13 Nov 2021

Letdown though it was, BACE inhibitors’ fall from grace as the up-and-coming Alzheimer’s disease treatment may not have been in vain. According to a study published November 8 in Nature Cancer, verubecestat, the first of a class of BACE inhibitors to fail big in AD trials, may yet hold promise as a treatment for glioblastoma. Researchers led by Shideng Bao at the Cleveland Clinic in Ohio reported that the drug rallied tumor-associated macrophages (TAMs) to transform from glioma promoters to glioma slayers. Verubecestat did this by shutting off IL-6 signaling in the macrophages, which lifted the lid on the cells’ otherwise-healthy appetite for tumor cells. Especially when combined with low-dose radiation—a rallying cry for macrophages to enter a tumor—verubecestat treatment slowed tumor growth in the mouse brain.

“The paper raises the exciting possibility of a second life for BACE inhibitors in glioblastoma treatment,” wrote Stefan Lichtenthaler of the German Center for Neurodegenerative Diseases in Munich. “Additionally, the paper suggests that BACE1 may have more substrates/functions than anticipated and that they may not be restricted to neurons, where BACE1 is highly expressed.”

Glioblastoma (GBM) is the most common and fatal type of brain cancer. Within GBM tumors, TAMs fall into two broad categories: tumor-promoting, pTAMs, and tumor-suppressing, sTAMs. The vast majority of TAMs in GBM tumors are pTAMs, which tend to suppress immune responses to tumors (Sørensen et al., 2018; Klemm et al., 2020). 

First author Kui Zhai and colleagues happened upon verubecestat, aka MK-8931, while searching for ways to rouse TAMs into destroying glioma cells. The BACE inhibitor emerged as a top candidate in a screen for small molecules that triggered iPSC-derived macrophages to nosh on co-cultured glioblastoma stem cells. What’s more, the researchers found that within GBM tumors, BACE1 was predominantly expressed by pTAMs, but not sTAMs. This suggested that suppression of BACE1 activity may somehow free macrophages from their immunosuppressive shackles, and enable them to internalize nearby tumor cells.

Would verubecestat slow tumors growing in the brain? To find out, Zhai and colleagues injected glioblastoma stem cells derived from patient tumors into the brains of mice. Treatment with verubecestat dramatically slowed tumor growth, and the mice survived for longer. The researchers attributed this to more functional TAMs, including the cells' enhanced phagocytosis of tumor cells. RNA sequencing of TAMs extracted from the mouse GBM xenografts revealed that verubecestat treatment promoted expression of genes associated with the tumor-suppressive phenotype.

BACE Inhibitor, Tumor Warrior? In mice given verubecestat eight days following a GBM tumor transplant (right panels), the tumors grew not nearly as fast as they did in mice receiving control injections (left panels). [Courtesy of Zhai et al., Nature Cancer, 2021.]

Verubecestat’s anti-tumor effects were amplified when the scientists beckoned macrophages to the GBM xenografts by treating mice with low-dose radiation, suggesting a combination therapy could prove beneficial.

How might BACE inhibition turn TAMs into tumor eaters? The researchers ultimately pinned this effect to suppression of IL-6 signaling. BACE1 is known to cleave the full-length, membrane-bound IL-6 receptor, releasing a soluble form of the receptor. Once released, sIL-6R forms a complex with IL-6, which then latches onto Gp-130 on the surface of cells, activating STAT3 signaling and holding macrophages in a suppressive state (see Johnson et al., 2018, for review).

The researchers found that verubecestat treatment prevented the cleavage of IL-6R, and that this released TAMs into an activated state capable of mopping up tumor cells. Notably, sIL-6R shedding has previously been tied to suppression of T cell responses to tumors (Tsukamoto et al., 2017). 

Finally, the scientists investigated whether BACE1 expression in GBM tumors related to patient survival. Among tumor samples surgically removed from 12 people with GBM, the researchers detected BACE1 expression in about two-thirds of TAMs. Notably, BACE1 was predominantly expressed in pTAMs, not sTAMs. Finally, the researchers scoured GBM patient databases, finding that patients with higher BACE1 expression levels in their tumors tended to die sooner.

In all, the findings suggest that dousing BACE1 activity holds promise for treating people with GBM.

This is not the first time verubecestat has been implicated in messing with the IL-6 signaling pathway. Previous studies found that BACE1 can cleave Gp130, thus reducing binding of the IL-6/sIL-6R complexes and their downstream signaling. In this scenario, verubecestat enhanced IL-6 signaling, rather than squelching it. Those studies focused on IL-6 signaling in neurons, not macrophages (Apr 2021 conference news).—Jessica Shugart 

Comments

1. • Stefan Lichtenthaler
     German Center for Neurodegenerative Diseases (DZNE)
   • Posted: 13 Nov 2021

   This paper raises the exciting possibility of a second life for BACE inhibitors in glioblastoma treatment.

   Additionally, the paper suggests that BACE1 may have more substrates/functions than anticipated, and that they may not be restricted to neurons, where BACE1 is highly expressed. Whether such additional substrates will be cleaved in a healthy tissue or specifically in the context of disease or inflammation remains to be seen.

   The potential use of BACE inhibitors for glioblastoma should be further investigated. Given the possibility of off-target effects of drugs and shRNAs, I would specifically like to see a confirmation using BACE1-deficient mice. I’d also like to see the test of whether BACE2, which is also inhibited by BACE1-targeted drugs, may also be involved.

   View all comments by Stefan Lichtenthaler

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References

News Citations

1. What BACE Hits: New Substrates Create New Headaches 9 Apr 2021

Paper Citations

1. Sørensen MD, Dahlrot RH, Boldt HB, Hansen S, Kristensen BW. Tumour-associated microglia/macrophages predict poor prognosis in high-grade gliomas and correlate with an aggressive tumour subtype. Neuropathol Appl Neurobiol. 2018 Feb;44(2):185-206. Epub 2017 Sep 5 PubMed.
2. Klemm F, Maas RR, Bowman RL, Kornete M, Soukup K, Nassiri S, Brouland JP, Iacobuzio-Donahue CA, Brennan C, Tabar V, Gutin PH, Daniel RT, Hegi ME, Joyce JA. Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells. Cell. 2020 Jun 25;181(7):1643-1660.e17. Epub 2020 May 28 PubMed.
3. Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018 Apr;15(4):234-248. Epub 2018 Feb 6 PubMed.
4. Tsukamoto H, Fujieda K, Hirayama M, Ikeda T, Yuno A, Matsumura K, Fukuma D, Araki K, Mizuta H, Nakayama H, Senju S, Nishimura Y. Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression. Cancer Res. 2017 May 1;77(9):2279-2291. Epub 2017 Feb 24 PubMed.

Further Reading

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