Outsmart cancer with RNA, ‘genome tuning’ drugs and other gene modifying therapies

Drugs that slow tumor growth by targeting genetic abnormalities in the cancer itself are now well established in oncology. But what if doctors could treat cancer by changing the activity of genes throughout the body, causing it to fight the disease?

A handful of startups and academics are working in this direction. They are not gene therapy in the traditional sense, as they do not remove or replace pathogenic genes. Instead, they use new drugs to increase or decrease the expression of certain genes in order to achieve an anti-cancer effect.

“We are unlocking new biological pathways so that we can target non-drug targets and treat diseases in very new ways,” Robert Habib, CEO of London-based MiNA Therapeutics, said in an interview. MiNA is developing a pipeline of small activator RNAs (sRNAs), which are short, double-stranded oligonucleotides designed to enter cells and stimulate the activity of target genes for therapeutic effect.

In September, MiNA raised approximately $ 30 million to advance its core asset, MTL-CEBPA, into a Phase 2 trial. The drug saRNA is designed to target the CEBPA gene, which encodes a transcription factor essential for human health. the body’s production of anti-cancer myeloid cells. These cells can be depleted in the tumor microenvironment, contributing to drug resistance in cancer.

MTL-CEBPA enters the cell nucleus and uses the activation of RNA to increase the levels of the CEBPA protein. MiNA’s drug is being tested alongside Bayer’s Nexavar, initially in liver cancer, although Habib and his colleagues believe its unique mechanism of action could prove useful in a range of solid tumors.

“Myeloid cells are a problem in liver cancer but also in many other solid tumors,” he said.

MiNA is now planning a second clinical trial in combination with Merck Keytruda’s immuno-oncology blockbuster in a larger set of solid tumors, Habib said.

RELATED: MiNA Raises $ 30 Million to Take Small Activation RNA to Phase 2

A related technology called small interfering RNAs (siRNAs) has long been of interest for its potential to shut down cancer-promoting genes, but translating it into therapies has been a challenge. “It has been hampered by tissue bioaccumulation, ensuring that the delivery system is safe and provides a sufficiently wide therapeutic window in tissues beyond the liver,” said Anna Perdrix Rosell, Ph.D., co- Founder and Managing Director of London. -based on Sixfold Biosciences, in an interview.

Sixfold is working on an siRNA technology called Mergo, the goal of which is to prove that it can deliver siRNAs to cancer cells in specific organs while leaving healthy tissue alone. The company’s preclinical testing is supported by an Innovate UK smart grant, and the company is currently working to define its primary cancer targets, with the goal of moving to clinical trials in 2022, Rosell said.

Sirnaomics, a specialist in gene silencing, is working on several drugs that interfere with RNA to treat solid tumors. Its main active ingredient, STP705, uses a polypeptide nanoparticle to deliver two siRNAs targeting the TGFB1 and COX-2 genes.

Removing these genes inhibits cancer-associated fibroblasts, which are cells in the tumor microenvironment that promote tumor growth, the Gaithersburg, Md., Company tried to show. It is in the early stages of clinical trials in solid liver tumors, squamous cell carcinoma and basal cell carcinoma.

Another gene-driven approach is to inject DNA into tumors with the aim of making them more responsive to immunotherapy or transforming them from “cold” tumors to “hot” tumors. One company working on this technology is OncoSec Immunotherapies, based in Pennington, New Jersey. Its advanced technology, called tavokinogene telseplasmid (TAVO), uses electrical pulses to temporarily open the membranes of cancer cells, after which DNA is injected into them.

The DNA produces IL-12, a naturally occurring immunostimulatory protein that the company’s scientists believe may help overcome resistance to checkpoint inhibitors like Keytruda, a PD-1 blocker. It is a common problem in cancer care: it is estimated that 60 to 80% of patients with melanoma, for example, do not respond to PD-1 blockade. And IL-12 cannot be administered systemically because it causes toxic side effects.

OncoSec’s DNA delivery system is designed to make the body make more of its own IL-12. “DNA essentially co-opted the cell’s function to cause it to produce IL-12,” Daniel O’Connor, CEO of OncoSec, explained in an interview.

OncoSec has partnered with Merck to test TAVO in combination with Keytruda in advanced melanoma and triple negative breast cancer. TAVO is given every six weeks as an injection into tumors, although not all tumors need to be medicated, O’Connor said. “We are seeing shrinkage in tumors treated, but also in those that are not,” he said. In April, OncoSec presented interim data from the melanoma trial, showing an overall response rate of 30%, with complete responses and no serious side effects.

RELATED: Omega Takes $ 126 Million to Introduce ‘Genome Tuning’ Cancer Treatment to Clinic

Investors continue to show enthusiasm for the idea of ​​manipulating gene activity for an anti-cancer response. Omega Therapeutics, a Cambridge, Massachusetts-based company that recently raised $ 126 million in March to advance its “genome-tuning” drugs, including its leading liver cancer treatment, OTX-2002, recently benefited from their largesse.

Omega calls the drug an “epigenetic controller” because it is designed to control the expression of the carcinogenic C-MYC gene. The company’s technology adjusts gene expression without permanently altering DNA, and it does so by targeting regulatory factors in DNA loops known as isolated genomic domains (IGDs), explained CEO Mahesh Karande at Fierce Biotech in March.

“We are treating diseases created by functional or structural changes in IGDs,” Karande said at the time.

Meanwhile, in academia, researchers are constantly looking for new technologies to make the process of adjusting gene activity safer and applicable to a wider variety of tumor types.

In May, for example, researchers at MUSC Hollings Cancer Center described a peptide they are designing that can deliver siRNA into cells by adhering to antennae-like protrusions on cell surfaces known as filopodia. Researchers are initially developing the technology to target oral cancers, which typically have high levels of filopodia.

MUSC researcher leading the effort Andrew Jakymiw, Ph.D., associate professor of oral health sciences, said in an interview that while the SiRNA delivery system targeting filopodia was working, it could be applicable to a range of cancers.

“Many invasive carcinomas have high levels of filopodia, while normal cells usually have very little,” Jakymiw said. “So this could potentially be used as a strategy to target the more aggressive forms of this type of cancer. “

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