Whitehead Institute for Biomedical Research

Massachusetts Institute of Technology

Dana-farber-cancer Institute Inc.

The United States of America, As Represented by the Secretary, Department of Health and Human Services

Harvard College

The Broad Institute, Inc.

Howard Hughes Medical Institute

David Sabatini

Dos D Sarbassov

Do-Hyung Kim

Nathanael Schiander Gray

Jae Won Chang

Jianming Zhang

Omer Yilmaz

Qingsong Liu

Michael Pacold

Carson C Thoreen

Lynne Chantranupong

Seong Woo Anthony Kang

Jose Orozco

Robert A Saxton

Joseph M Jacobson

Li Liu

Eric Lander

Min Shen

Matthew Brian Boxer

Steven P Gygi

Kyle Ryan Brimacombe

Jason Matthew Rohde

Thijn Reinout Brummelkamp

Noah Michael Jakimo

Shomit Sengupta

Ganesha Rai Bantukallu

Dan Yi Gui

Richard Possemato

Maria Mihaylova

Erin O'Shea

Timothy Peterson

Xin Gu

Tim Wang

Nora Kory

Kivanc Birsoy

Matthew George Vander Heiden

Jason Cantor

Rachel L Wolfson

Lucas Bryan Sullivan

Shuyu Wang

Melanie P Gygi

Zhi Tsun

Naama Kanarek

Yoav D Shaul

Pekka Katajisto

Dohoon Kim

In some aspects, the disclosure provides methods for modulating mitochondrial transport of serine in a cell, the methods comprising modulating expression or activity of one or more sideroflexins. In some aspects, methods of identifying agents that modulate sideroflexin expression or activity are provided. In some aspects, methods of treating cancer are provided.

Sideroflexins as mitochondrial serine transporters

The invention relates to methods of identifying compounds that modulate mTORC1 activity in a cell by modulating the activity of SAMTOR, as well as to the use of such identified compounds in the modulation of mTORC1 and the treatment of diseases and conditions characterized by aberrant mTORC1 activity.

Methods of identifying modulators of SAMTOR-GATOR1 interaction and use of same to modulate mTORC1

In some aspects, described herein are cell culture media that are useful for in vitro culture of mammalian cells. The culture media contain a variety of small organic compounds that are found in normal adult human blood. Also described are methods of using the culture media for a variety of purposes. Also described are methods of treating cancer.

Human plasma-like medium

The present invention relates to a cell based genomic Recorded Accumulative Memory (geRAM) system (also referred to herein as Genomically Encoded Memory (GEM)) for recoding data (i.e., changes in nucleic acid sequences in cellular DNA in response to physical and/or chemical signal(s)) from the cellular environment.

Cell-based genomic recorded accumulative memory

The present invention provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, pro-drugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I), (II) or (III) for treating diseases associated with the over-expression of phosphoglycerate dehydrogenase (PHGDH) in a subject, such as proliferative diseases (e.g., cancers (e.g., breast cancer, ER negative breast cancer, melanoma, cervical cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases). Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the activity of PHGDH or inhibit the serine biosynthetic pathway, or both.

Inhibitors of phosphoglycerate dehydrogenase (PHGDH) and uses thereof

The present invention generally relates to libraries, kits, methods, applications and screens used in functional genomics that focus on gene function in a cell and that may use vector systems and other aspects related to Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas systems and components thereof. The present invention also relates to rules for making potent single guide RNAs (sgRNAs) for use in CRISPR-Cas systems. Provided are genomic libraries and genome wide libraries, kits, methods of knocking out in parallel every gene in the genome, methods of selecting individual cell knock outs that survive under a selective pressure, methods of identifying the genetic basis of one or more medical symptoms exhibited by a patient, and methods for designing a genome-scale sgRNA library.

Functional genomics using CRISPR-Cas systems, compositions, methods, screens and applications thereof

The invention relates to methods of identifying compounds that modulate mTORC1 activity in a cell by modulating the activity of CASTOR1, as well as to the use of such identified compounds in the modulation of mTORC1 and the treatment of diseases and conditions characterized by aberrant mTORC1 activity.

Methods of identifying modulators of CASTOR1-GATOR2 interaction and use of same to modulate mTORC1

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).

Compositions and methods for promoting intestinal stem cell and/or non-stem progenitor cell function

The present invention provides methods of identifying modulators of mTORC1 based upon their effect on GATOR2-Sestrin binding or Sestrin-leucine binding; and the use of such modulators to alter mTORC1 activity in a cell and to treat disease and conditions that are effected by mTORC1 activity.

Methods of identifying modulators of sestrin-gator-2 interaction for modulating mTORC1 activity

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 mTORC1 and the treatment of diseases and conditions characterized by aberrant mTORC1 activity.

Methods for identifying compounds as modulators of SLC38A9 interactions

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.

Therapeutic strategies for treating mitochondrial disorders

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.

Metabolic gene mesenchymal signatures and uses thereof

Compositions and methods for promoting intestinal stem cell function

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.

Inhibition of the glycine cleavage system for treatment of cancer

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.

Methods Relating to Mammalian Rictor Polypeptide

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Cambridge, MA, United States of America

David Sabatini