Sloan-kettering Institute for Cancer Research

Memorial Sloan Kettering Cancer Center

Other

Neal Rosen

Samuel J Danishefsky

Laura Sepp-Lorenzino

Scott D Kuduk

Pamela Munster

Furzhong F Zheng

Ouatek Ouerfelli

David Solit

Samuel L Graham

Steven R Magnuson

Shawn J Stachel

Gabriela Chiosis

George C Prendergast

Robert M Garbaccio

Ouathek Ouerfelli

Scott William Lowe

Allen I Oliff

Daniel Baeschlin

Noa Shelach

Jackson B Gibbs

Poulikos Poulikakos

Christine Pratilas

Eusebio Manchado-Robles

Susann Weissmueller

Mark M Moasser

Nancy Kohl

Mary Srethapakdi

The present technology relates to compositions comprising BRAF inhibitors and uses thereof for treating and/or preventing a MEK inhibitor-associated cutaneous condition in a subject. Kits for use in practicing the methods are also provided.

Use of BRAF inhibitors for treating cutaneous reactions caused by treatment with a MEK inhibitor

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 present invention provides methods and compositions for the detection of novel BRAF splice variants that mediate resistance to BRAF and/or pan-RAF inhibitors. In particular, the invention provides PCR primer(s) to be used in the disclosed methods of detection. In some embodiments, the compositions and methods of the present invention are used to predict resistance to BRAF and/or pan-RAF inhibitors in a subject suffering from or suspected of having cancer and further provides alternative treatment strategy(ies) for a subject predicted to be resistant to BRAF and/or pan-RAF inhibitors. In a further embodiment, methods and composition for the identification of novel agents useful to overcome resistance to BRAF and/or pan-RAF inhibitors are disclosed. The present invention also provides isolated polynucleotide sequences of novel 5' BRAF splice variant(s) and proteins produced from such polynucleotide sequences as well as cell line(s) that endogenously or exogenously express the splice variant(s).

Methods and compositions for the detection of drug resistant BRAF isoforms

Novel methods of treating proliferative disorders characterized by elevated Her-2, and the patient is then administered an effective amount of an HSP90 inhibitor.

Method of treatment for cancers associated with elevated HER2 levels

Method of treatment for cancers associated with elevated HER 2 levels

The present invention provides identification of a thirty-five gene set that predicts the anticancer activity of inhibitors of the RAF/MEK/MAPK pathway, methods of qualifying cancer status in a subject, methods of identifying an anti-tumor response in a subject, methods of monitoring the efficacy of a therapeutic drug in a subject, and methods of identifying an agent useful in the treatment of a cancer based on expression of the thirty-five gene set.

Biomarkers for cancer treatment

Structural differences in binding pockets of members of the HSP90 family can be exploited to achieve differential degradation of kinases and other signaling proteins through the use of designed small molecules which interact with the N-terminal binding pocket with an affinity which is greater than ADP and different from the ansamycin antibiotics for at least one species of the HSP90 family. Moreover, these small molecules can be designed to be soluble in aqueous media, thus providing a further advantage over the use of ansamycin antibiotics. Pharmaceutical compositions can be formulated containing a pharmaceutically acceptable carrier and a molecule that includes a binding moiety which binds to the N-terminal pocket of at least one member of the HSP90 family of proteins. Such binding moieties were found to have antiproliferative activity against tumor cells which are dependent on proteins requiring chaperones of the HSP90 family for their function. Different chemical species have different activity, however, allowing the selection of, for example Her2 degradation without degradation of Raf kinase. Thus, the binding moieties possess an inherent targeting capacity. In addition, the small molecules can be linked to targeting moieties to provide targeting of the activity to specific classes of cells. Thus, the invention further provides a method for treatment of diseases, including cancers, by administration of these compositions. Dimeric forms of the binding moieties may also be employed.

Small molecule compositions for binding to hsp90

Bifunctional molecules comprising two hsp-binding moieties which bind to hspin the pocket to which ansamycin antibiotics bind connected via a linker are effective for inducing the degradation and/or inhibition of HER-family tyrosine kinases. For example, a compound of two geldanamycin moities joined by a four-carbon linker provides selective degradation of HER-family tyrosine kinases, without substantially affecting other kinases. These compounds can be used for treatment of HER-positive cancers with reduced toxicity, since these compounds potently kill cancer cells but affect fewer proteins than geldanamycin.

Methods and compositions for degradation and/or inhibition of HER-family tyrosine kinases

Bifunctional molecules comprising two hsp-binding moieties which bind to hsp90 in the pocket to which ansamycin antibiotics bind connected via a linker are effective for inducing the degradation and/or inhibition of HER-family tyrosine kinases. For example, a compound of two geldanamycin moities joined by a four-carbon linker provides selective degradation of HER-family tyrosine kinases, without substantially affecting other kinases. These compounds can be used for treatment of HER-positive cancers with reduced toxicity, since these compounds potently kill cancer cells but affect fewer proteins than geldanamycin.

The administration of cytotoxic agents followed by the administration of heat shock protein 90 inhibitors, such as ansamycins, has a synergistic effect on the growth inhibition of cells. This synergy occurs at doses of each cytotoxic agent that normally only causes minimal growth inhibition of cells. Such combination therapy thus allows one to use lower doses of cytotoxic agents to avoid or reduce their respective toxicity to patients without compromising their growth inhibitory effects. Thus, these combinations can be used for the treatment of an animal, preferably a mammal, that has a cell proliferative disorder, whether the cells have wild-type Rb or are Rb deficient or Rb negative. One such method, directed to treating cell proliferative disorders includes the step of administering a therapeutic effective amount of a cytotoxic agent followed by administering a therapeutic effective amount of a heat shock protein 90 inhibitor. The cytotoxic agent may be a microtubule-affecting agent, topoisomerase II inhibitor, a platinum complex, paclitaxel, or a paclitaxel derivative. The HSP90 inhibitor may be an ansamycin, radicicol or a synthetic compound that binds to the ATP-binding site of HSP90.

Methods for enhancing the efficacy of cytotoxic agents through the use of HSP90 inhibitors

The present invention relates to compounds having the structure (and pharmaceutically acceptable derivatives thereof) 

Macrocycles and uses thereof

The present invention relates to methods of treating cancer using a combination of a compound which is an antineoplastic agent and a compound which is a inhibitor of prenyl-protein transferase, which methods comprise administering to said mammal, either sequentially in any order or simultaneously, amounts of at lest two therapeutic agents selected from a group consisting of a compound which is an antineoplastic agent and a compound which is an inhibitor or prenyl-protein transferase. The invention also relates to methods of preparing such compositions.

Method of treating cancer

The present invention concerns methods for treating cell proliferative diseases, tumors associated with viral infections, and certain viral infections. The disclosed methods use compounds which inhibit heat shock protein 90 proteins. Such methods block Rb negative or deficient cells in the G2/M phase of the cell cycle and rapidly causes their destruction.

Methods for treating cell proliferative disorders and viral infections

Compounds having an ansamycin anitibiotic, or other moiety which binds to hsp90, coupled to a targeting moiety which binds specifically to a protein, receptor or marker can provide effective targeted delivery of the ansamycin antibiotic leading to the degradation of proteins and death of the targeted cells. These compositions may have different specificity than the ansamycin alone, allowing for a more specific targeting of the therapy, and can be effective in instances where the ansamycin alone has no effect. Thus, these compounds provide an entirely new class of targeted chemotherapy agents with application, depending on the nature of the targeting moiety, to treatment of a variety of different forms of cancer. Such agents can further be used to promote selective degradation of proteins associated with the pathogenesis of others diseases, including antigens associated with autoimmune disorders and pathogenic proteins associated with Alzheimer's disease. Exemplary targeting moieties which may be employed in compounds of the invention include testosterone, estradiol, tamoxifen and wortmannin.

Methods and compositions for destruction of selected proteins

This invention provides a process for the preparation of a racemic mixture of dysidiolide a method for inhibiting growth of cancerous cells comprising contracting an amount of the racemic mixture of dysidiolide effective to inhibit the growth of said cells. Further provided is a method for treating cancer in a subject which comprises administering to the subject a therapeutically effective amount of the racemic mixture of dysidiolide.

Growing community of inventors

Englewood, NJ, United States of America

Neal Rosen