacid (ILA) had no effect on the growth of Trp-starved cells (FIG. 7F). Like HLIH7 cells, the growth of HCC53N cells was partially rescued by I3P (FIG. 7G, 7H). No growth advantages were observed in Trp-fed HCC53N cells (FIG. 7I). Supplementation with products downstream of I3P had no effect on growth (FIG. 7J). It was confirmed that I3P can be taken up by HCC53N cells grown in complete media in vitro (FIG. 7K) and that overnight starvation of Trp in HCC53N cells is sufficient to cause a reduction in Trp, I3P and its downstream metabolites (FIG. 7I). Strikingly, I3P is present at very high levels, much higher levels than T rp itself, in liver cancer cells, an indication that this metabolite likely plays a major role in the biology of these cells.

[0198] To determine whether I3P can rescue tumor growth in vivo, HCC53N cells were transplanted into NOD SCID mice fed a No-Trp diet and treated these mice daily with intra peritoneal (IP) injections of either vehicle or I3P (FIG. 7M). I3P was biologically active in vivo and drove the growth of Trp-starved HCC53N cells (FIG. 7N, 70) but I3P treatment had no effect on the body weight of Trp-starved mice (FIG. 7P). Importantly, these xenografts demonstrated an increase in I3P when animals were fed a No-Trp diet supplemented with I3P301415446 - 60 -Attorney Docket No. UTSDP4183WO-1001375084(FIG. 7Q). However, the levels of products downstream of I3P were modestly affected (FIG.7Q). Other Trp metabolites in the Kyn pathway were unaffected by I3P supplementation. Example 8: 13P levels are higher in MYC-ON liver tumors and rescue the growth of Trp-starved tumors in vivo

[0199] Although the metabolites in the Kyn pathway were lower with MYC activation in the liver (FIG. 1), the I3P level was much higher than in the WT mice (FIG. 8A). The levels of the products downstream of I3P were not altered. Like the liver cancer cell lines, liver tumors display high levels of I3P, an indication of its biological relevance (FIG. 8A) Importantly, Trp starvation causes a reduction of I3P in the liver (FIG. 8B), thus strengthening the possibility that I3P is a potential mediator of the oncogenic function of Trp. In agreement with elevated levels of I3P, the enzyme IL4I1, which generates I3P from Trp, was also higher in MYC-ON tumors (FIG. 8C). Expression of IL4I1 correlates negatively with survival of patients with HCC (FIG. 8D) and IL4I1 expression is higher human HCC tumor samples in comparison with normal samples deposited in the TCGA (FIG. 8E). The increase in IL4I1 in liver tumors compared with other Trp-metabolizing enzymes is also in agreement with the results.

[0200] To determine whether I3P rescues tumor growth of MYC-ON Trp-starved mice, MYC-ON mice were fed the No-Trp diet (FIG. 8F) with daily IP injections of either vehicle or I3P. I3P potently rescued the growth of liver tumors as shown by liver morphology (FIG. 8G) and liver weight (FIG. 8H) without affecting the overall weight of the mice (FIG.8I). It was confirmed that I3P levels, but not Trp, were elevated in the livers of MYC-ON mice fed a No-Trp diet supplemented with I3P (FIG. 8J). As opposed to the results obtained using xenografts, Kyn and the serotonin precursor, 5HIAA, were reduced in the livers of MYC-ON mice fed No-Trp diet supplemented with I3P. However, it is not likely that this decrease plays a role on the oncogenic functions of I3P. Metabolites altered in the liver were also altered in circulation. Importantly incubation I3P supplementation in cells grown in media with or without Trp had no effects on cellular Trp levels (FIG. 8K). These results indicate that I3P supplementation in vitro and in vitro cannot reconstitute Trp levels.

[0201] I3P was previously shown to perform growth- promoting functions via the ability to bind to and drive the nuclear translocation of the transcription factor AHR in glioblastoma cells. Moreover, it was found that silencing AHR in HCC53N cells partially reduced their growth in the No-Trp media supplemented with I3P (FIG. 8I). To determine whether I3P had the ability to promote AHR translocation in liver cancer cells, the nuclear and cytosolic AHR fractions in HCC53N cells 1 h after incubation with I3P (FIG. 8M) were measured and it was found that I3P efficiently drove nuclear translocation of AHR but had no effect of MYC levels or localization. Longer incubations with I3P confirmed that I3P promotes the expression of the301415446 - 61 -Attorney Docket No. UTSDP4183WO-1001375084canonical AHR targets CYP1A1, NQO1, AHRR, and to a lower extent SCIN and UMPS (FIG.8N), suggesting that AHR activation may be involved in mediating l3P-induced growth. However, I3P had no effect on MYC or its partner MAX (FIG. 8N). Moreover, it was found that protein synthesis or MYC levels (FIGs. 8M, N,) were not consistently affected in cells or tumors supplemented with I3P, indicating that these do not mediate cancer cell growth induced by I3P. It was therefore, concluded that I3P promotes cell growth by mechanisms that are independent of MYC activation that may require AHR-dependent pathways FIG. 9.Example 9: Discussion of the results in Examples 1-8

[0202] Excessive alcohol consumption, viral hepatitis, metabolic syndrome, and obesity are all major causes of chronic inflammation and liver damage. The culmination of these insults dramatically increases the risk of HCC8. Likely due to these environmental factors, the incidence of HCC has tripled in recent decades. However, the overall survival rate of patients with HCC has remained poor. These population-wide factors necessitate the discovery of new treatments for HCC. It is proposed that a better understanding of the nutritional needs of liver cancer cells may open avenues for novel therapeutic interventions.

[0203] It is demonstrated here that MYC-driven liver tumors display enhanced Trp uptake compared to normal livers yet downregulate metabolism along the Kyn pathway. This is opposite to many cancers such as cancers of the colon, pancreas, breast, and brain in which noncancerous tissue displays a significantly lower expression of Kyn pathway enzymes than tumor tissue. Instead unexpectedly, it was found that MYC-driven liver oncogenesis requires Trp (FIG. 9). When MYC-ON mice were starved of Trp, their livers retained a normal phenotype with a transcriptome more akin to the normal liver than tumor.

[0204] Although the activity of most Trp-metabolizing enzymes in the Kyn pathway is less in HCC, it was found that the T rp-metabolizing enzyme I L411 is higher in human and mouse liver tumors than in noncancerous tissues. Furthermore, we identified I3P, the enzymatic product of IL4I1, to be the sole Trp catabolite capable of rescuing the growth of Trp-starved liver tumors in vitro and in vivo. Interestingly, MYC-driven tumors specifically accumulated I3P as opposed to its catabolites. This finding is seemingly in opposition to the findings of previous studies, which found that I L4I1 -expressing glioblastoma cells had undetectable I3P levels and high levels I3A, ILA, and KA27.

[0205] It was found that I3P is a ligand for AHR in HCC cells and can drive its nuclear translocation. The specific link between I3P, AHR, and HCC has not yet been explored except in this work. IL4I1, its metabolic pathway, and its role in tumorigenesis are relatively new considerations that require additional research. It is possible that the developing “I3P pathway” like the Kyn pathway has a nuanced role in cancer with distinct activities not solely dependent301415446 - 62 -Attorney Docket No. UTSDP4183WO-1001375084on AHR. The results demonstrate a major cell autonomous component in limiting tumor growth by Trp starvation and in the pro-tumoral role of IL4I1 in HCC. However, future studies are necessary to determine how long-term administration of a reduced Trp diet may affect the tumor microenvironment. It is possible that reducing I3P levels may promote an enhanced immune response.Example 10: Summary of Examples 12- 17

[0206] Although tryptophan (Trp) is the largest and most structurally complex amino acid, it is the least abundant in the proteome. Its distinct indole ring and high carbon content enable it to generate various biologically active metabolites such as serotonin, kynurenine (Kyn), and indole-3-pyruvate (I3P). Dysregulation of Trp metabolism has been implicated in diseases ranging from depression to cancer. Investigating Trp and its metabolites in healthy tissues offers pathways to target disease-associated disruptions selectively, while preserving essential functions. In this study, Trp metabolites across the Kyn, serotonin, and I3P pathways, as well as the microbiome-derived metabolite tryptamine, were comprehensively mapped in C57BL / 6 mice. The comprehensive analysis covered 12 peripheral organs, the central nervous system, and serum in both male and female mice at three life stages: young (3 weeks), adult (54 weeks), and aged (74 weeks). Significant tissue-, sex-, and age-specific variations was found in Trp metabolism, with notably higher levels of the oncometabolites I3P and Kyn in aging males. These findings emphasize the value of organ-specific analysis of Trp metabolism for understanding its role in disease progression and identifying targeted therapeutic opportunities.Example 11: Introduction of Examples 12-17

[0207] Trp can be metabolized through three primary pathways: the serotonin pathway, which is predominantly active in the central and peripheral nervous systems; the kynurenine (Kyn) pathway, mainly functioning in the liver; and the indole-3-pyruvate (I3P) pathway, whose function is not entirely understood but has effects in the immune system and cancer. The most extensively studied Trp-metabolizing pathway is the Kyn pathway, which generates a range of biologically active metabolites, including Kyn, kynurenic acid (KA), cinnabarinic acid (CA), xanthurenic acid (XA) and NAD+. The levels and activity of specific enzymes within the Kyn pathway determine both the production rate and stability of Trp metabolites. The initial step of the Kyn pathway can be catalyzed by indoleamine 2,3-dioxygenase 1 (IDO1), IDO2, and tryptophan 2,3-dioxygenase (TDO2). Previous studies have found Kyn and one or more of these Kyn-generating enzymes upregulated in tumors of several organs. Kyn serves as a ligand for the transcription factor, Aryl Hydrocarbon receptor (AHR), which promotes growth pathways in cancer cells. The newly identified metabolite I3P is generated via the activity of301415446 - 63 -Attorney Docket No. UTSDP4183WO-1001375084the enzyme interleukin 4-induced 1 (IL4I1), a secreted L-amino acid oxidase, which catabolizes phenylalanine, arginine, tyrosine, and Trp. I3P’S downstream metabolites are also proposed to function as ligands for AHR.

[0208] Tryptophan hydroxylases (TPH1, TPH2) are essential for serotonin production, with most synthesis occurring in the peripheral nervous system specifically in the distal gastrointestinal tract (90%) and a smaller amount in the central nervous system (10%). TPH initiates the rate-limiting step that converts Trp into serotonin. In the gut, TPH1 is expressed in enterochromaffin cells, while TPH2 is present in serotonergic neurons of the central and enteric nervous systems. Both TPH1 and TPH2 catalyze the transformation of Trp into L-5-hydroxytryptophan (5-HTP), which is then converted into serotonin (5- hydroxytryptamine, 5-HT) by L-amino acid decarboxylase. In the pineal gland, TPH1 also converts Trp into serotonin, which can subsequently be converted into melatonin. Furthermore, serotonin can be catabolized by monoamine oxidase (MAO) into 5-hydroxyindole acetaldehyde, and further processed by aldehyde dehydrogenase into 5-hydroxyindole acetic acid (5-HIAA), which is excreted in urine. The complexity of Trp metabolism is further compounded by the gut microbiome, which directly and indirectly influences Trp catabolite production, leading to associated changes in behavior and cognition. Consequently, the gut microbiome has attracted significant interest as a therapeutic target for neurological and psychiatric disorders, where Trp and its metabolites are central players.

[0209] The disclosure provided herein identifies an upregulation of enzymes involved in Kyn production and thus, an increase in Kyn levels in colon cancer, which leads to the activation of AHR. In contrast, MYC- driven liver tumors exhibit repression of these Kyn pathway enzymes, along with decreased levels of Kyn15. Interestingly, liver tumors upregulate IL4I1 and its product I3P, which acts as a potent oncometabolite in the liver. To better understand Trp utilization in normal tissues, LC-MS / MS was used to quantify 17 Trp catabolites across the three main Trp-metabolizing pathways. The metabolites in circulation were measured across visceral organs and the central nervous system in male and female C57BL / 6 during aging. This is the first comprehensive quantification of Trp metabolites in vivo. This platform may serve as a resource for other scientists interested in investigating Trp metabolism in health and disease.Example 12: Comprehensive mapping of Trp metabolites across ages, sexes, and tissues

[0210] With the goal of generating an atlas of Trp metabolites in vivo, LC-MS / MS was employed to precisely quantify 17 Trp catabolites across the three main Trp-metabolizing pathways (FIG. 10A). We quantified metabolites in the Kyn pathway: Kyn, NFK, KA, anthranilic301415446 - 64 -Attorney Docket No. UTSDP4183WO-1001375084acid (AA), N- formylanthranilic acid (NFAA), quinolinic acid, picolinic acid, 3-hydroxyanthranilic acid (3HAA) and CA; in the serotonin pathway: serotonin, melatonin, 5-hydroxyindoleacetic acid (5-HIAA), and 5- hydroxytryptophan (5-HTP); and in the I3P pathway: I3P, indole-3-carboxaldehyde (I3A), and indole-3- lactic acid (ILA) (FIG. 10A). Additionally, the microbiome-derived metabolite tryptamine was quantified (FIG. 10A). Table 2 summarizes the known functions and regulators of these metabolites.Table 2: Description of Trp metabolites: abbreviations, functions, related enzymes, and disease associationsMetabolite Abbreviatio Function Producing Disease n enzyme association T ryptophan Trp, W • Protein synthesis NA —• MetaboliteproductionKynurenine Kyn • AHR ligand TDO2JDO1 Cancer,• Immune cell, IDO2, colitis inhibition AFMIDKynurenic acid KA • Allosteric KAT Schizophreni inhibitor of a7 a nicotinicreceptors• Glutamatereceptorantagonist• Inhibits dopaminerelease in thestriatumAnthranilic acid AA • Neurotoxicity KYNU Depression,(uptake triggers Dementia apoptosis)• Inhibits cytotoxicactivity ofmacrophagesXanthurenic XA • Activates KAT Schizophreni acid m a etabotropicglutamatereceptorsmGlu2 / 3• Stimulatesdopamine releaseCinnabarinic CA • Agonist of type 4acid metabotropicglutamate(mGlu4)receptors• Neuroprotective• Hepatoprotectiveand anti- steatotic301415446 - 65 -Attorney Docket No. UTSDP4183WO-10013750845- Hydroxy 5-HTP • Anti-inflammatory TPH1 / 2T ryptophan • ROS scavengerSerotonin • Neurotransmitter DDC Depression • Modulategastrointestinalmotility5- Hydroxy 5-HIAA • Used to estimate MAOA Carcinoid i the levels of tumors, ndole acetic serotonin in Autism acid humans to spectrum determine signs disorder of depression Celiac disease lndole-3- I3PA • AHR ligand IL4I1 Cancer pyruvic acid • Immune cellinhibitionlndole-3- I3CA • AHR ligandcarboxaldehyd • Amelioratese intestinal barrierdamage

[0211] Using freshly excised, snap-frozen mouse tissues (FIG. 10B), Trp and its metabolites were measured across a comprehensive set of organs, including gonads, liver, spleen, muscle, colon, heart, lung, kidney, brown adipose tissue (BAT), thymus, inguinal white adipose tissue (ingWAT), and serum from male and female mice at three distinct life stages: 3 weeks (approximating preadolescents at 12.5 years in human terms), 53 weeks (representing adult age, 38-47 years), and 74 weeks (analogous to humans ages 56-69 years) (FIG. 10C). Additionally, we examined the same Trp metabolites in segmented regions of the central nervous system: cortex, cerebellum, diencephalon, and brainstem of the same mice (FIG. 10D).

[0212] Although Trp, I3P, and Kyn are present in most tissues, certain metabolites were either absent or undetectable in mouse tissues. For instance, melatonin was absent in C57BL / 6 mice, 3-hydroxyanthranilic acid (3HAA) and 5-hydroxytryptophan (5HTP) were only detectable in serum, and N-formylanthranilic acid (NFAA) was undetectable in all tissues (FIG. 10A). These metabolites were not be included in further analysis. Min-max normalization of each metabolite was performed to generate a heatmap displaying the relative levels of each Trp metabolite in both sexes across all organs at the time points sampled (FIG. 10C and FIG. 10E). The heatmap revealed tissue-specific patterns in Trp metabolite composition, with nearly all metabolites detected in the serum, indicating their potential to circulate within organs.

[0213] Trp levels were highest in the liver, kidney, and spleen, while metabolites in the Kyn pathway were most abundant in the liver (FIG. 10C). I3P was highest in the liver and kidney (FIG. 10C). The liver also displayed the largest amounts of tryptamine and anthranilic acid301415446 - 66 -Attorney Docket No. UTSDP4183WO-1001375084(FIG. 10C). Circulating Trp levels were markedly lower than those in the liver, kidney, lung, and colon, suggesting rapid uptake by these organs (FIG. 10C). Serotonin and its precursor 5-HTP were most prevalent in circulation, indicating a broad, whole body signaling role for serotonin pathway metabolites. Additionally, the serotonin breakdown product 5-HIAA was highest in the colon, where serotonin-producing enterochromaffin cells are located (FIG. 10C).Melatonin, 3HAA, 5HTP, and NFAA were undetectable in these tissues, and therefore, they will not be shown in the subsequent analyses.

[0214] In the central nervous system (cortex, cerebellum, brainstem, and diencephalon; FIG.10D), 9 out of the 17 metabolites were detectable. Among these, Trp, I3P, Kyn, the Kyn precursor NFK, and the serotonin product 5-HIAA were the most abundant (FIG. 10E). The heatmap revealed a clear spatial specification pattern for these metabolites, with the diencephalon showing the lowest levels of Trp and its related metabolites (FIG. 10E).Example 13: Trp metabolite abundance across different organs and tissues in adult mice

[0215] Quantitative comparison of Trp metabolites across various organs in 53-week-old (adult) male and female mice highlighted significant differences between sexes and organs (FIG. 11). Levels of all metabolites in circulation (serum) were compared to identify the organs with higher Trp uptake or decreased processing (FIG. 11 A). Trp levels were noticeably higher in the liver, kidney, and spleen, suggesting that these organs have a significant need for Trp (FIG. 11 A). Conversely, ingWAT and the heart exhibited Trp levels that were lower than serum levels (FIG. 11 A). Among the I3P pathway metabolites, I3P and I3A generally surpassed serum levels across most organs, whereas ILA did not exceed circulating levels (FIG. 11B).In addition to higher levels of Trp, the liver and kidneys also predominantly featured elevated levels of metabolites of the kynurenine pathway, except for CA, which was most abundant in the spleen and thymus (FIG. 11C). CA concentrations were higher in organs than serum. NFK was also higher in all male organs than serum, but this trend was reversed in females (FIG.11C). While AA and KA were present in the serum, these metabolites were only detectable in the liver and kidneys, respectively (FIG. 11 C). Kyn levels were particularly elevated in the liver. XA and AA were more abundant in the liver than in the bloodstream. Most metabolites in the serotonin pathway were at lower levels in the organs than serum except for 5HIAA was higher in the serum than in the colon, indicating localized metabolic activity (FIG. 11D). Tryptamine was only measurable in the liver and did not show a sex difference (FIG. 11E). The most prevalent metabolites across all examined peripheral organs included Trp, Kyn, I3P and 5-HIAA, underscoring their pivotal roles in systemic and organ-specific function. These data suggest that metabolites with higher levels in specific organs than in serum may indicate more efficient production and suggest functional specializations within those organs.301415446 - 67 -Attorney Docket No. UTSDP4183WO-1001375084Example 14: Sex differences in Trp metabolite levels

[0216] To uncover sex specificities, all Trp metabolites were compared between the sexes at each age stage (FIG. 12). At 3 weeks of age, male and female mice had similar levels of Trp metabolites across tissues (FIG. 12A); however, some organs in older mice exhibited differing metabolite levels between sexes (FIG. 12B-12C), suggesting that aging affects Trp metabolism in a sex-dependent manner. Young male mice exhibited higher levels of Trp metabolites than female mice of the same age: Kyn in the spleen, tryptamine in the liver, I3A in ingWAT, and KA in the kidney (FIG. 12A). In contrast, female mice had higher levels of Trp in the ingWAT (FIG. 12A). The serum adult females had significantly higher levels of Trp metabolites than adult males (FIG. 12B, ). Notably, males had elevated levels of I3P in the liver and gonads, and higher levels of I3A in the ingWAT and XA in the kidney than females (FIG. 12B). In aged mice, females exhibited markedly higher levels of I3A in the liver, kidney, serum, and gonads, along with other metabolites like CA and NFK when compared to males of the same age. Conversely, aged male mice maintained significantly higher levels of I3P in the liver and gonads (FIG. 12C).Example 15: Alterations in Trp metabolite levels during aging

[0217] To identify organ-specific Trp-metabolic trends across age, statistically significant changes occurring among young, adult, and aged mice were analyzed and identified. PCA plots (FIG. 13A) were generated to identify differences in Trp utilization across sex and age for each specific organ. The liver plot reveals a distinct pattern of Trp metabolites in older male mice. In BAT, there is a noticeable shift between young and older mice. Lastly, in the colon, we observed a clear difference between young and older males.

[0218] At the metabolite level, Kyn and I3P concentrations increased in liver tissues from male mice with age, and ILA concentrations in adult mice were higher than in young mice (FIG.13B). Additionally, tryptamine, which was only detectable in the liver, displayed an opposite trend: tryptamine decreased significantly with age (FIG. 13B). Given that tryptamine is primarily metabolized by the microbiome, this may indicate a change in microbiota with age not related with dietary intake. Trp, Kyn, I3P, and I3A concentrations in the colon were higher in, older male mice than in young or adult mice. Trp and Kyn concentrations in the colon of female mice also displayed significant changes: Trp concentration increased as a gradient while Kyn showed a significant change only between young and adult mice (FIG. 13C). Both I3P and I3A in the heart significantly decreased in female mice as they reach adulthood, meanwhile Trp and Kyn increase with age (FIG. 13D). A clear metabolic switch in BAT occurred between young and adult mice; Trp dramatically increased in adulthood while Trp301415446 - 68 -Attorney Docket No. UTSDP4183WO-1001375084catabolites I3A, NFK, Kyn, and CA significantly decreased (FIG. 13E-13F), suggesting that Trp metabolism may play a role in BAT growth in young mice.Example 16: Age- and sex-dependent variations in brain Trp metabolite

[0219] By comparing the levels of Trp metabolites in the various regions of the brain with those circulating in the serum at age 53 weeks (FIGS. 14A-14I), it was found that Trp concentrations were notably higher in the cortex, cerebellum, and brainstem than in circulation (FIG. 14A). All metabolites, except for Kyn in the brainstem and XA in the diencephalon and other brain regions in males, exhibited higher concentrations in the central nervous system than that circulating in the serum (FIGS. 14B-14I). To identify sex specificities, all Trp metabolites were compared between sexes at each age stage (FIGS. 14J-14L). XA displayed clear sex differences in various brain regions at all 3 ages (FIGS. 14F, 14J-14L). Trp was higher in the brainstem of females when compared to males at 3 weeks of age. At 74 weeks males have higher concentrations of Trp (FIGS. 14J, 14L). l3P was higher in the brainstem of males than in females at 74 weeks (FIG. 14L). Additionally, PCA plots did not reveal any we any aging-related trends in sex specificities of metabolites except for Brainstem showing some shifts between males and females (FIG. 14M).

[0220] Given the elevated levels of certain metabolites, particularly I3P, in mice, the presence of Trp metabolites in both chow and defined diets were analyzed. All 17 Trp metabolites were quantified in the standard chow provided by the animal facility, which includes all essential amino acids from complex protein sources. Additionally, two defined diets containing single amino acids: one containing Trp and one lacking Trp were evaluated. I3P and tryptamine were present at significantly higher levels in chow compared to defined diets (Table 3). These findings suggest that the high I3P content in the chow diet may contribute to its accumulation in tissues, as observed in the mice used in this study. Collectively, these results highlight the complexity of producing storing Trp metabolites in vivo.Table 3: Trp metabolite content in Chow, defined amino acid diet (AA) compared to Trp-free diet (TF) measured by LC-MS / MSMetabolites DietsChow (ng / g) AA (ng / g) TF (ng / g)Trp 190800.5 1474940.5 393.3NFK 195.3 552.8 11.0Kyn 2871.0 5260.8 66.0KA 308.0 3627.3 8.3AA 132.0 19.3 2.8NFAA 0 0 0XA 147.4 188.9 191.13HAA 0 0 0301415446 - 69 -Attorney Docket No. UTSDP4183WO-1001375084CA 3137.8 649.0 30.3I3P 141531.5 3250.5 2475.0ILA 858.0 324.5 33.0I3A 1248.5 522.5 11.05HTP 90.8 214.5 2.8Serotonin 2035.0 1534.5 409.85HIAA 6272.8 211.8 115.5Melatonin 11.0 0 0Tryptamine 3778.5 1193.5 88.0

[0221] In summary, organ-specific metabolic trends by sex in adult mice. The analysis indicates that most metabolites are most highly detected in the liver and kidney (FIG. 15A).Additionally, within the brain, the cerebellum and brainstem exhibited the highest levels of Trp metabolites in adult mice (FIG. 15B).Example 17: Discussion of Examples 12-16

[0222] Despite extensive data on RNA and protein expression across organs, tissues, and developmental stages, quantifying metabolites requires specialized methods, which ultimately limits the capacity for high-throughput analyses. Yet, studying metabolites has the potential to fundamentally shift the approach to understanding, diagnosing, and treating disease. Gaining a deeper understanding of the production and utilization of Trp metabolites in healthy tissues will lead to a better understanding of the deregulation of this pathway in pathological conditions. In the current study, age-, sex-, and tissue-specific variations in Trp metabolites were uncovered, including oncometabolites like Kyn and I3P, which were elevated in aging male mice. These findings suggest that T rp metabolism dysregulation may not only result from disease but could also contribute to disease susceptibility. For instance, elevated Kyn levels in the colon with aging may correlate with increased risks of colorectal cancer and inflammatory bowel diseases, which are conditions with higher prevalence in aging males. Such inflammatory diseases and cancer are often associated with shifts in the gut microbiome. Interestingly, there are also numerous associations between Trp metabolite levels and neurological conditions. For example, low serotonin levels are linked to depression, and disruptions in metabolites like Kyn, XA, CA, and KA have been associated with various neurological disorders. Clarifying these connections through further studies could significantly improve the understanding of mental health disorders.Example 18: Tryptophan-Depleted Diet (“Trypt-out”) and High-Fat Diet Synergistically Suppress Hepatocellular Carcinoma in Mouse Models

[0223] This example demonstrates that a tryptophan-deficient diet (“Trypt-out”) reduces hepatocellular carcinoma (HCC) burden in mice models and that adding a high-fat diet (HFD;301415446 - 70 -Attorney Docket No. UTSDP4183WO-100137508460% kcal from fat) to Trypt-out diet produces a further, synergistic suppression of tumor growth, yielding livers of near-normal weight and gross morphology in most animals.Materials and Methods

[0224] Twenty-week-old male FVB mice were used for all experiments. Hepatocellular carcinoma (HCC) was induced by hydrodynamic tail vein injection as previously described. Briefly, mice were injected with plasmids encoding MYC alone or in combination with dominant-negative β-catenin (DN-β-catenin), NRAS with p53 loss, all of which result in rapid and fully penetrant liver tumorigenesis. All injections were performed using a volume corresponding to 10% of body weight delivered within 5-7 seconds.

[0225] Two weeks after hydrodynamic gene delivery, mice were randomized to one of four diets administered ad libitum for three weeks: (1) Control diet, (2) Trypt-out diet (tryptophan-deficient, isocaloric), (3) High-fat control diet (HFD; 60% of calories from fat), or (4) High-fat Trypt-out (HFD Trypt-out; 60% fat with tryptophan-deficient formulation).

[0226] Diets were matched for caloric content, and animals consumed equivalent amounts across groups during the intervention period; monitoring revealed no changes in respiratory rate, locomotion, activity, or circadian rhythm and glucose tolerance improved in both Trypt-out and HFD Trypt-out groups.

[0227] At the end of the three-week dietary period, mice were euthanized, and livers were excised for gross examination, weight measurement (FIG. 16A - liver weight; 16B - overall weight), and nodule quantification (FIG. 16C); representative sections were collected for histological assessment.Results

[0228] Across all tested oncogenic drivers, Trypt-out feeding alone markedly reduced tumor growth relative to the control diet. By contrast, high-fat feeding alone (HFD) did not measurably change tumor burden compared to the control diet. Strikingly, combining HFD with Trypt-out further reduced tumor growth, leading to additional decreases in liver weight and visible nodules, beyond Trypt-out alone. In the HFD Trypt-out group, livers were of normal weight and showed near-normal gross morphology in the majority of animals, indicating a robust synergistic effect of high-fat feeding with tryptophan depletion. Operational observations across diet groups confirmed that caloric intake was equivalent, with no detectable changes in activity or circadian parameters, and glucose tolerance improved comparably in Trypt-out and HFD Trypt-out cohorts.301415446 - 71 -

Claims

Attorney Docket No. UTSDP4183WO-1001375084CLAIMSWhat is claimed is:

1. A dietary product for treating or reducing the symptoms of cancer in a subject in need thereof, the dietary product comprising at least 3 essential amino acids selected from a group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, and valine; wherein the dietary product is substantially devoid of tryptophan.

2. A method of treating or reducing the symptoms of cancer in a subject in need thereof, the method comprising administering a controlled diet to the subject, wherein the controlled diet is substantially devoid of tryptophan.

3. The dietary product of claim 1 or the method of claim 2, wherein the subject obtains at least about 25% to 50% of the daily calories from fat.

4. The dietary product of claim 1 or the method of claim 2 or 3, wherein the subject is on a ketogenic diet.

5. The dietary product of claim 1, wherein the dietary product provides about 50% to about 80% of its total calorie amount from fat.

6. The dietary product of any one of claims 1, or 3-5, wherein the dietary product comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of the dietary product.

7. The dietary product of any one of claims 1, 3-5, or 6 wherein the composition comprises no tryptophan.

8. The dietary product of any one of claims 1, or 3-7, wherein the dietary product is part of a controlled diet for a subject in need thereof; wherein the controlled diet comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food intake.

9. The dietary product of any one of claims 1, or 3-8, wherein the product comprises at least 4, at least 5, at least 6, at least 7, or 8 of the essential amino acids (excluding tryptophan).

10. The dietary product of any one of claims 1, 3-9, wherein each of the at least 4, at least 5, at least 6, at least 7, or 8 of the essential amino acids are in an amount of 0.01 mg to 10 mg per 100 grams of the dietary product.301415446 - 72 -Attorney Docket No. UTSDP4183WO-100137508411. The dietary product of any one of claims 1, or 3-10, further comprising one or more non-essential amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine.

12. The dietary product of claim 11, wherein the dietary product comprises at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or all of the non-essential amino acids.

13. The dietary product of any one of claims 1, or 3-12, further comprising one or more macronutrient and / or one or more micronutrient source, or any combination thereof.

14. The dietary product of claim 13, wherein the micronutrient comprises one or more vitamins, one or more macro minerals, or one or more trace minerals.

15. The dietary product of any one of claims 1, 3-14 wherein the subject is a mammal.

16. The dietary product of claim 15, wherein the subject is a human.

17. The dietary product of any one of claims 1, or 3-16, wherein the dietary product comprises about 7-10 g of leucine, 4-6 g of isoleucine, 4-5 g of valine, 6-8 g of lysine, 1-3 g of methionine, 2-3 g of phenylalanine, 5-7 g of threonine, 1-2 g of histidine, 4-5 g of alanine, 2-3 g of arginine, 9-13 g of aspartic acid, 14-16 g of glutamic acid, 1-2 g of glycine, 4-5 g of proline, 3-5 g of serine, or 2-3 g of tyrosine, or any combination thereof, per 100 g of protein.

18. The dietary product of any one of claims 1, or 3-16, wherein the dietary product comprises about 7-10 g of leucine, 4-6 g of isoleucine, 4-5 g of valine, 6-8 g of lysine, 1-3 g of methionine, 2-3 g of phenylalanine, 5-7 g of threonine, 1-2 g of histidine, 3-5 g of alanine, 2-3 g of arginine, 9-13 g of aspartic acid, 14-16 g of glutamic acid, 1-2 g of glycine, 4-5 g of proline, 3-5 g of serine, and 2-3 g of tyrosine per 100 g of protein.

19. The dietary product of any one of claims 1, or 3-16, wherein the dietary product comprises, per kilogram of the dietary product, about 9-13 g of leucine, 6-10 g of isoleucine, 6-10 g of valine, 16-20 g of lysine, 6-10 g of methionine, 6-10 g of phenylalanine, 6-10 g of threonine, 3-6 g of histidine, 2-6 g of alanine, 10-14 g of arginine, 2-6 g of aspartic acid, 38-301415446 - 73 -Attorney Docket No. UTSDP4183WO-100137508442 g of glutamic acid, 21-25 g of glycine, 2-6 g of proline, 2-6 g of serine, or 3-7 g of tyrosine, or any combination thereof.

20. The dietary product of any one of claims 1, or 3-19, further comprising a serotonin supplement.

21. The dietary product of any one of claims 1, or 3-20, further comprising one or more of 5-hydroxytryptophan (5-HTP), St. John’s Wort, S-adenosylmethionine (SAMe), vitamin B6, L-methylfolate, magnesium, omega-3 fatty acids, or vitamin D.

22. The dietary product of any one of claims 1, or 3-21, wherein the dietary product is in the form of a powder, a gel, a solution, a suspension, a paste, a solid, a pellet, a liquid, a liquid concentrate, a powder which may be reconstituted, a shake, a concentrate, a pill, a bar, a tablet, a capsule, injectable solution, or a ready-to-use product.

23. A method of treating or preventing a cancer in a subject in need thereof, the method comprising administering to the subject a controlled diet, wherein the controlled diet comprises administering to the subject the dietary product of any one of claims 1, or 3-22.

24. The method of any one of claims 2 or 23, wherein the cancer is a MYC-related cancer.

25. The method of claim 24, wherein the cancer is Burkitt lymphoma, diffuse large B-cell lymphoma, multiple myeloma, medulloblastoma, neuroblastoma, small cell lung cancer, colorectal cancer, breast cancer, prostate cancer, hepatocellular carcinoma (HCC), ovarian cancer, pancreatic cancer, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, esophageal cancer, gastric cancer.

26. The method of claim 25, wherein the cancer is HCC.

27. The method of any one of claims 23-26, wherein the controlled diet comprises less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food intake.

28. The method of any one of claims 23-27, wherein the controlled diet comprises no tryptophan.301415446 - 74 -Attorney Docket No. UTSDP4183WO-100137508429. The method of any one of claims 23-28 the dietary product comprises at least about 50% - 100% of the subjects diet.

30. The method of any one of claims 2, or 23-29, wherein the controlled diet changes the overall calorie intake by less than 1%-25%.

31. The method of any one of claims 2, or 23-30, wherein the method further comprises additional cancer therapies comprising chemotherapy, radiation therapy, surgery, immunotherapy, cell therapy, theragnostic, or any combination thereof.

32. The method of any one of claims 2, or 23-31, further comprising administering to the subject a serotonin supplement.

33. The method of any one of claims 2, or 23-32, further comprising one or more of 5-hydroxytryptophan (5-HTP), St. John’s Wort, S-adenosylmethionine (SAMe), vitamin B6, L-methylfolate, magnesium, omega-3 fatty acids, or vitamin D.

34. The method of any one of claims 23-33, wherein the controlled diet is for less than 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 3 weeks, or 2 weeks.

35. A method of treating or preventing a neurological disease in a subject in need thereof, the method comprising administering to the subject a controlled diet, wherein the controlled diet is substantially devoid of tryptophan.

36. The method of claim 35, wherein the neurological disease is depression, anxiety disorders, obsessive-compulsive disorder (OCD), bipolar disorder, schizophrenia, migraine, fibromyalgia, autism spectrum disorder (ASD), and irritable bowel syndrome (IBS).

37. A dietary regimen kit for treating or reducing the symptoms of cancer, the regimen kit comprising meals for a controlled diet, wherein the controlled diet is substantially devoid of tryptophan.

38. The dietary regimen kit of claim 37, wherein the meals provide about 25%-60% of calories in fat.

39. The dietary regimen kit of claim 37 or claim 38, comprising the dietary composition of any one of claims 1, or 7-24.

40. The dietary regimen kit of claim 37, or 38, wherein the meals comprise pre-packaged meals, each comprising less than 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.05 mg, or 0.001 mg of tryptophan per 100 grams of food.301415446 - 75 -Attorney Docket No. UTSDP4183WO-100137508441. The dietary regimen kit of any one of claims 37, 38, or 39, wherein the dietary regimen kit further comprises instructions for using the kit.

42. The dietary regimen kit of claim 37 or 38, 40, or 41, wherein the dietary regimen kit if for use for treating or reducing the symptoms of cancer.301415446 - 76 -

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