Manipulation of the Mitochondrial Network as a Therapeutic Strategy for Multi-drug Resistant Triple-Negative Breast Cancer
Autor: Roc Bellostas Carreras
Centre: INST.JOAN ORÓ-LLEIDA
Premi: Accèssit
Document:
Introduction
Triple-negative breast cancer (TNBC) has the highest mortality rate within the first 3 to 5 years of diagnosis among all the breast cancer subtypes. Currently, the lack of targeted therapies for TNBC remains one of the biggest challenges in cancer therapy. Chemotherapeutic drugs continue to be the primordial treatment for patients with TNBC. However, recent studies have shown that TNBC can acquire chemo-resistance and, as a result, multi-drug resistance (MDR) is the major cause of therapeutic failure with TNBC. Moreover, it has also been shown that drug resistant TNBC cells show high levels of mitochondrial fusion, which is the physical merging of the outer and the inner membrane of two distinct mitochondria, and this process results in blocking the programmed cell death system. The goal of this project is to manipulate mitochondria in MDR TNBC cells as a therapeutic approach.
Hypothesis
Mitochondrial hyperfusion is a common phenotype in multidrug resistant cancer cells and, if this fusion is inhibited, they will be sensitized to chemotherapeutic drugs that will kill the cells and eliminate the tumor.
Objectives
Design and test a new therapeutic approach for TNBC in order to decrease its high mortality rate and eradicate it in a near future.
Come up with an innovative treatment for chemo-resistant cancers, which currently have a very poor prognosis, contributing to the scientific community in the goal to overcome one of the major obstacles in cancer therapy.
Learn all the methodologies and procedures that have to be carried out to be able to conduct and design the different experimentations that will allow us to prove our hypothesis.
Methodology
This project is based on the problem-solving approach called scientific method. First of all, we came up with a specific problem related to cancer, which is chemotherapy resistance. Then, the following question was formulated: “How can we increase the effectiveness of chemotherapy in MDR cancers?”. After having done an extensive bibliographic research about the topic, the hypothesis was formulated, and several experiments were designed. They consist of two main parts: the fluorescence microscopy, which was used to obtain and compare different images of the mitochondrial network from cells treated in different conditions; and the MTS cell proliferation assay, where the cell viability was measured for different treatments involving a mitochondrial fusion inhibitor peptide, chemotherapy drugs and liposomes. Finally, after having performed the experiments the results were obtained and discussed in order to prove right or wrong our hypothesis.
Results & Conclusions
After doing the MTS analysis, results have shown that the combination treatment involving different chemotherapeutic drugs combined with the mitochondrial fusion inhibitor peptide had a significant effect in all the different conditions tested, but specially in multi-drug resistant cells. Thus, our research seems promising in the goal to sensitize MDR TNBC cells to chemotherapeutic treatments.
In conclusion, this therapy could be potentially used as a second line therapy for MDR cancer cells. In a near future, research will be continued on TNBC in order to corroborate and refute our hypothesis. After having performed several trials in vitro, this treatment will be tested in vivo on a model organism such as mice.
Triple-negative breast cancer (TNBC) has the highest mortality rate within the first 3 to 5 years of diagnosis among all the breast cancer subtypes. Currently, the lack of targeted therapies for TNBC remains one of the biggest challenges in cancer therapy. Chemotherapeutic drugs continue to be the primordial treatment for patients with TNBC. However, recent studies have shown that TNBC can acquire chemo-resistance and, as a result, multi-drug resistance (MDR) is the major cause of therapeutic failure with TNBC. Moreover, it has also been shown that drug resistant TNBC cells show high levels of mitochondrial fusion, which is the physical merging of the outer and the inner membrane of two distinct mitochondria, and this process results in blocking the programmed cell death system. The goal of this project is to manipulate mitochondria in MDR TNBC cells as a therapeutic approach.
Hypothesis
Mitochondrial hyperfusion is a common phenotype in multidrug resistant cancer cells and, if this fusion is inhibited, they will be sensitized to chemotherapeutic drugs that will kill the cells and eliminate the tumor.
Objectives
Design and test a new therapeutic approach for TNBC in order to decrease its high mortality rate and eradicate it in a near future.
Come up with an innovative treatment for chemo-resistant cancers, which currently have a very poor prognosis, contributing to the scientific community in the goal to overcome one of the major obstacles in cancer therapy.
Learn all the methodologies and procedures that have to be carried out to be able to conduct and design the different experimentations that will allow us to prove our hypothesis.
Methodology
This project is based on the problem-solving approach called scientific method. First of all, we came up with a specific problem related to cancer, which is chemotherapy resistance. Then, the following question was formulated: “How can we increase the effectiveness of chemotherapy in MDR cancers?”. After having done an extensive bibliographic research about the topic, the hypothesis was formulated, and several experiments were designed. They consist of two main parts: the fluorescence microscopy, which was used to obtain and compare different images of the mitochondrial network from cells treated in different conditions; and the MTS cell proliferation assay, where the cell viability was measured for different treatments involving a mitochondrial fusion inhibitor peptide, chemotherapy drugs and liposomes. Finally, after having performed the experiments the results were obtained and discussed in order to prove right or wrong our hypothesis.
Results & Conclusions
After doing the MTS analysis, results have shown that the combination treatment involving different chemotherapeutic drugs combined with the mitochondrial fusion inhibitor peptide had a significant effect in all the different conditions tested, but specially in multi-drug resistant cells. Thus, our research seems promising in the goal to sensitize MDR TNBC cells to chemotherapeutic treatments.
In conclusion, this therapy could be potentially used as a second line therapy for MDR cancer cells. In a near future, research will be continued on TNBC in order to corroborate and refute our hypothesis. After having performed several trials in vitro, this treatment will be tested in vivo on a model organism such as mice.