The combination of three existing drugs extends survival in mouse models of fatal brain cancer

The combination of three existing drugs extends survival in mouse models of fatal brain cancer

A study by Ludwig Cancer Research has identified a combination of three existing drugs that significantly extends survival in mouse models of the deadly brain tumor Glioblastoma multiforme (GBM). Researchers led by Douglas Hanahan from Ludwig Lausanne report in the current issue of Cancer Cell how the drugs used in the combination - an antidepressant, an immune checkpoint blockade antibody and a mouse analogue of a cancer therapy, which alone do not offer a survival advantage against GBM - ; synergize to trigger strong therapeutic immune responses against the tumor.

Our research shows the great potential of reusing drugs for cancer therapy. “We have shown here that three extensively characterized drugs already used in the clinic can be recombined to disrupt the tumor’s immunosuppressive barrier and induce a therapeutic immune response that significantly extends survival in mouse models of GBM, a cancer that has so far eluded all therapy used to treat it.”

Hanahan, Distinguished Scholar, Ludwig Institute for Cancer Research Lausanne Branch

Hanahan and his colleagues conducted preclinical studies to examine whether drug combinations that target specific growth-promoting properties of tumors could work synergistically to halt or reverse disease progression. Previous studies in Hanahan's lab had shown that a generic "tricyclic" antidepressant, imipramine, could be used in combination with an anticoagulant drug to hyperactivate a process known as autophagy, in which cells cannibalize their own proteins and organelles to get the nutrients they need for growth. Hyperactivation of autophagy by these drugs slightly prolonged the survival of mice with GBM.

In this study, researchers tested whether a drug that targets an unrelated phenomenon, the abnormal blood vessels of tumors, when combined with imipramine could further improve outcomes. They used a mouse analog of the human anti-VEGF antibody bevacizumab, which has been approved as a second-line treatment for GBM, not so much to prolong survival but to provide relief to patients by relieving edema caused by the abnormal vasculature. Bevacizumab is known to virtually normalize leaky tumor blood vessels, the abnormalities of which also interfere with both chemotherapy and immunotherapy.

The researchers found that the combination of imipramine and the VEGF-blocking antibody significantly delayed tumor progression and extended survival times in mice with GBM. The combination, they discovered, disrupts the tumor's immune defenses through multiple mechanisms and triggers a strong anti-tumor immune response characterized by the recruitment of helper and cytotoxic T cells that are critical for anti-tumor immunity.

An analogue of human-specific bevacizumab, which targets the angiogenic factor VEGF in mice, remodeled the tumor's blood vessels in a way known to promote T cell infiltration. At the same time, hyperactivation of autophagy by imipramine stimulated anti-tumor immunity.

But that wasn't all. Hanahan and his team found that the antidepressant also had a separate and unexpected effect on a type of immune cell known as macrophages, which are found in large numbers in GBM tumors. As it turns out, imipramine also targets a biochemical pathway that helps keep macrophages in a so-called “M2” state, in which they support tumor growth. Blocking this signal with the antidepressant reprogrammed them into an “M1” state, which promotes T cell infiltration and killing of cancer cells.

But although this drug combination increased survival, its effects were not very lasting. However, Hanahan and his team saw an opportunity in reconditioning the tumor's immune microenvironment. To take advantage of this opportunity, they added a checkpoint blockade antibody to the mix, which boosts anti-tumor immune responses.

Such treatments have so far failed miserably against GBM in humans. But when added to the bevacizumab-imipramine combination, an anti-PD-L1 antibody drug significantly extended the survival of the mice.

"Because each of these therapies is already in clinical use," Hanahan said, "they do not need to undergo the time-consuming pharmacological development and safety testing required for novel drugs. For this reason, we hope that the combination therapy we found in this study can be tested relatively soon in human clinical trials for GBM, an extremely aggressive cancer for which there is an urgent need." new treatment strategies exist.”

In fact, plans are already underway for a phase I pilot study to evaluate the combination of active ingredients. If regulatory approval is granted, the study will be led by Hanahan and Andreas Hottinger from the Center Hospitalier Universitaire Vaudois in Lausanne.

Source:

Ludwig Institute for Cancer Research

Reference:

Chrysplewicz, A., et al. (2022) Cancer cell autophagy, reprogrammed macrophages and remodeled vessels in glioblastoma trigger tumor immunity. Cancer cell. doi.org/10.1016/j.ccell.2022.08.014.

.