Precision medicine aims to create specialized treatment regimens that are tailored to each individual’s unique genetics, environment, and lifestyle.
What is precision medicine?
By definition, precision medicine, which is often also referred to as personalized medicine, is the medical approach to understanding how an individual’s genetics, environment, and lifestyle can be used to determine the best method of disease treatment or prevention.
Precision medicine differs greatly from the traditional approach to disease treatment, which instead utilizes a “one-size-fits-all” approach that is limited in its ability to consider the unique differences that exist between each patient.
Today, there are numerous clinical applications of precision medicine that are expected to continue to shape how medicine and research are conducted for years to come. Precision medicine has been particularly successful in targeting various aspects of DNA in the treatment of various diseases, particularly cancer.
In fact, numerous therapies that target molecular alterations have successfully improved the treatment outcome of individuals diagnosed with several different types of cancer. Tyrosine kinase inhibitors, for example, have largely changed the way in which EGFR mutated lung cancer, BRAF mutated melanoma, and translocated Bcr-Abl forms of chronic myelogenous leukemia are treated.
What is DNA repair?
Deoxyribonucleic acid (DNA) contains the genetic information required for every cell in the body to function properly. To this end, DNA provides information on cellular growth, proliferation, metabolism, communication, and even death. DNA is exposed to constant stress and damage in several different forms; however, several different repair pathways are available to maintain genetic integrity.
During the replication of DNA, for example, incorrect bases can be added to the DNA strand. When this occurs, the mismatch repair (MMR) pathway is initiated. Comparatively, simple damage that occurs to a single DNA base will be repaired by a process known as base excision repair (BER). In the event that more significant damage occurs to DNA, a process known as homologous recombination (HR) can occur to correct breaks in both strands. While HR is initiated if this significant damage occurs when the cell is in the S or G2 phase of the cell cycle, nonhomologous end joining (NHEJ) is used when this damage occurs during other phases of mitosis.
Although these DNA repair pathways are highly specialized, there is some level of redundancy that is incorporated into these pathways to allow one pathway to compensate for another as needed.
Precision Medicine. Image Credit: bangoland/Shutterstock.com
Targeting BRCA mutant cancers
Both breast cancer 1 (BRCA1) and BRCA2 are human tumor suppressor genes that play active roles in HR repair. BRCA1, for example, interacts with the MRN complex, which is a protein complex that senses, signals, and facilitates the repair of DNA damage by resecting the damaged nucleotides before the initiation of HR or NHEJ.
Comparatively, BRCA2 recruits Rad51 to double-strand break sites, thereby allowing Rad51 to mediate strand pairing during HR.
Individuals with mutations in BRCA1, BRCA2, or both, are often at a greater risk of developing various types of cancer, namely breast, ovarian, fallopian tube, peritoneal, prostate, and pancreatic. Although these mutations can increase the risk of these cancers developing, they can also be used to predict what treatment approach will likely elicit the best response in patients.
For example, defects in these BRCA genes often lead other DNA repair pathways to instead be heavily relied upon in the body. This increased burden on these other pathways thereby creates an alternate pathway by which clinicians can target their therapeutic approach to achieve synthetic lethality. As a result, poly (ADP-ribose) polymerase (PARP) inhibitors are often used to induce synthetic lethality in BRCA-mutant cancers.
The promising results of PARP inhibitors in the treatment of both breast and ovarian cancers have led several clinical trials to also utilize this class of cancer therapeutic drugs in the treatment of gastrointestinal (GI) malignancies, particularly those involving the pancreas. Pancreatic cancer currently has a survival rate of about 9%, which is the lowest of all cancer types. Therefore, further investigation of how emerging agents like PARP inhibitors, both alone and in combination with cytotoxic agents, must be conducted to determine the best approach to treating this aggressive type of cancer.
In addition to demonstrating a high level of efficacy in treating BRCA-mutant subtypes of cancer, particularly in breast cancer, PARP inhibitors are also promising candidates in the treatment of aggressive metastatic, castration-resistant prostate cancer with both BRCA and ATM, which is another type of DNA repair protein that is involved in HR.
Predicting sensitivity to DNA-targeting agents
In addition to the specialized anti-cancer drugs that have been developed to target specific molecular targets, several pre-existing drugs are often used without molecular-based stratification. Some examples of these commonly used DNA-targeting drugs include cisplatin, etoposide, topotecan, and gemcitabine.
In an effort to continue to create targeted treatment approaches for each individual patient, several studies have investigated how these established drugs might elicit more effective responses in certain subtypes of cancer.
Cancer cell lines expression SLFN11, which is a gene that has been associated with inducing irreversible cell cycle arrest following treatment with several DNA replication inhibitors, may be more sensitive to certain DNA-targeting agents. In particular, topoisomerase I and II inhibitors, alkylating agents, and DNA synthesis inhibitors have each been found to elicit a significant response in cell lines that have a high expression of SLFN11.
Currently, there is a lack of validated assays available for the detection of SLFN11 expression in patient tumors; however, studies indicate that the expression of this gene is highly variable in many patient populations and across different tumor types. Therefore, the development of treatment regimens that utilize this information has the potential to be significantly more effective in eradicating cancerous cells.
- What is precision medicine? [Online]. Available from: medlineplus.gov/genetics/understanding/precisionmedicine/definition/.
- Beggs, R., & Yang, E. S. (2019). Chapter Five – Targeting DNA repair in precision medicine. Advances in Protein Chemistry and Structural Biology 115; 135-155. doi:10.1016/bs.apcsb.2018.10.005.
- Molinaro, E., Andrikou, K., Casadei-Gardini, A., & Rovesti, G. (2020). BRCA in Gastrointestinal Cancers: Current Treatments and Future Perspectives. Cancers (Basel) 12(11). doi:10.3390/cancers12113346.
- Reinhold, W. C., Thomas, A., & Pommier, Y. (2017). DNA-Targeted Precision Medicine; Have We Been Caught Sleeping? Trends in Cancer 3(1); 2-6. doi:10.1016/j.trecan.2016.11.002.