By Rolando Garcia
Natural Science and Mathematics
The day when an ovarian cancer patient can treat her tumor with a single, painless pill instead of a toxic drug cocktail is the ultimate goal of the pioneering research of a 葫芦影业 scientist.
Preethi Gunaratne, assistant professor in the department of biology and biochemistry, is studying a class of tiny genetic molecules known as microRNA鈥檚 and pinpointing those that could unleash the body鈥檚 natural cancer-fighting agents. Additionally, she is developing a novel method to effectively deliver this treatment to the targeted cells using an unusual carrier 鈥� nano-particles of gold 鈥� through the work of Lalithya Jayarathne, a postdoctoral researcher in Gunaratne鈥檚 lab.
Gunaratne鈥檚 potentially ground-breaking work in ovarian cancer has gained exceptional notice and momentum this year with a series of high-profile research grants. In October, her ovarian cancer project was awarded a $200,000 High Impact/High Risk grant from the Cancer Prevention and Research Institute of Texas (CPRIT), which oversees the state鈥檚 billion-dollar war on cancer.
That followed a $250,000 grant from Houston鈥檚 Cullen Foundation and earlier this year, Gunaratne was chosen as a beneficiary of the Baylor College of Medicine Partnership Fund. Each year the Partnership undertakes a major fundraising campaign for a specific health project, and for 2010-11, the Partnership will be raising money to fund the collaborative ovarian cancer project of Gunaratne and Baylor researchers Matthew Anderson and Martin Matzuk.
This promising research has its origins in a revolution in genetic science that began just a few years ago. Attention has long centered on nucleic acids known as DNA, with little consideration given to its cousin RNA or to microRNA鈥檚, which were considered 鈥済enetic junk鈥� that played no significant role in the human genome, Gunaratne said.
That began to change earlier this decade as scientists discovered that microRNA鈥檚 might actually be the hidden regulators controlling the 30,000 genes in the human body by silencing gene expression. Gunaratne has been at the vanguard of this development and 鈥� with its 2008 acquisition of a $1 million device 鈥� the Illumina Genome Analyzer 鈥� UH instantly became a major player in this cutting-edge research. This state-of-the-art machine can rapidly deconstruct and analyze millions of pages worth of genetic data and allowed Gunaratne鈥檚 lab to sequence hundreds of normal and disease tissue samples.
Gunaratne set her sights on a variety of cancers, including ovarian tumors, pediatric neuroblastoma and multiple myeloma. Using the sequencer in collaboration with Baylor, Texas Children鈥檚 Cancer Center and the Lurie Cancer Center at Northwestern University, her team created a unique database documenting genome-wide patters of microRNA and gene expression across an array of human tissues and cancers. The ultimate goal is to connect specific microRNA鈥檚 with the genes they regulate.
From this database, Gunaratne鈥檚 team was able to pinpoint a handful of microRNA鈥檚 in the human body that can significantly or completely suppress the growth of cancer cells. One in particular, miR-31, discovered by Gunaratne and her Baylor collaborators, shows promise as a potent tumor suppressor in ovarian cancer, glioblastoma, osteosarcoma and prostate cancer.
They discovered that miR-31 can specifically target and kill cancer cells that are deficient in p53, a crucial gene that guards the integrity of the genome and prevents cancer. Over half of all cancers and 90 percent of papillary serous tumors (the most common type of malignant ovarian cancer) are p53-deficient.
In cell cultures miR-31 suppressed and killed tumor cells deficient in p53 while sparing cells with a normal p53 gene. Since all non-cancerous cells in the body would be resistant to miR-31, it can fight tumors without the side-effects associated with chemotherapy.
But delivering these microRNA鈥檚 into human patients is a much trickier proposition than working on cell cultures and has never been done, Gunaratne said. Other types of gene therapy have been delivered with modified viruses in clinical trials, but ongoing safety concerns will likely prevent its widespread use, she said.
However, Gunaratne believes gold, which is biocompatible and easily functionalized to carry hundreds of microRNA鈥檚 on the surface, can act as an effective carrier of genetic molecules. In lab tests, gold nanoparticles containing miR-31 penetrated 90 percent of targeted cells within 20 minutes, killing cancer cells three times faster than microRNA鈥檚 delivered through lentiviruses.
The next step is to test these microRNA-conjugated gold particles on tumors in mice to see if they can be delivered orally or through injection to shrink the tumors. If all goes as planned, at the end of the two-year CPRIT grant this potentially revolutionary ovarian cancer treatment could be ready for Phase One clinical trials, Gunaratne said.
Ovarian cancer is the fifth deadliest cancer among women, with about 15,000 deaths annually in the U.S. Thus far, in cancer treatment generally, genetic markers have been helpful in assessing cancer patients鈥� risk and channeling them into the most effective treatment options.
But if scientists like Gunaratne are successful, doctors will go beyond observing and reacting to a cancer patient鈥檚 gene expression to actually changing that gene expression, activating the body鈥檚 natural tumor suppressants and making grueling, toxic chemotherapy a thing of the past.
Although ovarian tumors are the focus of this project, Gunaratne鈥檚 microRNA research is applicable to other cancers and diseases too. Because a single microRNA can regulate hundreds of genes across diverse signaling pathways, they provide an especially promising way to control the patterns of gene expression that cause disease, Gunaratne said.
In fact, Gunaratne is a co-investigator, along with Baylor researchers, on two other CPRIT grants announced in October totaling $2.5 million studying siRNA鈥檚 with Baylor鈥檚 Larry Donehower and epigenetic signals associated with cancer with Margaret Goodell. This most recent round of CPRIT grant awards is marks the first time that UH has received a research grant from CPRIT. Previous awards were for training graduate students and for raising cancer awareness.
The grants to UH are part of the $3 billion in cancer research that Texas voters approved in 2007 to be distributed over 10 years. The first batch of funded projects was announced in 2009. The CPRIT awards underscores UH鈥檚 growing role in biomedical research and demonstrates it can compete with other research powerhouses both locally and nationally, Gunaratne said.