Abstract: The invention relates to methods of identifying compounds that modulate mTORC1 activity in a cell by modulating the activity of SLC38A9 (NCBI Gene ID: 153129), as well as to the use of such identified compounds in the modulation of mTORC 1 and the treatment of diseases and conditions characterized by aberrant mTORC1 activity.

Abstract: Disclosed herein are methods for modulating mTORC1 activation in cells or a subject, and related compositions, kits, and agents for use in those methods. Also disclosed is the treatment of diseases and conditions characterized by decreased mTORC1 activation.

Abstract: Aspects of the invention relate to methods and compositions for characterizing or modulating the expression of metabolic mesenchymal genes. In some embodiments, methods for assessing the expression of metabolic mesenchymal genes and related gene signatures are provided that are useful for cancer classification, prognosis, diagnosis, or treatment selection.

Abstract: Disclosed herein are novel methods and compositions useful for promoting intestinal stem cell function. The methods and compositions are particularly useful for stimulating the proliferation of and/or self-renewal of intestinal stem cells, as well as for minimizing, preventing, or ameliorating cellular damage resulting from incidental or accidental exposure to radiation (e.g., cancer radiation therapy).

Abstract: Provided herein are methods, compositions, and systems for treating mitochondrial disorders (e.g., MERRF, MELAS, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia, diabetes mellitus and deafness, lactic acidosis, Leber's hereditary optic neuropathy, Wolff-Parkinson-White syndrome, Leigh syndrome, NARP, myoneurogenic gastrointestinal encephalopathy, mitochondrial DNA depletion syndrome) or neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease) by administering aspartate, or an analog or prodrug thereof, or an agent that increases intracellular levels of aspartate. Pharmaceutical compositions and kits for use in treating mitochondrial disorders and neurodegenerative diseases are also described herein. Also provided are methods for treating disease by modulating the redox state of a cell, and methods of treating a proliferative disease by administering a cytosolic aspartate aminotransferase (GOT1) inhibitor.

Abstract: In some aspects, methods of inhibiting survival or proliferation of a tumor cell are provided, the methods comprising inhibiting the glycine cleavage system (GCS) of the tumor cell. In some aspects, methods of treating a subject in need of treatment for a tumor, the method comprising inhibiting the GCS in the tumor. In some embodiments, the methods comprise contacting a tumor cell or tumor with a GCS inhibitor. In some embodiments, the tumor cell or tumor has elevated expression of serine hydroxymethyltransferase 2 (SH1VIT2). In some aspects, methods of identifying a tumor cell or tumor that is sensitive to inhibiting the GCS are provided, the methods comprising determining whether the tumor cell or tumor overexpresses SHMT2. In some aspects, methods of identifying a candidate anti-cancer agent are provided, the methods comprising identifying or modifying a GCS inhibitor.

Abstract: Disclosed herein are novel methods and compositions useful for promoting intestinal stem cell function. The methods and compositions are particularly useful for stimulating the proliferation of and/or self-renewal of intestinal stem cells, as well as for minimizing, preventing, or ameliorating cellular damage resulting from incidental or accidental exposure to radiation (e.g., cancer radiation therapy).

Abstract: The invention describes isolated mTOR-associated proteins (“mTOR-APs”) as well as isolated variants and fragments thereof and the isolated nucleic acids encoding them. The invention also describes vectors and host cells containing nucleic acid encoding an mTOR-AP polypeptide and methods for producing an mTOR-AP polypeptide. Also described are methods for screening for compounds which modulate mTOR-AP activity and methods for treating or preventing a disorder that is responsive to mTOR-AP modulation.

Abstract: In some aspects, compositions and methods for identifying therapeutic targets for treatment of mitochondrial disorders are provided. In some aspects compositions and methods for identifying therapeutic agents for treatment of mitochondrial disorders. In some aspects, the disclosure identifies ATPIF1 as a therapeutic target for mitochondrial disorders.

Abstract: In some aspects, methods of inhibiting survival or proliferation of a tumor cell are provided, the methods comprising inhibiting the glycine cleavage system (GCS) of the tumor cell. In some aspects, methods of treating a subject in need of treatment for a tumor, the method comprising inhibiting the GCS in the tumor. In some embodiments, the methods comprise contacting a tumor cell or tumor with a GCS inhibitor. In some embodiments, the tumor cell or tumor has elevated expression of serine hydroxymethyltransferase 2 (SH1VIT2). In some aspects, methods of identifying a tumor cell or tumor that is sensitive to inhibiting the GCS are provided, the methods comprising determining whether the tumor cell or tumor overexpresses SHMT2. In some aspects, methods of identifying a candidate anti-cancer agent are provided, the methods comprising identifying or modifying a GCS inhibitor.

Abstract: Aspects of the invention relate to methods and compositions for characterizing or modulating the expression of metabolic mesenchymal genes. In some embodiments, methods for assessing the expression of metabolic mesenchymal genes and related gene signatures are provided that are useful for cancer classification, prognosis, diagnosis, or treatment selection.

Abstract: In some aspects, compositions and methods useful for classifying tumor cells, tumor cell lines, or tumors according to predicted sensitivity to glucose restriction are provided. In some aspects, compositions and methods useful for classifying tumor cells, tumor cell lines, or tumors according to predicted sensitivity to OXPHOS inhibitors are provided. In some aspects, compositions and methods useful for classifying tumor cells, tumor cell lines, or tumors according to predicted sensitivity to biguanides are provided. In some aspects, methods of identifying subjects with cancer who are candidates for treatment with an OXPHOS inhibitor are provided. In some aspects, methods of identifying subjects with cancer who are candidates for treatment with a biguanide are provided. In some aspects, methods of treating subjects with cancers that are sensitive to glucose restriction are provided.

Abstract: The present invention relates to small molecule modulators of mTORC1 and mTORC2, syntheses thereof, and intermediates thereto. Such small molecule modulators are useful in the treatment of proliferative diseases (e.g., benign neoplasms, cancers, inflammatory diseases, autoimmune diseases, diabetic retinopathy) and metabolic diseases. Novel small molecules are provided that inhibit one or more of mTORC1, mTORC2, and PI3K-related proteins. Novel methods of providing soluble mTORC1 and mTORC2 complexes are discussed, as well as methods of using the soluble complexes in a high-throughput manner to screen for inhibitory compounds.

Abstract: The present invention relates to isolated raptor nucleic acid molecules of mammalian origin (e.g., human) and complements, portions and variants thereof. Another aspect of the invention are isolated raptor polypeptides of mammalian origin and portions thereof, and antibodies or antigen binding fragments thereof that specifically bind a raptor polypeptide. The present invention also relates to constructs and host cells comprising the nucleic acid molecules described herein. In addition, the present invention relates to uses of the nucleic acid and polypeptide molecules provided herein.

Abstract: The present invention provides systems for identifying genes and gene products associated with nitrogenous bisphosphonate treatment (NBP) treatment of calcium disorders. The invention also provides systems for identify and/or characterizing agents in treating calcium disorders. The invention further provides systems for diagnosing a calcium disorder and monitoring treatment of a subject.

Abstract: In some aspects, compositions and methods useful for classifying tumor cells, tumor cell lines, or tumors according to predicted sensitivity to 3-bromopyruvate (3-BrPA) are provided. In some aspects, methods of identifying subjects with cancer who are candidates for treatment with 3-BrPA are provided. In some aspects, compositions useful for subjects with cancers that express increased levels of MCT1 are provided. In some aspects, methods of treating subjects with cancers that express increased levels of MCT1 are provided. In some aspects, methods of identifying anti-tumor agents the efficacy of which is at least in part dependent on transporter-mediated uptake are provided.

Abstract: In some aspects, the invention provides compounds and methods of use for treating tumors. In some aspects, the methods comprise administering a serine biosynthesis pathway inhibitor to a subject, wherein the subject has a tumor that overexpresses PHGDH In some embodiments, the tumor is an ER negative breast cancer. In some aspects, the invention provides an in vivo RNAi-based negative selection screen of use to identify drug targets for treatment of tumors.

Abstract: The present invention relates to isolated raptor nucleic acid molecules of mammalian origin (e.g., human) and complements, portions and variants thereof. Another aspect of the invention are isolated raptor polypeptides of mammalian origin and portions thereof, and antibodies or antigen binding fragments thereof that specifically bind a raptor polypeptide. The present invention also relates to constructs and host cells comprising the nucleic acid molecules described herein. In addition, the present invention relates to uses of the nucleic acid and polypeptide molecules provided herein.

Abstract: The present invention relates to isolated raptor nucleic acid molecules of mammalian origin (e.g., human) and complements, portions and variants thereof. Another aspect of the invention are isolated raptor polypeptides of mammalian origin and portions thereof, and antibodies or antigen binding fragments thereof that specifically bind a raptor polypeptide. The present invention also relates to constructs and host cells comprising the nucleic acid molecules described herein. In addition, the present invention relates to uses of the nucleic acid and polypeptide molecules provided herein.

Abstract: Methods for identifying compounds that inhibit or stimulate the autophagy pathway are described. Devices for detecting the expression of autophagy-related genes and kits for assaying the expression of autophagy-related genes are also described. Also described are methods for identifying individuals susceptible to or afflicted with a disease state associated with an autophagy pathway defect.