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“We need to foster risky projects that can have large rewards”

07 February 2023 | Opinion | By Ayesha Siddiqui

Synthetic lethality is a promising area of cancer therapy. Anticancer Bioscience (ACB) is a precision oncology company, applying synthetic lethal approaches to develop targeted cancer therapies. Dr Jing Zhang, Co-Founder, Vice President, High Throughput and High Content Screening, ACB highlights the main advantages of synthetic lethality, drug programmes at ACB and trends in cancer research.

What is Anticancer Bioscience’s  competitive edge and what is unique about the pipeline you are developing? 

Anticancer Bioscience (ACB) specialises in the development of synthetic lethal therapies. A  synthetic lethal drug interaction occurs when the very same genetic and epigenetic changes that  promote cancer, confer unique vulnerabilities to cancer cells. These can include apoptotic, metabolic  or mitotic vulnerabilities, among others. Identifying and developing drugs that target these  vulnerabilities is extremely difficult, and that is what ACB has fostered expertise in accomplishing. 

We have several synthetic lethal drug programmes at ACB, but the most advanced programme aims to  produce small molecule therapeutics that are synthetic lethal with hyper-activity of the oncoprotein  MYC. Accomplishing this goal has required the development of novel screening methods, new sources  of small molecule diversity, and unique synthetic lethality validation assays. ACB’s novel, mechanism-informed phenotypic screening system is capable of guiding the identification and optimisation of lead  compounds, and uncovering drug targets and predictive biomarkers. Together, our effort has  culminated in the identification of multiple classes of highly potent MYC synthetic lethal compounds  that are highly efficacious in vivo and readily orally bioavailable.  

Biomarker studies are a vital component of any targeted drug development programme, and this is  especially true for synthetic lethal therapies. ACB has uncovered markers that alongside MYC  expression predict which tumours will be hyper-responsive to our synthetic lethal compounds. Bringing  our drugs to the clinic alongside this screening strategy to stratify patients will enable focused and  effective targeting of patient tumours. 

A final edge for the compounds we are developing lies in the MYC synthetic lethal target that our  drugs bind and inhibit. Our lead compounds bind a novel synthetic lethal target. Our studies suggest  its inhibition confers lethality in MYC-overexpressing cells, not normal cells. This means that while  tumour  cells succumb to our drugs, normal tissues will be left relatively healthy.  

Another unique programme in the pipeline is contact inhibition restoration, a promising approach  that has not yet been fully explored. Loss of contact inhibition is a hallmark of cancer cells. As an  innovative cancer therapy, CIR drugs do not necessarily aim to kill dividing tumour  cells as most current  cancer therapies do. Instead, they can enable cancer cells to re-establish contact inhibition. ACB has established a unique image-based high-throughput screening assay to identify agents that restore  contact inhibition and has developed a combination treatment with two drugs identified from the  screening. ACB is exploring nanoformulation of this drug combination for selective accumulation and  controlled release of active pharmaceutical ingredients into tumour  tissues. 

 

What potential do you see for this class of targets? 

We see enormous potential for synthetic lethal therapies. The ultimate goal for synthetic lethal  therapy is to be able to target indirectly, the oncogenes and tumour  suppressor losses that we know are  drivers of carcinogenesis, but have until now proven difficult to drug using traditional means. One  thing to keep in mind is that we are developing synthetic lethal therapies as stand-alone therapies, but  once proven in the clinic they may prove especially potent alongside other therapeutic modalities as  components of combination therapies. 

At ACB we have deliberately focused on the development of compounds that can be used in a  wide variety of cancer indications. MYC, for example, is arguably the most widely expressed cancer  protein, as it is overexpressed in more than 70 per cent of human malignancies. It is mutated in some types  of lymphomas but genetically amplified in about 28 per cent of solid cancers. In many more cases, however,  the overexpression of MYC is due to the loss of transcriptional or post-translational control mechanisms. With our lead MYC synthetic lethal compounds, we observe anticancer activity against  cancers derived from a large variety of indications including lymphoma and solid cancers such as  stomach, colon, and non-small cell lung cancer. 

A second programme at ACB, which is currently in an early preclinical stage, aims to target cancer  cells that have lost activity of the p53 tumour  suppressor protein. Like MYC, loss of p53 is found in a  wide array of human cancers, and developing drugs that attack vulnerabilities enabled by p53 genetic  loss-of-function will have a large impact. We aim to make a large difference for patients at ACB, not an incremental one. 

 

What are the latest trends and challenges in cancer drugs development? 

There are lots of great ideas and truly brilliant people working in the areas of both basic cancer research and cancer drug development. However, despite the large VC-driven funding rounds that some companies are able to achieve, most ideas do not move forward. We fear that with an ailing  economy, this may become an even deeper problem. For Innovation to be the driver of the next  generation of drug development, we need to foster risky projects that can have large rewards. We are  grateful to our funding partners for seeing this potential in Anticancer Bioscience and are grateful to  the talented people that choose to work at ACB. 

Oncology has been the primary focus of precision medicine in the past decade. The latest  trends in cancer drug development include targeted immunotherapies like immune checkpoint  therapies, CAR-T, and mRNA vaccines, and synthetic lethal cancer therapies. ACB, as the pioneer in  synthetic lethal approaches to precision oncology, has developed its unique and innovative pipeline  based on over 20 years of collaborative research between the founder Dr Dun Yang and his Nobel  laureate mentor Dr J. Michael Bishop.  

The lack of biomarkers to guide treatments has been a challenge in the field and remains so.  Apart from traditional molecular or biochemical biomarkers, new types of biomarkers are arising.  Signatures detected in genomic, transcriptomic, proteomic, and metabolomic data can be used as a  prediction for treatment response and prognosis. With this knowledge, the next challenge would be  how to effectively apply it to provide new avenues for therapeutic strategies. At least, understanding  the treatment resistance and developing a rationale combination is certainly needed for durable efficacy.

 

Ayesha Siddiqui

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