How would you feel about cancer if you knew, that following treatment, it would all be gone forever? Still hate cancer? Yeah me too, but at least we are getting closer to curing it according to new research.¹

Three takeaways to tell your friends

• IRE1 inhibitors are effective at helping chemotherapy treat cancer, with active clinical trials.
• Discovered an IRE1 inhibitor that can cross the blood-brain barrier and cure the most common and aggressive brain cancer, in mice.
• Notoriously, this cancer is known to reappear after successful treatment; the IRE1 inhibitor treatment saw no reappearance of the cancerous cells 182 mouse days after beginning, or 70 human years.²

What is cancer? Cancer occurs when a group of cells continue to grow and spread without being able to go through the natural cycle of cell death. Problems arise when the cells grow into vital organs, blood vessels, and nerves or impede any essential systems.

So, kill the cancerous cells? Yes, but their typical cell-death pathways are altered, hence their cancerous status. To bypass this, we use chemotherapy drugs to kill all rapidly dividing cells: cancerous cells, hair cells, etc. While this treatment is effective, what if we paired it with a drug that increased its efficacy?

IRE1, or Inositol-Requiring Enzyme 1, is an enzyme responsible for the cell’s stress response. When cells become stressed, IRE1 fixes the problem to keep the cell alive. Therefore, IRE1 keeps cells alive under stress, like cancer cells. So, inhibiting the function of IRE1 may be beneficial for treating cancer. As a matter of fact, IRE1 inhibition combined with chemotherapy drugs was effective at treating breast cancer,^3-5 blood cancer,^6,7 and prostate cancer⁸ in mice. These developments are responsible for two currently active clinical trials with pending results: a breast cancer trial, and a diverse cancer trial.

But how do we treat the most common and aggressive form of brain cancer, Glioblastomas? Glioblastomas, with a median patient life span of 15 months following diagnosis, are notorious for their ability to reappear following treatment⁹; however, IRE1 inhibition combined with cancer treatment performed significantly better than cancer treatment alone in mice.¹⁰ But this is in the brain.

For those who don’t know, it is immeasurably difficult to treat brain diseases due to the blood-brain barrier (BBB). The BBB is a tight junction between blood vessels and the brain. It prevents unwanted material from entering our vulnerable brains. You see, our brains have a separate immune system from our body. If the BBB were to break down, which it does in diseases including Multiple Sclerosis, our body’s immune cells wreak havoc on the brain. Now, how do we get IRE1 inhibitors into the brain?

Using a computer program, they looked at 13 million compounds. Testing both how well they bind to IRE1 and if they can pass through the BBB. They found one. First, they tested, in a petri dish, its ability to inhibit IRE1. After successful inhibition, the final step was alleviating cancer in mouse brains.

They injected mouse brains with the cancerous cells and let them grow for four days. Then began daily IRE1 inhibitor treatments, which lasted the entire experiment, or 200 days. The IRE1 inhibitor was injected directly into the mice’s stomachs. The chemotherapy drugs were administered from day 11 to day 21. Given that mice have shorter life spans than humans, the 10-day treatment on adult mice is approximately 3.8 human years.² Learn more here. The combination treatment annihilated the cancer cells and maintained their disappearance for the entire 200-day trial,¹ or 76.9 human years.²

I think we have a candidate for treating cancer in the near future. We know IRE1 inhibition, in conjunction with chemotherapy treatment, can successfully treat various types of cancers in mice.^1,3-8,10 Now, an IRE1 inhibitor with access to the brain, combined with chemotherapy drugs, can cure the most aggressive brain cancer in mice.¹ I am eagerly awaiting the results of clinical trials. If you are interested in learning more about this research, the same group published another study the following year, showing the mechanism by which IRE1 prevents cell death.¹¹ We are getting closer each day.

REFERENCES

1. Pelizzari-Raymundo D, Doultsinos D, Pineau R, Sauzay C, Koutsandreas T, Langlais T, et al. A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment. iScience. 2023;26(5):106687.

2. Dutta S, Sengupta P. Men and mice: Relating their ages. Life Sci. 2016;152:244-8.

3. Ming J, Ruan S, Wang M, Ye D, Fan N, Meng Q, et al. A novel chemical, STF-083010, reverses tamoxifen-related drug resistance in breast cancer by inhibiting IRE1/XBP1. Oncotarget. 2015;6(38):40692-703.

4. Harnoss JM, Le Thomas A, Reichelt M, Guttman O, Wu TD, Marsters SA, et al. IRE1alpha Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment. Cancer Res. 2020;80(11):2368-79.

5. Logue SE, McGrath EP, Cleary P, Greene S, Mnich K, Almanza A, et al. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nat Commun. 2018;9(1):3267.

6. Mimura N, Fulciniti M, Gorgun G, Tai YT, Cirstea D, Santo L, et al. Blockade of XBP1 splicing by inhibition of IRE1alpha is a promising therapeutic option in multiple myeloma. Blood. 2012;119(24):5772-81.

7. Sun H, Lin DC, Guo X, Kharabi Masouleh B, Gery S, Cao Q, et al. Inhibition of IRE1alpha-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia. Oncotarget. 2016;7(14):18736-49.

8. Sheng X, Nenseth HZ, Qu S, Kuzu OF, Frahnow T, Simon L, et al. IRE1alpha-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nat Commun. 2019;10(1):323.

9. Campos B, Olsen LR, Urup T, Poulsen HS. A comprehensive profile of recurrent glioblastoma. Oncogene. 2016;35(45):5819-25.

10. Le Reste PJ, Pineau R, Voutetakis K, Samal J, Jegou G, Lhomond S, et al. Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo. Cancer Lett. 2020;494:73-83.

11. Pelizzari-Raymundo D, Maltret V, Nivet M, Pineau R, Papaioannou A, Zhou X, et al. IRE1 RNase controls CD95-mediated cell death. EMBO Rep. 2024.