Finding a drug for a friend, sometimes it’s okay

When cancer strikes, precise and accurate information is critically valuable. As a scientist and researcher, I obviously place my value on scientific observation, so when a friend of mine was recently diagnosed in 2016 with cancer, I focused on scientific research to help dig up information of value.

I found out that my friend was diagnosed with an unusual form of cancer - epithelioid sarcoma -and I launched myself into the research behind this condition. Parts of this epithelioid sarcoma cancer story I have recounted previously. Along the way, through discussion with some high profile researchers in the field, I found out about one pharmaceutical company called Epizyme, that was also involved in the study of this cancer.

Epizyme is a company that has two novel drugs in development. Their current predominant focus is on the analysis of a drug called tazemetostat for the treatment of multiple types of cancer. I had the opportunity to investigate a lot of their published information in search of the related use of this therapeutic in the treatment of epithelioid sarcoma. This is a very rare type of cancer that is very hard to treat, and really, there are no known medications for this condition. So the development of a new drug against this type of cancer is exciting news!

Epigenetics cancer drug

In many ways, this is quite a unique drug. It is the first drug to target the epigenetic dysregulation of genetic expression. “Huh?”, you ask? This means that the gene function is affected without any actual mutations in the gene itself. Rather, the mechanism that is supposed keep the regulation of that gene expression in check has malfunctioned.

Specifically, a protein (or a tiny molecular robot as I like to call proteins), that is involved in the coiling or uncoiling of the DNA is being affected. Think of a reel on a fishing rod, with the fishing line being DNA. If you want to package the DNA nice and tight, you wind it up just like you would with reeling in a fishing line. Or you can unwind it, so that the DNA could actually be used by exposing it and providing access to a whole army of different tiny molecular robots.

These spools for DNA to wrap itself around are called nucleosomes, and they are made up of proteins called histones. If you chemically alter a histone (meaning some tiny chemical is either attached to it, or removed, like a new LEGO piece), it can either allow DNA packing around it, or not. This chemical alteration is like a molecular switch: if it is there, one event happens, and if it is removed, usually the opposite event occurs. In this case, we are talking about a simple chemical addition of a methyl group to a histone; one tiny carbon atom, but what a difference!

Methylation of the histone results in the winding of DNA around it, and prevents DNA from being used for expression. If that histone (called H3 – scientists are either extremely creative or extremely uncreative with naming cellular components!), is methylated too much, it impedes proper gene expression. The molecular robot that performs this action is called EZH2 (so it even has a robot sounding name). Because it moves a methyl group around, it is known as a methyl transferase (and it usually is an assembly of multiple components into a large protein complex, but let’s keep things simple).

The aberrant methylation of histone H3 has been observed in many different cancers, which results in the hyper repression of some genes and oncogenic transformation. For example, the increase in activity of this methyl transferase is observed in many non-Hodgkin lymphomas. Hyper repression means that you can beg all you want, but that DNA is not going to be available for other proteins to interact with it, and some genes become inactivated not due to mutations in them specifically, but due to their inaccessibility.

But it is not just the methyl transferase malfunction that can lead to the hypermethylation of histones with subsequent gene hyper repression. As you can imagine, a robot that has such an important role as determining when the DNA is opened up for use should be well managed, and indeed there is a molecular boss above it. The methyl transferase is regulated by another protein complex (a bunch of molecular robots assembled together just like in Transformers). That protein complex, nicknamed SWI/SNF (names retained from past studies in yeast when the little yeast was outshining humans in genetic studies), which helps to promote normal gene expression by inhibiting the function of the histone methyl transferase.

Though here is the kicker: it is the components of this SWI/SNF protein complex that can be mutated, preventing its proper work and leaving the methyl transferases totally unchecked in their merry function, which then can result in cancer. One such SWI/SNF component is a protein encoded by a SMARCB1 gene, also called INI1 (and since proteins are often named after genes, we italicize the gene names to differentiate them from proteins). I am sure for many this will be a familiar story, of a boss not doing their job right! And that is the gene that is often found mutated in some solid tumor cancers, including epithelioid sarcoma, so hence my interest in investigating this company in the first place. Another one is SMARCA4 which is deleted in some ovarian cancers.

So where does Epizyme come into the picture? They have developed a compound called tezemetostat that targets the EZH2 methyl transferase and inhibits its function. So the drug is sent to the rescue to replace the job of the molecular boss that was supposed to keep EZH2 in check in the first place, but fell apart when its components ended up being mutated, leading to cancer development.

Therefore tazemetostat is also a drug for patients with specific genetically-defined tumors. This is how the future of both clinical trials and personalized targeted therapy is going to be defined. Well, perhaps more accurately, that future had arrived a long time ago, it is just that unfortunately not many oncologists are yet aware of or know how to apply such medications. But everything requires its time to mature, and eventually all of our oncologists will be sequencing patient cancer DNA without a second thought.

Behind the scenes of drug development

The journey of how the drug was developed is also quite fascinating and promising. The company utilized the latest hot molecular technique of knocking out gene function with the CRISPR–Cas9 technology by looking into the function of 600 different epigenetic-related genes in about 100 different cell lines. So they literally used the CRISPR technology to break down these genes. This was important because it allowed for the observation of which genes that epigenetically regulate function of other genes were essential in all cell lines for proliferation or survival, because such genes would not be proper targets. The targeting function of such genes would likely produce toxic side effects. But epigenetic targets were also identified that influence cell proliferation of only the subset of cell lines, and histone methyl transferases were included in such epigenetic-related genes.

Once histone methyltransferase containing EZH2 was identified as a target, the process of finding an inhibitor could commence. Few people realize how difficult this process is to produce a potential drug, and to even get to preclinical trials. The vast, vast, vast majority never make it! Once the first inhibitory compound was identified from a screen of compounds (probably hundreds if not thousands of these), other analogues could be tested with similar structures to improve compound potency and solubility.

From there, chemical modifications were undertaken to further hone potency and selectivity. The final product was tazemetostat, which was shown to be highly selective for the EZH2 containing histone methyltransferase, with good bioavailability in animals and very promising anti-tumour activity. The results of the tazemetostat discovery were first published only in 2013.

The drug quickly proceeded into clinical trials. In their first Phase 1 clinical trial of 58 patients, only three were patients with epithelioid sarcoma showing inactivated function of INI1 gene. The information showed that in the treatment of non-Hodgkin lymphoma, tazemetostat exhibited effective and durable activity with a good safety profile, either as monotherapy or combination therapy (used as a solo drug treatment or with other drugs). The majority of all side effects were grade 1 or 2, of the milder effect. Success of the initial phase has lead to a Phase 2 trial in patients with non-Hodgkin lymphoma, and the results presented so far are very promising, both in terms of drug activity and tolerance. They were also being noticed, as at the time Epizyme announced that it has entered into a collaboration agreement with Genentech and the Lymphoma Study Association to test tazemetostat in a combination therapy against non-Hodgkin lymphoma.

What did that mean for my friend with sarcoma?

In the initial Phase 1 trial, eight patients had INI1-negative tumors, five with malignant rhabdoid tumors (a nasty childhood cancer), and three with epithelioid sarcomas. One individual with a malignant rhabdoid tumor exhibited a complete response after 6 weeks of treatment, and remained so after 65 weeks at that time. More importantly, of the three epithelioid sarcoma patients, one achieved a partial response but only for a short duration, exhibiting a stable disease for at least 25 weeks when that information was made available. Another patient also managed to show stable disease through the same duration. There was no mention of the third patient impact.

I contacted the Epizyme company asking for further details on the epithelioid sarcoma patients, but I was not able to obtain more information. However, the success so far has lead to subsequent Phase 2 clinical trial including epitheloid sarcoma patients that exhibit INI1 function loss. The study is headed by the medical director of the clinical study, Dr. Maria Roche, who was gracious in providing lots of background information. Whenever they could, the Epizyme representatives were also kind in answering all of my questions.

So this looked like a very promising potential, albeit experimental, option for my friend. I pleaded with my friend to consider this option. However, in the end, my friend did not want to participate in such an experiment, not being willing to deal with the potential unknown consequences, while her own condition was actually improving at the time. In the end, I was a recipient of good news anyway, but I felt distraught that I was not able to convey the importance of this opportunity to my friend. Much later I even joined the Breakthrough Crew of Clara Health, an organization dedicated to helping patients access clinical trials, in order to help promote the understanding of the importance and utility of clinical trials.

The bottom line is that Epizyme is on top of some sophisticated research with very promising results for the future treatment of a variety of cancers, and tazemetostat is not their only drug in the works (for example, pinometostat for advanced leukemia). For the sake of all the patients that have not been able to obtain prior successful treatment, let’s hope that the observed success so far will continue!

What has happened since?

The phase 2 clinical trial turned out to be successful so far, showing promising results in stabilizing the disease in cancer patients with tolerable tazemetostat side effects. How was that success defined? The study included 31 participants, in which seven patients (23%) had disease progression, and of these, three died (10%). The best effect observed was partial response in 4 patients (13%), and the stabilization of the disease (not getting better or worse), for 32 weeks or more in 2 patients (6%). 13 patients remained on treatment, so future updates will be needed. In fact, this success rate was just good enough for the clinical study to be expanded to include 60 patients.

Where is it supposed to go from here? If the effectiveness and low toxicity profile continues to be demonstrated, the drug will enter the third and final phase of clinical trials - the biggest and most expensive one - and usually the one that is the dealbreaker for many drugs that are being developed. We are talking about millions upon millions of dollars already poured into such studies by that point, so you can image how insanely expensive it is to actually produce a single medicine that enters the market. Only if Phase 3 trials are successful can a drug be considered for public market use. Obviously I hope Epizyme makes it, and yes, I hope they make loads of money and get their return on their investment, while tons of people will have access to a drug that could save their lives.

As of the summer of 2017, the FDA granted an “orphan drug” status to tazemetostat for the treatment of patients with soft tissue sarcoma, which is a status given for drugs that are meant to treat very rare diseases, such as is the case with epithelioid sarcoma. It is a special status to incentivise companies to invest into the development of medications in order to help people with such rare conditions, and which otherwise would not be happening due to the inability to recover the enormous costs associated with drug development. Why is there the “orphan drug” nickname? Because the diseases these drugs are meant to treat are typically so uncommon, they are also nicknamed “orphan diseases”. However, having orphan drug status does not mean that the drug has passed all the safety trials and is available for sale. It means that financial incentives are provided while the assessment of safety and efficacy continues.

This is just one example of cancer treatment drugs in development. The current reality is that companies that develop drugs, for cancer or otherwise, have to take the genetic information of their patients into account as it can make a world of difference, pin-pointing for whom each drug is actually applicable to. This is one of the exciting developments behind how cancer is analyzed, as the genomic profiling of cancers can in high likelihood determine how a specific cancer should be treated. Merogenomics aims to expose people to such DNA sequencing technology use, and cancer molecular profiling is one of the most obvious applications of sequencing to obtain crucial information of value. And believe me, I told my friend all about it too! But as is the case with all cancer patients I talk to, I respect all of the decisions made.

This article has been produced by Merogenomics Inc. and edited by Kerri Bryant. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

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