Taking aim at the fundamental biology of cancer cells, the National Institutes of Health (NIH) has awarded $747,000 to Worcester Polytechnic Institute (WPI) for a three-year research project to explore the molecular mechanisms associated with the genetic mutations and chromosome instability observed in all cancer cells. The goal is to turn the genetic tables against cancer by learning more about the molecular basis of cancer cells' uncontrolled growth so that knowledge could one day bolster the effectiveness of cancer treatments and improve patient outcomes.
Led by Amity Manning, PhD, assistant professor of biology and biotechnology at WPI, the research will examine how specific molecules can change the way DNA is packaged and organized within cells causing genetic errors that can, in turn, transform normal cells into cancer cells. The study will also explore whether the same factors that affect DNA and cause chromosomal instability can be controlled to make cancer cells more susceptible to existing chemotherapy drugs.
"These are basic studies that we hope will give us a better understanding of the genetic changes and cellular processes that allow cancers to grow and spread," Manning said. "The more we understand about the changing biology of the cancer cells, the more leverage we will have in treating the disease."
A fundamental feature of all cancers is uncontrolled, aberrant cell division. When human cells divide normally, their chromosomes (DNA) are duplicated accurately, neatly organized into pairs, and then pulled apart into two equal groups that form the nuclei of two normally functioning daughter cells.
When the cell-division process goes wrong, errors in DNA duplication can spawn mutant genes that drive cells to abandon their normal processes. These anomalous cells divide out of control and take over surrounding tissue—the hallmark of cancer. Problems during cell division can also disrupt the organization of chromosomes, producing daughter cells with more or fewer than the normal number. This chromosomal instability can also be a precursor of cancer.
As cancer cells multiply unchecked, they can also undergo additional genetic mutations and chromosomal instability, giving the growing tumor an ever-changing genetic profile that can make it resistant to chemotherapy drugs. As a result, a drug that is initially effective against a known type of cancer may lose its effectiveness over time, allowing the cancer to recur.
In her previous work as a post-doctoral researcher at Massachusetts General Hospital, Manning identified several DNA regulatory molecules that are common to many solid-tumor cancers, including non-small cell lung cancer. Those molecules appear to play a role in chromosomal instability, genetic mutations, and drug resistance that are characteristic of these cancers.
In the new NIH-funded project at WPI, Manning and her lab team will build on that work by using genetic screening techniques to further test those molecules, and to search for additional molecules that change the way DNA is packaged and processed in cancer cells. They will also see whether reducing those molecules, and thereby increasing genetic stability in cancer cells, has an effect on the cells' long-term survival. Finally, they will determine whether manipulating these regulatory molecules can make cancer cells less able to resist the therapeutic effect of chemotherapy drugs.
"Chromosomal instability gives cancer cells an advantage," Manning said. "It enables the cells to grow and spread in ways that evade the body’s natural defenses and resist the drugs we throw at them. We have to find out what the cancer cells know, so that we can fight back."