Researchers at the National Institutes of Health (NIH) are taking a different approach to treating cancer, focusing on the disease’s deadly and perplexing process of metastasis, the migration of tumor cells beyond their original site.

“There is no single drug approved for targeting (cancer) metastasis,” said Juan Jose Marugan, Ph.D., of the NIH’s National Center for Advancing Translational Sciences (NCATS). “Another thing is we don’t completely understand the process of metastasis.”

Marugan, along with NIH colleagues and primary collaborators from Northwestern University and the University of Kansas, have developed a small molecule, called metarrestin, which in pre-clinical animal models of solid tumor cancers, such as pancreatic cancer, blocked metastasis.

The NIH has been granted a patent on metarrestin and Marugan and his team have completed the work for filing an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) to begin clinical trials in patients with pancreatic cancer. The plan is to evaluate metarrestin up to Phase 2 trials and out-license the small molecule to a commercial drug company for continuing clinical development and eventual FDA approval.

As part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Marugan about the process of cancer metastasis, the discovery of metarrestin, and the decision to focus initial clinical development on pancreatic cancer.

Marugan is the chemistry leader in NCATS’ Division of Pre-Clinical Innovation. He has more than 20 years of experience in drug discovery and development in academia and the pharmaceutical industry. He joined the NIH in 2008 and moved to NCATS when it was formed in 2013.

Marugan holds a Ph.D. in organic chemistry from the Universidad Complutense de Madrid and a B.S. in chemistry from the Universidad de Salamanca.

WuXi: How is your research and the drug you discovered different from existing pancreatic cancer treatments? Is it a new approach?

Juan Jose Marugan: Pancreatic cancer is one of the most difficult cancers to treat. Ninety percent of the patients don’t survive for a year. And most of the treatments – the standard of care – increase the life expectancy by a few months. So this is a really, really bad cancer.

One of the main reasons is that, in the majority of cases, pancreatic cancer works in stealth, so it doesn’t have any manifestations until it is already in clinical stage 3 or 4.

This is also the main cause of death among other types of cancer. Over the years we have developed good chemotherapy treatments for primary tumors along other solutions like surgery and radiation. But when the cancer becomes metastatic and is already in an advanced stage, the patients don’t respond to medications. This is not only true for pancreatic cancer; it’s true for all kinds of solid tumor cancers.

Of all the cancer drugs we have out there approved by the FDA, there is no single drug approved for metastases. All the drugs we have are for treating the primary tumor and somehow they are able to reduce the production of metastases because you are able to reduce the primary tumor.

But we don’t have anything that treats a specific metastasis. One of the reasons is because we don’t understand very well the process of metastasis. We have a sense of some of the mechanisms involved in epithelial-mesenchymal transition and some of the basic receptors and factors that they involve in his process. We have an idea, but we don’t have the whole picture.

What we did to address this problem is to use a phenotypic approach, instead of going towards a specific (genetic) target. We identified a marker of metastasis, which we call the perinucleolar compartment (PNC). The PNC is a sub-nuclear body that is attached to the nucleolus, and can be observed only in highly evolved cancer cells, therefore in metastatic cells, for all kinds of cancers.

For any kind of cancer in early stage, the cells don’t have the PNC, but when they are in a metastatic state there is a high prevalence of cells with the PNC. In metastatic lesions, the prevalence is 100%.

We did high-throughput screening, looking for molecules able to disassemble the PNC without killing the cells. We were not looking for molecules that were toxic. We found several of those molecules and we optimized one of them; and from there we obtained the molecule we call metarrestin, which is extraordinarily effective in disassembling the PNC across solid tumors. Then we attempted to evaluate metarrestin in different kinds of cancer (animal) models, among them pancreatic cancer.

What we saw was that metarrestin was able to prevent the production of metastatic lesions if you start the treatment before the cancer is metastatic. If you start the treatment after the cancer is metastatic, you increase the life span and you reduce the number of metastases.

Metarrestin does not have much of an impact in the primary tumor. It mostly has an impact in the metastatic condition, and all of this is done without affecting the viability of normal cells. So, the compound does not have any kind of acute toxicity and is very well tolerated. It also has really good oral bioavailability and distribution.

WuXi: What is the drug’s mechanism of action?

Juan Jose Marugan: We disclosed part of our studies in a manuscript in 2018 in Science Translational Medicine: “Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis”

One of the things in doing phenotypic high-throughput screening is the tendency to discover very novel and interesting biology. When you have a molecule with a novel and peculiar pharmacology – like being able to kill metastatic cells without killing normal cells and without affecting much in earlier stage cancer – then it can take a while to find the target and to fully understand the biology.

What we know is that the target of the molecule is a protein, which is expressed in all cells. It is called eEF1A, and there are two isoforms, eEF1A1 and eEF1A2. eEF1A is an elongation factor that has functions in transcription elongation and protein synthesis. However, many other cell functions have been described for the same protein.

Re-expression of the eEF1A2 isoform has been previously linked to tumor genesis and cancer progress and is not expressed in the majority of normal cells.  We found that eEF1A2 has important function in cancer controlling ribosomal biogenesis; specifically, eEF1A2 controls the function of RNA polymerase 1, which synthesizes ribosomal RNA. So what this protein does in cancer cells is increase the levels of ribosomal biogenesis, which is absolutely crucial for elevating the number of ribosomes, and carrying out cellular division and cancer evolution.

Metarrestin binds eEF1A2 and specifically blocks this particular function involved in the synthesis of new ribosomes in highly evolved cancer cells.

WuXi: You are targeting the tumor as it spreads beyond the pancreas, but are you also able to slow progression of the disease within the pancreas?

Juan Jose Marugan: For patients who have pancreatic cancer, the first thing to do is surgery, and try to eliminate the primary tumor. Many patients who die of pancreatic cancer, don’t die because of the primary tumor, they die from the metastatic lesions.

In late stages, they develop the metastatic lesions all over the body, in the liver, in the brain and in the lung. We don’t have effective treatments to treat these lesions. You cannot operate on every lesion and we don’t have a way to deal with micro-metastases. So when you eliminate one metastatic lesion, in a few months another lesion might show up in a different place.

What we encountered is a novel mechanism that affects the viability of these metastatic lesions. This has to do with specific mechanisms that increase ribosomal biogenesis in metastatic cells.

The mechanisms we knew until now that control ribosomal biogenesis, if you block them, it would impair ribosomal biogenesis in every cell in the body. And that has toxic consequences.

WuXi:  What is the status of metarrestin’s development? Are you working with any companies for its clinical development?

Juan Jose Marugan: We just finished filing the IND application. We have done all the preclinical development. This has been a collaboration among many different people.

Early on, the idea for the PNC screening came from Sui Huang, MD, Ph.D., associate professor of cell and developmental biology at Northwestern University’s Feinberg School of Medicine.

Also, we worked with Kansas University’s Specialized Chemistry Center; they helped us with part of the medicinal chemistry studies.

Then we worked with Udo Rudloff, MD, Ph.D, an investigator with the National Cancer Institute (NCI), whose clinicians will evaluate the molecule in Phase 1 and Phase 2 clinical trials. Rudloff already has the clinical protocol approved.

The preclinical development was done in NCATS – the GMP (Good Manufacturing Practice) scale-up, toxicity studies and formulation. We just finished putting together all the files for the IND and we are about to send the IND application to FDA for approval in the next couple of months.

We are not working with any companies right now. We have a patent that the technology has been developed internally at NIH. Eventually the technology will be out-licensed. NCATS Office of Strategic Alliance, takes care of the licensing. As a public entity, anybody can come to us and request a license.

WuXi: Why did you choose to focus on pancreatic cancer? It has been a very difficult disease to treat?

Juan Jose Marugan: We did evaluate the molecule in a number of other animal models of cancer, including metastatic prostate cancer and metastatic breast cancer, and it worked really, really well.

We focused on pancreatic cancer because, for prostate cancer and breast cancer, there are some solutions; and much of the prostate and breast cancer is detected in earlier stages and there are good clinical practices for taking care of those cancers.

But, for pancreatic cancer there is almost nothing, so this is the reason why we decided to go with pancreatic cancer.

WuXi: Are you developing any other drugs for cancer and are you looking at metarrestin as a possible combination drug for immunotherapies?

Juan Jose Marugan: Yes we are in the process of looking at combinations, not only with standard of care, but with immunotherapy.

One of the approaches is to activate the innate immunity. Most people who work in immunotherapy work with antibodies and conjugates that block specific markers of the cancer; or they are working in CAR-T. They produce a monoclonal antibody that they develop into a chimeric antibody, and they produce CAR-T cells that specifically kill one type of tumor which has the (targeted) antigen. Those treatments are difficult, especially CAR-T. They are very expensive and they are very personalized. The PDL-1 antibody is the standard care these days.

But there is not much being done in innate immunity. Recently we found a novel mechanism that we are about to publish (in a journal article). We found a way to reactivate the immune system of the patient that also is highly effective to treat pancreatic cancer and other forms of cancer.

WuXi: What is your opinion about the challenges in early screening and diagnosis of pancreatic cancer? Are there any biomarkers?

Juan Jose Marugan: Many people are working to develop metabolomics markers. Others are also working in exosomes, which are highly involved in the metastasis of cancer.

We have been doing something like that with Udo Rudloff. We are trying to measure circulating cancer cells as a way to diagnose the stage of pancreatic cancer and also the effect of our molecule. If we are killing metastasis, we should have fewer circulating cancer cells.

But this is a tricky area. We published a paper in 2018 on some work with exosomes in prostate cancer. We are actively working in this area of biomarkers, which is always tricky.

WuXi: Let’s talk about NCATS. What is its focus?

Juan Jose Marugan: NCATS is a very new institute. We are the youngest institute at NIH. We officially became an independent institute in 2013.

We are not the national center for translation. We are the national center for advancing translation. I always say that the production of new drugs, as they go into clinical trials, is kind of a side effect. It is not exactly what we are looking for. It is a side effect that happens and it is desirable, but our goal is to understand why we fail so much in translation. Ninety percent of drugs that reach human clinical trials fail.

The reason for this institute is to have a better sense of why we are failing so much. In the case of my group, we work in the early translational branch, our goal is not only to validate new approaches, but also to have a better sense of why the approaches we are using to select and develop drugs fail so much.

There are basically two reasons why we fail so much. The first reason is because the (animal) models we use to validate our approaches and our molecules don’t really represent the human condition. We have cured Alzheimer’s in mice – I don’t know how many times – but everything that goes to clinical trials doesn’t pass; and there are many other examples.

Thirty-five percent of the drugs that enter human clinical trials fail in Phase 1, so all these (pre-clinical) toxicity studies we do don’t catch the toxicity of 35% of the drugs. The toxicity in mouse and dog models is not exactly the same toxicity as in humans.

What we do is develop models that are more human-like. We work a lot in reprograming and producing pluripotent cells and differentiating them into somatic cells for whatever phenotype. We also work with organoids. We like bioprinting and biochips. Our Tox 21 program tries to detect early on the toxicity in humans instead of just trying to do that in clinical trials.

The second reason why we fail so much is the way we select our targets for therapeutic intervention. Most of the time we select our targets by association studies. We just take a cohort of patients that have, let’s say, Parkinson’s disease and (people) in the same family who don’t have Parkinson’s and we do our association studies. We find LRRK2 (gene) or PINK1 (gene) or glucocerebrosidase (protein) that have mutations, which predispose you to Parkinson’s. But in reality, 90% of the people who have Parkinson’s are idiopathic. We don’t know why they have Parkinson’s.

And this is the same for most diseases. Even the diseases that are very rare, the genetic background has a tremendous impact on progression of the disease. So what we do in our team is see the development of disease from a different perspective, more from the point of view of loss of homeostasis, the capacity of the cell to respond to a stress. It could be stress due to genetic mutation, to environmental reasons, and to aging, which is something people don’t talk much about.

There are a number of stressors that overtime impair a cell to respond properly to a stress and to properly reach homeostasis. Much of what we develop are interventions that promote the capacity of the cell to deal with all kinds of stress, like oxidative stress, ER (endoplasmic reticulum) stress and (protein) folding, translocation and elimination of (waste).

We also work on homeostasis of tissue; how the (immune) system affects the homeostasis. We work in fibrosis because we believe that these interventions work across diseases. So if we do develop something that is able to regulate the capacity of the neurons to get rid of (waste), it may work not only for Parkinson’s disease, but also for Huntington’s disease, for ALS (amyotrophic lateral sclerosis), and for Alzheimer’s disease.

Much of what we do is develop new approaches for selecting targets for interventions and see in a much more comprehensive way, beyond just one particular mutation, what might affect the activity of the cell in one particular way.