A vast uncharted territory

For decades, drug discovery has focused on modulating proteins or the genetic instructions that encode those proteins — targets that collectively account for just 2% of the human genome.

It’s past time to explore the rest. At ROME, we are illuminating the “repeatome,” the 60% of our genome that consists of repetitive sequences of nucleic acids, known as repeats.

These repeats have long been dismissed as “junk DNA.” We disagree.

We believe that medicines targeting the repeatome will revolutionize the way we treat cancer and debilitating autoimmune diseases, enabling patients to live long and productive lives.

A peek inside the repeatome

A peek inside the repeatome A peek inside the repeatome

The repeatome is a vast uncharted landscape of DNA that connects the entire genome. The repeats themselves consist of many different families, including small simple sequence repeats, large arrays of tandem repeats in the center and ends of chromosomes (satellite and telomere DNA) and complex mobile repeats that can transpose to different locations in the genome (SINEs, LINEs and HERVs).

On the surface, this landscape appears unimportant, but it contains a complex ecosystem of repeat families that can alter the very structure of our chromosomes. They can expand, contract and rearrange our genes to change the behavior of individual cells.

The origins of this rich ecosystem, activated in times of stress and in specific diseases such as cancer, can be traced back to particular moments in our evolutionary and developmental history.

Infographic adapted from the-scientist.com

From ancient hitchhikers to modern guardians

Many repeat sequences are derived from ancient retroviruses that integrated into the human genome throughout evolution. Over hundreds of millions of years, these sequences have become an integral part of what makes us human.

Just as dark matter in the universe is essential for galaxy formation, the “dark genome” — the repeatome — plays an important role in early embryonic development. The system then deactivates. In healthy people, the repeats remain dormant. However, under the stress of disease onset, the DNA repeats “switch on” and are transcribed into RNA.

This activation sets off alarm bells in the body. The repeats are perceived as foreign invaders and can switch on the innate immune system, signaling the body to remove damaged cells and thereby quiet the repeats. In this way, repeats serve as guardians; they sound an alarm at the emergence of disease and draw the body’s natural immune defense mechanisms into the fray.

From ancient hitchhikers to modern guardians From ancient hitchhikers to modern guardians

Repeats: A powerful force

Activating the repeatome
Activating the repeatome

Long-dormant repeats can activate when the cell is under stress, such as during cancer. At first, that can be helpful.

Long-dormant repeats can activate when the cell is under stress, such as during cancer. At first, that can be helpful.

The awakening The awakening
The awakening

As a cell transforms from healthy to malignant, the DNA repeats within the genome switch on and are transcribed into RNA.

Viral mimicry
Viral mimicry

As they do, they generate strands of RNA that look very much like virus RNA.

An alarm sounds
An alarm sounds

This surge in viral-like RNA can act like an alarm bell, switching on the innate immune system…

An army attacks
An army attacks

… and leading to an immune response that can cause the cancer cell’s death either directly or indirectly by signaling immune cells to attack.

Cancer’s clever defense
Cancer’s clever defense

But too often, cancer cells find a way to survive. They co-opt the powerful force of the repeats for their own defense.

But too often, cancer cells find a way to survive. They co-opt the powerful force of the repeats for their own defense.

A defensive maneuver
A defensive maneuver

To stop the repeats from harming it, a cancer cell can modify the viral-like RNA into DNA that it then reintegrates into its genome. By reducing quantities of viral-like RNA, this process mutes the alarm bell.

A dangerous quiet
A dangerous quiet

Switching off the alarm helps cancer cells evade the immune system. The tumor infiltrating lymphocytes cease their attack. The cancer grows and spreads.

Evasion and growth
Evasion and growth

Integrating the repeat DNA back into the genome can give cancer cells another advantage, too. They use the process to repair breaks in their DNA. That leads to structural changes in chromosomes – and those changes help cancer cells adapt to new environments.

Our mission
Our mission

At ROME, we are developing medicines that intervene in this process. We will strip cancer cells of their powerful survival mechanisms.

We will bring new hope to patients with intractable disease.

Activating the repeatome
Activating the repeatome

Long-dormant repeats can activate when the cell is under stress, such as during cancer. At first, that can be helpful.

Long-dormant repeats can activate when the cell is under stress, such as during cancer. At first, that can be helpful.

Our call to action is clear

Our call to action is clear

As a society, we have made significant progress against cancer in recent decades, yet there are still far too many patients who do not respond to any therapy, and far too many whose response lasts just a few months or years.

That’s not good enough.

At ROME, our mission is to drive even the most intractable cancers and autoimmune diseases into sustained remission. We take as our model the advances made in treating HIV, diabetes and cardiovascular disease. Replicating this success with intractable cancers is wildly ambitious — but we believe it is within our reach. The repeatome points the way.

Advancing a new frontier

This is a new frontier of biology and there is still much to learn, but already we have made tremendous strides. We know how to switch off the viral-like mechanism that gives cancer cells an unfair survival advantage. We have identified promising targets for intervention.

We have the team and the tools we need. And we have the motivation.

We will bring powerful new treatments for cancer and autoimmune diseases to the patients who need them most.

Explore the scientific literature

It’s only in the last decade or so that scientists have had the tools to shine light upon the “dark genome.” This research has uncovered the role repeats play in human disease and suggested a path forward for drug discovery that leverages the repeatome.

Here are some of the scientific papers that informed and inspired us when we first began to explore this field. We have since added our own insights and expertise; we will share more in the months to come.

A tumor-specific repetitive element is induced by herpesviruses | Nature Communications | 2019

Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer | Cell | 2019

Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma | PNAS | 2019

Global cancer transcriptome quantifies repeat element polarization between immunotherapy responsive and T cell suppressive classes | Cell Reports | 2018

Diverse repetitive element RNA expression defines epigenetic and immunologic features of colon cancerJCI Insight | 2017

Transcriptional dissection of melanoma identifies a high-risk subtype underlying TP53 family genes and epigenome deregulation | JCI insight | 2017

Sequence-specific sensing of nucleic acids | Trends in Immunology | 2016

Pericentromeric satellite repeat expansions through RNA-derived DNA intermediates in cancer | PNAS | 2015

Distinguishing the immunostimulatory properties of non‑coding RNAs expressed in cancer cells | PNAS | 2015

Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers | Science | 2011