The deeper we dig, the more surprises we find

Professor Robert J. Schneider, the newest member of the NCCRs’ Scientific Advisory Board, shares his view on the NCCR RNA & Disease, the role of RNA in cancer, the rethink in drugging translation, and the value of scientific collaboration.

How did you become a member of the Scientific Advisory Board of the NCCR?

About a year ago, I was speaking at a conference where some of the NCCR members were present. My work tends to be much more translational, directed much more to human medicine, but it does range from basic research to clinical trials. The NCCR members were intrigued by the possibility of bringing an advisor on who helps translate more basic research into much more clinical understanding. That’s how it occurred.

What will be your task at this advisory position?

This is my first round and we will meet on Friday [at the Swiss RNA Workshop]. So I don’t have experience as an advisory member. However, I think that what the NCCR has done is really extraordinary – bringing together this di- verse group of biologists, all working on RNA with an understanding that it is at the basis of human disease. I cannot think of any other program like it in the world. This immense density of RNA-based research you have to capitalize on. It is a brilliant thing to do.

Which of the three NCCR work packages represents most of your own work?

I actually work in most of those areas. My work has traditionally been very much involved in the translational control of gene expression, particularly in human cancer and cancer stem cells, but I also work on the control of mRNA stability. Now we are showing that the control of mRNA stability is a master regulator of adult stem cell fate as well. The deeper we dig, the more surprises we find. And some of our most basic understanding is being challenged the more we investigate. For example, proteins, I like to call them “dumb” mRNA binding proteins, which simply were known as hnRNP proteins, turn out to have enormous biological activities. Their entire function is based on whom they interact with, so they can control major physiological pathways in cells without possessing any enzymatic activity. And now we understand that they are master regulators of the adult stem cells, and that mutations in some of these mRNA binding proteins are key players in many human diseases. Thus, it makes a great deal of sense to focus on these three areas of RNA biology.

What do we know about translational control in cancer?

A number of years ago when my lab and others began trying to understand the role of mRNA translation in human cancer, most people believed that the translational control of mRNA was simply a secondary effect. We and others have now demonstrated that it actually is a driver of human cancer, particularly in cancer stem cells, which are the cells we know cause cancer recurrences, metastases and in many cases resistances to chemotherapies. So it is important to understand the biology of cancer with respect to translation. But we also know that translation in cancer cells is druggable, and there in lies the real promise. My work is very much involved in drugging the translation apparatus in human cancer. We had an observation – it was a paper in Molecular Cell – that in four years we will manage to develop a drug and we will bring it all the way through phase II clinical trial to block the translation of VEGF, which is one of the major factors that promote angiogenesis in tumor cells. All this work can be translated into new drug discoveries.

You did your PhD in biophysical chemistry. When did you become interested in molecular pathology of cancer?

I wanted to start my career by getting the most rigorous training in the understanding of macromolecules and their interactions. Biophysical chemistry gave me that. But at the same time I found it too far removed from where I wanted to be, namely to bring science into the clinic. So while it was an excellent training I felt very happy to move into biology. We now come full circle. When I first trained, structural biology was just a dream. Being able to do the kinds of studies we now routinely do, such as to look at the kinetics of interaction of macromolecules, that was not possible then. Now it is possible, and the training I received 35 years ago for my PhD we now use all the time.

Did you ever consider a medical training?

In fact, I did. I was in a program doing much of the first two years of medical school while we worked on our PhDs at the same time. There I received considerable training, at least in terms of book knowledge. Later I was able to learn how to conduct clinical trials. That is something you just learn – courses don’t teach you how to develop clinical trials. So, I am a PhD but I am also a leader of the breast cancer program, and I co-direct a number of clinical trials. There is no reason that with a PhD you can’t do all of that.

When did you get sparked to focus on investigating the role of RNA in human diseases?

It started actually in my post-doctoral research where I was working on adenovirus, which is a prototypic virus for cancer. In humans this virus just causes common colds, but in rodents adenovirus causes tumors. It was one of the first approaches to begin to understand the development of cancer. I became a RNA biologist when we investigated what were called the virus-associated RNAs and how they regulated interferon signaling and ultimately translational control. I still remember my great disappointment because I wanted to work on RNA splicing, which was incredible hot at that time. I was very disappointed until I published my discovery that these small RNAs were regulators of translation in a paper in Cell. Then, of course, I decided this is a great new field to enter. This work brought me to translational control when very few people were thinking about it at that time.

One of your biggest research efforts is in the field of advanced breast cancers for which there is no cure at the moment. Are new treatment options on the horizon?

We have made no progress when breast cancer is metastatic and we still cannot speak of cures. Once a woman has late stage 3 and stage 4 breast cancer we no longer speak of cures. That’s a real problem. In fact, there are certain forms of breast cancer that begin as metastatic disease – one of which I have dedicated quite a bit of my research effort to – known as inflammatory breast cancer. While that is only about five percent of breast cancer it is up to 15 to 20% of annual mortality. The field has made absolutely no progress on inflammatory breast cancer survival, which in a third of the cases begins as a metastatic disease and roughly 30% is pregnancy associated, with a mean survival of 2.5 years. It might start to change now that we are beginning to see small effects of the immune checkpoint inhibitors. There is a concentrated research effort solely on metastatic disease now. It is very hard to work on metastasis because the animal models are not good, and by the time metastases have occurred in patients there are a lot of mutations as well. We have to change our view of the way of treating cancer because we can’t any longer think about treating cancer one mutation at the time. We need to bring into the clinic drugs that act on immune checkpoint changes – and that is also where translational control comes to bear. If we drug translation then we are able to block entire hubs or centers of translation for specific types of mR- NAs, such as survival mRNAs, DNA damage, DNA repair mRNAs in tumors and mRNAs that are involved in development of T regulatory cells that suppress the anti-tumor immune response. The mRNAs all have specific requirements. So drugging protein synthesis offers us the ability to downregulate entire constellations of genes at the translational level. Genes that are required for the survival and metastasis of tumor cells and other specific functions can also be drugged selectively at the mRNA level. That’s why I focused on this area. And we had some successes here.

You co-founded several biotech companies, such as PTC Therapeutics. How does the development of PTC299 an inhibitor of VEGF mRNA translation go along?

We took it all the way through phase II clinical trial. That was actually a remarkable experience. From the time I had published a paper on the mechanism of tumor-specific translation under hypoxia in 2009, we began work with PTC Therapeutics. It was four years from the time of discovery to the time we had a drug that PTC filed for an IND [Investigational New Drug Application] with the FDA. With PTC we received a grant of 2.5 million dollars to actually take the drug into the clinic. We saw remarkably good responses in phase II clinical trial in metastatic estrogen receptor positive breast cancer. We saw excellent results in pediatric glioma as well. The problem with the drug was its hepatotoxicity, which was not that severe and was related to the drug, not its mechanism of action. The company decided to put the drug on a shelf, so they are not developing it any more. But we do have back-up drugs that don’t show this hepatotoxicity. The discussion now is whether it makes sense to bring those drugs back into the clinic. But it was the first time that anybody had drugged translation by creating a small molecule that actually selectively blocks translation at the mRNA level.

What should be considered when developing RNA-based cancer drugs?

If we want to drug translation in cancer we – the pharmaceutical industry and other major players – need to think differently. When drugging translation, we should not do it at a level that does not cause a large decrease in overall protein synthesis. We only need to decrease protein synthesis by about 20 percent. It isn’t necessary to block protein synthesis severely because selectively decreasing the translation of specific mRNAs, those that provide cancer cell survival, drug resistance and proliferation of the cancer cell, have increased requirements for translation and are more readily inhibited. The problem in cancer drug studies is that drugs are used at what is called the maximum tolerated dose [MTD]. All that we do by drugging cancer cells at the MTD level when targeting protein synthesis is to increase toxicity. Instead, we need to drug cancer cells at the level that achieves synergy with established anti-cancer agents such as genotoxic DNA damage agents – many of the common chemotherapeutics. Translation inhibiting drugs on their own should have little or no impact but when combined with existing chemotherapy can actually be quite useful. This different way of thinking about going after cancer requires a conceptual change in clinic trials.

Your lab also focuses on the regulation of the inflammatory response and its intersection with cancer development, i.e. the control of degradation of short-lived inflammatory cytokine and proto-oncogene mRNAs. How does your work progress within basic research?

What we have done is to knock out some of these key proteins that control mRNA stability. Because much of my work is also translational and my eye is almost always on the clinic, we have been able to take those findings and directly connect them to a number of human disorders. We have a paper going out the door showing that some of these mRNA binding proteins that control mRNA stability go to the heart of human skin disorders such as psoriasis, and that they are involved in the control of stem cells in the epidermis. In another paper to be submit- ted soon, we also show that mice develop a form of muscular dystrophy through the loss of control of mRNA stability within adult muscle stem cells. If you keep your eyes open and you move it from the cell to the animal, it is not that hard to make the connection to human disease. So, basic research can be easily translated.

Where do you see progress in disease areas that make you feel optimistic?

In many areas. In particular, now that I am Associate Dean for Drug Discovery, which is something, I am very excited about. A tremendous amount of my effort goes into that. I am excited and I am really hopeful. I would say that I give the NYU administration enormous credit for two things: one, giving me this large budget to be able to translate research – not my own but everybody’s research – into both drug discovery and new clinical observations. And secondly, enabling me to have the biggest thrill and the biggest satisfaction, which is in helping my colleagues translate their basic research into drug discovery efforts that will impact on human diseases. When you think about it, at the NYU as at so many academic medical centers, we have well over a hundred world-class laboratories. To be able to help them translate their research into new drug discovery is extraordinary. It is bigger than any pharmaceutical company. The institution is allowing me, with a staff of 20 people, to invest in this and conduct what is basically a virtual biotech within academia. To do new drug discovery is extraordinary and we have a lot to show for that in just a few years time.

And what about areas where progress is slow no matter the effort?

Let me tell you why I am optimistic. I am optimistic because the old model of the pharmaceutical industry has failed and they now understand that it is failed. So here is what happened: the majority of the failure that we have had in the last 20 years or so in making new inroads in cancer and other human diseases is largely because there was this enormous separation between pharmaceutical industry drug discovery efforts and academic laboratories. Pharma now understands that and has come back to embrace academic research, not just in terms of funding, but in terms of direct collaboration. The amount of discovery that takes place in academic institutions is extraordinary. Almost none of this enormous research effort in academia has been captured in the past, other than industry reading the literature but not gaining the expertise and insight of real experts on a day-to-day basis. Now that they are working closer together with academia, and now that you can start your own virtual biotechs because you can outsource much of what you needed to do, things are changing rapidly compared to the past. And so many more people are starting their own companies and stay in academia at the same time, so I am really very hopeful.

You have several academic appointments and many responsibilities. How do you manage to keep the overview over ongoing research relevant to you?

You can’t. You have to work as a team and you have to rely on your team members and collaborators. That’s why I think what the NCCR is doing is really brilliant. You have to be able to work collaboratively and collegially, because nobody can keep up anymore.

What would you advise scientists who want to work collaboratively? Where does collaboration end and where does competition start?

My view is that the easiest way for people to become comfortable collaborating with each other is first to protect your discoveries by filing for intellectual property patent applications. Because a patent application is not a secret but a disclosure where you are protecting your discovery. I think worldwide academics need to become much more sophisticated about protecting their discoveries. Once you file the patent application there is no reason not to collaborate. In fact, you can have mutual intellectual properties. So I think much of the competition and secrecy come from people not protecting their own inventions.

Interview: Thomas Schnyder

Biography Dr. Robert J. Schneider - NYU School of Medicine, USA

Dr. Robert J. Schneider is the Albert Sabin Professor of Molecular Pathogenesis and Professor of Radiation Oncology at the NYU School of Medicine, and Associate Dean for the Office of Therapeutics and Industry Alliances. His research focuses on the molecular basis of metastatic breast and ovarian cancers and the develop- ment of new therapeutics. His work also includes investigation of cancer stem cells and adult stem cells, and interconnections with the inflammatory response. He is the author of more than 150 peer-reviewed papers and has received numerous awards and prizes in recognition of his achievements. He is a co-founding scientist of six biotech companies focused on translating oncology research to the clinic. Since 2015 Robert Schneider is a member of the NCCR RNA & Disease Scientific Advisory Board.

Dr. Robert J. Schneider online

Interview: Thomas Schnyder