This is the first in a series of articles written by research students in the University of Toledo College of Medicine’s Biomedical Science graduate program exploring basic issues of human health.
Cancer is one of the deadliest diseases of our times. The cure rates for many types of cancer remain low and are dependent on how early the tumor is detected.
At the University of Toledo College of Medicine (formerly the Medical College of Ohio), researchers are experimenting with different ways to block a cancer cell’s ability to reproduce.
Despite many different treatment plans available, cancer cells frequently find ways to become resistant. The driving force of the school’s research is to understand how those cells develop that resistance and to provide an effective treatment to combat them.
Simply put, cancer cells are normal cells gone bad. How does this happen? Within your body, many different types of normal cells come together during very early development to form each organ, such as your heart or kidney. Each cell has instructions for these different functions contained in its DNA. Before cells divide they replicate their DNA so each cell can pass on these instructions to the next generation of cells. This DNA replication process is well guarded to keep mistakes from happening. However, very rarely an error occurs that produces an abnormal cell that has lost the “stop dividing” part of the instructions. Such cells keep dividing and form a mass of cells that eventually grow into a tumor.
These tumors can even form their own blood vessels to bring food and oxygen so that the tumor grows even larger. Some of the cancer cells can also break off and travel through the blood vessels and invade different parts of the body to grow more tumors. These are metastatic tumors. If left untreated, both the primary and metastatic tumors continue to grow and invade normal tissue, ultimately sabotaging normal organ functions.
The mistakes in DNA replication that become permanent and passed on to future generations of abnormal cells are called mutations. Mutations can happen during normal cellular functions or can happen by exposure to high amounts of radiation or cancer causing chemicals that are called carcinogens.
Your normal cells actually have strong defenses to fight against such attacks on its DNA. Each cell has several different “military units” of DNA proteins that repair different types of damage to prevent mutations.
Treatment for many cancers involves surgery, as well as radiation and chemotherapy to help kill cancer cells. Radiation and many of the chemicals used for chemotherapy are strong DNA damaging agents that kill cancer cells that are rapidly dividing. Cisplatin is one of the most widely used chemotherapy agents for treatment of many human cancers. Cisplatin binds tightly to the DNA, preventing the DNA from replicating, and therefore keeping the cell from dividing. If the cells can’t divide, they die. This is why cisplatin and other chemotherapy drugs kill rapidly dividing cancer cells, which often results in a visible shrinking of the tumor over time.
However, cancer cells operate like very smart automated factories; throw a wrench into one part of it and another part compensates to keep it running.
Cancer cells that survive cisplatin become very efficient at directing their military units of DNA repair proteins to quickly repair DNA damage caused by cisplatin. Increased doses of cisplatin do not work as the tumor cells develop even more ways to fight the drug. Also, if too many normal cells die, normal organ function is in danger.
Despite all the defenses that cancer cells can develop against cisplatin, this drug remains one of the most successful anticancer agents today. This creates a dire need for a combination therapy with another drug that will help to make cisplatin a more effective cancer cell killer.
UT researchers are seeking a drug that will inhibit the repair of cisplatin-damaged cancer cells. Studies from our lab and from around the world have shown that a DNA repair protein called XPF-ERCC1 plays a vital role in the repair of DNA damage caused by cisplatin. If the XPF-ERCC1 DNA repair protein can be stopped, then cisplatin would be more effective, even at lower doses. A wonderful example of overlapping biomedical research knowledge is that testicular cancer cells have lower than normal levels of XPF-ERCC1. Consequently, cisplatin has proven to be very effective in the treatment of this cancer with cure rates approaching 95 percent.
With this in mind, researchers started looking at different compounds that inhibit XPF-ERCC1. After screening thousands of compounds, a handful showed promising results. We tested these compounds on cancer cells in a petri dish to measure how much they help cisplatin kill cancer cells. In the near future, with the use of animal models and human clinical trials, the team aim to translate its results into an improved cisplatin combination therapy with minimal side effects.
Despite an increased understanding of the repair of cisplatin damaged DNA, there are still many unanswered questions. We still do not understand how many different DNA repair pathways are involved in the repair of cisplatin damage. By gaining a better understanding of these pathways, we can identify additional proteins in the cell that affect cisplatin repair. These additional proteins may be even better targets for combination therapy than XPF-ERCC1.
We, and our cancer research colleagues, now understand that there is no single solution for all types of cancer. We need to study biological mechanisms in depth that produce different types of cancer cells, especially cell mechanisms that prevent effective cancer treatment and make cancer cells resistant. In the future era of personalized medicine, there is a vast amount of research to be done to find such targets that will ultimately help us cure patients afflicted with this deadly disease.
Akshada Sawant is a student earning her Doctor of Philosophy in the UT-College of Medicine and Life Sciences Biomedical Science Program (Akshada’s Ph.D. advisor is Dr. Steve Patrick).