Tag Archives: Baylor College of Medicine

Glutamine Ratio is Key Ovarian Cancer Indicator

Posted on by

Glutamine plays an important role in cellular growth in several cancers. A Rice University-led study shows how ovarian cancer metabolism changes between early and late stages. In this study, a further link between glutamine dependency and tumor invasiveness is established in ovarian cancer.

A Rice University-led analysis of the metabolic profiles of hundreds of ovarian tumors has revealed a new test to determine whether ovarian cancer cells have the potential to metastasize, or spread to other parts of the body. The study also suggests how ovarian cancer treatments can be tailored based on the metabolic profile of a particular tumor.

The research, which appears online this week in Molecular Systems Biology, was conducted at the Texas Medical Center in Houston by researchers from Rice University, the University of Texas M.D. Anderson Cancer Center, and the Baylor College of Medicine.

Deepak Nagrath

Deepak Nagrath, Assistant Professor of Chemical and Biomolecular Engineering at Rice University

“We found a striking difference between the metabolic profiles of poorly aggressive and highly aggressive ovarian tumor cells, particularly with respect to their production and use of the amino acid glutamine,” said lead researcher Deepak Nagrath Ph.D. of Rice University. “For example, we found that highly aggressive ovarian cancer cells are glutamine-dependent, and in our laboratory studies, we showed that depriving such cells of external sources of glutamine — as some experimental drugs do — was an effective way to kill late-stage cells.

“The story for poorly aggressive cells was quite different,” said Nagrath, Assistant Professor of Chemical and Biomolecular Engineering at Rice. “These cells use an internal metabolic pathway to produce a significant portion of the glutamine that they consume, so a different type of treatment — one aimed toward internal glutamine sources — will be needed to target cells of this type.”

The research is part of a growing effort among cancer researchers worldwide to create treatments that target the altered metabolism of cancer cells. It has long been known that cancer cells adjust their metabolism in subtle ways that allow them to proliferate faster and survive better. In 1924, Otto Warburg showed that cancer cells produced far more energy from glycolysis than did normal cells. The Nobel Prize-winning discovery became known as the “Warburg effect,” and researchers long believed that all cancers behaved in this way. Intense research in recent decades has revealed a more nuanced picture.

“Each type of cancer appears to have its own metabolic signature,” Nagrath said. “For instance, kidney cancer does not rely on glutamine, and though breast cancer gets some of its energy from glutamine, it gets even more from glycolysis. For other cancers, including glioblastoma and pancreatic cancer, glutamine appears to be the primary energy source.”

Rice University Researchers

Researchers at Rice University’s Laboratory for Systems Biology of Human Diseases analyzed the metabolic profiles of hundreds of ovarian tumors and discovered a new test to determine whether ovarian cancer cells have the potential to metastasize. Study co-authors include, from left, Julia Win, Stephen Wahlig, Deepak Nagrath, Hongyun Zhao, Lifeng Yang and Abhinav Achreja.

Nagrath, director of Rice University’s Laboratory for Systems Biology of Human Diseases, said the new metabolic analysis indicates that ovarian cancer may be susceptible to multidrug cocktails, particularly if the amounts of the drugs can be tailored to match the metabolic profile of a patient’s tumor.

The research also revealed a specific biochemical test that pathologists could use to guide such treatments. The test involves measuring the ratio between the amount of glutamine that a cell takes up from outside and the amount of glutamine it makes internally.

“This ratio proved to be a robust marker for prognosis,” said University of Texas M.D. Anderson Cancer Center co-author Anil Sood, M.D., Professor of Gynecologic Oncology and Reproductive Medicine and co-director of the Center for RNA Interference and Non-Coding RNA. “A high ratio was directly correlated to tumor aggression and metastatic capability. Patients with this profile had the worst prognosis for survival.”

The three-year study included cell culture studies at Rice as well as a detailed analysis of gene-expression profiles of more than 500 patients from the Cancer Genome Atlas and protein-expression profiles from about 200 M.D. Anderson patients.

“The enzyme glutaminase is key to glutamine uptake from outside the cell, and glutaminase is the primary target that everybody is thinking about right now in developing drugs,” Nagrath said. “We found that targeting only glutaminase will miss the less aggressive ovarian cancer cells because they are at a metabolic stage where they are not yet glutamine-dependent.”

Lifeng

Lifeng Yang, Study Lead Author & Graduate Student, Systems Biology of Human Diseases, Rice University

Rice University graduate student Lifeng Yang, lead author of the study, designed a preclinical experiment to test the feasibility of a multidrug approach, involving the use of a JAK inhibitor and a glutaminase inhibitor. This “drug cocktail” approach inhibited the early stage production of internal glutamine, while also limiting the uptake of external glutamine.

“That depleted all sources of glutamine for the cells, and we found that cell proliferation decreased significantly,” Yang said.

Nagrath said the study also revealed another key finding — a direct relationship between glutamine and an ovarian cancer biomarker called “STAT3” (Signal Transducer And Activator Of Transcription 3).

“A systems-level understanding of the interactions between metabolism and signaling is vital to developing novel strategies to tackle cancer,” said M.D. Anderson co-author Prahlad Ram Ph.D., Associate Professor of Systems Biology and co-director of the M.D. Anderson Cancer Center’s Systems Biology Program. “STAT3 is the primary marker that is used today to ascertain malignancy, tumor aggression and metastasis in ovarian cancer.”

Nagrath said, “The higher STAT3 is, the more aggressive the cancer. For the first time, we were able to show how glutamine regulates STAT3 expression through a well-known metabolic pathway called the TCA cycle, which is also known as the ‘Krebs cycle.’”

Nagrath said the research is ongoing. Ultimately, Dr. Nagrath hopes the investigations will lead to new treatment regimens for cancer as well as a better understanding of the role of cancer-cell metabolism in metastasis and drug resistance.

Co-authors include Hongyun Zhao, Stephen Wahlig, Abhinav Achreja and Julia Win (all affiliated with Rice University); Tyler Moss, Lingegowda Mangala, Guillermo Armaiz-Pena, Dahai Jiang, Rajesha Roopaimoole, Cristian Rodriguez-Aguayo, Imelda Mercado-Uribe, Gabriel Lopez-Berestein and Jinsong Liu (all affiliated with M.D. Anderson Cancer Center); Juan Marini of Baylor College of Medicine; and Takashi Tsukamoto of Johns Hopkins University.

The research was supported by seed funding from (i) the Collaborative Advances in Biomedical Computing Program at Rice Univesity’s Ken Kennedy Institute for Information Technology, (ii) Rice University’s John and Ann Doerr Fund for Computational Biomedicine, (iii) the Odyssey Fellowship Program at the MD Anderson Cancer Center, (iv) the estate of C.G. Johnson Jr., (v) the National Institutes of Health, (vi) the Cancer Prevention and Research Institute of Texas, (v) the Ovarian Cancer Research Fund, (vi) the Blanton-Davis Ovarian Cancer Research Program, (vii) the Gilder Foundation, and (viii) the MD Anderson Cancer Center.

Sources: 

UH Biochemist Works To Revolutionize Ovarian Cancer Treatment By Unleashing the Power of MicroRNAs & Nanotechnology

Posted on by

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 University of Houston (UH) scientist.  Preethi Gunaratnee, assistant professor in the department of biology and biochemistry, is studying a class of tiny genetic molecules known as microRNAs and pinpointing those that could unleash the body’s natural cancer-fighting agents.

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 University of Houston (UH) scientist.

Preethi Gunaratnee, Ph.D., Assistant Professor, Department of Biology & Biochemistry, University of Houston

Preethi Gunaratnee, assistant professor in the department of biology and biochemistry, is studying a class of tiny genetic molecules known as microRNAs and pinpointing those that could unleash the body’s natural cancer-fighting agents. Additionally, she is developing a novel method to effectively deliver this treatment to the targeted cells by using an unusual carrier – nanoparticles of gold – through the work of Lalithya Jayarathne, a postdoctoral researcher in Gunaratne’s lab.

Gunaratne’s potentially groundbreaking 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’s billion-dollar war on cancer. In November, she was approved for a $250,000 grant from Houston’s Cullen Foundation. Earlier this year, she was chosen a beneficiary of the Baylor College of Medicine Partnership Fund.

Each year, the Baylor partnership undertakes a major fundraising campaign for a specific health project. For 2010-11, the partnership is raising money to fund the collaborative ovarian cancer project of Gunaratne and Baylor researchers Matthew Anderson, M.D., Ph.D. and Martin Matzuk, M.D., Ph.D.

All 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 microRNAs, which were considered “genetic junk” that played no significant role in the human genome, Gunaratne said.

MicroRNA Expression (Rosetta Genomics)

That began to change earlier this decade as scientists discovered that microRNAs might actually be the hidden regulators that control the 30,000 genes in the human body by silencing gene expression. Gunaratne has been at the vanguard of this development. With its 2008 acquisition of a $1 million genome sequencer device – the Illumina Genome Analyzer – 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’s lab to sequence hundreds of normal and diseased 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’s 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 microRNAs with the genes they regulate, individualized to attack specific genomes.

From this database, Gunaratne’s team was able to pinpoint a handful of microRNAs in the human body that can significantly or completely suppress the growth of cancer cells. One in particular, miR-31, discovered by Baylor collaborators and Gunaratne, 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. More than 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.

“Delivering these microRNAs 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.”

However, Gunaratne believes gold, which is biocompatible and easily functionalized to carry hundreds of microRNAs 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 microRNAs delivered through lentiviruses, which are traditionally used in carrying gene-based treatments to diseased cells.

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, this potentially revolutionary ovarian cancer treatment could be ready for phase I clinical trials in humans at the end of the two-year CPRIT grant, Gunaratne said.

Ovarian cancer is the fifth deadliest cancer among women, with about 15,000 deaths annually in the United States. Thus far, in cancer treatment generally, genetic markers have been helpful in assessing cancer patients’ risk and channeling them into the most effective treatment options. If scientists like Gunaratne are successful, doctors will go beyond just observing and reacting to a cancer patient’s gene expression to actually changing it, activating the body’s natural tumor suppressants. This could make chemotherapy a thing of the past.

“Although ovarian tumors are the focus of this project, our microRNA research is applicable to other cancers and diseases, too,” Gunaratne said. “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 also is a co-investigator with Baylor researchers on two other CPRIT grants announced in October, totaling $2.5 million. In one they will test siRNA-conjugated gold particles as an anti-cancer agent with Baylor’s Dr. Larry Donehower, and in the other they will use next-generation sequencing to look at epigenetic signals in malignant blood-related cancers with Dr. Margaret Goodell.

This most recent round of CPRIT grant awards marks the first time UH has received a research grant from CPRIT. Previous awards were for training graduate students and for raising cancer awareness.

“All these awards, CPRIT included, underscore UH’s growing role in biomedical research and demonstrate we can compete with other research powerhouses both locally and nationally,” Gunaratne said.

About the University of Houston

The University of Houston is a comprehensive national research institution serving the globally competitive Houston and Gulf Coast Region by providing world-class faculty, experiential learning and strategic industry partnerships. UH serves more than 38,500 students in the nation’s fourth-largest city, located in the most ethnically and culturally diverse region of the country.

About the College of Natural Sciences and Mathematics

The UH College of Natural Sciences and Mathematics, with 181 ranked faculty and approximately 4,500 students, offers bachelor’s, master’s and doctoral degrees in the natural sciences, computational sciences and mathematics. Faculty members in the departments of biology and biochemistry, chemistry, computer science, earth and atmospheric sciences, mathematics and physics conduct internationally recognized research in collaboration with industry, Texas Medical Center institutions, NASA and others worldwide.

Source: UH Biochemist Works to Revolutionize Ovarian Cancer Treatment – Preethi Gunaratne Wins Key Grants to Unleash Body’s Natural Cancer-fighting Agents, News Release, University of Houston, December 21, 2010.

MK-0457 Alone and in Combination With Docetaxel Inhibits Ovarian Cancer Growth In Vivo

Posted on by

…[T]he [M.D. Anderson Cancer Center & Baylor College of Medicine] researchers concluded that [Aurora kinase] AK inhibition [produced by MK-0457] significantly reduces ovarian cancer tumor burden and cell proliferation, and increases tumor cell apoptosis in preclinical ovarian cancer mouse models. The researchers noted that the role of Aurora kinase inhibition in ovarian cancer merits further investigation in clinical trials.

Chemotherapeutic drugs that interfere with the normal progression of cell division are used regularly for anti-cancer treatment. These so-called “antimitotic” drugs work by halting the cell cycle in mitosis, thereby inducing cell death (apoptosis) in tumor cells. Unfortunately, these compounds act not only on proliferating tumor cells, but exhibit significant side effects on non-proliferating or normal cells.

Aurora kinases (AKs), a specific family of protein kinases, are essential for various steps in human cell division. The cell division process is one of the hallmarks of every living organism. Within the complete cell-cycle process, mitosis constitutes one of the most critical steps. The main purpose of mitosis is to segregate sister chromatids into two daughter cells. This process is tightly regulated by several proteins, some of them acting as check points that ultimately ensure the correct coordination of this critical biologic process.

There is evidence linking AK overexpression with various types of malignant human cancer cells. Given the potential selectivity to target tumor cells while leaving normal cells unaffected, several “AK inhibitors” have been developed by various drug companies. Researchers at the University of Texas M.D. Anderson Cancer Center (Departments of Gynecologic Oncology, Surgical Oncology, and Cancer Biology) and the Baylor College of Medicine (Departments of Molecular and Cellular Biology and Obstetrics and Gynecology) tested MK-0457, a small molecule AK inhibitor, alone and in combination with docetaxel against ovarian cancer growth in vitro and in vivo. MK0457, initially developed by Vertex Pharmaceuticals Inc. (Vertex), is now being developed clinically by Merck & Co., Inc (Merck) for use against treatment-resistant forms of advanced leukemias.

The in vitro testing conducted by M.D. Anderson and Baylor researchers compared the use of docetaxel alone with the combination use of docetaxel and MK-0457, against two lines of chemosensitive ovarian cancer cells. Notably, the M.D. Anderson and Baylor researchers determined that the docetaxel and MK-0457 combination produced cytotoxicity that was 10 times greater than that produced by docetaxel alone. The in vivo testing, conducted in mouse models, compared the use of MK-0457 monotherapy against lines of chemosensitive and chemoresistant ovarian cancer cells. The AK inhibitor MK-0457, when used alone, significantly reduced ovarian cancer cell tumor burden. Combination treatment with docetaxel and MK-0457 resulted in significantly improved reduction in tumor growth, as well as a threefold increase in cell death, as compared to docetaxel monotherapy.

Based upon the foregoing results, the researchers concluded that AK inhibition significantly reduces ovarian cancer tumor burden and cell proliferation, and increases tumor cell apoptosis in preclinical ovarian cancer mouse models. The researchers noted that the role of Aurora kinase inhibition in ovarian cancer merits further investigation in clinical trials.

Note: In November 2007, Merck suspended new patient enrollment in two leukemia trials which involve the use of MK-0457. The suspension of new enrollees was attributable to preliminary safety data that indicated a potential cardiovascular effect in one patient. The safety findings from that patient indicated “QTc prolongation” (or “Long QT Syndrome“), a condition that can precede sudden cardiac arrest. Patients already enrolled in the two leukemia trials were permitted to continue treatment with MK-0457, provided that they were monitored for QTc prolongation. To our knowledge, based upon publicly available information, there have been no further reports of QTc prolongation within those two clinical trials.

Primary Reference: Targeting Aurora Kinase with MK-0457 Inhibits Ovarian Cancer Growth; Lin, YG et. al., Clin Cancer Res. 2008 Sep 1;14(17):5437-5446

Secondary References: