The Brigham and Women's Hospital, Inc.

The General Hospital Corporation

Dana-Farber-Cancer Institute Inc.

The Broad Institute, Inc.

Massachusetts Institute of Technology

Harvard College

University of California

Children's Medical Center Corporation

Benjamin L Ebert

Siddhartha Jaiswal

Steven A Carr

Emma Fink

Quinlan Sievers

Jan Krönke

Namrata D Udeshi

David T Scadden

Todd R Golub

Sekar Kathiresan

Rafael Bejar

Jun Lu

Donna Neuberg

Shangqin Guo

Kristen Stevenson

Josephine Kahn

Marcela V Maus

Denisa D Wagner

Bruce D Walker

Tarjei Mikkelsen

Kimberly Martinod

W Nicholas Haining

Rob Sellar

Ofir Wolach

Max Jan

The present invention features methods for increasing sensitivity and/or reversing resistance to chemotherapy, methods for treating or preventing a cancer in a subject, methods for treating clonal hematopoiesis of indeterminate potential in a subject, and methods of identifying resistance or sensitivity to chemotherapy in a subject. In some embodiments, the methods contain the step of administering an agent that inhibits the expression or activity of a Protein phosphatase 1D (PPM1D) polypeptide or polynucleotide. The present invention also features compositions for increasing sensitivity and/or reversing resistance to chemotherapy.

Compositions and methods for treating chemotherapy resistant cancer

The present disclosure relates to therapeutic methods and clinically useful molecular switches, for which activity or degradation of a switch-presenting polypeptide can be precisely induced via administration or withdrawal of an FDA-approved drug. Certain aspects of the disclosure relate to an engineered drug-inducible heterodimeric system including a first polypeptide presenting a CRBN polypeptide disrupted for or lacking a DDB 1-interacting domain and a second polypeptide presenting a CRBN polypeptide substrate, where binding between the CRBN polypeptide and the CRBN polypeptide substrate are inducible via administration of an CFDA-approved thalidomide analog immunomodulatory drug (IMiD). Another aspect of the disclosure relates to a chimeric antigen receptor (CAR) that presents a minimal fragment of the CRBN polypeptide substrate IKZF3 capable of triggering proteasomal degradation of CAR upon administration of an FDA-approved IMiD.

Molecular switch-mediated control of engineered cells

The present invention features a knock-in mouse comprising a mutation in an endogenous CRBN locus and methods of use thereof.

Disease biomarkers and treatment methods related thereto

The invention relates to method for identifying and selecting a subject with increased risk of developing a cardiometabolic disease and optionally, providing a personalized medicine method, which may involve sequencing at least part of a genome of one or more cells in a blood sample of the subject and identifying from the sequencing one or more mutations in one or more somatic mutations.

Methods of identifying and treating a person having a predisposition to or afflicted with a cardiometabolic disease

In one aspect, the present invention features method of identifying a cell resistant to a modulator of Cereblon (CRBN). In another aspect, the present invention features a method of characterizing sensitivity of a subject to a modulator of CRBN. In yet another aspect, the present invention features a method of monitoring sensitivity of a subject to a modulator of CRBN.

Methods of characterizing resistance to modulators of Cereblon

The methods described herein include methods for the treatment of subjects who have Clonal Hematopoiesis of Indeterminate Potential (CHIP) or a Philadelphia-negative myeloproliferative neoplasm (MPN), e.g., polycythaemia vera (PV) or essential thrombocythaemia (ET), using inhibitors of JAK-STAT signaling.

Inhibition of JAK-STAT signaling inhibits formation of neutrophil extracellular traps (NETs)

The invention relates to method for identifying and selecting a subject with increased risk of developing a cardiometabolic disease and optionally, providing a personalized medicine method, which may involve sequencing at least part of a genome of one or more cells in a blood sample of the subject and identifying from said sequencing one or more mutations in one or more somatic mutations.

Method of identifying and treating a person having a predisposition to or afflicted with a cardiometabolic disease

In one aspect, the invention features a method for identifying a drug-modulated polypeptide substrate of cereblon (CRBN). In another aspect, the invention features a method of identifying a polypeptide target of a modulator of CRBN. In yet another aspect, the invention provides methods of monitoring or characterizing the sensitivity of a subject to a modulator of CRBN.

Methods of identifying a polypeptide target for degradation by a modulator of CRBN

Disclosed are methods for predicting a response of a subject with myelodysplastic syndrome to treatment with a hypomethylating agent, for example using a sample obtained from the subject. The methods can be used to select a subject for treatment with a hypomethylating agent, and/or measure a subject's response to therapy and/or disease progression/regression. The methods include detecting, in a nucleic acid sample obtained from a subject, one or more mutations of any one or more genes selected from Table 3a.

Methods for determining response to a hypomethylating agent

Somatic non-silent mutations on selected biomarkers are reliable indicators for the overall survival of Myelodysplastic Syndrome subjects.

Mutation signatures for predicting the survivability of myelodysplastic syndrome subjects

IMiD screening methods IMiD-sensitive cells with mutant CRBN

Knock-in rodent comprising a mutation in an endogenous CRBN locus and methods of use thereof

The invention relates to expression profiles of HIV-specific T-cells and their methods of use, including but not limited to treatment of HIV, increasing T-cell function and/or survival in HIV infected subjects, monitoring HIV disease progression and classifying HIV infected subjects as controllers or chronic progressors.

Biomarkers to identify HIV-specific T-cell subsets

The invention provides methods of treating certain blood related disorders, in particular, thrombocytopenia and anemia comprising increasing miR-150 expression or inhibiting miR-150 in progenitor cells respectively.

Growing community of inventors

Brookline, MA, United States of America

Benjamin L Ebert