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Methods for treating ER+, HER2-, HRG+ breast cancer using combination therapies comprising an anti-ERBB3 antibody

A breast cancer, stop treatment technology, applied in the direction of antibody medical components, antibodies, chemical instruments and methods, can solve the problems of accelerated cytotoxic chemotherapy, short duration of treatment, etc.

Inactive Publication Date: 2019-02-05
MERRIMACK PHARMACEUTICALS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In this context, congenital and acquired resistance to endocrine therapy poses a major therapeutic challenge, as only those patients who are persistently sensitive to endocrine therapy survive long-term with a good quality of life
Unfortunately, many patients develop resistance to endocrine therapy, sometimes resulting in a very short duration of therapy, accelerating the need to initiate cytotoxic chemotherapy

Method used

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  • Methods for treating ER+, HER2-, HRG+ breast cancer using combination therapies comprising an anti-ERBB3 antibody
  • Methods for treating ER+, HER2-, HRG+ breast cancer using combination therapies comprising an anti-ERBB3 antibody
  • Methods for treating ER+, HER2-, HRG+ breast cancer using combination therapies comprising an anti-ERBB3 antibody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] Example 1: Phenotypically distinct HRG-positive cancer cells impact standard of care treatment in metastatic breast cancer models.

[0140] ErbB3 is a member of the human epidermal growth factor receptor (ErbB or HER) family, which consists of four receptors (ErbB1-4). A typical feature of ErbB networks is that the two members of the family, ErbB2 and ErbB3, are nonautonomous. ErbB2 lacks the ability to interact with growth factor ligands, while ErbB3 is defective in its kinase activity. Heregulin (HRG) is an ErbB 3 ligand that has been identified as a potent driver of proliferation and enhanced survival. HRG expression results in a distinct tumor cell phenotype characterized by an inability to respond to the effects of a variety of standard-of-care (SOC) therapies, including chemotherapy, antihormonal agents, and other targeted therapies.

[0141] In surveys of HRG expression, HRG+ cells are present in about 50% of cases in most solid tumor types. It is hypothesiz...

Embodiment 2

[0144] Example 2: Heregulin mRNA is prevalent in patients with ER+, HER2- breast cancer.

[0145] HRG expression in breast cancer cells can promote cancer progression and resistance to therapy by activating HER3 signaling. To elaborate on this finding, the prevalence of HRG mRNA was examined in the TCGA public database and by direct measurement of HRG mRNA in 197 ER-positive, HER2-negative breast cancer tumors using a clinically relevant HRG RNA-ISH assay. Both the TCGA database and patient samples were found to exhibit a prevalence of HRG mRNA with 45% ( figure 1 ).

Embodiment 3

[0146] Example 3: Heregulin induces proliferation of ER+, HER2- breast cancer cell lines

[0147] ER+, HER2- breast cancer cell lines with HRG were stimulated for 6 days and proliferation was measured in vitro. result( figure 2 ) showed that HRG induces the proliferation of MCF7, T47D and HCC1428 cell lines, all of which are ER+, HER2- cell models. These data support the conclusion that the presence of HRG drives cancer cell proliferation.

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Abstract

Provided herein are compositions and methods for treating ER+, HER2- HRG+ breast cancer (e.g., metastatic ER+, HER2- breast cancer) in a patient by administering to the patient an anti-ErbB3 antibody(e.g., seribantumab), a CDK4 / 6 inhibitor (e.g., palbociclib), and an endocrine based therapy (e.g., letrozole or fulvestrant) according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a specific dosing schedule). Also provided herein are compositions and methods for treating ER+, HER2- HRG+ breast cancer (e.g., metastatic ER+, HER2- breast cancer) in a patient by administering to the patient an anti-ErbB3 antibody (e.g., seribantumab) and an endocrine based therapy (e.g., letrozole or fulvestrant) according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a specific dosing schedule).

Description

[0001] related application [0002] This application claims priority to U.S. Provisional Application Nos. 62 / 308,783, filed March 15, 2016, 62 / 356,127, filed June 29, 2016, and 62 / 431,242, filed December 7, 2016. The content of the above application is incorporated herein by reference. Background technique [0003] Cyclin-dependent kinase 4 (CDK4) and the closely related cyclin-dependent kinase 6 (CDK6) are regulators of mitosis in mammals, acting to facilitate the initiation of DNA synthesis in preparation for cell division. Several selective inhibitors of CDK4 and 6 ("CDK4 / 6" inhibitors) are in various stages of development, one of which, palbociclib, is currently approved in the United States for use in combination with endocrine-based therapeutics (letrozole or fulvestrant) in combination therapy for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. These combinations are highly effective and ar...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K45/06A61K31/4196A61K31/519A61K31/565
CPCA61K45/06A61K31/4196A61K31/565C07K16/32A61K2039/505A61K2039/55A61K31/519A61P35/00A61K2300/00A61K39/3955A61K9/0019A61K39/39558
Inventor A·齐拜雷G·J·费恩H·张
Owner MERRIMACK PHARMACEUTICALS INC
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