HOUSTON—Molecular markers are a critical tool in the fight against cancer, indicating the presence of abnormal cellular activity and measuring the body’s response to treatment experiments. Also known as biomarkers, these warning molecules can present in the form of molecular, biochemical, physiological or anatomical properties. Because of cancer's broad presentation, such biomarkers have been difficult to categorize, isolate or treat. But researchers at the University of Houston College of Pharmacy have discovered that a known protein, plectin, is appearing on cancer stem cells, serving as a precise biomarker for a key treatment avenue.
Also involved with the NIH-Career Development Award-funded research were John D. Minna and colleagues at the University of Texas Southwestern Medical Center.
“We have found a new biomarker, the protein plectin, on cancer stem cells. We believe plectin may be a more common biomarker that could lead to broadly applicable drug development,” reports Gomika Udugamasooriya in the journal Nature Scientific Reports. “Plectin is a structural protein, predominantly expressed intracellularly, but whose translocation onto the cell surface is linked to tumor invasion and metastasis.”
Researchers have been probing the role of plectin as a biomarker in various cancers, including ovarian, pancreatic, esophageal and head/neck, and a tentatively effective target for tumor-fighting drugs. What makes the University of Houston research significant is the refined exploration of plectin on cancer stem cells (CSCs) specifically.
CSCs are a small subpopulation of cells within tumors that are capable of self-renewal, differentiation and tumorigenicity. These cells have proven to be resistant to conventional chemotherapy and radiation treatment, and very likely are the origin of cancer metastasis.
All cancerous tumors contain a small subset of these cancer stem cells, which are responsible for up to 90 percent of cancer deaths.
“Scientists are desperately trying to find ways to handle these stubborn cancer stem cells to wipe out tumors. We predict this will be a more common drug target than current ones, because all tumors want to spread,” says Udugamasooriya.
Despite significant advances in cancer treatment that focus on the specific mechanisms of the cancer type and the tumor properties, most cancer treatments have failed in eliminating small subpopulations of therapy-resistant CSCs, which can self-renew, divide asymmetrically and form tumors in isolation. Developing treatment strategies targeting CSCs has been a challenge, due to the paucity of reliable biomarkers identifying such subpopulations. This is what makes Udugamasooriya’s discovery so important.
According to the Nature Scientific Reports article, one other element of the Houston research stands out as unique. In conventional two-step discoveries, researchers first find a biomarker and then develop a drug to target it. Udugamasooriya, however, did both at once while exploring the capacity in lung cancer samples.
He developed 400,000 potential synthetic chemical compounds (peptoids) and used them to capture the specific biomarker by performing his proprietary two-color cell screen. From almost half a million samples, he discovered only three peptoids that targeted CSCs and not the remaining cancer cells from the same patient. When those peptoids were used to pull down their targets, one of them was identified as plectin, proving that it is a unique biomarker for cancer stem cells.
“Our studies show both genotypic and phenotypic correlations between plectin and lung cancer stem cells, as well as association of high plectin expression with poor patient survival in lung adenocarcinoma, potentially identifying plectin as a biomarker for lung cancer stem cells,” Udugamasooriya explains.
Udugamasooriya said the team is now successfully exploring the peptoid chemical compound that targets plectin as a potential drug-lead and drug delivery agent.