Customized antibody-drug conjugate offers hope for aggressive breast cancer

Scientists have exploited weaknesses in breast cancer cells themselves to destroy hard-to-treat tumors by combining tumor-selective antibodies with cell-killing drugs.

This research today clinical cancer research The research, developed by a team at King's College London and funded by Breast Cancer Now, represents a new approach to cancer treatment.

This finding is unique to triple-negative breast cancer, which accounts for 15% of all breast cancers diagnosed. This type of breast cancer is usually aggressive, resistant to chemotherapy, has a low survival rate, and occurs more often in women under 40.

Typical treatments include surgery, chemotherapy, and radiation therapy, but this type of cancer can evade drugs and come back and spread again.

Scientists conducted data analysis using more than 6,000 breast cancer samples to investigate the characteristics of breast cancer cells associated with aggressive cancers and cancers that are resistant to chemotherapy.

They studied the biology of cancer, what is expressed in tumors, on the cell surface and inside the cells, to understand how cancer cells evade anti-cancer drugs. They established the presence of the cancer cell surface marker EGFR, along with the oncogenic molecules cyclin-dependent kinases (CDKs), which are involved in cell division and proliferation.

They used this knowledge of cancer cells to create a drug specifically for breast cancer by combining cetuximab, a tumor-selective antibody that targets the EGFR protein expressed in this type of cancer, with a CDK inhibitor. Because antibody-drug conjugates specifically target cancer cells, it may be possible to administer lower doses of inhibitor than usual, meaning less toxicity to patients.

Lead author Professor Sophia Karagiannis from King's College London said: “We have been looking for vulnerabilities in cancer and now we have found a way to direct treatments to one of these. “We combined these two drugs to create a tailored antibody.” This drug conjugate for patients with aggressive cancers may have lower doses and fewer side effects because the antibodies direct the toxic drug to cancer cells.

“Although further research is needed before this therapy can reach the clinic, we are hopeful that it will provide a new treatment option for cancers with poor prognosis. Beyond this antibody-drug conjugate, We hope that our concept will lead the way to new antibodies – this type of drug conjugate will need to be tailored to the patient groups most likely to benefit. ”

“Triple-negative breast cancer is a molecularly and clinically diverse disease. By taking advantage of the overexpression of EGFR and dysregulated cell cycle molecules in a select group of patients, it may be possible that an antibody-drug conjugate, rather than an antibody alone, can halt the division of cancer cells and trigger a cytotoxic function specifically against cancer cells.”

Dr Anthony Chan, Principal Research Fellow, King's College London

Dr Simon Vincent, director of services, support and impact at Breast Cancer Now, which funded the research, said: “Around 8,000 women in the UK are diagnosed with triple-negative breast cancer each year and it is usually a more aggressive form of breast cancer than other types, making it more likely to recur or spread after treatment.

“This exciting research not only improves our understanding of the characteristics of aggressive breast cancer cells that are resistant to chemotherapy, but also allows us to destroy these cancer cells with minimal side effects to patients. We were also able to get closer to developing targeted therapy.

“Although further research is required before this treatment can be used in humans, this is an exciting step forward in the development of targeted therapies for triple-negative breast cancer and how these discoveries will pave the way for new and effective approaches to tackling breast cancer.” We look forward to seeing what will lead to this devastating disease. ”