Massachusetts Institute of Technology

Dana-farber-cancer Institute Inc.

The Broad Institute, Inc.

Harvard College

Asaf Rotem

David A Weitz

Aviv Regev

Orit Rozenblatt-Rosen

Benjamin Izar

Kevin Struhl

Livnat Jerby

Paul Blainey

Levi A Garraway

Anindita Basu

Liyi Xu

Christopher B Ford

Itay Tirosh

Elizabeth Stover

The subject matter disclosed herein is generally directed to detecting and modulating novel gene signatures for the treatment and prognosis of cancer. The novel gene signatures predict overall survival in cancer and can be targeted therapeutically. Specifically, disclosed is a resistance program identified by a comprehensive single-cell profiling study in melanoma patients, which was validated in two large validation cohorts. Using a large-scale in silico prediction, CDK4/6 inhibitors were identified as a class of drugs that may reverse this resistance program. These predictions were validated in melanoma cell lines, patient-derived co-culture models, and melanoma in vivo models, which show that the combination of abemaciclib and immune checkpoint blockade (ICB) overcome intrinsic drug resistance. The present invention provides for detecting an immunotherapy resistance signature and modulating the signature with CDK4/6 inhibition. Also provided is a novel phased immunotherapy and CDK4/6 inhibitor combination therapy regimen.

Methods and compositions for detecting and modulating an immunotherapy resistance gene signature in cancer

Described herein are compositions and methods of using single-cell RNA-sequencing to identify treatment resistance in patients with ovarian cancer. Also, described herein are compositions and methods for treatment targeting resistance in patients with ovarian cancer.

Compositions and methods for treating ovarian tumors

The subject matter disclosed herein is generally directed to detecting and modulating novel gene signatures for the treatment and prognosis of cancer. The novel gene signatures predict overall survival in cancer and can be targeted therapeutically.

The present invention generally relates to a controlled fluidic device to develop spatially complex environments to enhance the rate of evolution in cell populations. The method further provides an enhanced understanding in the emergence, for example, drug resistance during cancer chemotherapy.

High-throughput dynamic reagent delivery system

A method for detecting oncogenic growth and viability, and/or degree of cellular transformation and/or identifying an agent that inhibits cellular transformation is disclosed. The method including: providing a cellular sample, such as a sample of cells obtained from a subject or a cell line; culturing the cellular sample in low attachment conditions; and detecting growth and7or cell viability of the sample, wherein increased growth relative and/or viability relative to a control or control level indicative of basal growth and/or viability indicates cellular transformation. In some embodiments, the method includes introducing a n expression vector into cells of the cellular sample, wherein the expression vector comprises a gene product expression sequence being tested for transformation ability. In some embodiments the cellular sample is contacted with a test agent and growth and/or cell viability of the sample is determined to determine if the agent inhibits transformation.

High-throughput drug and genetic assays for cellular transformation

Growing community of inventors

Boston, MA, United States of America

Asaf Rotem