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A novel immunotherapy against brain metastasis: Anti-Galectin-3

Periodic Reporting for period 1 - Gal3-BrainMets (A novel immunotherapy against brain metastasis: Anti-Galectin-3)

Reporting period: 2019-02-01 to 2021-01-31

Breast cancer is the most commonly occurring cancer in women and the second most common cancer overall. The treatments for this disease are improving patients’ life expectancy. Unfortunately, the increase of free-disease survival also comes with a higher probability for suffering from the dissemination of the cancer cells to distant organs (metastasis). Amongst all the potential sites that circulating tumour cells may colonise, the central nervous system has the worst prognosis: 1 month without treatment or ca. 14 months even after the most advanced therapies.

Harnessing the body's immune response to tumours (immunotherapy) has recently shown promise for the treatment of primary cancers outside the brain. Together with surgery, radiation and chemotherapy, it has become the fourth pillar for the treatment of a broad panel of cancer types. Although this strategy has gained great momentum in the clinic, only a few studies have tested its validity for breast cancer brain metastasis.

The neuroinflammatory scenario driven by the immune system during the brain colonisation of tumour cells is a hallmark. One key molecule in the immunogenic response within the brain is β-galactoside-specific animal lectin galectin-3 (Gal-3). Galectin-3 is a promiscuous protein of the lectin family expressed both in cancer cells and a variety of immune system cell types (microglia included), constitutively or in response to different kinds of insults. In other diseases within the central nervous system, microglial Galectin-3 has shown a negative effect on disease progression (e.g. Alzheimer’s and Parkinson’s’ disease) turning microglia into a harmful phenotype. Since microglial cells are the resident macrophages in the brain, it is of vital importance to study the role that this protein may exert on microglial activation during brain metastasis progression.

This project seeks to find new strategies to shift the microglial response into an anti-metastatic state, and thus, improve survival in breast cancer brain metastasis (BCBM) patients, an urgent and unmet clinical need. Our approach will use a balanced combination of established and novel in vitro and in vivo brain metastasis models, in which anti-tumourigenic therapies that have not previously been considered in a BCBM context will be tested.
The first part of the project has encompassed a comprehensive in vitro study of the potential role of Galectin-3 in microglial and tumour biology. I have performed studies with different cell lines together with primary cell cultures in order to test changes at a pre- and post-transcriptional level. Galectin-3 seems to exert a clear pro-tumourigenic role in microglial response after being exposed to tumour-conditioned media. At the same time, tumour cells up-regulate classical pro-tumourigenic genes in the presence of Galectin-3, suggesting again the pro-metastatic role of this protein.

Additionally, the first round of breast cancer cells has been injected in wt and Gal-3 K.O. mice. Samples are being processed and soon will allow us to analyse the role of host Galectin-3 in tumour growth in in vivo conditions.
For the first time, the use of transgenic mice with a complete lack of expression of Galectin-3 in a breast cancer brain metastasis model will allow us to clearly elucidate the role of this important protein during metastasis progression. Specifically, we will study the impact of this molecule on the microglial response in the presence of metastatic cells, and how these important brain cell types can be shifted into a more anti-cancerous phenotype (immunotherapy).

Furthermore, the existence of current available anti-Galectin-3 drugs used in clinical trials allows us a great opportunity to re-purpose these drugs against BCBM, therefore, shortening the long steps towards human validation. Moreover, the existence of healthy Gal-3 K.O. mice suggest no potential side effects during the course of the anti-Galectin-3 treatment.
Impact of the research proposal