Cancer’s craftiness is perhaps on its greatest display in the cases when genetic lesions in cancer stop a person’s genes from working. Losing certain genes (tumor suppressors) that are designed to prevent uncontrolled cell growth suggests cancer has more up its sleeve than random linear growth. Some scientists believe cancers act more like parasites that must be targeted using some of the same crafty tools they use against humans. In any case, synthetic lethality’s promise may be that it works because it gets at the true nature of the disease and also why cancer is often underestimated.
Loss of function among certain genes has mixed implications for cancer cells. Some of these genes are involved in DNA damage repair, which the cancer cells need to maintain their rapid division and growth. In many cases, another gene can support these functions, creating a weak spot for therapeutic exploitation. It is possible to indirectly target loss-of-function mutations and treat patients bearing what were thought to be ‘undruggable’ cancers. DNA repair mechanisms greatly affect the response to cytotoxic treatments, so understanding the ways to turn dysregulated repair processes against themselves to induce cell tumor death is the goal of all DNA repair inhibition efforts. Interrupting DNA repair in such a way that shuts down a tumor’s compensatory repair mechanisms and induces cell death is the goal of all research surrounding DNA repair inhibition.
Synthetic lethality is the technique of finding pairs of genes that cause cell death when simultaneously inactivated. The first synthetic lethal pairing discovered involved the well-known BRCA1/BRCA2 genes. When the DNA repair activity of either of the BRCA genes is impaired, cells become dependent on the parallel PARP pathway — making it a useful drug target. Several PARP pathway drugs have been approved by FDA since 2014.
Thanks to advances in gene editing tools and next-generation sequencing, researchers are looking for new synthetic lethal gene pairs. CRISPR allows researchers to systematically silence the activity of individual genes in cells that carry a known mutation. Scientists can identify new synthetic lethal gene pairings by examining the viability of each cell. Together with the growing knowledge of which mutations are commonly found in specific cancers, they can work out which genes are worth targeting for particular patients.
Repare Therapeutics
Repare is a pre-clinical biotech company developing gene therapies for solid tumors based on a synthetic lethality (SL) approach to drug development. The company has advanced a proprietary, genome-wide, CRISPR-enabled SNIPRx® platform to systematically discover and develop highly targeted cancer therapies focused on genomic instability, including DNA damage repair. The company’s SL-based approach to the development of new precision oncology therapeutics has multiple potential benefits:
• Ability to address previously untargetable tumor biology, including, for example, loss-of-function mutations;
• Enhanced benefit-risk profile, by precisely targeting tumor cells with the defined mutation while sparing normal, non-cancerous cells;
• Genetic stratification of patients, potentially enabling higher response rates; and
• Tumor-agnostic approach, focusing on specific genetics and enabling the application to multiple tumor types.
NCI/CCR
At the National Cancer Institute’s Center for Cancer Research (CCR), researchers have shown how their tumor analysis pipeline, called SELECT, can identify which therapies may be beneficial for individual patients. When applied to data from over 30 different targeted and immunotherapy clinical trials, SELECT was successfully predictive of patient responses to these therapies in about 80 percent of the trials. These findings were reported April 13, 2021, in Cell. SELECT stands for SynthEtic LEthality and rescue-mediated precision onCology via the Transcriptome. The approach is based on identifying synthetic lethal interactions. These interactions provide an opportunity to selectively kill only tumor cells while sparing normal cells by targeting synthetic lethal pairs of specific genes inactivated in a tumor. According to the CCR, synthetic lethality is being investigated as a means to treat cancer, with some specific treatment regimens already used in the clinic. However, it is thought that many such treatment opportunities remain to be discovered, and SELECT offers a computational method for identifying such treatment options for individual patients. By analyzing tumor transcriptomics data, this approach can identify actionable tumor vulnerabilities that are not readily evident by traditional mutational- and gene fusion-based sequencing approaches.
Cancer’s Ambitions
Alexander Panchin, a senior researcher at the Russian Academy of Sciences, and his colleagues have an intriguing hypothesis to explain how new species may have evolved from cancers. In 2019, they proposed that parasites, myxosporeans, initially branched off from their cnidarian kin not as independent animals but as tumors. Knowing the idea of cancer-derived animals sounds far-fetched — so much so that, in the paper, Panchin and his co-authors refer to them as Scandals (an acronym for “speciated by cancer development animals”). Panchin and his team compared the genomes of a variety of simple species (most of them parasitic) with those of five myxosporeans, three single-celled creatures and 29 other animals. They looked for hints of a cancerous past by checking for the absence of genes that are often lost when cells turn malignant. These include genes involved in apoptosis, the regulated self-sacrifice that purges abnormal cells from the body. Any organism evolving from a transmissible tumor would presumably lack such genes.
