One of the most difficult aspects of treating cancer is fighting against the speed at which the cancer spreads throughout the body. As cells grow and multiply, they begin to affect larger systems in the body, and can metastasize to different systems entirely. Once a cancer has spread from the initial site to a distant region of the body, it can be all but impossible to treat.
Breast cancers typically metastasize to the bones, liver, or brain through the lymph nodes or blood vessels. A recent study published in Cancer Growth and Metastasis sheds light on the progression of cancerous cells, and offers a potential solution to stopping the progression of a tumor in the form of human-made peptides.
The WASF3 Protein
Researchers at the Georgia Cancer Center identified the WASF3 protein following suspicions that it was responsible for helping cancer become mobile throughout the body. The team was led by Dr. John K. Cowell, a professor in the Department of Pathology at the Medical College of Georgia at Augusta University, who is also serving as the interim director of the Georgia Cancer Center.
WASF3 was found to be present in almost all aggressive forms of breast cancer, and especially abundant in the somewhat rarer ‘triple negative’ diagnosis. They were able to determine that the WASF3 protein, along with two other proteins that regulate the stability and function of the parent protein, were in large part responsible for how aggressive a cancer is.
Progression of a Cancerous Tumor
Cancerous tumors do not always begin as aggressive, rapidly spreading threats. Cowell says that “at some point, as a tumor progresses, it switches on a bunch of genes which allow it to metastasize.” The genes in question are the WASF family, which among other functions are clearly part of the process of wound healing, where cells need to move in order to cover damaged tissues.
Cowell theorizes that when a cancer cell begins to grow, it slowly begins to express the WASF3 protein. Over time, cells with this protein survive and begin to outlast the other less aggressive cells in the area, until cells with the WASF3 protein become the dominant group. It is at this point that the tumor begins shedding cancerous cells into the bloodstream, where the strongest and most aggressive cells are able to take up residence in neighboring systems.
Manufacturing a Human-made Peptide
Once the WASF3 gene was identified as one of the primary factor in metastatic cancers, Cowell and his team sought to manufacture a chain of amino acids that could interfere with it. These human-made proteins, called peptides, would ideally compete with the WASF3 proteins and its regulating proteins for bonding sites, disrupting the activity of WASF3 proteins. These proteins would still exist in the body, but without protein bonding sites to attach to, the peptide treatment would render WASF3 proteins unstable and dysfunctional.
The research team’s hopes were that blocking the WASF3 protein would stop breast cancer’s tendencies to spread to the lungs and liver. Cowell collaborated with Dr. Eileen J. Kennedy, an associate professor in the College of Pharmacy at the University of Georgia, in order to manufacture the peptides. Kennedy has been interested in improving the quality of human-made peptides in the hopes of seeing them used more commonly in cancer treatments.
Effective Mouse Trials
The research team tested the peptide on a mouse which was given HR-/HER2- breast cancer, called triple negative breast cancer. It is called this because the cancer is not receptive to the three most targeted areas of treatment: the estrogen and progesterone hormones, and the HER2 proteins. Triple negative breast cancer is considerably aggressive and difficult to treat by conventional therapies.
Upon introducing the peptides into a mouse model of breast cancer, the team was pleased to find that metastasis was drastically reduced. This is the first case in which a human-made peptide has been able to positively affect a living model of cancer. Though tests have not been conducted on humans yet, the results of the tests on mice suggest that the peptides could become an effective part of human cancer treatment in the near future.
Expanding Upon Previous Studies
Cowell and his team had previous experimented with deleting the WASF3 gene in isolated cancerous tumors. By deleting the gene that regulates the production of WASF3, the team was able to observe the tumor’s impaired ability to metastasize and grow. Unfortunately, the technology does not currently exist to delete the genes in humans, but the study provided a base for the team’s research.
The team first identified the gene and its role in metastasis when a child was diagnosed with neuroblastoma in 2002. The child was found to have the gene that expressed the WASF3 protein, and the cancer metastasized unusually quickly. By activating the WASF3 protein in low-risk tumors, researchers were able to observe a drastic increase in the aggressive nature of the newly activated tumors. Cowell was able to conclude from these observations that aggressive tumors all express the WASF3 gene, while less aggressive tumors do not.
Peptide Treatment vs. Chemotherapy
Chemotherapy is the standard of treatment for most cancers across the board. It functions by targeting fast-spreading cells and interrupting cell division processes. The molecules themselves, however, are small compared to the sizes of the cells that they are targeting, and chemotherapy falls short in that the molecules are unable to interact with the sites of protein interaction.
Peptides are able to target the larger protein bonding sites, and are able to do so without many of the severe side effects that people experience while undergoing chemotherapy. If peptides become common treatment for cancer, they will likely go hand in hand with other conventional treatments, as they do not reduce the size of the existent tumor the way that chemotherapy does.
Improving the Staying Power of Peptides
Although effective, the peptides do not stay in the bloodstream for more than 30 minutes. This prevents much of the peptide from defeating cancerous objects in the blood, and translates to a lower percentage of the peptide that arrives at the tumor. Despite the short window, the mice were able to experience significant benefits after receiving the peptides every other day for four weeks.
In order to improve their effectiveness, Cowell and Kennedy hope to extend the life of the peptide to more than 3 hours. This would prevent cancerous cells in the bloodstream from settling on distant systems, and would ensure that more of the peptide lands on the cancerous tumor. With more of the peptide arriving at the tumor, the chances of the tumor spreading would decrease significantly, as the peptides were found to be present on the tumor for up to 72 hours after a single dose.
The WASF family of genes is suspected to be a factor in all cancers, and the research team is hopeful for the development of peptide solutions to other prevalent forms of cancer. Future breakthroughs depend upon a greater understanding of the role that the WASF gene family has to play in the spread of cancer. For example, part of the benefit of this specific study of peptide treatment is that it specifically targets WASF3, while leaving the other two WASF proteins alone.
Human-made peptides are being explored in patients with lymphomas, or with solid tumors. The studies are focused upon preventing the blockage of naturally occurring tumor inhibitors. Should these studies be successful, peptides may become a common treatment for all forms of tumorous bodies, cancerous or no.