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2 minute read
DNA damage is one of the primary triggers of cancer development and has been linked to many types of cancers, including prostate, stomach, liver, and skin cancers, as well as leukemia. Within cells, the DNA sequence encodes all the instructions required for building proteins that are needed for cellular functions such as metabolism, replication, tissue, and organ maintenance.
The fidelity of the DNA sequence in a cell is maintained by multiple mechanisms, including the DNA damage repair mechanism, but errors and mutations can occur, which sets off a chain of events that leads to tumor growth.
DNA damage can be caused by exogenous sources, such as UV radiation, chemical carcinogens, and infection with human papillomavirus or Helicobacter pylori. Endogenous DNA damage can also be caused by multiple factors, including unchecked metabolites like reactive oxygen species (ROS) and defects in DNA damage repair enzymes. Since DNA damage mechanisms have been known to cause numerous cancers, several drugs, particularly small molecule inhibitors, have been developed to target DNA damage repair pathways.
Improvements in animal models for cancer have revolutionized how anti-cancer drugs are evaluated and developed, including drugs targeting DNA damage. Patient-derived xenograft (PDX) models have been particularly powerful tools since they use patient-derived tumor tissue engrafted into mice. Tumor cell lines, solid tumor tissue, or hematological tumors can be transplanted into immunodeficient mice to study DNA damage repair mechanisms. These immunocompromised mice can also be humanized by inoculating human immune cells or made to express components of the human immune system, like immune checkpoint molecules, to better screen for the effectiveness of various anti-cancer treatments.
In this era of rapid, high-throughput DNA sequencing, individual tumors can be sequenced and specific defects in DNA damage repair pathways can be defined. This same tumor tissue can be engrafted into a PDX mouse model for screening of drugs or therapeutics that tackle the appropriate DNA damage repair defect.
Different assays can also be used to study DNA damage and repair mechanisms:
- comet assay is used to detect DNA single/double-strand breaks in single cells,
- γH2AX detection by IHC staining or western blot can be used to detect, measure, and localize DNA breaks.
This approach is powerful for screening preclinical drug candidates targeting DNA damage and repair for efficacy against a range of tumors and it also provides insights into potential off-target effects or toxicities. From the patient's perspective, pre-screening potential treatment options in mice can lead to the selection of the most appropriate drug or therapeutic targeting DNA damage and repair and help avoid treatments that may be ineffective.
DNA damage events can lead to tumor growth and this area of research continues to inform drug development on the bench and patient care in the clinic.
Champions Oncology is the ideal partner to accelerate your DNA damage-targeted drug pipeline. We offer a large bank of PDX models, particularly PDX models with high microsatellite instability (MSI-H), that have dysregulated DNA damage repair mechanisms, for ex vivo and in vivo studies. We also provide DNA sequencing, comet assay, and γH2AX detection by IHC staining or western blot, to support your DNA damage targeting drug programs. To add DNA damage evaluation to your upcoming study, contact us today.
