Turning up acidity in cancer cells
With a new drug, Professor Ebbe Bødtkjer aims to weaken breast cancer cells and enhance the effect of other cancer treatments. He has identified a weak point in cancer cells - and it will be exploited.
Physician and Professor Ebbe Bødtkjer from the Department of Biomedicine at Aarhus University.
By science journalist Antje Gerd Poulsen
One in eight women will develop breast cancer at some point in their lives. A particularly aggressive type of breast cancer that is difficult to treat affects 15 per cent of those diagnosed. In the future, however, it may be possible to treat this type of cancer more effectively. At least, that is the goal of a new drug currently being developed by physician and Professor Ebbe Bødtkjer from the Department of Biomedicine at Aarhus University.
The particularly aggressive form of breast cancer is known as triple-negative breast cancer, which grows and spreads more rapidly than other types of breast cancer. Its weak point lies in the cancer cells’ adaptation to the acidic microenvironment of the tumour.
Ebbe Bødtkjer has discovered that triple-negative breast cancer depends on a single transport protein that carries the acid-neutralising substance bicarbonate across the cell membrane to prevent the internal environment of the cancer cells from becoming too acidic.
“In many other cancer types, several transport proteins work together to protect cancer cells against an acidic environment. In this particular cancer, however, a single protein is so crucial—and that is our good fortune. It means that we can alter acidity regulation in the tumour by disabling just one mechanism,” explains Ebbe Bødtkjer.
“Every year, a significant number of women die from this disease, and many also go through some relatively harsh courses of treatment. I hope that we can develop a drug that is effective enough to allow more women to survive, and that can also spare them some of the worst side effects - because we may be able to treat with lower doses, or achieve greater effect from the drugs that are already being used,” says Ebbe Bødtkjer.
Together with his team, he has developed an antibody that can inhibit the transporter, thereby slowing tumour growth and making the tumour more responsive to treatment.
The researchers thus have a candidate for a new drug that is intended to work in synergy with other treatment modalities and effectively reduce an important survival mechanism for cancer cells.
Ebbe Bødtkjer has just received a Frontier Grant from the Lundbeck Foundation to develop the drug over an 18-month period and prepare a presentation for potential investors.
“Such a grant means a great deal, because academic funding does not cover this phase of development, which is aimed at launching a drug,” says Ebbe Bødtkjer.
Cancer cells can adapt to an acidic environment
All cells in the human body depend on maintaining a specific pH level inside the cell in order to survive and divide. Acidity plays a crucial role in a wide range of biochemical processes.
Most cells can adapt to small variations in pH, but a highly acidic intracellular environment will impair their function, weaken them, and may lead to cell death. The pH of the surrounding fluid is also important for cellular function and well-being.
In a tumour, cancer cells are surrounded by fluid that is more acidic than blood and normal bodily fluids. This is because cancer cells are voracious consumers of energy, and waste products from sugar metabolism create the acidic microenvironment. Compared with normal cells and immune cells, however, cancer cells possess mechanisms that protect them more effectively against acidification.
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As a result, while cancer cells in the tumour adapt and thrive, normal cells and immune cells suffer under the acidic tumour environment. Cancer cells thus enjoy ideal conditions for invading healthy tissue.
Ebbe Bødtkjer wants to turn this picture completely upside down by preventing cancer cells from getting rid of excess acid, causing it instead to accumulate inside the cells and impair their function. When cancer cells’ ability to adapt to an acidic environment is weakened, they also become more sensitive to attacks from immune cells, which are then better able to act and contribute to a more effective treatment outcome.
The protein was identified through biopsy analyses
Ebbe Bødtkjer’s interest in acid–base physiology began during his medical studies, inspired by an engaging lecturer. In his PhD research, he studied acid–base regulation in cells lining the blood vessels of the cardiovascular system.
Later, he began analysing biopsies from breast cancer patients who were found to share certain genetic variants. It was here that he identified the transporter.
“We observed a function that was upregulated, and that was this protein, which can prevent acidification of the cells.”
This work has led to several studies, which among other things have shown that the protein influences how quickly a tumour grows, and that there is a negative correlation between the protein and survival in this aggressive cancer type.
Most recently, Ebbe Bødtkjer has also developed and described an antibody that can disable the transporter. As a result, there is a substantial body of data to draw on in the development of the drug. Nevertheless, some studies are still missing.
Now it is time for the mice
With the grant in place, the researchers will, among other things, develop mouse models and experimental designs to test the antibody. They will also investigate whether the new drug may be relevant for treating additional cancer types. This could be the case if the protein proves to play a decisive role in other cancers, such as pancreatic or lung cancer.
First and foremost, however, they face a major challenge: finding an antibody that works in mouse models.
“Sometimes an antibody works in both humans and mice, but that is not the case here. So the prerequisite for moving forward is that we have a mouse antibody that resembles our human antibody,” he explains.
“It’s somewhat paradoxical that we now have a human antibody that works extremely well. We’ve demonstrated that in experiments, and we have solid data to support it. And yet we still have to take a step backwards and return to the mouse in order to obtain the knowledge that can confirm that it works and that it is safe. That has presented more challenges than I had anticipated.”
Nevertheless, Ebbe Bødtkjer looks forward to delving even deeper into the microcosm of tumours.
“The most exciting part will be when we can conduct experiments in mice with a functioning immune system and investigate whether we can achieve a synergistic effect when our antibody is combined with other treatment forms. I’ve been dreaming of that for several years now, but we’ve been limited by the fact that we haven’t had an antibody for use in mice.”
Read more about the Lundbeck Foundation Frontier Grant:
Frontier Grants facilitate transitions from basic research to attractive prospects for biotech investors
