November 26, 2012
For some time, researchers have known about disparities in diagnoses and outcomes among breast cancer patients based on race and age. However, they have been challenged to develop a set of criteria that can be used to reliably target drug delivery mechanisms based on an individual patient’s tumor.
Dr. Debra Auguste, associate professor of biomedical engineering in the Grove School of Engineering at The City College of New York, will investigate personalized therapies to inhibit breast cancer metastasis supported by the National Institutes of Health Director’s New Innovator Award. The grant, which provides $1.5 million over five years, funds “exceptionally creative new investigators who propose highly innovative projects that have the potential for unusually high impact.”
“By applying our knowledge and experience in chemical engineering, materials science and nanotechnology, we hope to develop therapeutics that will increase breast cancer patient survival by inhibiting tumor progression and metastasis,” said Professor Auguste, who joined the Grove School faculty in September from the Harvard University School of Engineering and Applied Science.
“Our goal is to use biological information to design new drug delivery vehicles that can target tumors. We have been studying what the cell surface looks like, how proteins relate to one another, how they are organized and what their ratios are.”
The strategy marks a departure from other investigations that have focused on the role of messenger RNA, which is transcribed into proteins. “People often think if you have a large amount of messenger RNA you have a large amount of protein, but we don’t necessarily know how much protein is being produced,” she said.
Current breast cancer treatments are regulated by cell surface presentation. For example, breast cancer cells that express estrogen receptor and human epidermal growth receptor-2 on their surface are treated with hormone (anti-estrogen or aromatase inhibitors) or targeted therapies such as the monoclonal antibody trastuzamab (Herceptin), respectively.
Professor Auguste plans to develop personalized treatment approaches for four metastatic breast cancer populations: black women, white women, women over 40 and women under 40. Epidemiological studies have found that white women are more likely than black women to be diagnosed with breast cancer, however black women are more likely to die from it. In addition, women under 40 are more prone to aggressive forms of the disease.
She expects to characterize the surface density and proximity of two receptors that govern cell recruitment: CXC chemokine receptor type 4 (CXCR4) and CC chemokine receptor type 7 (CCR7). This information will then be used to synthesize complementary engineered liposomes (CELs) that cooperatively bind CXCR4 and CCR7 and deliver short interfering RNA (siRNA) to knock down lipocalin-2 (Lcn2), which has been shown to induce the epithelial to mesenchymal transition (EMT).
Lipocalins are a family of proteins that transport small, hydrophobic molecules such as steroids, retinoids and lipids. A growing body of evidence points to the EMT playing a role in metastasis of cancers.
Professor Auguste hopes to produce CEL therapies that will enhance cooperative binding to each cell type and reduce cell migration and invasion. Homogeneous and biphasic CELs are designed to complement the relative surface density and organization of receptors on breast cancer cells. They do so by allowing conjugated antibodies to rearrange on the surface or by clustering antibodies within gel-phase lipid domains.
“The binding event is regulated by multiple receptors. We need to understand how multiple proteins work together to engineer adhesion,” she explained. “If we can understand that, we can hopefully go from a non-adhesive vehicle to one that is adhesive in order to trigger a favorable response. The key is adhesion of the drug delivery vehicle to tumor cells.”
In previous research targeting cytokine-activated endothelial cells, Professor Auguste reported evidence that vehicles that complement the cell surface enhance binding.
Professor Auguste plans to encapsulate cancer drugs inside a lipid shell that will be very similar to a cell membrane and decorate the shell with one or more antibodies arranged in different ratios. She also intends to “play around” with the molecules’ surface mobility and organization. “We’ll test lots of different engineering parameters in order to achieve optimal efficacy.”
To assess the effect of CEL on cell migration, activation survival and the EMT process, she will conduct mechanistic studies involving the expression of various proteins and enzymes.
Professor Auguste intends to demonstrate similarities and differences among six different breast cancer cell lines and deliver a platform technology designed to address tumor metastasis. The cell lines chosen represent the most metastatic and invasive forms of breast cancer with the poorest prognoses for survival. “We want to learn what is different about these breast cancers and whether we can develop a better treatment that can more effectively target the tumor and control it,” she said.