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Journalism of Courage
Nirali (name changed), 45, is hoping a new therapy can help her battle triple-negative breast cancer (TNBC), an aggressive kind of breast cancer where cells lack most receptors and proteins for targeted therapies to work. Chemotherapy is currently the only way out but since the cancer tends to come back, a patient requires more cycles of it. “The risk is very high as the disease can spread to more parts of the body. So if a new therapy can take care of drug-resistant tumour cells and can kill them effectively, I hope it can help patients like me and others,” says Nirali, who is waiting to avail novel treatment at the Tata Memorial Centre-Advanced Centre for Treatment, Research, and Education in Cancer (TMC-ACTREC).
Researchers there have found a critical vulnerability in triple-negative breast cancer, which makes up almost 31 per cent of breast cancer cases in India.Led by Dr Nandini Verma, principal investigator from the Cancer Research Institute (CRI) division of TMC-ACTREC, they have found that although chemotherapy kills a majority of these cancer cells, some stubborn cells are able to quickly reprogramme themselves to survive and sprout back to divide into more aggressive and drug-resistant ones.
They are in a temporary dormant state in between, which is when researchers have found the culprit molecules that make the cancer resistant. “This study represents a significant step forward in tackling a disease known for its high recurrence rates and poor long-term prognosis,” says Dr Verma. The study has been published in the November issue of Redox Biology.
Triple-negative breast cancer is a particularly challenging malignancy because it lacks the three receptors — estrogen, progesterone and HER2 — that traditional targeted therapies rely on for treating more than 70% of breast cancer patients. Therefore, triple negative breast cancer patients can only be treated with combinations of intensive chemotherapy. While this often works initially, nearly half of patients with residual disease experience a rapid relapse, typically within two to five years. The resistant tumour cell then spreads to the lungs, liver and brain.
The new study focussed on these residual cancer cells, known as Drug-Tolerant Persisters (DTPs), to spot their vulnerabilities in their weakest moments. “Our study modelled how these cells first enter a dormant state to survive the drug attack and then, once chemotherapy is stopped, transition into a highly aggressive, growing state, which is responsible for tumour recurrence and its spread to different organs. Managing patients, who fail to achieve a complete remission of the disease, is particularly challenging due to the limited biological understanding of this residual disease,” says Dr Verma. She and her team have now mapped the molecular changes that allow the identification of these persistent cells. It will also help them understand how they survive chemotherapy and become more aggressive.
Two molecules, GPX4 and FSP1, make the cancer cells resistant to chemotherapy. Researchers found that blocking FSP1 can make the cells sensitive to treatment again. Researchers also demonstrated how to “trip off” a cellular switch to change the status of cancer cells from “chemo resistant” to “chemo sensitive” by targeting the shield of FSP1. They created a stronger therapy that blocks both GPX4 and FSP1, killing the tough cancer cells by damaging their membranes.
This new molecular understanding has immediate clinical implications in two key areas: prediction and treatment. “This is a powerful biomarker for high-risk patients,” Dr Verma says. It can help patients who may not respond well to chemotherapy. The new combination therapy can then force the drug-resistant cells to rust themselves to death.
The leading authors, Dr Nazia Chaudhary and Dibita Mandal, explain that a combined targeting approach could be a very promising treatment strategy. “The next important step is to test these findings in clinical trials to see if this strategy can help patients,” they say.
