Studying Synthetic Lethality in Cancer

I have recently been awarded a Sir. Henry Wellcome Research Fellowship, and thought I would explain as plainly as possible what it is I plan to study.

A major challenge in cancer therapeutics is to kill tumour cells without harming other cells in the body. Traditional chemotherapy tries to do this by killing fast dividing cells. As tumour cells are typically fast dividing, this approach is reasonably effective in many cancers. However many other cells in the body are also fast dividing – such as those in the hair and the gut – resulting in some of the side effects of chemotherapy.

A more desirable approach would be to specifically target tumour cells. One means to achieve this is to exploit the genetic changes that distinguish tumour cells from normal cells. In the process of becoming cancerous tumour cells accumulate a wide variety of mutations, so that in a typical tumour hundreds or even thousands of genes are mutated in some way. If these mutations occurred randomly, in the sense that any gene was as likely as any other to be mutated, it would not be useful for the development of therapeutics. However that is not the case – the same genes are mutated again and again in cancer. An example of these recurrently mutated genes are the BRCA1 and BRCA2 genes that are found mutated in many hereditary breast and ovarian cancers. You may have heard of these genes last year due to Angelina Jolie’s op-ed and legal battles over the patenting of genetic variants.

If we know that a given tumour has a specific mutation, such as in the BRCA2 gene, and we know something about the consequences of this mutation, we can start to think about developing targetted therapeutics. One approach for the development of such targetted therapeutics is known as synthetic lethality – whereby the function of one gene only becomes essential in the presence of a mutation in another gene. An example of this occurs between the BRCA2 mutations and a gene called PARP1. In cells with functioning versions of BRCA2, PARP1 can be inhibited (e.g. with a drug) without any major consequences for the cell. However, in cells with broken versions of BRCA2, such as those found in breast cancers, inhibition of PARP1 results in cell death. So inhibition of PARP1 should selectively kill tumour cells with the mutant form of BRCA2. Indeed clinical trials are underway to investigate the effectiveness of drugs that inhibit PARP1 for treating both BRCA1 and BRCA2 mutant cancers.

The synthetic lethal relationship between the BRCA mutations and PARP was the first really successful example of a synthetic lethal approach in cancer, and it spurred a lot of other researchers to try and identify synthetic lethal relationships with other cancer associated mutations. Through high throughput techniques, whereby many experiments are performed at once, different labs have been trying to identify genes whose function is only essential in the presence of specific mutations. Unfortunately, many of the synthetic lethal relationships identified using this approach have failed to be reproduced. One lab will report that in the presence of mutation A, gene B is essential. A second lab will test the same relationship and find gene B to be non-essential. This is obviously a problem if the hope is to develop new treatments based on these results.

The reasons for this lack of reproducibility are poorly understood – it may be due to differences in experimental techniques, it may be due to experimental error, it may be due to genetic differences in the cancer cells used to perform the experiments. The latter I find particularly interesting – at a very fundamental level we have almost no understanding of how genetic differences between cells and individuals can impact on synthetic lethality. Trying to address this gap in understanding will be the focus of my fellowship.

If a cell has a broken form of BRCA2 will it definitely be sensitive to inhibition of PARP1? Or are there some mutations that can ‘rescue’ it? There is evidence to suggest that there are such mutations, but we don’t know how many there are or whether this is a common feature of synthetic lethality.

Are some synthetic lethal relationships more ‘robust’ than others? A robust synthetic lethal relationship would be one where gene B is always essential in the presence of mutation A. A non-robust synthetic lethal relationship would be one where gene B was only sometimes essential in the presence of mutation A. If these two classes exist, can we reliably predict which synthetic lethal relationships are likely to be robust? These would be the best candidates for follow on studies.

These are some of the questions I hope to answer.

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