New cancer treatments have been discovered in the "dark matter" of the human genome

Cancer is the second leading cause of death worldwide
.
Among the different types of cancer, non-small cell lung cancer (NSCLC) is the cancer that causes the most deaths, and most patients still have no cure
.
Unfortunately, even newly approved treatments can only extend a patient's life by a few months, and only a few people survive long-term
.
As a result, people are seeking new therapies
to treat cancer in novel ways.
In a recent study published in the journal Cell Genomics, researchers at the University of Bern and Insel Hospital identified new targets for drug development for this cancer
.

Dark matter in the genome

To find new targets, they studied a class of little-known genes
known as "long non-coding RNAs (lncRNAs).
" LncRNAs are abundantly present in so-called "dark matter" or non-protein-coding DNA and make up the vast majority
of our genome.
The human genome contains about 20,000 "classical" protein-coding genes, but that number pales in comparison to 100,000 lncRNAs
.
The biological function of 99% of lncRNAs is unknown
.

As the name lncRNAs suggest, unlike mRNAs, they do not code for the protein's build plan
.
But like mRNAs, the building instructions for lncRNAs are also contained in the cell's DNA
.

New tools identify potential targets

To investigate the role of lncRNAs in non-small cell lung cancer, the researchers began analyzing the published dataset to see which lncRNAs are present in
non-small cell lung cancer.
This analysis led to a list of more than 800 lncRNAs of importance
for the NSCLC cells that the researchers hoped to study.
In this study, they developed a screening system that blocks the production of selected lncRNAs by removing part of the build instructions from DNA
.

They applied their screening system to two NSCLC cell lines from patients and looked at how inhibition of selected lncRNAs affected the so-called "characteristics" of
cancer cells.
The markers are cellular behaviors that contribute to disease progression: proliferation, metastasis formation, and treatment of drug resistance
.
Rory Johnson, an assistant professor at the University of Bern, said: "The advantage of evaluating the characteristics of three different cancers is that we have a comprehensive perspective, but also a lot of data from different experiments from which we need to come up with a single list
of long noncoding RNAs that are important for non-small cell lung cancer.
" He led the NCCR RNA and Disease Grant Project
.
The analysis resulted in 80 high-confidence candidate lncRNAs that are important
for NSCLC.
From these 80 genes, the researchers selected several lncRNAs for subsequent experiments
.

Destroy long RNAs with short RNAs

In these follow-up experiments, we used a method that does not work at the DNA level, but rather targets lncRNAs after they are produced
.
To do this, the researchers used chemically synthesized small RNAs called antisense oligonucleotides (ASOs), which bind to the lncRNA of interest and cause its degradation
.
Notably, some ASOs have been approved for the treatment of human diseases, but not yet a single ASO has been used for cancer
.

These follow-up experiments showed that for most of the extracted lncRNAs, ASO's disruption of them inhibited cancer cell division
in cell culture.
Importantly, the same treatment has little effect on non-cancerous lung cells that should not be harmed
by cancer treatment.
In a three-dimensional model of non-small cell lung cancer (NSCLC) that is closer to a tumor than cell culture, inhibition of a single lncRNAs with ASO can reduce tumor growth by more than
half.
"We were very surprised by the effect of antisense oligonucleotides in inhibiting tumor growth in different models," said
co-first author Taisia Polidori.

Therapeutic progress and application of other types of tumors

The researchers are continuing their work on preclinical cancer models and considering partnering with existing companies or creating a startup to develop a drug
to treat patients.
Regarding other cancers, Roberta Esposito, a postdoc at the University of Bern, said: "Just as telescopes can easily reposition to study different parts of space, our approach should be easily adapted to reveal new potential treatments for other cancer types
.
" Now they will apply a "telescope" to identify new targets for
colorectal cancer.

NCCR RNA and Disease – The Role of RNA in the Pathogenesis of Disease

RNA (ribonucleic acid), which is essential for many life processes and functions much more
complex than originally envisaged.
For example, RNA defines the conditions under
which a particular gene in a particular cell is activated or not activated.
If any part of this gene regulatory process fails or does not run smoothly, it can lead to heart disease, cancer, brain diseases and metabolic disorders
.
NCCR brings together Swiss research groups
studying different aspects of RNA biology.
By studying the dysregulation of regulatory mechanisms in disease, NCCR has identified new therapeutic targets
.

Roberta Esposito, Taisia Polidori, Dominik F.
Meise, Carlos Pulido-Quetglas, Panagiotis Chouvardas, Stefan Forster, Paulina Schaerer, Andrea Kobel, Juliette Schlatter, Erik Kerkhof, Michaela Roemmele, Emily S.
Rice, Lina Zhu, André s Lanzó s, Hugo A.
Guillen-Ramirez, Giulia Basile, Irene Carrozzo, Adrienne Vancura, Sebastian Ullrich, Alvaro Andrades, Dylan Harvey, Pedro P.
Medina, Patrick C.
Ma, Simon Haefliger, Xin Wang, Ivan Martinez, Adrian F.
Ochsenbein, Carsten Riether, Rory Johnson.
Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities.
Cell Genomics, 2022; 2 (9): 100171