Using the venom from 312 honeybees and bumblebees in Perth Western Australia, Ireland, and England, a team from the laboratory of Cancer Epigenetics at the Harry Perkins Institute of Medical Research (University of Western Australia) directed by Associate Professor Pilar Blancafort, tested the effect of the venom on the clinical subtypes of breast cancer. The research was led by Dr Ciara Duffy, with results published in the international journal npj Precision Oncology, revealing that honeybee venom rapidly destroyed triple-negative breast cancer and HER2-enriched breast cancer cells. Wrays worked alongside the research team and UWA’s Technology Transfer Office to draft a provisional patent application in order to protect the valuable intellectual property generated as a result of this exciting research.
Congratulations on your recent ground-breaking research studying the effects of honeybee venom on breast cancer cells. Why did you decide to use bee venom to target breast cancer?
Thank you very much! For thousands of years, humans have been using products from bees for medicinal purposes, including honey, propolis, and venom. In the past few decades, interest has grown substantially into the anticancer effects of honeybee venom, but no one had previously compared the effects of the venom across all of the different subtypes of breast cancer and normal cells, and the mechanism of action is still not fully understood. Triple-negative breast cancer is one of the main clinical subtypes of breast cancer for which there is no clinically effective targeted therapy currently available, so, unfortunately, this subtype is associated with some of the worst prognoses and outcomes. Therefore, in addition to the other clinical types of breast cancer (such as the hormone receptor-positive and HER2-enriched subtypes), we wanted to see if the venom could kill these cancer cells more than normal cells and try to understand the molecular processes underlying these effects.
The results are incredibly exciting. Can you tell us a little bit about your research and what you found?
The first step was to collect honeybee venom. The bees were collected from hives at the University of Western Australia and put to sleep with carbon dioxide before the venom barb was pulled out from the abdomen of the bee and the venom extracted by careful dissection. Breast cancer and normal breast cells were also grown in tissue culture. We tested the diluted honeybee venom across 11 different cell lines and found that the venom was extremely potent. Melittin is the main component in honeybee venom, which accounts for about half of the dry weight of the venom. It’s a small, positively charged peptide that opens up pores, or holes, on cell membranes that electrically destabilise and kill the targeted cell in a matter of minutes. We reproduced melittin synthetically and found that the synthetic product mirrored the majority of the anti-cancer effects of honeybee venom. We found both honeybee venom and melittin rapidly killed triple-negative breast cancer and HER2-enriched breast cancer cells.
Melittin in honeybee venom also had another remarkable effect. Within minutes, melittin was able to substantially reduce the chemical messages of cancer cells that are essential to cancer cell growth and cell division. We found that melittin modulated the signalling in breast cancer cells by suppressing the activation of the receptor that is commonly overexpressed in triple-negative breast cancer, the epidermal growth factor receptor, and it suppressed the activation of HER2 which is over-expressed in HER2- enriched breast cancer. Considering melittin forms pores in breast cancer cell membranes, we assessed whether melittin could be used with existing chemotherapy drugs, potentially enabling the entry of other treatments into the cancer cell to enhance cell death. We found that melittin can be used with small molecules or chemotherapies, such as docetaxel, to treat highly aggressive types of breast cancer. The combination of melittin and docetaxel was extremely efficient in reducing breast tumour growth in mice.
One of the problems that are often seen with cancer therapies is that compounds that kill cancer cells also kill healthy cells. Did you experience the same issue with the active ingredient in honeybee venom and did you do anything to target the active compound to cancer cells?
Many chemotherapy drugs used clinically today are often associated with awful side effects that can reduce the quality of life of patients. Interestingly in our research, we found that a specific concentration of honeybee venom can induce 100% breast cancer cell death while having minimal effects on normal cells. We also further enhanced the specificity of melittin by attaching a protein sequence, RGD1, to target proteins overexpressed on the membrane of triple-negative breast cancer cells, and found that this peptide ‘RGD1-melittin’ was even more selective than melittin in targeting these aggressive breast cancers.
Your research compared honeybee venom collected from populations in Western Australia, Ireland and England. Why are Perth honeybees some of the healthiest in the world – what makes them so special?
Honeybees, as well as other insects, are dramatically declining on a global scale, a phenomenon sometimes referred to as Insectageddon. Declines in bee health are triggered by multiple factors and interactions between them including parasites, pesticide exposure, environmental changes, as well as inferior beekeeping practices. We are very lucky in Perth to have some of the healthiest honeybees in the world, and the main reason for this is due to our isolation. Bees in Western Australia are not exposed to pesticides at the same levels as elsewhere, are primarily kept in pristine and natural environments rather than in intensified agricultural landscapes, and a number of diseases that have devastated bee populations elsewhere have not yet made landfall in Western Australia. This is why it is so important not to bring bees, honey, or other bee products into Western Australia, and I hope we can continue to protect our beautiful honeybees and native bees!
Had you had much exposure to intellectual property considerations before this research and what did you learn about IP along the way?
I had learned about patents and intellectual property considerations through my courses at The Centre for Entrepreneurial Research and Innovation, and Perth Biodesign, but I had never worked on a patent before protecting our research. I now understand how important the use of language is to craft a patent and specific claims to protect your intellectual property.
Identifying potentially useful compounds for treating cancer is the first step – what would be the next steps for this research to translate into clinical outcomes?
The next steps would involve studies to formally assess the optimum method of delivery of melittin to breast cancer cells, as well as toxicities and maximum tolerated doses. Melittin could also be combined with other drugs to find the most effective combination for different breast cancer subtypes, and also other types of cancer.
About the Harry Perkins Institute of Medical Research
The Harry Perkins Institute of Medical Research is one of Australia’s leading medical research institutes investigating diseases affecting the community. With over 250 researchers located on three hospital campuses in Perth, the Perkins is uniquely positioned to fast track the development of discoveries and treatments. Its wholly-owned clinical trials facility, Linear Clinical Research, provides international and local pharmaceutical and biotechnology companies the facilities to trial the latest drugs and treatments in healthy volunteers and patients. The Harry Perkins Institute of Medical Research is proudly West Australian, providing career opportunities to our best and brightest graduates and bringing to the State international scientists. As a registered charity, the Harry Perkins Institute relies on grants and donations to fund its medical research.