Working primarily in mouse models of disease, and also in people (through a Phase I clinical trial), the researchers have shown that triple negative breast tumors - which are the most aggressive and have the fewest treatment options - might one day be treated with a drug that cuts the 'phone lines' between normal cells and tumor cells.

The researchers analyzed in the journal Nature Communications the genetic output of thousands of individual cells within the tumor. Importantly, they found that cancer cells send signals to neighboring non-cancerous cells (known as cancer-associated fibroblasts or CAFs). And CAFs talk back: they send back their own signals that help the cancer cells become drug-resistant and enter a dangerous state the researchers call 'stem-like'.

The researchers disrupted the hotline between CAFs and cancer cells by using a drug called SMOi, which targets CAFs and stops them from pushing tumor cells towards a 'stem-like' state. In mouse models of triple negative breast cancer, treatment with SMOi reduced the spread of cancer, slowed tumor growth, increased sensitivity to chemotherapy and improved survival.

Following the success in mice, researchers carried out a Phase I clinical trial in 12 advanced triple negative breast cancer patients who had relapsed after previously being treated with chemotherapy. Patients were given SMOi together with a standard chemotherapy drug (docetaxel) to determine whether the combination was tolerated by patients.

While the combination treatment did not halt cancer progression in nine patients, disease was stabilized in two patients and tumors fully disappeared in one patient.

"The combination of SMOi plus docetaxel produced a tumor shrinkage in some individuals with triple negative breast cancer, who were not expected to have such responses with docetaxel alone," says principal investigator of the trial. "The challenge now is the identification of the molecular characteristics of the patients most likely to respond to the combination."

"We observed that the trial participants who responded best to the treatment were the ones with evidence of the highest levels of chatter between CAFs and tumor cells," remarks the author. "This is a preliminary finding, but is exciting, because it suggests that it might be possible in the future to identify patients who would respond best to this approach."

"It's the stem-like cells in breast tumors that are particularly bad players, as they can travel to distant parts of the body to create new tumors and are resistant to treatment," says the principal investigator. "We knew that CAFs played a role in turning cancer cells into a stem-like state, but now we know one way in which they communicate with tumors - and how to stop them talking to one another."

Phase I clinical trials in a small number of patients are now complete, and the researchers are currently working on designing and funding Phase II trials to test the effectiveness of this treatment in a larger group of patients. In parallel, A/Prof Swarbrick has plans to investigate prostate cancer, where the same.

https://www.garvan.org.au/news-events/news/breast-cancers-enlist-the-help-of-normal-cells-to-help-them-spread-and-survive

https://www.nature.com/articles/s41467-018-05220-6