The National Institutes of Health has awarded a $360,000 grant to a team of researchers at New York's Mount Sinai School of Medicine and New York University School of Medicine to study the impact that race has on prostate cancer.
Entitled, "Signaling pathway alterations in the racial disparity of prostate cancer," the grant was awarded July 1 and is set to continue until June 2016.
Principal investigator Peng Lee estimated that the five-year project may receive up to $1.3 million by the time it ends.
Together with David Zhang, a professor of pathology at Mount Sinai School of Medicine, Lee aims to profile protein expression in "hundreds" of African American and Caucasian prostate-cancer patients to identify markers that can stratify individuals in both populations based on the cancer's aggressiveness.
To do so, the researchers will rely on an internally developed method called Protein Pathway Array that measures relative protein levels among different cell lines and tissues and can be used to identify global functional changes in the complex signaling network that drives cellular behavior.
The Protein Pathway Array approach was developed using two-dimensional gel electrophoresis, but for this new project will be transferred to the Luminex bead array platform, Lee told BioArray News.
"This method has increased sensitivity and can detect a low amount of proteins," he said. "The proteins you detect are very specific."
Lee and Zhang have been studying prostate cancer together for a decade. A central tenet of the new project is the fact that African Americans "have the highest rates of prostate cancer" and their disease-related mortality rates are "two times higher" than in Caucasians, according to grant abstract.
Between 2000 and 2004, the incidence for prostate cancer in African Americans was 256 cases per 100,000, 62 percent of which resulted in death, according to the National Cancer Institute. Among Caucasians, the incidence was 161 cases per 100,000 and 26 percent — less than half of African Americans' — resulted in death.
According to Lee and Zhang's abstract, the reason for the disparity remains unclear, but the researchers believe that genetic differences between the populations may impact the occurrence and severity of the disease.
They aim to use the Proteomic Pathway Array method to better understand the mechanism of these molecules and explain the incidence and mortality gulf.
"African Americans have aggressive prostate cancer," said Lee. "They have a higher risk, it occurs at a younger age, and the mortality rate is higher.
"We have found that there is a biological reason at the genomic level, but all the genomic or genetic alterations in the end will repeat in protein expression [and] thought it better to study the level of change at protein level," he added.
Lee noted that by looking at protein expression, the researchers can also study protein modifications, like phosphorylation, that cannot be surveyed using genomic research tools.
Lee estimated that the study will involve "hundreds" of African American and Caucasian prostate cancer cases.
"To reach a statistically significant finding, we will have to look at hundreds of cases for each ethnic group," said Lee. "We will use a subset to do the screening, but the second step — the validation step — will require hundreds of cases," he said.
The researchers said they are interested in correlating protein-expression profiles with aggressive cancers, and therefore will look at recurrence, metastasis, and survival. Patients will also be matched according to age, stage of cancer, and other criteria.
"That is the information we will have on the patient, particularly if they are related to the racial difference," said Lee.
"Our ultimate goal is to discover markers that can be used at the time of diagnosis," said Lee, adding that some, but not all, African Americans have more aggressive cancers.
Lee and his fellow researchers hope that the Proteomic Pathway Array method will help them to "distinguish those patients who will develop aggressive prostate cancer" — who will likely require closer surveillance — "from those who will have a less aggressive course," according to the abstract.
They also maintain that the "identification and functional studies of molecules responsible for the aggressive behavior of prostate cancer in African Americans will help to design anti-cancer drugs and strategies."
Lee said he believes that translating markers discovered in the study into useful clinical applications can be achieved soon after the project wraps up.
"We should be able to distinguish different short and long survival based on proteins identified on this particular proteomic analysis," he said.
According to a paper provided to BioArray News by Zhang, the Proteomic Pathway Array method relies on an immunoblot-based assay and enables researchers to screen for global changes in protein expression and post-translational modifications, like phosphorylation.
The paper said the focus of the Pathway Array is to determine the signaling network that controls cancer development, including initiation, promotion, progression, and metastasis.
The proteins typically selected for study in the array are highly expressed in cancer cells and are functionally linked to angiogenesis, apoptosis, cell-cycle regulation, DNA repair, migration, proliferation, signaling, stem-cell association, and transcription activity, the paper said.
The Pathway Array system consists of three integrated components: a bead array, an image-acquisition and -analysis tool; and computational-analysis software that integrates the results with known protein-protein, cell-signaling, and gene-regulation cancer biology pathways, the paper said.
While the method was originally developed using immunoblots and 2D gels, the new study will be based on the Luminex bead-array system using multiple, different fluorescent beads that are spectrally distinguishable and coated with a different capture antibody.
According to the paper, the beads are incubated with a sample to allow protein binding to the capture antibodies. The mixture is then incubated with a mixture of detection antibodies, each corresponding to one of the capture antibodies.
The detection antibodies are tagged to allow fluorescent detection. The beads are passed through a flow cytometer and each bead is probed by two lasers: one to determine the identity of the bead based on the bead's color and another to read the amount of detection antibody on the bead.
Lee said that the researchers will use other protein screening methods, such as 2D gels and mass spectrometry in the study, but that they would "like to focus" on using the Proteomic Pathway Array platform.
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