Malaysian researchers, in collaboration with scientists in the United Kingdom, are on track to identify potential drugs to treat oral cancer.
The first part of the job is already done: three years of hard laboratory work using 16 unique Malaysian oral cancer cell lines and the Crispr-Cas9 gene editing technology, has resulted in a list of 918 genes critical for the survival of the cancer.
Switch any one of these genes off and you can potentially stop oral cancer in its tracks.
According to principal investigator and Cancer Research Malaysia (CRM) Head and Neck Cancer Research senior group leader Professor Dr Cheong Sok Ching, the next step now is to identify which drugs can target and knock out these essential genes.
The research team is working with international pharmaceutical companies via their collaboration with the Wellcome Sanger Institute in the UK, as well as through their own connections, to utilise the companies' libraries of existing drug molecules for this purpose.
Around 300 drugs have already been chosen to be tested.
"Some of them have already been approved for other indications, for example, breast cancer and colorectal cancer.
"And some of them are in development – close to or already in clinical trials," explains Prof Cheong, who also holds the Dr Siti Hasmah Mohd Ali Professorial Chair at Universiti Malaya.
She adds that some drugs have been specifically chosen as they are known to target certain genes that are in their list, e.g. the Nutlin drug compound that targets the TP53 gene.
In fact, she shares that CRM has already started discussions with some pharmaceutical companies who own drugs like these, on how they can work together to develop the drugs for oral cancer.
Testing and analysis
The 300 drugs will be tested against each of the 16 unique Malaysian oral cancer cell lines Prof Cheong and her team have developed and grown in the CRM lab.
This step will be done by the team's collaborator Dr Mathew Garnett from the Wellcome Sanger Institute, whose lab is a global leader in high throughput screening (i.e. rapid automated screening of up to millions of samples).
Explains Prof Cheong: "The reason why we are working with Mathew is that worldwide, he is renowned for his ability to test many drugs in a high throughput manner and he has done it for many cancers, including colon, breast and other common cancers.
"But there is still a big gap with regards to Asian cancers, including oral cancer; so that's why he's very excited to work together with us."
The results of which drugs work on which oral cancer cell line will then be combined with the genetic information already in hand to determine the exact target gene that is being knocked out by each effective drug.
"We will use powerful bioinformatic analysis to combine the essential genes with drug response and find out which of these In drugs is possibly going to work in oral cancer," she shares.
In addition, the analysis will help them to identify biomarkers that can be used to pinpoint patients with the gene that will respond to a specific drug and/or monitor the progress of the patient.
Biomarkers, a portmanteau of "biological markers", are natural molecules, genes or characteristics that can be measured to indicate or predict the progress of a physiological or pathological process.
As not all patients have the same set of cancer genes, biomarkers are vital to differentiate which patients will benefit from which drugs.
With the tremendous amount of data that will be generated from this study, Prof Cheong says that they will be setting up a database with this information.
"In the world, not many people work on oral cancer – that's where we're very unique.
"Because oral cancer is very much an Asian disease, a lot of the Western pharmaceuticals – the big boys – they don't actually put it as a very high priority.
"So if CRM doesn't do this work, then actually, there is very little information for drug development on these types of cancers," she explains.
Currently, the main treatment for oral cancer is surgery, which is usually accompanied by radiotherapy or chemotherapy.
While surgery is quite successful in treating localised or early stage oral cancer, the success rate decreases significantly once the cancer returns and/or spreads beyond the mouth.
While some targeted therapies can be used to treat such advanced cases, the lack of research into oral cancers means that doctors have to rely on the best available evidence and their experience to choose treatments for their patients, but they cannot predict for certain which patients will respond and which won't, says Prof Cheong.
A stumbling block
The study is being partially funded by a grant Prof Cheong and her team won from the 2019 Newton Fund Impact Scheme, which is being provided by the UK Medical Research Council and the Malaysian Industry-Government Group for High Technology (MIGHT).
She says: "This scheme is specifically for scientists who have found results using fundamental research that now needs to be translated into some impact in the clinic or for patients."
She notes, however, that grants like this are usually just enough to cover the chemicals they are using.
"They don't really pay for the rent, the scientists' salaries and things like that, so therefore, we are actually very thankful to our current donors, such as Yayasan Petronas and Yayasan Sime Darby, who have been supporting us all the way.
"But we would like to reach out to the public to help them understand that it is important to do research here in Malaysia, especially in Asian cancers where it is most relevant to us," she says.
The lack of funding is also what is preventing a homegrown oral cancer vaccine developed by Prof Cheong's team and led by Cancer Immunotherapy team leader Dr Lim Kue Peng, from being tested in clinical trials here in Malaysia.
"We're planning phase 1 clinical trials in the UK with our partner (the University of Southhampton) for next year.
"We want to do it in Malaysia, but we are currently trying to secure funding to do so," explains Prof Cheong.
In mice models, the second-generation DNA vaccine has been shown to inhibit the growth of oral cancer, and when used together with a specific immunotherapy, it appears to eliminate the cancer.
The phase 1 trials will test for its safety in humans.
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