(MUC1 agonist to reverse multiple resistances) MUC1* is a determinant of trastuzumab
 

<dl class="EC_AbstractPlusReport"><dt class="head">1: Breast Cancer Res Treat. 2009 May 5. [Epub ahead of print]
</dt><dd class="EC_abstract"> MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells.

Fessler SP, Wotkowicz MT, Mahanta SK, Bamdad C.
Minerva Biotechnologies, Waltham, MA, 02451, USA.
In the United States, 211,000 women are diagnosed each year with breast cancer. Of the 42,000 breast cancer patients who overexpress the HER2 growth factor receptor, <35% are responsive to treatment with the HER2-disabling antibody, called trastuzumab (Herceptin). Despite those statistics, women diagnosed with breast cancer are now tested to determine how much of this important growth factor receptor is present in their tumor because patients whose treatment includes trastuzumab are three-times more likely to survive for at least 5 years and are two-times more likely to survive without a cancer recurrence. Unfortunately, even among the group whose cancers originally respond to trastuzumab, 25% of the metastatic breast cancer patients acquire resistance to trastuzumab within the first year of treatment. Follow-on "salvage" therapies have prolonged life for this group but have not been curative. Thus, it is critically important to understand the mechanisms of trastuzumab resistance and develop therapies that reverse or prevent it. Here, we report that molecular analysis of a cancer cell line that was induced to acquire trastuzumab resistance showed a dramatic increase in the amount of the cleaved form of the MUC1 protein, called MUC1*. We recently reported that MUC1* functions as a growth factor receptor on cancer cells and on embryonic stem cells. Here, we show that treating trastuzumab-resistant cancer cells with a combination of MUC1* antagonists and trastuzumab, reverses the drug resistance. Further, HER2-positive cancer cells that are intrinsically resistant to trastuzumab became trastuzumab-sensitive when treated with MUC1* antagonists and trastuzumab. Additionally, we found that tumor cells that had acquired Herceptin resistance had also acquired resistance to standard chemotherapy agents like Taxol, Doxorubicin, and Cyclophosphamide. Acquired resistance to these standard chemotherapy drugs was also reversed by combined treatment with the original drug plus a MUC1* inhibitor.
PMID: 19415485 [PubMed - as supplied by publishe
</dd></dl>

Clinical Cancer Research 15, 100, January 1, 2009. doi: 10.1158/1078-0432.CCR-08-1745
© 2009 American Association for Cancer Research

Cancer Therapy: Preclinical

Intracellular MUC1 Peptides Inhibit Cancer Progression

<nobr>Benjamin G. Bitler²</nobr>, <nobr>Ina Menzl²</nobr>, <nobr>Carmen L. Huerta¹</nobr>, <nobr>Barbara Sands¹</nobr>, <nobr>Wendy Knowlton¹</nobr>, <nobr>Andrew Chang¹</nobr> and <nobr>Joyce A. Schroeder¹^,2^,3</nobr> Authors' Affiliations: ¹ Department of Molecular and Cellular Biology, ² Arizona Cancer Center, and ³ Bio5 Institute, University of Arizona, Tucson, Arizona
Requests for reprints: Joyce A. Schroeder, Molecular and Cellular Biology, Arizona Cancer Center, PO Box 245024, Tucson, AZ 85724-5024. Phone: 520-626-1384; Fax: 520-626-3764; E-mail: jschroeder@azcc.arizona.edu<script type="text/javascript"><!-- var u = "jschroeder", d = "azcc.arizona.edu"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>.
<!-- ABS --> Purpose: During cancer progression, the oncoprotein MUC1 bindsβ-catenin while simultaneously inhibiting the degradationof the epidermal growth factor receptor (EGFR), resulting inenhanced transformation and metastasis. The purpose of thisstudy was to design a peptide-based therapy that would blockthese intracellular protein-protein interactions as a treatmentfor metastatic breast cancer.
Experimental Design: The amino acid residues responsible forthese interactions lie in tandem in the cytoplasmic domain ofMUC1, and we have targeted this sequence to produce a MUC1 peptidethat blocks the protumorigenic functions of MUC1. We designedthe MUC1 inhibitory peptide (MIP) to block the intracellularinteractions between MUC1/β-catenin and MUC1/EGFR. To allowfor cellular uptake we synthesized MIP adjacent to the proteintransduction domain, PTD4 (PMIP).
Results: We have found that PMIP acts in a dominant-negativefashion, blocking both MUC1/β-catenin and MUC1/EGFR interactions.In addition, PMIP induces ligand-dependent reduction of EGFRlevels. These effects correspond to a significant reductionin proliferation, migration, and invasion of metastatic breastcancer cells in vitro, and inhibition of tumor growth and recurrencein an established MDA-MB-231 immunocompromised (SCID) mousemodel. Importantly, PMIP also inhibits genetically driven breastcancer progression, as injection of tumor-bearing MMTV-pyV mTtransgenic mice with PMIP results in tumor regression and asignificant inhibition of tumor growth rate.
Conclusions: These data show that intracellular MUC1 peptidespossess significant antitumor activity and have important clinicalapplications in the treatment of cancer.

Anyone know if MUC1 inhibitors are available?

?
 

"Of the 42,000 breast cancer patients who overexpress the HER2 growth factor receptor, <35% are responsive to treatment with the HER2-disabling antibody, called trastuzumab (Herceptin)."

I'd like to see how they arrived at this stat.

Hopeful

That stat sounds unfortunately familiar to me. Maybe the MUC1 approach would change that.

The stat is meaningless unless we know what it represents - is this 35% of ALL Her2+ patients, both metastatic and early stage bc? Stats that lump those two groups together are not useful.

Hopeful

Yup. Very vague considering it is used in mono and combination therapy for various stages. Just meant I seemd to have read elsewhere about a 25-30% response

From Genentech:
http://www.gene.com/gene/products/in...factsheet.html

Whatever teh response rate is..it's good to see something in the works to improve it or reverse acquired resistance. of course, never fast enough.