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

The Ludwig Cancer Research study identified a combination of three existing drugs that significantly prolong survival in mouse models of the deadly brain cancer of glioblastoma multiforme (GBM). Researchers led by Douglas Hanahan report from Ludwig Lausanne in the current issue of cancer cells How drugs are used in combination-; antidepressants, checkpoint immunoglobulin and mouse immunoglobulin from a cancer therapy that does not in itself provide any survival benefit against GBM-; They synergize to trigger effective therapeutic immune responses against tumor.

Our investigation demonstrates the great potential of drug reuse for cancer treatment. Here we have shown that the combination of three drugs with broad properties already in use in the clinic to raise the tumor immune barrier and stimulate a therapeutic immune response can significantly prolong survival in mouse models of GBM, a cancer that has so far escaped everything. treatment used to treat it.”

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

In preclinical studies, Hanahan and colleagues have been exploring whether combinations of drugs that target distinct tumor growth-promoting properties might act synergistically to halt or reverse disease progression. Previous studies in Hanahan’s lab have shown that the generic “tricyclic” antidepressant, imipramine, can be used with an anticoagulant drug to activate a process known as autophagy, in which cells break down their own proteins and organelles to get the nutrients they need to maintain. growth. Hyperactivation of autophagy with these drugs prolonged the survival of GBM-infected mice.

In this study, the researchers tested whether a drug that targets an unrelated phenomenon, the abnormal blood vessels of tumors, which is used with imipramine, might improve outcomes further. They used a mouse analog of the human anti-VEGF antibody bevacizumab, which is approved as a second line treatment for GBM, although not to extend survival to provide relief for patients by relieving edema caused by aberrant angiogenesis. Bevacizumab is known to normalize leaky tumor blood vessels, abnormalities of which also affect both chemotherapy and immunotherapy.

The researchers found that the combination of imipramine and a vascular endothelial growth factor-blocking antibody significantly delayed tumor progression and increased survival times in mice with GBM. They discovered that this combination disrupts tumor immune defenses through multiple mechanisms, unleashing a potent antitumor immune response characterized by the recruitment of both helper and cytotoxic T cells, which are essential for antitumor immunity.

A human analog of bevacizumab that targets angiogenic factor VEGF in mice has been shown to remodel tumor blood vessels in ways known to promote T-cell infiltration. At the same time, imipramine autophagy hyperactivity stimulated antitumor immunity.

But that was not all. Hanahan and his team found that antidepressants also have a separate and unexpected effect on a type of immune cell known as macrophages, which are found in large numbers in GBM tumors. It has also been shown that imipramine also targets a biochemical signaling pathway that helps keep macrophages in a state called “M2,” where they support tumor growth. Blocking that signal with the antidepressant reprogrammed it to an “M1” state that supports the infiltration and killing of tumor cells by T cells.

However, although this drug combination prolongs survival, its effects were not very permanent. However, Hanahan and his team saw an opportunity in regenerating the tumor immune microenvironment. To take advantage of this opportunity, they added to the mix a checkpoint-blocking antibody that amplifies anti-tumor immune responses.

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

“Because each of these treatments is already in clinical use, they won’t have to go through the time-consuming pharmacological development and safety tests required for new drugs,” Hanahan said. “For this reason, we hope that the combination therapy we identified in this study can be tested relatively soon in the Human clinical trials for GBM, a highly aggressive cancer where new treatment strategies are urgently needed.”

In fact, the first phase of a pilot trial to evaluate the drug combination is already being planned. If approved by regulators, the experiment will be led by Hanahan and Andreas Hottinger of the Hospitalier Universitaire Vaudois in Lausanne.

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Journal reference:

Chryplewicz, A., et al. (2022) Autophagy of tumor cells, reprogrammed macrophages, and remodeled vasculature in glioblastomas induce tumor immunity. Cancer cells. doi.org/10.1016/j.ccell.2022.08.014.