Fatima Mechta-Grigoriou: her battle against triple negative breast cancer
A breast cancer diagnosis can lead to a variety of outcomes. Although when detected early many breast cancers have relatively good outcomes, this is not the case for triple negative breast cancers, which too often leave physicians powerless.
Once again, Fatima Mechta-Grigoriou is battling the most aggressive breast cancers known to date: triple negative (TN) breast cancers and HER2. “For the latter we have some targeted therapies, namely Herceptin, which have changed the outlook for this disease“, explains the researcher. “However resistances arise, hence the need to pursue research for new avenues of treatment for these cancers.”
The most frequent cancers affecting women can be divided into 3 sub-groups: luminal cancers - which are sensitive to Hormone therapy and often have good outcomes -, HER2 and TN. Triple negative breast cancers represent 10 to 20% of breast cancers and are characterised by a lack of hormone receptors and HER2 overexpression. They are a priority for this researcher since there is currently no effective targeted treatment for women suffering from this form of cancer.
A possible marker...
TN cancers have a tendency to form distant metastases, whereas HER2 cancers generally spread to the lymph nodes. Once these cancers have begun to spread, chemotherapy is the only option.
Patients suffering from TN cancer do not all respond to chemotherapy in the same way, and in the long term over half of them will develop resistance. At the start of 2016, Fatima Mechta-Grigoriou and her Stress and cancer team (Inserm/Institut Curie, approved by the Ligue nationale contre le cancer) identified a marker for sensitivity to chemotherapy. “The decrease in the H2AX protein under chemotherapy appears as an indicator of effectiveness of treatment and survival of patients with TN breast cancer,” explains the researcher.
... an avenue of treatment for HER2 but not for TN
The result is a positive one although it does not take away this researcher’s recent disappointment. “Studies had shown the potential of CXCR4/CXCL12 pathway inhibitors to block not only the growth but also the development of metastases in cellular models of breast cancer,” explains Fatima Mechta-Grigoriou. Everything pointed to these inhibitors being a promising lead for treatment of breast cancers, both HER2 and TN. A lead that her team explored using animal models obtained from human tumours that they had at their disposal.
The first positive result: the two CXCR4/CXCL12 inhibitors tested reduced the size of HER2 tumours, including in models that are resistant to targeted treatments on HER2. However, they show no effectiveness on TN tumours. But the thing that most surprised and worried the biologist, was that in around 25% of cases these inhibitors actually had harmful effects: they would increase the proportion of metastases.
Although the CXCR4/CXCL12 inhibitors seem to be a promising area to explore for HER2 breast cancers, Fatima’s team is already back in the lab looking for other strategies to combat TN cancers, such as chloroquine. In 2014 her team demonstrated that this anti-malarial drug, known to inhibit autophagy, a cellular mechanism heavily implicated in growth and resistance to chemotherapy of TN breast cancers, could be prescribed in addition to chemotherapies - with the exception of taxanes - to increase their effectiveness. The fight goes on.
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CXCR4 inhibitors could benefit to HER2 but not to Triple-Negative breast cancer patients
Lefort S., Thuleau A., Kieffer Y., Sirven P., Bieche I., Marangoni E., Vincent-Salomon A., and Mechta-Grigoriou F.
Oncogene