CRISPR for cancer: targeting cancer-specific genes in solid tumors
Targeted CRISPR lipid nanoparticles eliminated 50% of tumors in mice with head and neck cancer.
Researchers from Tel Aviv University (Israel), led by Razan Masarwy, have investigated utilizing CRISPR in lipid nanoparticle (LNP) delivery systems to target cancer-specific genes in head and neck cancers. By cutting out an essential cancer gene, 50% of tumors were successfully eliminated from in vivo mouse models, indicating the potential of targeted CRISPR-LNP delivery systems for cancer treatment.
Head and neck squamous cell carcinomas (HNSCC) are localized solid cancers that originate in the upper aerodigestive tract, including the oral cavity, pharynx and larynx. There are nearly 600,000 new cases of HNSCC every year, with high rates of treatment failure and disease recurrence, and poor survival rates.
Advancements in mRNA technologies and LNP delivery systems have led to preclinical research into LNP-CRISPR-Cas9 mRNA-based therapeutics for solid tumors. However, accumulation of LNPs in the liver and efficient cancer-cell-specific targeting have created challenges for gene editing efficiency. Therefore, additional layers of cellular specificity in the CRISPR-Cas9 delivery system are required to effectively target cancer cells and minimize off-target effects.
The researchers previously demonstrated the use of CRISPR to cut cancer cells from mouse models in a cancer-cell-specific manner; however, this is the first time they have applied this technique to head and neck cancers.
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To achieve cell-type specific extrahepatic mRNA delivery, the researchers developed a targeted LNP delivery system that co-encapsulates Cas9 mRNA and single guide RNA that specifically targets SOX2. SOX2 is a cancer-specific gene that is expressed in several cancers and overexpressed in HNSCC. The targeted LNPs were also coated with anti-EGFR antibodies – as the cancer cells express the epidermal growth factor receptor (EGFR) – to enhance their uptake in the tumors.
The researchers then tested the viability of cancer cells treated with these LNPs, evaluating the therapeutic effects both in vitro and in vivo using xenograft HNSCC mouse models. The results demonstrated a 60% reduction of HNSCC viability in vitro and a 90% inhibition of tumor growth in vivo. A 90% increase in survival and a 50% disappearance of tumors was also observed in the mouse models after 84 days.
“Using our nano-lipid delivery system, we injected the drug directly into the tumor in a tumor model and successfully took out the gene – literally cutting it out from the cancer cell’s DNA with the CRISPR ‘scissors’,” commented corresponding author Dan Peer.
Next, the researchers are investigating the efficiency of this CRISPR therapy in other types of cancer cells such as myeloma, lymphoma and liver cancer. “Generally, CRISPR isn’t used for cancer because the assumption is that knocking out one gene wouldn’t collapse the whole pyramid. In this study we demonstrated that there are in fact some genes without which a cancer cell cannot survive, making them excellent targets for CRISPR therapy,” concluded Peer.
