In a study published today in the journal Cancer Cell, the investigators found that the agent THZ1 caused human-like small cell lung tumors in mice to shrink significantly, with no apparent side effects. The compound is now being developed into a drug for testing in human patients in clinical trials.
"Small cell lung cancer is a disease for which new treatments are desperately needed," said Kwok-Kin Wong, MD, PhD, co-senior author of the study and medical oncologist at Dana-Farber. "Patients generally respond well to initial chemotherapy, but the disease almost always returns. Less than 5 percent of patients are alive five years after being diagnosed with the disease." Small cell lung cancer (SCLC) accounts for 10-15 percent of lung cancer cases and is the most aggressive form of lung malignancy.
Extracting tumor tissue from the animals, the researchers screened more than 1,000 small molecule blockers in the cell samples to see if any halted tumor cell growth. The one that worked best was THZ1, a compound designed by chemical biologists at Dana-Farber that inhibits a cell protein known as cyclin-dependent kinase 7 (CDK7). CDK7 is known to play a key role in gene transcription, the process by which genetic information stored in DNA is copied onto RNA.
Inhibiting CDK7, therefore, strikes at the basic machinery of transcription. But since transcription occurs in all cells, researchers explored why THZ1 is effective at killing SCLC cells but left healthy cells unharmed. The answer lies in sections of genetic material known as super-enhancers, long stretches of DNA that exert extensive control over transcription in tumor cells. The researchers found that THZ1 suppresses certain genes within these regions that SCLC cells depend on to survive and grow.
Because normal cells do not rely on super-enhancers to the same degree, they are largely unaffected by THZ1. "We found that SCLC cells are 'addicted' to transcription in a way that normal cells are not," Wong observed. "They appear to depend on short-lived transcripts - briefly existing RNA copies - that aren't as critical to normal cells. This explains why normal cells can tolerate a drug that targets the basic transcription mechanism while SCLC cells cannot."
The key to the effectiveness of drugs derived from THZ1 will be finding the correct "therapeutic window" for patients - the dose and administration schedule that produces the greatest therapeutic effect while producing the fewest side effects, Wong continued. Clinical trials will help determine that window.
- » News Central
- » Popular News
- » Latest Health News
- » News Category A-Z (500+)
- » Health News and Press Release
- » News Archive
- » News Photo Gallery
- » Lifestyle and Wellness
- » Health Watch
- » Health In Focus
- » Celebrating Life
- » Breaking Health News
- » News From Other Resources
- » India Special
- » News Video Gallery
- » Medindia Exclusive - Interviews and In depth Reports