Cold Spring Harbor Laboratory

Memorial Sloan Kettering Cancer Center

Dana-farber-cancer Institute Inc.

Merck Sharp + Dohme Corp.

St. Jude Children's Research Hospital

Cold Spring Harbor Institute

Scott William Lowe

Gregory J Hannon

Johannes Zuber

Christopher Vakoc

Howard O Fearnhead

Mila Elena McCurrach

Yuri Lazebnik

James Elliott Bradner

Constantine S Mitsiades

Junwei Shi

Ross Dickins

Lars Zender

Peter S Linsley

Lee Lim

Neal Rosen

Charles J Sherr

Julja Burchard

Bruce W Stillman

Aimee L Jackson

Lin He

Michele A Cleary

Xingyue He

Jill F Magnus

Rachel R Wallace-Brodeur

John P Morris, Iv

Marcus Ruscetti

Katherine McJunkin

Rebecca A Kohnz

Scott Powers

Mona S Spector

Anthony Mazurek

Christof Fellmann

Amaia Lujambio

Chun-Hao Huang

Susann Weissmueller

Eusebio Manchado-Robles

The present technology provides methods for treating pancreatic cancer using a MEK inhibitor and a CDK4/6 inhibitor. Also disclosed herein are methods for increasing patient responsiveness to chemotherapeutic and/or immunotherapeutic regimes for pancreatic cancer. Kits for use in practicing the methods are also provided.

Combination therapy with MEK inhibitor and CDK4/6 inhibitor to treat pancreatic cancer

The use of mitogen activated kinase inhibition therapy in combination with receptor tyrosine kinase therapy for the treatment of cancer is described.

Synergistic cancer treatment

The invention provides compositions, methods, and kits for the treatment of acute myeloid leukemia in a subject.

Compositions and methods for treating leukemia

A method of determining sensitivity to cancer treatment includes the step of determining the presence of overexpression of MYC in a biological sample from a patient suffering from cancer, wherein the presence of overexpression of MYC indicates a sensitivity to a treatment by a CDK9 inhibitor and wherein the cancer is selected from the group consisting of carcinoma, leukemia, and lymphoma.

Method and kits for identifying of CDK9 inhibitors for the treatment of cancer

Provided is a single construct combining a sequence encoding an RNAi molecule, a sequence encoding a reporter, and a target sequence specific for the RNAi molecule. The construct can be used to determine the potency of the encoded RNAi molecule in a direct and unbiased way. These results can be used to inform the design of potent RNAi molecules of various types and can be extended to several other applications, including: (1) generation of tiled libraries comprising every possible RNAi molecule-encoding sequence for a given gene target; (2) large-scale parallel validation of RNAi molecules targeting many genes to generate validated RNAi molecule-encoding libraries; (3) experimental comparison of design algorithms and strategies; and (4) investigation of RNAi biology in target site mutagenesis assays by screening pools containing single nucleotide changes in target sites and/or in the RNAi molecule to identify the most relevant sequence characteristics of potent RNAi-target site predictions.

High throughput methods for functionally determining RNA interference efficiency

Provided is a mosaic mouse model for use in determining the potency of an shRNA in vivo for reducing survival of cancer cells of chemotherapy-resistant leukemia. The syngeneic mouse recipient is transplanted with tet-on competent leukemia cells carrying a bicistronic nucleic acid construct comprising a promoter operably linked to a fusion gene associated with chemotherapy-resistant leukemia, and a sequence encoding a reverse tet-transactivator protein, such that both coding sequences are co-expressed from the promoter. Also provided are methods of treating soft tissue cancers.

Identification of RNAI targets and use of RNAI for rational therapy of chemotherapy-resistant leukemia and other cancers

The invention relates to recombinant vectors for inducible and/or tissue specific expression of double-stranded RNA molecules that interfere with the expression of a target gene. In certain embodiments, the invention relates to the use of Tet (tetracycline)-responsive RNA Polymerase II (Pol II) promoters (e.g., TetON or TetOFF) to direct inducible knockdown in certain cells of an integrated or an endogenous gene, such as p53. The invention also relates to a method for producing transgenic animals (e.g., mice) expressing inducible (such as tetracycline-regulated), reversible, and/or tissue-specific double-stranded RNA molecules that interfere with the expression of a target gene.

Methods for producing microRNAs

In one aspect, the invention generally relates to use of miR-34 as a biomarker to estimate TP53 function in a cell. In another aspect, the invention generally relates to multiple uses of miR-34 and siRNAs functionally and structurally related to miR-34 for the treatment of cancer.

Methods of using MIR34 as a biomarker for TP53 functional status

This invention provides a genetically tractable in situ non-human animal model for hepatocellular carcinoma. The model is useful, inter alia, in understanding the molecular mechanisms of liver cancer, in understanding the genetic alterations that lead to chemoresistance or poor prognosis, and in identifying and evaluating new therapies against hepatocellular carcinomas. The liver cancer model of this invention is made by altering hepatocytes to increase oncogene expression, to reduce tumor suppressor gene expression or both and by transplanting the resulting hepatocytes into a recipient non-human animal. This invention also relates to the use of RNA interference (RNAi) technology in vivo to efficiently identify genes associated with liver cancer, in particular those encoding tumor suppressors, by knocking out candidate genes using RNAi and observing whether tumors would develop.

Orthotopic and genetically tractable non-human animal model for liver cancer and the uses thereof

The invention provides methods for diagnosing cancers in humans by detecting DNA amplifications in chromosomal region 8p22, which encompasses the FGF-20 gene and the EFHA2 gene. Also provided are cancer treatment methods using inhibitors of FGF-20 and EFHA2. The invention also provides methods for promoting successful regeneration of liver function. These methods can be used therapeutically to improve liver function following transplantation in both recipient and donor subjects.

Role of FGF-20 in cancer diagnosis and treatment

The present invention relates to a method of identifying a compound (agent) which modulates apoptosis in transformed cells. In one embodiment, the invention is a method of identifying a compound which selectively activates apoptosis in transformed cells. In an alternative embodiment, the present invention can be used as a method of identifying a compound which inhibits apoptosis in cells. The invention also relates to a method of selectively killing transformed cells, wherein the transformed cell is contacted with a compound which selectively activates apoptosis in transformed cells, as described herein. The invention also relates to methods of treating diseases associated with defective apoptotic machinery (e.g., cancer, neurodegenerative disease). The methods of the present invention are useful for defining the biochemical mechanisms of apoptosis. In addition, the invention provides an assay to identify compounds which modulate (inhibit, activate) apoptosis, supplying new drugs which target defective apoptotic machinery associated with disease (e.g., cancer, neurodegenerative diseases such as Huntington's Disease and Alzheimers Disease).

Cell-free assay using oncogene-induced apoptosis to identify inhibitors of apoptosis in drug-resistant cells

A mouse expressing myc in B cells, because of defective function of one or more tumor suppressor genes, is useful for the testing of anti-lymphoma agents and for the testing of genes which may have an effect on the apoptotic pathway. Preferred embodiments include mice of genotypes E&mgr;-myc/p53 , E&mgr;-myc/Rb and E&mgr;-myc/p16 , and cells derived from lymphomas arising in these mice, wherein the cells may have undergone further genetic alteration. Mouse strains, lymphoma cells and cell lines of the invention can be used in methods to discover new anti-lymphoma agents, methods to characterize tumors, and to characterize genes which may affect the development of resistance to anti-tumor agents. Such methods are also part of the invention.

Lymphoma-susceptible transgenic mice and methods for studying drug sensitivity of lymphomas

Oncogene-induced apoptosis in drug-resistant cells

Growing community of inventors

Cold Spring Harbor, NY, United States of America

Scott William Lowe