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Targeting DNA Damage in Cancer

Sep 3, 2020 10:05:00 AM / by Champions Oncology

DNA DamageDNA 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 but errors and mutations can occur, which sets off a chain of events that lead to tumor growth.

Human papillomavirusDNA 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 repair pathways.

Improvements in animal models for cancer have revolutionized how anti-cancer drugs are evaluated and developed. 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. These immunocompromised mice can also be made to have “humanized” immune systems or express components of the human immune system, like immune checkpoint inhibitors, 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. This approach is powerful for screening preclinical drug candidates for efficacy against a range of tumors and it also provides insights into potential off-target effects or toxicities. From the patient perspective, pre-screening potential treatment options in mice can lead to the selection of the most appropriate drug or therapeutic and helps 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. 

 

Download now: Champions' patient-derived xenograft (PDX) models for evaluating novel therapeutics targeting the DNA damage response mechanism

Tags: Solid Tumor Oncology