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Treatment of breast cancer brain metastases

A technology for breast cancer and brain metastases, applied in the field of Her3 antagonists and phosphatidylinositol 3 kinase inhibitors, which can solve the problems of limited treatment options and inability to control brain metastases

Active Publication Date: 2018-08-03
MASSACHUSETTS GENERAL HOSPITAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Treatment options are limited, the same anti-HER2 therapy that systemically slows growth often fails to control brain metastases

Method used

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  • Treatment of breast cancer brain metastases
  • Treatment of breast cancer brain metastases
  • Treatment of breast cancer brain metastases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0412] Example 1: Differential response of HER2-positive breast cancer to PI3K inhibition when grown in MFP or brain

[0413] 5-(2,6-Di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine (referred to herein as "compound A") is a potent and specific A broad-spectrum class I PI3K inhibitor active against breast cancer cells harboring HER2 amplification and oncogenic PI3K catalytic subunit alpha (PIK3CA) mutations. We compared the efficacy of Compound A against the same human HER2-positive breast cancer cells grown in nude mouse MFP or in the brain parenchyma. The three breast cancer cell lines examined included HER2 amplified BT474, HER2 amplified and PIK3CA mutated (E545K) MDA-MB-361, and PIK3CA mutated (H1047R) T-47D cell lines. While Compound A caused regression of HER2- or PI3K-driven breast tumors grown in MFP, established brain metastases were resistant to treatment ( figure 1 A and 1B). Tumor tissues collected 2 hours after the last dose of Compound A s...

Embodiment 2

[0414] Example 2: Resistance of HER2-positive breast cancer cells requires sustained influence from the brain microenvironment

[0415] We extended our investigation into breast cancer BM resistance to PI3K inhibition by asking whether breast cancer cells require persistent influence from the brain microenvironment. We isolated breast cancer cells (termed BT474-Gluc-BR) after dissociating brain metastases. After culturing in vitro for one week, most of the living cells were identified as cancer cells by GFP. These "brain microenvironment exposed" breast cancer cells were similarly sensitive to Compound A in vitro as the parental cells. This data demonstrates that the brain microenvironment did not induce permanent changes in breast cancer cells, nor was there preferential growth of Compound A resistant clones in the brain. Instead, breast cancer cells must receive continuous support from the brain microenvironment to maintain resistance.

Embodiment 3

[0416] Example 3: MFP and brain tumors have equivalent growth rates

[0417] We first hypothesized that the brain microenvironment induces breast cancer cells to be more proliferative, thereby reducing the ability to slow their growth with targeted drugs. Although fewer breast cancer cells formed tumors in the brain parenchyma compared to MFP, once tumors were established, cancer cells grew at the same rate in both environments.

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PUM

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Abstract

The present invention relates to a pharmaceutical combination which comprises (a) a phosphatidylinositol 3-kinase inhibitor or pharmaceutically acceptable salt thereof, and (b) a Her3 antagonist, forsimultaneous, separate or sequential administration for the treatment of breast cancer brain metastases; a method of treating a subject having a breast cancer brain metastases comprising administration of said combination to a subject in need thereof; use of such combination for the treatment of breast cancer brain metastases; and a commercial package comprising such combination.

Description

technical field [0001] The present invention relates to a drug combination for simultaneous, separate or sequential administration to treat metastatic breast cancer in the brain (referred to herein as breast cancer brain metastases) comprising (a) a phosphatidylinositol 3-kinase inhibitor or its alternative Pharmaceutically acceptable salts and (b) Her3 antagonists. Background technique [0002] Significant progress has been made in the development and optimization of HER2-targeted therapies for breast cancer. Examples of FDA-approved drugs with significant clinical efficacy in metastatic disease include the anti-HER2 antibody trastuzumab, the dual EGFR-HER2 kinase inhibitor lapatinib, the anti-HER2-HER3 dimerization Inhibitor pertuzumab and antibody-drug conjugate T-DM1 (Krop, I.E. et al. Lancet Oncol (2014); Slamon, D.J. et al. The New England journal of medicine 344, 783-792 (2001)). Clinical data revealed an increased incidence of brain metastases (BM) following adjuva...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4741A61K38/17A61K45/00A61K39/395
CPCA61K39/39558C07K16/30A61K2039/505C07K2317/73C07K2317/76A61K45/06A61K31/5377C07K16/32A61P35/04A61K2300/00A61K2039/545C07K2317/565
Inventor Q·盛R·K·贾殷V·阿斯考克斯拉基斯G·B·费拉罗福村大D·P·科达克
Owner MASSACHUSETTS GENERAL HOSPITAL
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