Methods and compositions for detecting and modulating cancer cells

A technology for binding agents, tissue samples, applied in chemical instruments and methods, biochemical equipment and methods, drug combinations, etc., which can solve problems such as limiting clinical benefit, secondary drug resistance, etc.

Inactive Publication Date: 2018-11-23
MASSACHUSETTS INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] A major limitation of therapies that selectively target tyrosine kinase signaling pathways or microtubule dynamics is the emergence of secondary drug resistance
After the initial response, secondary resistance invariably ensues, limiting the clinical benefit of these drugs

Method used

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  • Methods and compositions for detecting and modulating cancer cells
  • Methods and compositions for detecting and modulating cancer cells
  • Methods and compositions for detecting and modulating cancer cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0253] Increased Mena or Mena in Example 1.MDA-MB-231 cells INV Expression drives taxol-utilized therapy in vitro resistance to treatment with doxorubicin or cisplatin does not drive resistance to treatment with doxorubicin or cisplatin. Analysis of elevated Mena isoforms (Mena or Mena INV ) expression on the response of breast cancer cells to chemotherapy, said triple-negative breast cancer cell line expressing low endogenous levels of Mena and expressing undetectable levels of Mena in vitro INV ( Figure 1D ). Production of Stably Expressing GFP, GFP-Tagged Mena or Mena by Retroviral Infection INV MDA-MB-231 populations were then subjected to FACS to generate cell populations expressing uniform and equivalent levels of each construct. The resulting expressed GFP-Mena INV , GFP-Mena or GFP MDA-MB-231 populations were spread in 96-well plates, and treated with doxorubicin or taxol with a concentration range of 0.1nM to 100μM or cisplatin with a concentration range of 1...

Embodiment 2

[0254] Example 2. Endogenous levels of Mena in breast cancer cell lines correlate with their resistance to taxol treatment. Whereas initial experiments relied on ectopic expression in a single cell line, we examined the sensitivity to taxol in a small panel of breast cancer cell lines with varying levels of endogenous Mena expression. Anti-pan Mena antibodies from common subtypes (including Luminal A (MDA-MB 175IIV and T47D), HER2-positive (MDA-MD 453) and TNBC (SUM 159, BT-20, MDA-MB 436, LM2, BT-549, MDA-MB 231)) the expression levels of endogenous Mena protein among nine human breast cancer cell lines ( Figure 1D ; Note that the analysis is limited to Mena because MenaINV was not expressed at detectable levels in any of these cultured breast cancer cell lines). Measurement of taxol potency (fraction of viable cells after treatment with a range of taxol concentrations for 72 hours) ( Figure 1E ), and a highly significant inverse correlation was observed between Taxol po...

Embodiment 3

[0255] Example 3. Mena or Mena INV Expression blocks the efficacy of taxol on tumors in treated animals. By expressing GFP (control), GFP-Mena (Mena) or GFP-Mena INV (Mena INV ) MDA-MB-231 cells were injected into the mammary fat pad of NOD-SCID mice to generate mice with xenograft tumors. Once the primary tumor reached 1 cm in diameter, mice were treated with three doses of taxol (10 mg / kg) or two doses of doxorubicin (5 mg / kg). Tumor size was measured before and after treatment. Treatment with taxol or doxorubicin significantly reduced control tumor growth compared to vehicle-treated mice, however, Mena or Mena INV Tumor growth was not affected by taxol treatment ( Figure 2A ). These in vivo findings are consistent with those obtained in in vitro data, suggesting that Men / Mena INV Promoted resistance to taxol, as judged by tumor growth. Although in vitro experiments failed to reveal ectopic Mena or Mena INV The effect of expression on the sensitivity of cells to d...

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Abstract

The present disclosure provides methods of treatment and compositions for improving and determining the efficacy of anti-cancer therapies involving tubulin remodeling or protein tyrosine kinase activity by modulating and assaying the presence of certain Mena splicing isoforms.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 255,293, filed November 13, 2015, entitled "METHODS AND COMPOSITIONS FORDETECTING AND MODULATING CANCER CELLS," the entire disclosure of which is incorporated herein by reference. [0003] Statement of Government Funding [0004] This invention was made with government support under U54-CA112967 awarded by the National Institutes of Health. The government has certain rights in this invention. [0005] incorporated by reference [0006] Sequence information contained in electronic file title: 1515028_108WO2_Sequence_Listing_ST25.txt (size 4.23KB) created on November 14, 2016 using Patent-In 3.5 and Checker 4.4.0, in compliance with 37C.F.R.§1.52(e)(5) It is hereby incorporated by reference in its entirety. [0007] background 1. Technical field [0008] Methods and compositions for predicting, monitoring and enhancing the efficacy of anticance...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K14/435C12N15/113G01N33/53G01N33/574
CPCA61K39/395A61P1/04A61P1/16A61P1/18A61P11/00A61P13/08A61P15/00A61P25/00A61P35/00C07K14/435G01N33/57407G01N33/57484G01N2333/4706C12Q1/6886C12Q2600/106C12Q2600/158
Inventor F·B·戈特勒S·K·休斯M·J·奥丁D·A·劳芬伯格M·奥凯蒂J·S·康狄利斯
Owner MASSACHUSETTS INST OF TECH
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