Outsmarting cancer with RNA, ‘genome-tuning’ drugs and other gene-altering therapies – FierceBiotech

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 altering gene activity throughout the body, tricking it into fighting off the disease?

A handful of startups and academics are working towardthat goal. Its not gene therapy in the traditional sense, because theyre not removing or replacing disease-causing genes. Rather, theyre using novel drugs to turn the expression of certain genes up or down to achieve an anti-cancer effect.

Were unlocking new biological pathways so we can go after undruggable targets and treat diseases in very new ways, said Robert Habib, chief executive officer of London-based MiNA Therapeutics, in an interview. MiNA is developing a pipeline of small activating RNAs (saRNAs), which are short, double-stranded oligonucleotides designed to enter cells and boost the activity of target genes to achieve a therapeutic effect.

In September, MiNA raised about $30 million to advance its lead asset, MTL-CEBPA, into a phase 2 trial. The saRNA drug is designed to target the gene CEBPA, which encodes a transcription factor thats key to the bodys production of cancer-fighting 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 RNA activation to boost levels of the CEBPA protein. MiNAs drug is in testing alongside Bayers Nexavar, initially in liver cancer, though Habib and his colleagues believe its unique mechanism of action could prove useful across 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 trialin combination with Mercks immuno-oncology blockbuster Keytruda in a broader set of solid tumors, Habib said.

RELATED: MiNA raises $30M to take small activating RNA into 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 challenging. It has been hindered by tissue bio-accumulationmaking sure the delivery system is safe and provides a wide enough therapeutic window in tissues beyond the liver, said Anna Perdrix Rosell, Ph.D., co-founder and managing director of London-based Sixfold Biosciences, in an interview.

Sixfold is working on a siRNA technology called Mergo, which it aims to prove can deliver siRNAs to cancer cells within specific organs while leaving healthy tissues alone. The companys preclinical testing issupported by an Innovate UK Smart Grant, and the companyis now working to define its lead cancer targets, with the goal of moving into clinical trials in 2022, Rosell said.

Gene-silencing specialistSirnaomicsis working on several RNA-interfering drugs to treat solid tumors. Its lead asset, STP705, uses a polypeptide nanoparticle to deliver two siRNAs targeting the genes TGFB1 and COX-2.

Suppressing those genes inhibits cancer-associated fibroblasts, which are cells in the tumor microenvironment that promote tumor growth, the Gaithersburg, Maryland, company has set out to show. It is in early clinical trials in solid liver tumors, squamous cell carcinoma and basal cell carcinoma.

Another gene-directed approach involves injecting DNA into tumors with the goal of making them more responsive to immunotherapyor turning them from cold tumors to hot ones. One company working on this technology is Pennington, New Jersey-based OncoSec Immunotherapies. Its lead technology, called tavokinogene telseplasmid (TAVO), uses electrical pulses to temporarily open cancer cell membranes, after which DNA is injected into them.

The DNA makes IL-12, a naturally occurring, immune-stimulating protein that the companys scientists believe could help overcome resistance to checkpoint inhibitors like Keytruda, a PD-1 blocker. Its a common problem in cancer care: An estimated 60% to 80% of melanoma patients, for example, do not respond to PD-1 blockade. And IL-12 cant be given systemically because it causes toxic side effects.

OncoSecs DNA-delivery system is designed to prompt the body to make more of its own IL-12. The DNA essentially co-opts the cells function to cause it to make IL-12, explained Daniel OConnor, CEO off OncoSec, 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, though not every tumor has to be medicated, OConnor said. We see shrinkage in the tumors that are treated, but also in those that are untreated, he said. In April, OncoSec presented interim data from the melanoma trial, reporting an overall response rate of 30%, with some complete responses and no serious side effects.

RELATED: Omega grabs $126M to bring 'genome-tuning' cancer treatment into the clinic

Investors continue to show enthusiasm for the idea of manipulating gene activity to achieve an anti-cancer response. One recent beneficiary of their largesse was Omega Therapeutics, a Cambridge, Massachusetts-based company that raised $126 million in March to advance its genome-tuning drugs, including its lead treatment for liver cancer, OTX-2002.

Omega refers to the drug as an epigenetic controller, because its designed to control the expression of the cancer-promoting gene C-MYC. The companys technology tunes gene expression up or down without permanently changing DNA, and it does so by targeting regulatory factors in loops of DNA known as Insulated Genomic Domains (IGDs), CEO Mahesh Karande explained to Fierce Biotech in March.

We treat diseases created by functional or structural changes in IGDs, Karande said at the time.

Meanwhile, in academia, researchers are continuously searching 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 Centerdescribed a peptide theyre designing that can deliver aSiRNA into cells by adhering to antennae-like protrusions on cell surfaces known as filopodia. The researchers are initially developing the technology to target oral cancers, which typically have high levels of filopodia.

The MUSC researcher leading the effort, Andrew Jakymiw, Ph.D., an associate professor of oral health sciences, said in an interview that if the filopodia-targeted SiRNA delivery system pans out, it could prove applicable to a range of cancers.

Many invasive carcinomashave high levels of filopodia, while normal cells typically have very few, Jakymiw said. So this could potentially be used as a strategy to target more aggressive forms of this type of cancer.

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Outsmarting cancer with RNA, 'genome-tuning' drugs and other gene-altering therapies - FierceBiotech