Going After Immune Resistance and Metastases in Cancer Using RNA-Based Therapeutics
CSO and Co-Founder of TransCode Therapeutics, Dr Zdravka Medarova, tells us how she is developing oligonucleotide therapies and using RNA to target cancer-causing genes previously undruggable using traditional approaches.
What is the work you’re leading at TransCode Therapeutics?
We are focused on developing oligonucleotide therapeutics against cancer.
What is new or novel about the approach TransCode is taking to treat metastatic cancer and immune resistance?
TransCode has a proprietary drug design engine that allows us to build modular therapeutics against cancer, including metastatic cancer and immune resistance, because of the coded nature of DNA/RNA and the tunable chemistry behind how therapeutic oligonucleotides are formulated into drugs.
Because of the versatility of the drug design engine, new previously undruggable targets can be targeted for therapy creating a vast pipeline of cancer drugs and realizing the possibility for individualized cancer therapy.
Specifically, only about 20% of currently known cancer-causing genes are druggable to overcome cancer emergence, progression, resistance to therapy, and immune resistance. With the reliance on RNA/DNA to develop drugs against cancer, the remaining 80% of cancer-causing gene targets could become druggable vastly expanding the scope of therapeutic options.
"Our work has revealed new pathways for metastatic dissemination that could be targeted for therapy."
Why are you so passionate about pursuing RNA for cancer therapeutics?
Only 20% of cancer-causing genes are druggable using traditional approaches. With RNA, we can access any cancer-causing gene by taking advantage of the modularity of the genetic code.
The major challenge facing the development of RNA therapeutics for cancer is delivery. We are working to overcome these challenges by advancing a novel drug design engine.
How could your work in targeting immune resistance impact other IO endeavors or be combined with other approaches?
TransCode’s pipeline includes a PRR (pattern recognition receptor) agonist and a checkpoint inhibitor. Both are based on oligonucleotides as therapeutic agents.
These candidates could be combined with approved IO approaches in order to potentiate their effectiveness, expand the target patient population for these therapies, and permit effective treatment at lower doses increasing the therapeutic window of SOC IO therapeutics.
"With the reliance on RNA/DNA to develop drugs against cancer, the remaining 80% of cancer-causing gene targets could become druggable vastly expanding the scope of therapeutic options."
How has your work informed a broader understanding of cancer?
In terms of understanding cancer biology, our work has revealed new pathways for metastatic dissemination that could be targeted for therapy. For example, the target of our lead therapeutic candidate is a noncoding RNA, called microRNA-10b, that was originally described as a driver of tumor cell migration and invasion.
We and others also showed a role for this noncoding RNA in maintaining tumor cell viability and proliferation in the metastatic microenvironment. We also showed that the relevance of microRNA-10b to tumor cell viability was more pronounced in cells with a more mesenchymal phenotype and demonstrated a role for this microRNA on tumor cell stemness.
Importantly, the biological relevance of miR-10b appeared to be context dependent and manifested in the metastatic but not the primary tumor microenvironment, revealing the presence of a pathway related to the capacity of the tissue microenvironment to sustain the metastatic phenotype of tumor cells. Such pathways could be targeted to specifically treat metastatic disease.
What made you passionate about entering this field?
I entered this field because I was optimistic about the potential of oligonucleotide therapeutics to transform the treatment of disease, including cancer. My passion about tackling metastatic cancer, in particular, stems from early work as a PhD student, that helped me appreciate the power of the immune system to counteract malignancy.
What was a piece of career advice that helped you during your career?
“The one who knows how will always have a job. The one who knows why, will always be a leader.
What is your career advice, especially for young women entering science careers?
It will be harder for you but never give up.
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