Using Crispr-Cas9 to find vulnerable oral cancer genes for a potential cure

A man prunes branches on a tree next to a section of the Ming Dynasty City Wall in Beijing. If one imagines a cancer cell as a tree made out of genes, then its easy to see that the gene that needs to be targeted to kill off the cancer is the one that makes up the trunk, not one of the branches. Photo: Reuters

Certain cancers seem to have a predilect-ion for Asians.

Take, for example, oral cancer; Prof Dr Cheong Sok Ching says that according to the World Health Organization (WHO), oral cancer is responsible for 11% of cancer deaths in Asia, compared to 4% in the rest of the world.

Oral cancers are cancers that affect any part of the oral cavity, i.e. the mouth.

In Malaysia, Prof Cheong, who heads the Oral Cancer Research Group at Cancer Research Malaysia (CRM), says that this type of cancer is diagnosed in an average of two new patients a day.

She also says that this number is likely to be under-reported, meaning that the actual incidence of such cancers is probably higher.

“The sad thing is that the majority of these cases actually come quite late, so 75% of our patients come after their cancer has spread to other parts of the body – it’s no longer contained within the mouth, it has gone to the lymph nodes in the neck and spread to different parts of the body.

Prof Cheong and her team have developed a special method to grow oral cancer cell lines in the lab. — Photos: SAM THAM/The Star
Prof Cheong and her team have developed a special method to grow oral cancer cell lines in the lab. Photo: The Star/Sam Tham

“Therefore, in our part of the world, cancer survival is very poor, particularly for oral cancer, and our patients predominantly do not survive more than two years (after diagnosis),” says the adjunct professor at University Malaya’s Department of Oro-Maxillofacial Surgical and Medical Sciences.

Treatment usually consists of a combination of surgery, chemotherapy and/or radiotherapy, depending on the stage of the disease.

Prof Cheong notes that while surgery is an effective treatment for cancers that are confined to the oral cavity, this doesn’t apply to the majority of Malaysian patients who are diagnosed only when the cancer has spread beyond the mouth.

For the majority of patients, chemothera-py and radiotherapy are usually required as well – both of which, she says, have rather severe side effects and are not very effective in many patients.

“So, one of the challenges we have in treating oral cancers is that there are currently, limited types of therapy that patients can be effectively treated with,” she says.

“Therefore, the focus of the team at Cancer Research Malaysia is to develop new therapies based on genetic understanding that we gain from our laboratory studies.”

Finding a target

Among these therapies are immunotherapy and targeted therapy.

In immunotherapy, Prof Cheong shares that her team has developed a potential vaccine for oral cancer, which is now poised to enter safety evaluation before starting clinical trials in humans.

Meanwhile, in the area of targeted therapy, she and British medical oncologist Dr Ultan McDermott have recently secured a £450,328 (RM2.5mil) grant to identify “gene-tic vulnerabilities in head and neck cancers for the development of novel therapies”.

Oral cancers form the large majority of head and neck cancers.

Prof Cheong explains: “The important thing is to identify the key genetic feature of the cancer in order for us to design a drug.

“This brings us to the collaboration that we have with Dr McDermott and the Wellcome Trust, to use Crispr-Cas9 technology to really identify which are these driver genes that we can make drugs to target.

Dr McDermott says, ‘This project has never been done before... It’ll be of immense interest globally when we publish this data.’
Dr McDermott says, ‘This project has never been done before... It’ll be of immense interest globally when we publish this data.’ Photo: The Star/Sam Tham

“If you think about a cancer like a tree and each of its branches are genes, by deleting a gene that is a small little branch, you’re not going to kill the cancer.

“So, using Crispr-Cas9 technology, we are trying to identify which exactly is the gene that will allow us to cut off the trunk of the tree in order to destroy cancer.”

Dr McDermott is the Career Development Fellow group leader at the Wellcome Trust Sanger Institute Cancer Genome Project in Cambridge.

He describes the Crispr-Cas9 technology as “the biggest breakthrough in science” of the last decade.

“Crispr is essentially a way to target DNA,” he says, adding that a human’s DNA is an alphabet of three billion letters.

“And so, if one wants to target a specific letter extremely accurately, Crispr is the best way to do it.

“In the past, if you wanted to target one of those three billion letters, the risk was that you would target that letter, but you would also go to 20 other places.

“Crispr lets you go to one letter in three billion exactly.”

Cas9, meanwhile, is an enzyme that basically functions as a scissors to cut out the targeted genes, he explains.

Those removed genes could either be replaced with other genes or not replaced at all.

Dr McDermott adds that not replacing the targeted gene, which effectively stops its function in the body, is where the potential for cancer treatment lies.

“So, if you can imagine, a cancer cell has all these 20,000 genes (the number of functional, protein-coding genes in a human), some of which the cancer cell depends upon and some of which are its Achilles heel.

“If you identify the gene where the cancer cell dies when you turn it off, and you then have a drug that targets that gene, that’s a new drug for cancer treatment.”

While he notes that it could take up to five to 10 years to develop a completely new drug, the hope is that an appropriate drug or active molecule already exists in the libraries of one of the pharmaceutical companies or research institutions that can be developed quickly once the cancer-killing gene (or genes) is identified.

A unique collection

The project plan, according to Dr McDer-mott, is to use the Crispr-Cas9 technology on the collection of head and neck cancer cells Prof Cheong has collected over the last decade from Malaysian patients – a collection he describes as “very unique and no one else on the planet has”.

Prof Cheong has amassed 16 cancer cell lines in her lab.

She shares that part of the uniqueness of her collection is due to the fact that cancer cells are difficult to grow outside their natural habitat in the body.

“It is quite a special method that we use to make them grow in the lab, therefore it makes us unique – because we are able to do this really difficult thing and make cancers grow in the lab.”

She adds that the collection is also special because betel-nut chewing is a risk factor that is unique to South-East Asia, compared to similar cancer cell lines in the West, which are usually associated with the risk factors of excessive alcohol consumption and smoking.

“The carcinogens could have an effect on what kind of mutations occur within the cancer,” she explains.

CRM chief executive Prof Dr Teo Soo-Hwang says: “It’s important to add that not all oral cancers are associated with risk factors, and so, some of the lines that we have arise from individuals who do not have any risk factors.

“And actually, we are starting to see throughout the world, that there is an increase in oral cancer among individuals who are young and don’t have any known risk factors.

“So it is important that we have a diversity of (cancer cell) lines that are being used in these experiments because that is how we are going to be able to identify more effect-ive treatments in the future.”

Dr McDermott notes that the Crispr-Cas9 technology can also be used to explore the genetic factors behind why cancers stop responding to treatment.

“One of the challenges in the clinic is that eventually, cancer becomes resistant to drugs in the same way that if you use antibiotics too much for infections, you get drug resistance,” he says.

Prof Cheong and Dr McDermott’s grant was awarded by the Newton-Ungku Omar Fund via the Medical Research Council, United Kingdom, and the Academy of Sciences, Malaysia, for a duration of three years.

Their project is one of four grants CRM won from the fund this year. The total number of grants given out was 12.

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