Validated Discovery Platform
Repare has developed and deployed a proprietary, high-throughput, genomic and chemo-genomic synthetic lethal screening platform that starts and ends with the patient in mind, identifying important mutations (“lesions”) in the clinic that identify the target patient populations most likely to respond to its precision medicines. The platform harnesses the power of CRISPR/Cas9 genome editing to identify promising new targets for rapid small molecule drug discovery, leveraging high-resolution protein crystallography, advanced informatics, and the unprecedented ability to exploit DNA Damage Response (DDR) defects and genome instability found across virtually all cancers.
DNA Damage Response (DDR) and Genome Instability
Cancer is a disease caused by mistakes in our cellular blueprint, DNA. These modifications are invariably caused by DNA damage and its faulty repair. While healthy cells detect and repair DNA damage, cancer cells often have mutations that disable the machinery involved in detecting, signaling or repairing DNA. An impaired response to DNA damage is a hallmark of most cancers. BRCA1 and BRCA2 genes associated with breast, ovarian and pancreatic cancers code for DNA repair factors that protect cells from DNA breakage. However, loss of DNA repair pathways in tumor cells is consequential, as cells compensate by relying on other DNA repair pathways and mechanisms, creating unique opportunities for therapeutic intervention.
In addition to DNA repair problems, cancer cells are also characterized by increased levels of DNA damage. The genes that drive tumor cell proliferation (“oncogenes”) often cause problems during DNA replication, resulting in increased DNA damage load and, more generally, Genomic Instability. Oncogene activation in tumor cells often results in an increased reliance on the proteins that detect and repair DNA damage.
At Repare, we are exploiting the defective processes of the DNA damage response (DDR) and Genome Instability observed in cancer in order to develop new, precisely targeted cancer therapies. Our aim is to develop drugs that are tailored to specific cancer alterations through the concept of synthetic lethality.
Synthetic lethality is a genetic principle discovered decades ago that describes a phenomenon where two mutations are lethal only when combined together. Either alone is not. This is highly relevant to cancer, since cancer genomes are littered with mutations. It is only now that we have the capacity to rapidly identify synthetic lethal interactions in human cells.
Targeted cancer drugs should be toxic to tumors but harmless to the normal cells. Synthetic lethality represents a promising avenue to identify molecular pathways uniquely essential to cancer cells. This approach thus allows us to develop highly specific precision oncology drugs: toxic to cancer cells with specific mutations but not to normal cells.
A powerful example of synthetic lethality in oncology, PARP inhibitors were developed for the treatment of cancers with mutations in BRCA1 or BRCA2 and are revolutionizing cancer treatment. However, they often only work in a subset of patients and also fall prey to evolving resistance, reflecting the need for new, improved, and complementary approaches to treat many cancers.
The repurposing of the prokaryotic clustered regularly interspaced repeats (CRISPR)/Cas system for genome editing has heralded a true revolution in genetics, molecular biology and regenerative medicine. In its simplest form, the system is based on the reprogramming of an DNA cutting enzyme, an “endonuclease”, called Cas9 with a chimeric RNA molecule, the guide RNA (gRNA). When a gRNA and Cas9 are co-expressed in a cell, Cas9 becomes a site-specific endonuclease that induces DNA double-strand breaks at sequences complementary to the region targeted by the gRNA. The cellular DNA repair machinery then acts to repair the break to regenerate the parent DNA sequence; this sequence is then re-cut again until mutagenic end-joining produces a mutation (insertion or deletion) that blocks the action of Cas9. In many cases, the Cas9-induced mutation does not maintain the DNA reading frame, resulting in premature stop codons, which are signals to terminate gene transcription and expression.
The efficiency of Cas9-mediated DNA mutagenesis is such that it is possible to use this system in large-scale mutagenesis experiments, especially when coupled to highly efficient viral delivery to cells. CRISPR screens have been adapted to search for synthetic lethal interactions thereby providing an ideal platform for the development of new oncology drugs based on the synthetic lethality principle. At Repare, we have established a world-class CRISPR screening platform that is generating a pipeline of new targets that are specifically lethal when disrupted in the context of common genetic alterations (lesions) that underpin the viability and proliferation of cancer cells.
By combining world-class synthetic lethal screening technology, high-resolution crystallography and structure-based drug design with advanced biological and clinical informatics and translational insights, Repare is helping to revolutionize the treatment of cancer by discovering novel pathways, relationships and targets to selectively impact the DDR response and other Genome Instability-related mechanisms to precisely target cancer cells for death, while sparing normal cells.
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