Cover Image Fusion

by Steph Guerra
figures by Shannon McArdel

The Cancer Moonshot is an initiative that was launched by Joe Biden in 2016 with the goal of accelerating cancer research progress by bringing together world-class researchers and institutions in the battle against this disease. Armed with $300 million in startup funding, plus a total of $1.8 billion authorized over the next seven years, the Cancer Moonshot has already made significant progress in building new cancer-fighting coalitions.

2016 was a planning year for the Moonshot in which key stakeholders were convened to recommend projects to be completed over the next five years. As I did in my previous article, I hope to distill the science behind some of the 2016 recommendations. One such recommendation is to tackle a class of cancer-driving proteins: fusion oncoproteins in childhood cancers. This seemingly specific aim is important for many reasons. First, childhood cancers remain the leading cause of death from disease for American children and fusion oncoproteins are well-defined drivers of these tumors.  Second, understanding fusion oncoproteins in childhood cancers will help us understand fusion oncoproteins in adult cancers, expanding the reach of these discoveries. And third, as I will discuss later, fusion oncoproteins may be one of the most promising druggable drivers of cancer. But with so much to gain, why haven’t we been able to defeat these proteins (and cancer) already?

DNA mutations cause cancer

All the genetic information in our cells is stored in DNA arranged as twenty-three pairs of chromosomes. DNA is an instruction manual that our cells read to make proteins, or tiny machines that carry out tasks that help the cells in our bodies grow, move and divide.

Cancer happens when changes, or mutations, occur in our cellular DNA. These mutations alter proteins and, therefore, the tasks that they perform. There are two major classes of mutated proteins that can cause cancer: oncoproteins and tumor suppressor proteins. Oncoproteins are highly active versions of proteins that normally promote growth (like proteins on steroids), whereas tumor suppressor proteins are less active versions of proteins that normally prevent growth. If a cell were a car, oncoproteins are like a stuck gas pedal whereas tumor suppressors are like broken brakes, both of which can ultimately cause uncontrollable cellular growth (or an uncontrollable fast moving car). When DNA mutations result in oncoproteins, the volume of growth pathway activity is turned up and cells divide uncontrollably to form large masses of cancer cells, or tumors (see Figure 1).

Figure 1: The Path to Cancer. Cancer is caused by a series of mutations that turn up the volume of cell growth pathways. Ultimately, normal cells begin to grow uncontrollably, forming a tumor.
Figure 1: The Path to Cancer. Cancer is caused by a series of mutations that turn up the volume of cell growth pathways. Ultimately, normal cells begin to grow uncontrollably, forming a tumor.

There are many different types of mutations that can produce an oncoprotein. Some mutations involve small typos in the DNA sequence while others involve more global changes in chromosomes, all of which can turn up the volume on growth pathway activity (see Figure 2). One such global chromosomal change results in the production of fusion oncoproteins. Fusion oncoproteins are when two or more genes that originally were on separate chromosomes (and formed two different proteins) are aberrantly glued together to form a Frankenstein-like protein with a completely new function (see Figure 3)!

What makes fusion oncoproteins different from other oncoproteins?

Fusion oncoproteins differ from traditional oncoproteins because, whereas traditional oncoproteins typically just turn up the volume on their normal activity, fusion oncoproteins can gain completely new functions. Fusion oncoproteins can be difficult to study because, often times, the functions of the individual proteins that make up the fusion are unknown. Therefore, cancer researchers must first determine what each protein does on its own and then determine how two different parts of a protein are able to cooperate to promote cancer!

Figure 2: Chromosomal Alterations Cause Cancer. Sometimes cancer-causing mutations involve large changes in chromosomal structure such as duplications, deletions, inversions, translocations, and insertions. When these changes involve oncogenes and tumor suppressors, they can promote cell growth.
Figure 2: Chromosomal Alterations Cause Cancer. Sometimes cancer-causing mutations involve large changes in chromosomal structure such as duplications, deletions, inversions, translocations, and insertions. When these changes involve oncogenes and tumor suppressors, they can promote cell growth.

One example of a fusion oncoprotein in childhood cancer is EWS-FLI, a common driver of pediatric Ewing’s Sarcoma. Eighty-five percent of patients that present with this soft tissue cancer have tumors driven by this fusion oncoprotein, which fuses the EWS gene on chromosome 22 to the FLI1 gene on chromosome 11. FLI1 is a transcription factor, a protein that normally functions by controlling the levels of other proteins in the cell. In the EWS-FLI1 fusion, the part of the FLI1 protein that is important for its function gets fused to EWS in a way that turns up its activity. Thus, like a traditional oncoprotein, the EWS-FLI1 fusion protein turns up the volume on its normal FLI1 transcription factor activity, more potently increasing the levels of many, many proteins in the cell. There is also evidence that the EWS-FLI1 fusion protein increases levels of new proteins that FLI1 alone does not target, providing new function for this fusion protein. Therefore, by activating many of the typical targets and several new ones, this fusion is able to produce an army of cancer-promoting proteins.

Figure 3: Fusion Protein Formation. Fusion proteins are generated when a large chromosomal change occurs that cuts and pastes part of one chromosome onto another. When this cut/paste action fuses two genes in just the right way, it creates a fusion oncoprotein with a new function that results in high growth pathway activity. The resulting fusion oncoprotein contains part of each original protein.
Figure 3: Fusion Protein Formation. Fusion proteins are generated when a large chromosomal change occurs that cuts and pastes part of one chromosome onto another. When this cut/paste action fuses two genes in just the right way, it creates a fusion oncoprotein with a new function that results in high growth pathway activity. The resulting fusion oncoprotein contains part of each original protein.

Stopping a fusion oncoprotein in its tracks

The Cancer Moonshot aims to bring together new technologies, new collaborators, and new ideas to reinvigorate the battle against EWS-FLI1 and other fusion oncoproteins. When the EWS-FLI1 fusion oncoprotein was first discovered, researchers were hopeful that treating pediatric Ewing’s Sarcoma would be manageable. These cancer cells have very few additional oncoproteins, so it appeared that stopping EWS-FLI1 in its tracks would be enough to stop the tumor. Unfortunately, after decades of research, no drugs have been discovered that directly block EWS-FLI1 activity because it does not have a discrete binding pocket amenable to small molecule disruption (see Figure 4).  And since the EWS-FLI1 protein promotes a very large and diverse army of proteins within the cell, battling it indirectly through its targets has proven challenging.

Figure 4: New Strategy to Target Fusion Proteins. Traditionally, scientists can block oncoprotein activity (and lower growth pathway volume) by finding a small molecule that binds to the binding pocket of the oncoprotein. Fusion oncoproteins represent a unique challenge because they do not have a discrete binding pocket that can be targeted by a small molecule. Researchers instead have found a way to take advantage of the cellular destruction machinery by creating a drug that tricks the cell into marking the oncoprotein as trash. By this method, the fusion oncoprotein is essentially incinerated by the cellular destruction machinery in much the same way that trash is eliminated through a series of demarcation steps.
Figure 4: New Strategy to Target Fusion Proteins. Traditionally, scientists can block oncoprotein activity (and lower growth pathway volume) by finding a small molecule that binds to the binding pocket of the oncoprotein. Fusion oncoproteins represent a unique challenge because they do not have a discrete binding pocket that can be targeted by a small molecule. Researchers instead have found a way to take advantage of the cellular destruction machinery by creating a drug that tricks the cell into marking the oncoprotein as trash. By this method, the fusion oncoprotein is essentially incinerated by the cellular destruction machinery in much the same way that trash is eliminated through a series of demarcation steps.

One promising new technology being explored under The Cancer Moonshot is a new class of drugs that aims to directly destroy proteins like EWS-FLI1. There is normal destruction machinery within the cell that is responsible for eliminating proteins when they are no longer needed. The cell knows which proteins to destroy because they are tagged with labels that tell the cell’s destruction machinery to destroy them, much like we do when we put items into trashcans or recycling bins. A new class of drugs aims to direct this destruction machinery specifically to oncoproteins by tricking our cells into thinking that these proteins should be destroyed (see Figure 4). One half of the drug specifically binds to the oncoprotein and the other half of the drug is recognized by cellular machinery that labels the oncoprotein with those same trash tags so the destruction machinery can recognize the oncoprotein and destroy it.

This new therapeutic technology is making waves in the cancer research community as a potential way to target many types of traditionally “undruggable” proteins. Fusion oncoproteins, in particular, would benefit from the success of this technology for several reason. First, fusion oncoproteins are only found in cancer cells and not normal cells. Thus, if a drug can specifically target the fusion protein, but not either protein alone, a normal cell exposed to this drug will not be affected negatively. Second, fusion oncoproteins in childhood cancer often represent the sole driver of the disease. By destroying this protein, researchers hope that the cancer cells will die. More research is needed in this exciting field of degradation-inducing drugs, but treating childhood cancers could be a focus of this new technology.

What does the Cancer Moonshot recommend?

Besides exploration of new technologies like degradation drugs, the Cancer Moonshot aims to bring together researchers across many disciplines to learn more about fusion oncoproteins and how they lead to cancer. Key steps include developing more mouse models of these diseases so that new treatments can be tested, examining large datasets to determine more about the cancer-causing effects of fusion oncoproteins, and determining the 3-D structure of these fusion oncoproteins so we can better design drugs. In particular, determining the 3-D structure of these proteins is essential for the development of treatments (such as degradation-inducing drugs) so that we can properly target the destruction machinery.

Working on fusion oncoproteins can be challenging as they occur very rarely in cancers leading to very few model systems for pre-clinical work, few patients for clinical testing, and few colleagues studying the disease. Creating a cross-institutional team that shares data and resources will be key to obtaining tangible results in the clinic as soon as possible. This strategy is a clear emphasis of the overall mission of the Cancer Moonshot and is particularly important for focusing the target onto fusion oncoproteins.

Steph Guerra is a PhD student working in the field of cancer research at Harvard Medical School and a former co-director of SITN. @Steph_Guerra_

For more information:

Cancer Moonshot Update: https://www.theguardian.com/us-news/2016/oct/17/joe-biden-cancer-moonshot-program-update

Fusion Proteins in the Clinic: http://www.nature.com/news/cruel-fusion-what-a-young-man-s-death-means-for-childhood-cancer-1.21723

Degradation Drugs: https://phys.org/news/2017-03-death-drug-undruggable.html

 

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