An oncogene targetingandpyroptosis inducing system, this isMcGill iGEM’shighlymodular pancreatic cancer therapeutic.
We cut to the genotype.
The doctor says you have six months left to live. What do you do?
Pancreatic cancer patients across the world face this terrible question. Every day.
It is one of the most lethal cancers with the fewest treatment options. Little progress has been made towards improving patient outcomes in the past few decades.
It is one of the most lethal cancers with the fewest treatment options. Little progress has been made towards improving patient outcomes in the past few decades.
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Pancreatic cancer takes the lives of almost half a million people a year.
Each box is 10,000 people. Each dot is 1 person.
Pancreatic cancer is devastating.
Patients suffer from immense physical, mental and financial burden.
Healthcare system costs are exorbitant. The US spends $2.5 B a year on pancreatic cancer treatment.
Family members often give up work to care for patients. Social losses are nearly 17x health costs.
Current treatments are ineffective.
Cancer phenotype is plastic, even if driver mutations are stable. Cancer can develop resistance to treatment.
Not all patients have the same cancer phenotypes. For some patients, most treatments are ineffective.
The only option for stage IV patients is palliative care. Pancreatic cancer is thought to be incurable.
1. Proteus targets genotypes rather than phenotypes.
Cancer resistance to treatment often develops in a similar way to antibiotic resistance: cancer cells expressing particular phenotypes survive treatment and replicate, creating treatment-resistance tumour masses. Because Proteus targets cancer at the mRNA level instead of the expression level, it is capable of targeting cells with distinct and varied phenotypes as long as they have the same driver mutation: a gene often responsible for the cancerous properties of the cell.
This approach is especially relevant for pancreatic cancer, where KRAS driver mutations consist of up to 95% of cases. KRAS is a protein that is critical for the regulation of cell signalling for mitosis and proliferation. Mutations in KRAS G12 lead to constitutive activation of the protein, a Ras GTPase. This signals the cell to divide constantly.
By using KRAS as our guideRNA (gRNA) we can target specific mutations that cause the cancerous property–in this case, constant division. We can cut to the genotype instead of targeting different traits the cell may express as other drugs do.
This approach is especially relevant for pancreatic cancer, where KRAS driver mutations consist of up to 95% of cases. KRAS is a protein that is critical for the regulation of cell signalling for mitosis and proliferation. Mutations in KRAS G12 lead to constitutive activation of the protein, a Ras GTPase. This signals the cell to divide constantly.
By using KRAS as our guideRNA (gRNA) we can target specific mutations that cause the cancerous property–in this case, constant division. We can cut to the genotype instead of targeting different traits the cell may express as other drugs do.
3. Proteus is highly modular.
Proteus can also be optimized to bind to other mutations in a patient’s cancer profile, so it can be adapted even if the patient does not have the KRAS mutation in their tumour profile. To identify mutations in a cancer patient’s profile that would be ideal to select as a gRNA, we created a dry-lab tool that finds optimal targets for the Proteus system.
In addition, our approach of targeting cancer driver mutations means that this therapeutic can be applied beyond pancreatic cancer. Proteus can target mutations in different cancers or perhaps even be used to target other genotype-driven diseases.
Proteus is also a synthetic biology tool. The fusion protein cleaved can be modified with the insertion of a different Csx30 linker. Our BioBricks leverage the modularity of the system, and we encourage other iGEM teams and researchers to imagine the possibilities of leveraging the Craspase system. We’re excited to see what you come up with.
In addition, our approach of targeting cancer driver mutations means that this therapeutic can be applied beyond pancreatic cancer. Proteus can target mutations in different cancers or perhaps even be used to target other genotype-driven diseases.
Proteus is also a synthetic biology tool. The fusion protein cleaved can be modified with the insertion of a different Csx30 linker. Our BioBricks leverage the modularity of the system, and we encourage other iGEM teams and researchers to imagine the possibilities of leveraging the Craspase system. We’re excited to see what you come up with.
We're showing that Proteus works with our proof of concept.
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