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Novel Combination Therapy Against Lethal Breast Cancer
Background: Breast cancer that overexpress the HER2 tyrosine kinase receptor has been treated with the recombinant humanised monoclonal anti-HER2 antibody trastuzumap (Herceptin). Clinical trials in metastatic disease have shown that Herceptin has relevant clinical activity against HER2-positive breast cancer. However, despite the clinical success of Herceptin, the subsequent resistance to this therapy is a common problem that eventually results in the treatment failure. One hypothesis to explain this resistance is that the masking of the receptor or target epitope inaccessibility leading to diminished Herceptin-binding is associated with therapeutic resistance. This hypothesis is supported by the in-vitro research findings, which implicated a cell surface mucin, MUC4, for the target masking effect. MUC4 mucin is an aberrantly overexpressed protein in breast carcinomas with multiple functional implications in cancer development. Further, MUC4 is also known to be an intramebrane ligand for receptor tyrosine kinase HER2, and activates its downsteam signaling pathways that regulate proliferation, differentiation, and migration.
Objective/Hypothesis: Based on the important role of MUC4 in potentiation of HER2 signaling and Herceptin-resistance, we hypothesize that a combination therapy targeting both MUC4 and HER2 would provide improved clinical outcome.
Specific Aims: To test our hypothesis, following aims are proposed: The first aim is to investigate the combinatorial effect of MUC4 knockdown and Herceptin treatment on HER2 and its downstream signaling pathway(s) in breast cancer cells. The second aim is to examine the correlation of MUC4 with Herceptin-resistance and HER2-epitope accessibility.
Study Design: Paired breast cancer cell lines will be developed by ectopic expression of MUC4 and MUC4 gene silencing in MUC4-null and MUC4-expressing breast cancer cells, respectively. These derived cell lines will be used for treatment with Herceptin and it will be tested for in-vivo functional assays and HER2 downstream signaling pathways. The effect of Hereceptin-therapy in presence or absence of MUC4 (in paired cell lines) will be examined in preclinical studies. The expression of HER2 will be examined by immunohistochemical (protein) and fluorescent in situ hybridization (gene amplification) analyses and any discrepency in the resulting profiles will be correlated with MUC4 expression and response to Herceptin-therapy to support a role of MUC4.
Relevance: Novel therapeutic approaches are required for the effective treatment of breast cancer. The present proposal will explore the therapeutic utility of MUC4 as a target in combination with Herceptin-therapy. Our studies will highlight the biological importance of MUC4 in breast cancer, its potential role in Herceptin-resistance and as a marker in treatment planning, and may lead to a novel targeting approach that can synergistically improve the clinical outcome of Herceptin therapy.
Impact: Herceptin therapy is in clinical use for the treatment of HER2 positive breast cancer. The major limitation to this therapy is the subsequent development of resistance in most cases. Recent investigations have indicated that masking of the epitope targeted by Herceptin by a cell surface mucin, MUC4, may be one of the reasons for resistance. Our preliminary data is also in support of this proposition. The present proposal will explore the therapeutic utility of MUC4 as a target (alone and in combination with Herceptin) and may lead to a novel targeting approach that can synergistically improve the clinical outcome of Herceptin therapy.
Innovation: MUC4 is a large membrane-bound mucin implicated in cancer development and resistance to Herceptin therapy by masking the accessibility to the targeting epitope. We are taking an innovative approach to target MUC4 in combination with Herceptin, which should provide synergistic outcome by inhibiting the MUC4-dependent tumorigenic and metastatic processes and by improving the effect of Herceptin therapy (unmasking of the epitope).
HER2 is an ideal target for breast cancer treatment due to its selective membrane overexpression and functional implication in disease process. In fact, clinical trials in metastatic disease have shown that HER2-immune targeting by Herceptin (a humanized monoclonal antibody), has relevant clinical activity against HER2-positive breast cancer. However, the clinical success of Herceptin is often hindered by the subsequent development of resistance to this therapy and eventually results in the treatment failure. Recent studies have shown that the masking of the target epitope by a cell surface mucin, MUC4, may be associated with diminished Herceptin-binding leading to therapeutic resistance. MUC4 is a transmembrane glycoprotein, which is aberrantly overexpressed in breast carcinomas. MUC4 is a multi-functional protein and has also been shown to be involved in cancer development. The hypothesis of this grant proposal is that a combination therapy targeting both MUC4 and HER2 would provide improved clinical outcome.
The overall objective of this proposal is to develop an innovative approach to overcome the current limitation (acquired resistance) of the Herceptin-therapy. A first aim will be to investigate the combinatorial effect of MUC4 knockdown and Herceptin treatment on HER2 and its downstream signaling pathway(s) in breast cancer cells. The second aim is to examine the correlation of MUC4 with Herceptin-resistance and HER2-epitope accessibility. The IHC will examine the protein level and FISH will observe the RNA level in breast cancer samples. Any discrepency in the resulting profiles will be correlated with MUC4 and response to Herceptin-therapy.
The outcome from these studies will determine the functional role of MUC4 in Herceptin-resistance in breast cancer development. This proposal takes an innovative approach by simultaneous targeting of MUC4 and HER2 for improved therapeutic outcome in preclinical testing. The results obtained from this innovative study will have relevance for clinicians in treatment planning of Herceptin therapy and for researchers to develop a novel combination therapy aimed specifically to prevent MUC4-associated breast cancer growth and overcoming the Herceptin-resistance.