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Diagnostic and therapeutic methods for cancer

A cancer, therapeutic technology used in the field of diagnosis and treatment of cancer, which can solve the problems of detection and treatment difficulties

Pending Publication Date: 2020-07-03
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Certain cancers can rapidly grow and spread in an uncontrolled manner, making timely detection and treatment extremely difficult

Method used

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  • Diagnostic and therapeutic methods for cancer
  • Diagnostic and therapeutic methods for cancer
  • Diagnostic and therapeutic methods for cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0274] Example 1: Materials and methods

[0275] in vitro method

[0276] Cell Lines and Reagents

[0277] Anti-BRAF (sc-5284) and anti-CRAF (sc-133) antibodies were purchased from Santa Cruz Biotechnology. Anti-MEK1 (610122) and anti-CRAF (610152) antibodies were purchased from BD Biosciences. Anti-pMEK(S217 / S221)(9121), Anti-ERK(9107), Anti-pERK(T202 / Y204)(9101), Anti-pCRAF(S338)(9427), Anti-pEGFR(Y1068)(3777), AKT(9272) , pAKT(T308) (13038), cleaved PARP (9521), and anti-β-actin (4970) were purchased from CellSignaling Technology. IR-conjugated secondary antibodies goat anti-mouse 680LT (926-68020), goat anti-human 680LT (926-68032), and goat anti-rabbit 800CW (926-32211) were purchased from Li-Cor. All Western blots were scanned on Li-Cor CLX using dual IR-conjugated secondary antibodies. All cell lines were obtained from the American Type Culture Collection (ATCC) and supplemented with 10% heat-inactivated FBS (HyClone, SH3007003HI), 1X GlutaMAX (Gibco, 35050-061),...

Embodiment 2

[0318] Example 2: RAF Kinase Inhibitors Lack Potent Single Agent Efficacy in KRAS Mutant Cell Lines

[0319] To determine whether RAF kinase inhibitors could be used therapeutically in KRAS mutant cell lines, for type 1.5 RAF inhibitors, dabrafenib, vemurafenib, and the "paradox destroyer" PLX-8394, and type II RAF Inhibitors, AZ-628 and LY3009120, assessed cell viability in a panel of RAF inhibitors in KRAS mutant versus BRAF-V600E cell lines. The clinically approved type 1.5 BRAF inhibitors, vemurafenib and dabrafenib, and PLX-8394 showed activity in BRAF-V600E mutant cell lines (as indicated in black), but not in KRAS mutant cell lines otherwise (as indicated in red) ( Figure 1A ). As expected, the type 1.5 inhibitors vemurafenib and dabrafenib, but not PLX-8394, lead to paradoxical activation of downstream pMEK in KRAS mutant tumors ( Figure 1B ). In contrast to type 1.5 inhibitors, type II pan-RAF inhibitors showed better inhibition of KRAS mutant cell lines, however...

Embodiment 3

[0321] Example 3: Conformation-specific RAF and MEK inhibitors exhibit synergy in RAS mutant cell lines

[0322] Although the top hits from the screen were MEK inhibitors, not all MEK inhibitors were equally synergistic. While cobimetinib, pimasertib, ramitinib, and PD901 scored highest among the compounds tested, trametinib and GDC-0623 showed no difference in mean viability despite being potent MEK inhibitors ( Figure 1E ). MEK inhibitors were previously reported to have differential mechanisms of action depending on their ability to trap inactive RAF-MEK complexes (Hatzivassiliou et al., Nature 501:232-236 (2013)). This drug-stabilized complex prevents RAF from phosphorylating MEK. To determine whether the mechanism of action of MEK inhibitors affects synergy with AZ-628, several MEK inhibitors with different molecular mechanisms were tested, and it was found that MEK inhibitors that trap inactive RAF-MEK complexes and do not induce pMEK ( Such as Trametinib, GDC-0623,...

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PUM

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Abstract

The present invention provides diagnostic and therapeutic methods and compositions for cancer. The invention provides methods of determining whether an individual having a cancer is likely to respondto treatment comprising a pan-RAF dimer inhibitor and a MEK or PI3K inhibitor, methods of predicting responsiveness of an individual having a cancer to treatment comprising a pan-RAF dimer inhibitor and a MEK or PI3K inhibitor, methods of selecting a therapy for an individual having a cancer, and methods of treating an individual having cancer based on the presence of a biomarker of the invention(e.g., a KRAS activating mutation, e.g., a KRAS-G13D mutation, or an NRAS activating mutation).

Description

[0001] sequence listing [0002] This application, containing a Sequence Listing, has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on August 9, 2018, is named 50474-171WO2_Sequence_Listing_8.09.18_ST25 and is 1,738 bytes in size. [0003] field of invention [0004] The present invention relates to diagnostic and therapeutic methods for the treatment of proliferative cell disorders, such as cancer, using pan-RAF dimer inhibitors and MEK or PI3K inhibitors. Also provided are related kits and compositions. [0005] Background of the invention [0006] Cancer remains one of the deadliest threats to human health. Certain cancers can grow and metastasize rapidly in an uncontrolled manner, making timely detection and treatment extremely difficult. Cancer strikes nearly 1.3 million new patients each year in the United States and is the second leading cause of death after heart disease, accounting for ab...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886
CPCC12Q1/6886C12Q2600/106C12Q2600/156A61P35/00A61K31/519A61K31/553A61K45/06
Inventor C·N·克利金S·马莱克I·延
Owner F HOFFMANN LA ROCHE & CO AG
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