New findings have identified a potential new therapeutic target that can be used to treat some types of cancer
A potential new therapeutic target has been identified to treat some cancer types, all the while avoiding harm to healthy cells and reducing side effects. The study, published in the journal Nature Communications, was led by a Scripps Research research team in California. It showed how a protein known as Rad52 may be useful in targeting triple-negative breast cancer – an aggressive form of breast cancer affecting over 28,000 Americans on an annual basis.
For healthcare professionals and researchers, there is immense interest in uncovering new medications and therapies that can treat triple-negative breast cancer. Around 10-20% of breast cancers are found to be triple-negative. There is typically a lower survival rate with this type of cancer than other types, with 77% of women living past 5 years.
RAD52 – a desirable target in cancer therapy
Rad52 works by repairing a specific kind of DNA damage, known as double-strand-break. In healthy cells, repairing DNA is a good approach. However, in cancer cells, it keeps them alive in a harmful state and prevents therapies from working properly.
Certain triple-negative breast cancers have a mutation in the FANCM gene. This gene protects certain areas of DNA that are susceptible to breaking during the process of cell division. The research team found that tumors in mice without the FANCM gene need RAD52 to repair their DNA, whereas healthy cells do not. They stopped Rad52 from working in cells without the FANCM gene and found that the build-up of DNA damage led to cell death.
Moreover, a majority of chemotherapies affect healthy cells, thereby presenting unwanted side effects and complications. In this particular case, however, the researchers stressed a reduction in toxicity. “Normal cells are fine when you remove Rad52, so we think potential therapies would have a very low toxicity” said Xiaohua Wu, senior author of the study and a Scripps Research professor.
The researchers also suggested that any therapies to target Rad52 would exploit ‘synthetic lethality’. This phenomenon occurs when a combination of two or more gene deficiencies leads to cell death, whereas only one gene deficiency does not. Cancer cells have DNA mutations, meaning that they are lacking in some proteins to keep their DNA error-free. Therefore, targeting another function-related protein together with a drug may result in the death of cancer cells. In addition, the key to this approach is that the healthy cells are not missing the protein which is mutated in the cancer, so they survive when being treated by the drug that targets the other related protein. “The most important thing is to understand the defects in all these tumors, and then you can understand how to target them specifically” said Wu.
Tailoring therapy to ensure better patient care
Wu and fellow researchers now plan to develop inhibitor drugs targeting Rad52 and to test them as potential new therapies for certain types of cancers. Although synthetic lethality is not a new approach, the FDA recently approved a drug known as PARP inhibitor, which has shown great promise in treating hereditary breast and ovarian cancers with BRCA1 or BRCA2 gene mutations. The PARP inhibitor and the BRCA genes are also involved in the process of repairing DNA. As a result, the researchers are now analyzing other genes that can be used in combination with PARP inhibitors to take advantage of synthetic lethality.
The Scripps-led research study is still in the early stages and so far, it has only shown to reduce tumor growth and toxicity in mice. However, approval of drugs down the line is showing a good indication for the development of new therapies. A major step is to build on the current work and to test Rad52 in various combinations, which may take up to several years. Nevertheless, Wu is quite optimistic about what the future has in store. “This study shows why it’s very important to focus on basic research and then follow-up on findings that can benefit patients. That’s the future. That’s the goal for targeted cancer treatments--to make these treatments a part of precision medicine” she said.
When two is better than one
Back in 2016, a similar study was conducted by researchers from the Weizmann Institute, identifying a promising combination therapy for triple-negative breast cancer. In the study, professor Sima Lev, postdoctoral fellows Nandini Verma and Anna-Katharina Müller of the Weizmann Institute of Science’s Molecular Cell Biology Department and fellow researchers found a therapeutic approach that could not only stop tumor growth and survival, but it also prevent drug resistance. They enrolled the participation of a subset of triple-negative breast cancer patients whose tissue samples showed higher levels of two molecules: EGFR and PYK2. EGFR is a cell-surface receptor, while PYK2 is a robust molecule that plays a vital role in breast cancer metastasis. In animal models, the researchers found that either of the molecules used alone led to a slight reduction in tumor size, whereas their combination resulted in a more significant reduction in tumor size.
Upon further investigation, the research team were able to determine the precise molecular pathways and protein interactions through which EGFR and PYK2 lead to tumor growth and survival. With these results, the team discovered that the inhibition of PYK2 not only synergized with the EGFR inhibitors, but also bypassed the issue relating to drug resistance. On the contrary, the inhibitor of EGFR alone would not prove to be of clinical benefit because the cells tend to make up for the insufficient amount of EGFR by increasing levels of HER3, an alternative receptor molecule. HER3 is associated with drug resistance in EGFR therapy. Therefore, the researchers found that by inhibiting PYK2, this led to a chain of events that ultimately degraded HER3, thus allowing EGFR therapy to work in more effective manner. “We believe that this combination therapy – targeting both EGFR and PYK2 – provides a promising, more effective approach for a subset of triple negative breast cancer patients than other combinations that are currently being tested, owing to its ability to impede tumor growth and survival and prevent drug resistance” said Lev.