Understanding why certain tumor cells develop resistance to chemotherapy is a major problem in cancer research, given chemotherapy is still the first-line treatment for the majority of tumors.
The latest study demonstrates that tumor cells from neuroblastoma, a malignancy that arises in the body’s ‘fight or flight’ sympathetic nervous system, may switch between responding to chemotherapy and not reacting to it.
They “showed there is ‘noise’ in the process of cell death, which is what happens to cancer cells with chemotherapy treatment – and that this inherent noise, or randomness, in the system of gene expression is an important aspect of chemoresistance,” according to Associate Professor David Croucher.
15% of those diagnosed with neuroblastoma do not respond to chemotherapy.
The findings of the new study imply “that genetics don’t account for everything; other layers of regulation and other mechanisms of tumour progression can also underpin drug response, so we need to consider them,” adds co-lead author Dr. Sharissa Latham.
The study demonstrated that once neuroblastoma cells achieve a state of chemotherapy resistance, they cannot revert, indicating that there is a tiny window of opportunity for treatment to be effective on a cancer cell before it becomes irreversibly resistant.
“Combining chemotherapy with drugs that target this noise within tumours may have the best results as a first-line treatment after diagnosis, before tumours lock into a state of resistance,” points out Associate Professor Croucher.
This is the opposite of how clinical trials for cancer are usually done, where a new treatment is given to people who have tried everything else.
The findings were reported in the journal Science Advances.
To reduce the “noise” signals in the pathways of cell death in neuroblastoma tumors, the researchers applied mathematical modeling. Scientists then used it to patient cell samples, looking at individual cells in large groups to identify those that did not react to therapy visually.
They discovered a protein group involved in the apoptotic phase of cell death as a signal for resistance.
“We wanted to figure out what underlies that randomness. What is it about those cells and can anything be manipulated to make them respond,” adds Dr. Latham.
The team found some classes of approved drugs that could be used with chemotherapy to stabilize the expression of genes involved in cell death or to change the natural threshold that could cause a cancer cell to become resistant.
The next step is to get the work ready for a clinical trial.
Source: 10.1126/sciadv.abp8314
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