A new preclinical study on triple negative breast cancer (TNBC) reports that an experimental polo-like kinase 1 (PLK1) inhibitor shrank tumor four times more powerfully when used along with standard drugs than alone. The study, reported in the journal PLOS ONE, opens up a new door of opportunity for patients with this disease.
Triple negative breast cancer
TNBC is a form of breast cancer that is most common in African American and Hispanic women aged below 50 years. It is so called because tests show it to be negative for any of three hormone receptors – for estrogen, progesterone and human epidermal growth factor receptor 2 (also called HER2/neu). These are important because they are targeted by many drugs used for the treatment of breast cancer. In their absence, these patients show a poor response and generally have a worse outcome. While it generally shows a faster response to chemotherapy, it also behaves more aggressively than other types of breast cancer. It often relapses within 3-5 years of stopping a full course of adjuvant chemotherapy.
Treatment for these patients is generally limited to surgery, chemotherapy and radiation, alone or in various combinations. However, of late immunotherapy has been used to achieve better outcomes in a few of them, about 40% in stage 4 TNBC. No treatment is available for the remaining 60%.
The current study was motivated by the need to find a more effective mode of therapy for this subset of TNBC patients. The researchers wanted to know if using a PLK1 inhibitor along with a taxane drug that is part of the standard protocol for this disease would help improve the outcome compared to the first drug alone.
The rationale was that the use of the PLK1 inhibitor would restrict the ability of the cancer cell to proliferate without limit, and this would give space for the cytotoxic action of the chemotherapy drug. They view the PLK1 inhibitor as something like a traffic signal that hinders the barrelling pace of the multiplying cancer cells, thus preventing the tumor volume from growing at a pace that precludes any use for the chemotherapy drug. Researcher Antonio Giordano explains that it’s like “allowing the taxanes to actually catch up with the cancer cells and kill them. That's why we thought that combining a drug that blocks PLK1 with a standard chemotherapy drug like a taxane would work well together to kill the cancer cells that have lost total control of division.”
Taxanes are derivatives of the plant chemicals obtained from certain plants of genus Taxus, commonly called yews. The most commonly used include Paclitaxel (from the Pacific yew) and Docetaxel (from the European yew). They are the mainstay of treating breast cancer in both the early and late stages. They inhibit microtubular function; since this is crucial to cell division, the cell cycle is arrested, and the cell dies.
New bright green with yellow stripes foliage on yew Taxus baccata Fastigiata Aurea (English yew, European yew). Image Credit: Marinodenisenko / Shutterstock
Breast cancer affects one in 8 women, and though more of these tumors are now being detected in the early stages, the rate of recurrence or metastasis is about 33%, leading to a 5-year survival of less than 25%.
The PLK1 enzyme is often overly active in cancer cells in human beings, and it drives cell division or mitosis through many important functions. Among these, it activates the separation of centrosomes, to which the duplicated chromosomes attach to be drawn to opposite poles of the cell as it divides to form two new daughter cells.
PLK1 inhibitors cause the failure of centrosome separation and as a result the cell displays a characteristic polo ring of chromosomes attached in monopolar fashion to the unseparated centrosomes. This causes the arrest of cell division because of monopolar mitotic spindle formation. The cell then enters a programmed death pathway. Onvansertib is a PLK1 inhibitor which can be taken orally and is both safe and tolerable.
The researchers examined the growth pattern of TNBC cell lines that have been found to resist the effects of chemotherapy, when exposed to PLK1 alone or as part of a combined treatment.
The study found that when used together, the combination sensitized the TNBC cells to taxane drugs used for chemotherapy. Moreover, the number of cancer stem cells, which are responsible for the unbridled proliferation of cancer cells, and consequent metastasis, shrinks.
The scientists then switched to an animal model to see how the PLK1 inhibitor onvansertib worked when given along with the cytotoxic taxane drug paclitaxel. Onvansertib is a safe drug and is being used alone in clinical trials for other cancers. Paclitaxel used in weekly doses is much safer than docetaxel, another commonly used taxane.
In a mouse model, they found that giving onvansertib and paclitaxel brought the tumor volume down four times as much compared to paclitaxel alone, in a 21-day treatment period. Even more tellingly, the doses of the individual drugs were much lower than when they were used alone. This automatically reduces the risk of immediate and delayed toxicity. Overall, this study points to the possibility of a much more appealing combination of chemotherapy and PLK1 inhibitor drugs for TNBC.
The way ahead
In light of these findings, the next step for the researchers is to carry out a phase I clinical trial, recruitment for which will begin in 2020. Underlining the need for participants, Giordano points out, “Scientists are working hard every day to develop new drugs for triple negative breast cancer treatment, and the most important thing is for patients to participate and support clinical trials. That is the only way drugs can advance in clinical experimentation and get approved for patients. It is also the only way patients can receive drug therapies earlier in the course of the disease.”
Polo-like kinase 1 (Plk1) inhibition synergizes with taxanes in triple negative breast cancer, Antonio Giordano, Yueying Liu, Kent Armeson, Yeonhee Park, Maya Ridinger, Mark Erlander, James Reuben, Carolyn Britten, Christiana Kappler, Elizabeth Yeh, Stephen Ethier, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224420