Queensland researchers believe they have uncovered a mechanism to explain resistance to doxorubicin chemotherapy in patients with triple negative breast cancer.
They have found that the drug is sequestered by secreted cellular prion protein (PrPC), which prevents doxorubicin from entering the nuclei of target cells and thus blocks its cytotoxic activity.
This raises the possibility of pre-treatment screening for treatment prognosis to allow selection of a more appropriate alternative chemotherapy agent such as epirubicin, according to researchers in the QIMR Berghofer Medical Research Institute’s Tumour Micro-environment group.
The group conducted biochemical and in vitro experiments that showed PrPC sequestered doxorubicin in the tumour microenvironment and this could reduce bioavailability of the drug.
Doxorubicin had reduced cytotoxic efficacy in tumour sample where there was high levels of expression of the PrPC, in which the drug would bind onto the protein instead of the cancer cells. However there was much less effect seen with epirubicin.
“We found that the levels of PRNP transcript in pretreatment tumour biopsies stratified relapse-free survival after neoadjuvant treatment with anthracyclines, particularly among doxorubicin-treated patients with residual disease at surgery,” they wrote in JCI Insight.
The findings therefore suggested that assaying PrPC could have a place in the clinical diagnostic setting for patients with triple negative breast cancer to help determine the most appropriate chemotherapy regimen.
“These findings have important potential clinical implications for frontline regimen decision making,” the researchers said.
“Prior knowledge of tumour PrPC expression and/or levels of soluble, serum-derived PrPC perfusing the tumour could help to rationalize the prescription of doxorubicin- or epirubicin-based therapies in the clinic.”
Study lead author Associate Professor Adrian Wiegmans said doxorubicin was the front-line chemotherapy treatment given to the majority of women with triple negative breast cancer around the world, but up to 78 % of those who undergo extended treatment develop resistance and relapse.
“Women who relapse with triple negative breast cancer have a terrible prognosis of less than six months survival, so the ability to predict which patients will gain from treatment is the goal for all doctors,” he said.
“Based on this study, we believe early screening for prion levels in the blood would allow doctors to choose an alternative chemotherapy to doxorubicin and save patients from undergoing ineffective treatment and needlessly suffering side effects.”
“We hope that in future, triple negative breast cancer patients will be screened for this protein when they are diagnosed to help guide what treatment should be offered, and to eliminate what won’t work.
Associate Professor Wiegmans added that the study could have implications for several other cancers where doxorubicin was used, such as bladder, stomach, lung, ovarian, and thyroid cancers and some types of leukaemia and Hodgkin’s lymphoma.