Synthetic Lethality: Q&A with Oren Gilad, CEO of Aprea Therapeutics

Oren Gilad, PhD
President and CEO
Aprea Therapeutics

Precision medicine is gaining momentum in the life sciences industry. It’s also changing the way that researchers are approaching new treatments and therapies. Pharmaceutical Executive spoke with Oren Gilad, PhD, president and CEO of Aprea Therapeutics, about some of the ways that the company is approaching cancer treatment with this new mindset.

Pharmaceutical Executive: Can you discuss the concept of synthetic lethality and how it relates to your work?
Oren Gilad: Synthetic lethality is a concept where the combination of two genetic mutations leads to cell death, whereas each mutation on its own would not be lethal. Cancer cells often have specific genetic mutations that normal cells do not carry, generally because they exist because a normal mutated to become cancer. So, there’s already one mutation. Inhibiting a pathway with a drug could lead to the same effect as having two genetic mutations.

This is different than chemotherapy. My mother was treated with chemo for several years, but she eventually gave up because she couldn’t tolerate the side effects anymore. It’s also important to remember that cancer is a variety of different diseases. It’s like saying that someone has a virus. The first question is what kind of virus they have.

We get 50% of our DNA from our mother and the other half from our father. This means that babies are not born with cancer. Somewhere along the way, something has gone wrong and normal cells have transformed into cancer cells. That’s the difference between chemotherapy, targeted therapy, and synthetic lethality. We’re not killing every dividing cell; we’re matching the disease with the drug based on the genetic mutation.

It's a form of precision therapy, or personalized medicine.

PE: Can you discuss the ways that Aprea is challenging the status quo in cancer treatment?
Gilad: Precision medicine and targeted therapies are new approaches to matching diseases with therapies. The goal is to maximize the effect and minimize toxicity. These are treatments that are only given for one specific virus. That’s what our focus is. We want to understand the biology and what we should target to kill the cancer cell but have the normal cells tolerate the treatment without serious side effects.

PE: Does this mean the side effects would be reduced compared to other cancer treatments?
Gilad: We always consider how our drug is different from other drugs. I published a paper in 2010 that said that ATR is a good target for cancer therapy. Up until that point, everyone was looking at ATR as a mechanism of action or biological function. It was a very basic study since there were no drugs back then for ATR. We had a normal cell and then we had another normal that we reduced the level of ATR in. We also had two different groups of cancer cells, one of which had its ATR reduced.

What we found, in a tissue culture, was that the normal cell stayed healthy. The normal cell with ATR reduced also stayed healthy. The normal cancer cells remained healthy, but the cancer cells with ATR reduced were destroyed. That old us that ATR can be reduced in certain cancer cells and have a nice therapeutic index.

If you look at our clinical study, our side-effects and adverse events reported with patients are very well tolerated. They were so well tolerated that we went to FDA and requested to increase the dose. We wanted to get more of the drug into the body, and it was approved. When we submitted the IND to FDA, they came back to us and said that we could start testing patients as young as 12.

For us, that’s an indication that they like the safety profile and it’s a good translation from pre-clinical to the clinic. Studies are ongoing.

PE: Can you go into more detail about Aprea’s pipeline?
Gilad: The general pipeline is that we have the two main assets right now: the ATR inhibitor and the WEE1 inhibitor. Both are in clinical trials at the moment.

There’s a third program which is still undisclosed. This program is based on a platform which is designed to identify proteins that are coming on or off their indication either in response to genetic mutation or therapy. This is guiding us with the biomarker in the clinical program, along with additional targets to reach the pipeline. It hasn’t been disclosed yet because we haven’t filed that patent. Once we file the patent, we’ll disclose. From what we can tell from our competitors, however, is that none of them are going after this target.

The ATR inhibitor is in clinic on dose escalation and is on target to complete dose escalation this year. We’re going to propose treatment of twice-a-day as opposed to once-a-day, based on what we’re seeing with the dosing.

The WEE1 is also in the clinic. We completed financing back in March and the IND cleared in the first quarter of this year. We treated the second patient during the second quarter and the study is ongoing. The focus is on the execution and getting good translation from pre-clinical to the clinic.