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Treatment of Cancers Expressing p95 ErbB2

a cancer and erbb2 technology, applied in the field of solid tumor treatment, can solve the problems of poor response to therapy, damage or kill normal cells, and many existing anti-cancer chemotherapeutics are non-specifi

Inactive Publication Date: 2011-01-27
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

A further aspect of the present invention is a method of treating a subject with a solid tumor whose tumor expresses p95ErbB2, by administering a therapeutically effective amount of a p95ErbB2 inhibitor to the subject.
A further aspect of the present invention is a method of treating a subject with breast cancer who has shown resistance to a p185ErbB2 inhibitor and whose tumor p95ErbB2 expresses p95ErbB2, by administering a therapeutically effective amount of a inhibitor to the subject.
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Problems solved by technology

Many existing anti-cancer chemotherapeutics are non-specific, in that they typically damage or kill normal cells as well as malignant cells.
Elevated serum levels of ErbB2 ECD in women with breast cancer has also been correlated with a poorer response to therapy.
However, resistance to trastuzumab frequently occurs within the first year of treatment.

Method used

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  • Treatment of Cancers Expressing p95 ErbB2
  • Treatment of Cancers Expressing p95 ErbB2
  • Treatment of Cancers Expressing p95 ErbB2

Examples

Experimental program
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Effect test

example 1

Materials and Methods

Materials

HN5, an EGFR overexpressing LICR-LON-HN5 head and neck carcinoma cell line was kindly provided by Helmout Modjtahedi at the Institute of Cancer Research, Surrey, U.K. The ErbB2 overexpressing human breast adenocarcinoma cell line, BT474 was obtained from the American Type Culture Collection (Manassas, Va., USA). HB4a cells are derived from human mammary luminal tissue; ErbB2 transfection of parental HB4a cells yielded the HB4a C5.2 cell line (Harris et al., Int J. Cancer. 80:477 1999). 51 cells, which express elevated levels of p-ErbB2 were established by sub-cloning HB4a C5.2 (Xia et al., Oncogene, 21:6255 (2002)). EGF was purchased from Sigma Chemical (St. Louis, Mo., USA). Recombinant human NRG-1-B1 / HRGB1 EGFR domain (heregulin, HRG) was from RD system (Minneapolis, Minn., USA). Anti-phosphotyrosine antibody was purchased from Sigma and Upstate (Lake Placid, N.Y., USA). Anti-EGFR (Ab-12) and anti-c-ErbB2 (Ab-11) monoclonal antibodies were from Neo Ma...

example 2

Inhibition of p95 by GW572016

FIG. 1 demonstrates the effects of GW572016 on the expression of phospho-ErbB2 (p185), EGFR (p170), and p95 in BT474, HN5, 51 and Hb4a cell lines. Western blot analysis was performed using equal amounts of protein from whole cell extracts using anti-pTyr monoclonal antibody. Steady state protein levels of phosphorylated p185ErbB2 (top arrow), p170EGFR (lower arrow) and p95 (arrowhead) are shown in FIG. 1. Cells were treated with vehicle alone (DMSO at a final concentration of 0.1%; indicated by “−”) or GW572016 (1 μM for BT474; 5 μM for other cell lines, indicated by “+”) for 24 hours.

As shown in FIG. 1 (compare lanes 3 and 4), treating ErbB2 overexpressing BT474 breast cancer cells with 1 μM GW572016 inhibited not only p185ErbB2 phosphorylation (top arrow) but also inhibited a 95 kDa phosphotyrosine protein (p95, arrowhead).

In S1 cells, treatment with 5 μM GW572016 inhibited p185ErbB2 and p95 phosphorylation (FIG. 1, compare lanes 5 and 6). S1 cells are...

example 3

Identification of p95 as the Truncated ErbB2 Receptor (p95ErbB2)

Proteolytic cleavage of the extracellular domain of p185ErbB2 leads to the appearance of the truncated 95 kDa ErbB2 receptor (p95ErbB2), which is highly phosphorylated (Christianson et al., Cancer Res. 58:5123 (1998)). To determine whether the 95 kDa phosphotyrosine protein as identified in the Example 1 was p95ErbB2, equal amounts of protein from total cell extracts were subjected to Western blot analysis using anti-ErbB2 mAbs that recognized distinct epitopes.

As shown in FIG. 2, exponentially growing BT474 cells were co-cultured for 24 hours with vehicle alone (0.1% DMSO; lanes 1, 4 and 7), 0.5 μM GW572016 (lanes 2, 5 and 8), or 10 μg / ml trastuzumab (lanes 3, 6 and 9). Equal amounts of protein were separated by SDS-PAGE and then ErbB2, p95ErbB2, pTyr / p95ErbB2, and pTyr / ErbB2 steady state protein levels were assessed by Western blot. Blots were probed with the following monoclonal antibodies: (a) anti-ErbB2 ECD (lanes ...

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Abstract

The truncated ErbB2 receptor (p95ErbB2) is shown to differ from the full-length ErbB2 receptor in its association with other ErbB receptors. The truncated receptor preferentially associated with ErbB3, whereas full length ErbB2 heterodimerizes with either EGFR or ErbB3. Consistent with p95ErbB2 heterodimerization with ErbB3, it is shown that heregulin (an ErbB3 ligand) stimulates p95ErbB2 phosphorylation in breast cancer cell lines. Described herein are methods of identifying patients suitable for treatment with a p95ErbB2 inhibitor, and methods of treating such patients.

Description

FIELD OF THE INVENTIONThe present invention relates to methods of treating solid tumors that express p95ErbB2, and methods for selecting subjects suitable for such treatment.BACKGROUNDMany existing anti-cancer chemotherapeutics are non-specific, in that they typically damage or kill normal cells as well as malignant cells. Research in oncology is increasingly focused on targeted therapies, in which a therapeutic compound interacts with a specific molecule to interfere with a particular molecular pathway. Tumors in different individuals, even when found at the same anatomic location, can differ in their molecular signalling pathways. Accordingly, it is important to know which molecules and pathways are targeted by a therapeutic compound, so that the treatment can be provided to the appropriate patients. Determining which molecules and pathways are affected by a therapeutic compound also provides diagnostic techniques to identify those patients suitable for treatment with that therape...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K31/517A61P35/00A61KA61K31/519A61K38/00C07K2/00C07K4/00C07K5/00C07K7/00C07K14/00C07K16/00C07K17/00G01N33/574
CPCA61K31/519C12Q1/6886G01N33/57492G01N33/57415G01N33/57407A61K31/517A61P35/00A61K39/39558A61K2039/545G01N2333/71G01N2333/91205
Inventor SPECTOR, NEIL LEEXIA, WENLE
Owner NOVARTIS AG
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