The Wistar Institute’s Dr. Kazuko Nishikura Launches Preclinical Testing of New Melanoma Immunotherapy

Melanoma Research Foundation Grant Supports Preclinical Research

Wistar professor Kazuko Nishikura, Ph.D., has led the way in foundational biomedical research on RNA for decades. Her laboratory discovered the role genes in the ADAR family play in editing RNA. A new grant from the Melanoma Research Foundation supports Dr. Nishikura’s approach to a new immunotherapy for melanoma.

What problem does your project aim to solve?

We want to improve cancer immunotherapy, a class of cancer treatment that marshals the immune system against tumors. With funding from the Melanoma Research Foundation, we want to overcome resistance to immunotherapy in melanoma, which has posed a challenge for researchers and treatment providers.

Because cancers like melanoma develop resistance to immunotherapy through adaptive mutations, only about one in five patients receives the benefit of treatment. My hope for this project is that our approach will prevent resistance to immunotherapy and expand the potential benefits of treatment to more patients. In this case, we aim to improve immune therapy response in a melanoma model, but hopefully, this method will work for other immunotherapy-resistant cancers as well.

Can you explain your lab’s research?

My lab focuses on the role of the A-to-I RNA editing process in regulating the immune system, which is overseen by the ADAR1 gene that my lab discovered. The A-to-I RNA editing that ADAR1 causes is critical to our approach to cancer immunotherapy.

How we get from RNA editing to a new cancer therapy is a little complicated, so let’s start with the basics. RNA, unlike DNA, usually has just one strand. Instead of DNA’s double helix, single-stranded RNA is more or less a line, with the sugar molecules A, C, G, and U studded along its length.

But even though most of the RNA that our body makes is single-stranded, some is double-stranded, which we call dsRNA — and that can pose a problem because dsRNA triggers the immune system.

Even though the dsRNA we produce naturally is harmless, the immune system mounts a response against dsRNA because so many viruses are based on dsRNA. So the immune system needs a way to distinguish between viral dsRNA, which poses a threat, and naturally occurring dsRNA, which does not.

When our bodies make dsRNA, the ADAR1 gene kicks off A-to-I RNA editing, which swaps the A molecule in the dsRNA for an I. That way, the immune system has a signal that functions like a security badge. If a piece of dsRNA has A’s instead of I’s, then the immune system triggers a response.

How does your research on RNA editing help in cancer immunotherapy?

Our fundamental idea is that we can stop A-to-I RNA editing in and around tumors as a way of setting off the immune system’s alarms. By injecting our drug candidate in models of melanoma tumors, we anticipate that our molecule will prevent treatment resistance and allow immunotherapy to destroy the tumor.

At the most basic level, it works like this: we shut off ADAR1 in and around the tumor; dsRNAs in that area don’t get their security badges; the immune system’s alarms are triggered in and around the tumor; and the immune system attacks the tumor.

We’ll test our molecule’s ability to fight melanoma by disabling A-to-I RNA editing, which is exciting because this is the first small-molecule ADAR1 inhibitor molecule that anyone has identified, and from our preliminary testing, it seems to work well. With this melanoma project, I anticipate an exciting proof-of-concept for our drug candidate.

What are your hopes for the future of your molecule and its use in cancer treatment?

I’ve been at this work for quite a long time; I discovered the ADAR A-to-I editing mechanism back in 1989. Finally, after decades of foundational research, my lab has advanced our work to a point where it’s ready to be tested as a possible cancer therapy.

People ask me, ‘Kazuko, are you going to start a company?’ and I tell them, ‘What do you think? I’m almost ready to retire!’ No, I’m interested in doing the preclinical testing that will hopefully prepare our molecule for the next stage. It’s my job to make sure that it’s ready.

We scientists are driven by that search for the new; we want to discover something nobody else has found. I’ve done that, and it looks like my curiosity has led me to something that will help advance human health. And that’s a very satisfying experience.