Canadian Researchers Link DICER1 Gene Mutation to Non-Epithelial Ovarian Cancers & Other Rare Tumor Types

Canadian researchers affiliated with the Ovarian Cancer Research Program of British Columbia report that recurrent, lifetime-acquired mutations affecting the DICER1 gene occur in a range of nonepithelial ovarian tumors as well as other rare cancer tumor types, and appear common in Sertoli-Leydig ovarian tumors. The study findings were published online today in the New England Journal of Medicine.

Dr. Gregg Morin, Head of Proteomics, Michael Smith Genome Sciences Centre, BC Cancer Agency; DICER 1 Mutation Ovarian Cancer Study Co-Leader

Dr. David Huntsman, Genetic Pathologist & Director of the Ovarian Cancer Research Program of British Columbia at the BC Cancer Agency & Vancouver Coastal Health Research Institute; DICER 1 Mutation Ovarian Cancer Study Co-Leader

Scientists at the British Columbia (BC) Cancer Agency, Vancouver Coastal Health Research Institute, and the University of British Columbia (UBC) are excited over a discovery made while studying rare tumor types.

Dr. David Huntsman, genetic pathologist and director of the Ovarian Cancer Program of BC (OvCaRe) at the BC Cancer Agency and Vancouver Coastal Health Research Institute, and Dr. Gregg Morin, a lead scientist from the Michael Smith Genome Sciences Centre at the BC Cancer Agency, led a research team who discovered that mutations in rare, seemingly unrelated cancers were all linked to the same gene, known as “DICER1.” The study findings were published online today in the New England Journal of Medicine. [1]

Background: RNA Interference, MicroRNAs, and DICER.

Nucleic acids are molecules that carry genetic information and include DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). The DNA segments that carry genetic information are called “genes.” Together these molecules form the building blocks of life. DNA contains the genetic code or “blueprint” used in the development and functioning of all living organisms, while “messenger RNAs” or mRNAs help to translate that genetic code into proteins by acting as a messenger between the DNA instructions located in the cell nucleus and the protein synthesis which takes place in the cell cytoplasm (i.e., outside the cell nucleus, but inside the outer cell membrane). Accordingly, DNA is first “transcribed” or copied into mRNA, which, in turn, gets “translated” or synthesized into protein.

RNA interference” (RNAi) is a mechanism through which gene expression is inhibited at the translation stage, thereby disrupting the protein production within a cell. RNAi is considered one of the most important discoveries in the field of molecular biology. Andrew Fire, Ph.D., and Craig C. Mello, Ph.D. shared the 2006 Nobel Prize in Physiology or Medicine for work that led to the discovery of the RNAi mechanism. While the mechanism itself is termed “RNA interference,” there are two major types of RNA molecules that play a key role in effectuating that interference. The first type of RNA molecules consists of “microRNAs” or miRNAs, while the second type consists of “small interfering RNAs” or siRNAs.

Current thinking suggests that RNAi evolved as a cellular defense mechanism against invaders such as RNA viruses. When they replicate, RNA viruses temporarily exist in a double-stranded form. This double-stranded intermediate would trigger RNAi and inactivate the virus’ genes, thereby preventing viral infection. RNAi may also have evolved to combat the spread of genetic elements called “transposons” within a cell’s DNA. Transposons can wreak havoc by jumping from spot to spot on a genome, sometimes causing mutations that can lead to cancer or other diseases. Like RNA viruses, transposons can take on a double-stranded RNA form that would trigger RNAi to clamp down on the potentially harmful “jumping gene” activity. Also, as noted above, RNAi is important for regulating gene expression. For example, the turning down of specific genes is critical to proper embryonic development.

Of relevance to the Canadian study findings within the context of RNAi are miRNAs. MiRNAs can bind to mRNAs and either increase or decrease their activity, for example, by preventing a mRNA from producing a protein. [2] In this context, “gene silencing” can occur through mRNA degradation or prevention of mRNA translation.  MiRNAs play an integral role in numerous biological processes, including the immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation and human development. MiRNA expression or function is significantly altered in many disease states, including cancer.

Because of its involvement in miRNA processing, the DICER1 gene plays an important role in maintaining health. It carries out a “factory style” function which involves chopping up miRNAs to activate them. [Ref. 2] These miRNAs, in turn, control hundreds of other genes as noted above. Based upon a study led by investigators from the University of Texas M.D. Anderson Cancer Center, the expression levels of DICER have global effects on the biogenesis of miRNA, and reduced gene expression correlates with a poor outcome in ovarian cancer. [3] In the M.D. Anderson study, two somatic (i.e., lifetime-acquired) missense DICER mutations were discovered in two epithelial ovarian cancer tumors. The M.D. Anderson investigators concluded that the DICER mutations were not associated with the alterations in DICER expression found in mRNAs. It is important to note that the type of somatic missense DICER mutations discovered in the M.D. Anderson study were not the same as those discovered in the Canadian study as discussed below.

Recurrent DICER Mutations Are Predominant In A Rare Form of Non-Epithelial Ovarian Cancer.

At the outset of the Canadian study, the OvCaRe team sequenced ovarian, uterine, and testicular tumors, expecting to find that their genomes would be distinct with specific, differing abnormalities. Much to their amazement, the researchers discovered that the same fundamental mutation in the DICER1 gene represented a common process underlying the different cancers which they examined.

Specifically, the Canadian investigators sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors, which included two Sertoli–Leydig cell tumors, four juvenile (not adult) granulosa-cell tumors, and eight primitive germ-cell tumors of the yolk-sac type. The researchers identified closely clustered mutations in the region of DICER1 which encode the RNase IIIb domain in four samples. Based on these findings, the OvCaRe team sequenced the same region of DICER1 in additional ovarian tumors, and tested for the effect of the mutations on the enzymatic activity of DICER1.

Recurrent somatic (i.e., lifetime-acquired) DICER1 mutations in the RNase IIIb domain were identified in 30 of 102 nonepithelial ovarian tumors (29%), including 4 tumors which also possessed germline (i.e., inherited) DICER1 mutations. The highest frequency of somatic DICER1 mutations occurred in Sertoli–Leydig cell tumors (26 of 43, or 60%). Notably, the mutant DICER1 proteins identified in the samples possessed reduced RNase IIIb activity, but retained RNase IIIa activity.

The Canadian researchers also performed additional tumor testing and detected the DICER1 mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas.

The groundbreaking nature of this discovery is reflected in the fact that the DICER1 “hotspot” mutations are not present in the 1000 Genomes Project data or the public data repository of The Cancer Genome Atlas consortium. To date, no recurrent DICER1 mutations have been reported in the mutation database of the Catalogue of Somatic Mutations in Cancer (COSMIC), in which 4 of 938 reported cancers possess somatic mutations but none in the RNase IIIb domain hot spots or RNase IIIa equivalents. Moreover, the Canadian researchers note that the newly-discovered DICER1 mutations were not observed in any of the more than 1000 cancer sequencing libraries which were studied.

Based upon the foregoing , the researchers concluded that somatic missense mutations affecting the RNase IIIb domain of DICER1 occur in a range of nonepithelial ovarian tumors, and possibly other cancers. Furthermore, the DICER1 mutations appear to be common in Sertoli-Leydig ovarian tumors (which are a subtype of nonepithelial, sex cord-stromal ovarian tumors). The researchers believe that the recurrent DICER1 mutations identified implicate a novel defect in miRNA processing which does not entirely destroy DICER1 functionality, but alters it.

Accordingly, the Canadian researchers suggest that the newly-discovered DICER1 mutations may represent an oncogenic event within the specific context of nonepithelial ovarian tumors, rather than a permissive event in tumor onset (as may be expected for loss of function in a tumor suppressor gene). The researchers note that DICER1 expression in tumors possessing the hotspot DICER1 somatic mutations argues against a role for DICER1 as a classic tumor suppressor gene. They further explain that the localized and focal pattern of the identified DICER1 mutations is typical of dominantly acting oncogenes, like KRAS and BRAF.

In sum, the Canadian researchers believe that the recurrent and focal nature of the DICER1 mutations and their restriction to nonepithelial ovarian tumors suggest a common oncogenic mechanism associated with a specifically altered DICER1 function that is selected during tumor development in specific cell types.

The Canadian study was supported through funding by Canadian Institutes for Health Research, Terry Fox Foundation, BC Cancer Foundation, VGH & UBC Hospital Foundation, Michael Smith Foundation for Health Research, and Genome BC.

Expert Commentary

DICER is of great interest to cancer researchers” said Dr. Huntsman, who also holds the Dr. Chew Wei Memorial Professorship in the departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine at UBC. “There have been nearly 1,300 published studies about it in the last 10 years, but until now, it has not been known how the gene functions in relation to cancer.”

“This discovery shows researchers that these mutations change the function of DICER so that it participates directly in the initiation of cancer, but not in a typical ‘on-off’ fashion,” says Dr. Morin who is also assistant professor in the department of Medical Genetics at UBC. “DICER can be viewed as the conductor for an orchestra of functions critical for the development and behavior of normal cells. The mutations we discovered do not totally destroy the function of DICER rather they warp it—the orchestra is still there but the conductor is drunk.”

This finding is the third of a series of papers published recently in the New England Journal of Medicine (NEJM) in which the OvCaRe team used new genomic technologies to unlock the molecular basis of poorly understood types of ovarian cancer. The first finding, published in the NEJM in 2009, identified mutations in the FOXL2 (forkhead box L2) gene as the molecular basis of adult granulosa cell ovarian cancer tumors. The second finding, published in the NEJM in 2010, determined that approximately one-half of clear-cell ovarian cancers and one-third of endometrioid ovarian cancers possess ARID1A  (AT rich interactive domain 1A) gene mutations.

The DICER gene mutation breakthrough discovery is particularly pivotal because it could lead to solutions for treatment of more common cancers.

“Studying rare tumors not only is important for the patients and families who suffer from them but also provides unique opportunities to make discoveries critical to more common cancers – both in terms of personalized medicine, but also in applying what we learn from how we manage rare diseases to more common and prevalent cancers,” said Dr. Huntsman “The discovery of the DICER mutation in this varied group of rare tumors is the equivalent of finding not the needle in the haystack, but rather the same needle in many haystacks.”

Dr. Phillip A. Sharp, Professor, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Co-winner of the 1993 Nobel Prize in Physiology and Medicine

“This breakthrough will be of interest to both the clinical and the fundamental science communities,” says Dr. Phillip A. Sharp, Professor, Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, and co-winner of the 1993 Nobel Prize in Physiology or Medicine for the discovery that genes are not contiguous strings but contain introns, and that the splicing of mRNA to delete those introns can occur in different ways, thereby yielding different proteins from the same DNA sequence. “Huntsman, Morin and colleagues’ very exciting discovery of specific mutations in DICER, a factor essential for syntheses of small regulatory RNAs in ovarian and other human tumors, could lead to new approaches to treatment.”

The Canadian OvCaRe research team is now working to determine the frequency and role of DICER mutations in other types of cancers. The research team is also expanding its collaboration to discover whether mutant DICER and the pathways it controls can be modulated to treat the rare cancers in which the mutations were discovered and more common cancers.

The Michael Smith Genome Sciences Centre (Michael Smith GSC), located at the BC Cancer agency, played a key role in this discovery. By way of background, Dr. Michael Smith was a co-winner of the 1993 Nobel Prize in Chemistry for his development of oligonucleotide-based site-directed mutagenesis, a technique which allows the DNA sequence of any gene to be altered in a designated manner. His technique created a groundbreaking method for studying complex protein functions, the basis underlying a protein’s three-dimensional structure, and a protein’s interaction with other molecules inside the cell.

A decision was made more than 10 years ago, championed by Drs. Michael Smith, Victor Ling, and others to create and locate the Michael Smith GSC within the BC Cancer Agency and in close proximity to Vancouver General Hospital (VGH). The chosen location for this critical facility provided the multidisciplinary cancer research teams in Vancouver with access to state-of-the-art technologies.

“We are one of less than five places in the world doing this type of work successfully. This discovery is one of a series of recent landmark findings from Vancouver that are reshaping our understanding of many cancers,” says Dr. Huntsman. “Since my arrival in Vancouver 20 years ago I have never before sensed such a strong feeling of communal pride and excitement within our research community. Our next task is to bring the discoveries into the clinic.”

About the Ovarian Cancer Research Program of British Columbia (OvCaRe)

OvCaRe is a multidisciplinary research program involving clinicians and research scientists in gynecology, pathology, and medical oncology at VGH and BC Cancer Agency. OvCaRe is a unique collaboration between the BC Cancer Agency, Vancouver Coastal Health Research Institute, and UBC. The OvCaRe team is considered a leader in ovarian cancer research which is breaking new ground in better identifying, understanding, and treating this disease. The OvCaRe seminal paper in PLoS (Public Library of Science), which addresses ovarian cancer as a group of distinct diseases, has been embraced by the global research community who has adopted the BC approach to ovarian cancer research. To learn more, visit www.ovcare.ca.

About the Michael Smith Genome Sciences Centre

Canada’s Michael Smith Genome Sciences Centre is an internationally recognized state-of-the-art facility applying genomics and bioinformatics tools and technologies to cancer research. Led by Dr. Marco Marra, the Michael Smith GSC is one of ten leading genomic research centres in the world and the only one of its kind in the world integrated into a cancer facility. With a primary focus on cancer genomics research, its scientists have been involved in many world-class groundbreaking discoveries over the past decade. To learn more, visit www.bcgsc.ca.

About the Vancouver Coastal Health Research Institute

Vancouver Coastal Health Research Institute is the research body of Vancouver Coastal Health Authority, which includes BC’s largest academic and teaching health sciences centres: Vancouver General Hospital, UBC Hospital, and GF Strong Rehabilitation Centre. The institute is academically affiliated with the UBC Faculty of Medicine, and is one of Canada’s top-funded research centres, with $82.4 million in research funding for 2009/2010. To learn more, visit www.vchri.ca.

About the British Columbia Cancer Agency

The BC Cancer Agency, an agency of the Provincial Health Services Authority, is committed to reducing the incidence of cancer, reducing the mortality from cancer, and improving the quality of life of those living with cancer. It provides a comprehensive cancer control program for the people of British Columbia by working with community partners to deliver a range of oncology services, including prevention, early detection, diagnosis and treatment, research, education, supportive care, rehabilitation and palliative care. To learn more, visit www.bccancer.ca.

About the University of British Columbia

The University of British Columbia is one of North America’s largest public research and teaching institutions, and one of only two Canadian institutions consistently ranked among the world’s 40 best universities. Surrounded by the beauty of the Canadian West, it is a place that inspires bold, new ways of thinking that have helped make it a national leader in areas as diverse as community service learning, sustainability, and research commercialization. UBC offers more than 55,000 students a range of innovative programs and attracts $550 million per year in research funding from government, non-profit organizations, and industry through 7,000 grants. To learn more, visit www.ubc.ca.

References

1/Morin G, Hunstman, DG et al.  Recurrent Somatic DICER1 Mutations in Nonepithelial Ovarian CancersNEJM, published online December 21, 2011 (10.1056/NEJMoa1102903).

2/The Canadian investigators describe the operation of the RNAi pathway with respect to miRNA biogenesis as follows:

“MicroRNAs (miRNAs) are a functional class of noncoding RNA molecules that regulate translation and degradation of messenger RNA. MiRNA transcripts are processed from hairpin pre-miRNA precursors into short miRNA:  miRNA* duplexes consisting of the miRNA targeting strand and the imperfectly complementary miRNA* strand (star strand, or inert carrier strand) by Dicer, an endoribonuclease with two RNase III–like domains. The RNase IIIb domain cuts the miRNA strand, whereas the RNase IIIa domain cleaves the miRNA* strand. The resultant RNA duplex is loaded into the RNA-induced silencing complex (RISC) containing an Argonaute protein. The miRNA* strand is then removed, leaving the miRNA strand, which targets messenger RNAs (mRNAs) for degradation or interacts with the translation initiation complex to inhibit and destabilize translation of the targeted messenger RNAs.” [footnote citations omitted]

3/Merritt WM, et al. Dicer, Drosha, and outcomes in patients with ovarian cancer. N Engl J Med. 2008 Dec 18;359(25):2641-50. Erratum in: N Engl J Med. 2010 Nov 4;363(19):1877. PubMed PMID: 19092150; PubMed Central PMCID: PMC2710981.

Sources:

York University Researchers Identify Genetic Process That May Underlie Ovarian Cancer Chemoresistance

York University researchers have identified a genetic process that may allow ovarian cancer to resist chemotherapy.

York University researchers have zeroed in on a genetic process that may allow ovarian cancer to resist chemotherapy.

Researchers in the York University Faculty of Science & Engineering studied a tiny strand of our genetic makeup known as a microRNA (miRNA), involved in the regulation of gene expression. Cancer occurs when gene regulation goes haywire.

For many years, DNA and proteins have been viewed as the real movers and shakers in genomic studies, with RNA seen as little more than a messenger that shuttles information between the two. In fact, miRNA was considered relatively unimportant less than a decade ago; that is no longer the case. MiRNA seems to stifle the production of proteins exclusively — a function opposite that of its better-known relative, messenger RNA, or mRNA, which translates instructions from genes to create proteins.  MiRNA attaches to a piece of mRNA – which is the master template for building a protein, thereby acting as a signal to prevent translation of the mRNA into a protein. The “silencing” of proteins by miRNAs can be a good or a bad thing, depending on the circumstances.

Chun Peng, Ph.D., Professor of Biology, York University, and her team identified a genetic process involving a "microRNA" that may underlie a form of ovarian cancer chemoresistance.

“Ovarian cancer is a very deadly disease because it’s hard to detect,” says biology professor Chun Peng, who co-authored the study. “By the time it’s diagnosed, usually it is in its late stages. And by that point there’s really no way to treat the disease.” “Even when the disease is discovered in its early stages, chemotherapy doesn’t always work,” she says.

Peng was among a team of researchers that discovered a receptor, ALK7 (activin receptor-like kinase 7), that induces cell-death in epithelial ovarian cancer cells.[1] They have now discerned that miRNA 376c targets this crucial receptor, inhibiting its expression and allowing ovarian cancer cells to thrive.[2]

“Our evidence suggests that miRNA 376c is crucial to determining how a patient will respond to a chemotherapeutic agent,” says Peng. “It allows cancer cells to survive by targeting the very process that kills them off,” she says.

In examining tumors taken from patients who were non-responsive to chemotherapy, researchers found a higher expression of miRNA 376c and a much lower expression of ALK7.  Peng believes that this research is a step towards being able to make chemotherapy drugs more effective in the treatment of the disease.

“Further study is needed, but ultimately if we can introduce anti-microRNAs that would lower the level of those microRNAs that make cancer cells resistant to chemotherapeutic drugs, we will be able to make chemotherapy more effective against ovarian cancer,” Peng says.

She urges women to educate themselves about the risk factors and symptoms of the disease. For more information, visit http://www.ovariancanada.org.

Peng is a world expert in the area of ovarian cancer and the molecular basis of complications in pregnancy. Her research on chemoresistance has also contributed to knowledge and prediction of pre-eclampsia, a pregnancy disorder that is a leading cause of maternal and perinatal complications and death.

The article, MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance, was published in the Journal of Cell Science.[2]

The study’s lead author, Gang Ye, is a Research Associate in Peng’s lab. Several trainees in Peng’s lab, as well as scientists in Toronto’s Sunnybrook Research Institute and in China, also participated in the project.

The research was supported by an operating grant from the Canadian Institutes of Health Research (CIHR) and a mid-career award to Peng from the Ontario Women’s Health Council/CIHR. Ye was supported in part by a Fellowship from the Toronto Ovarian Cancer Research Network.

About York University

York University is the leading interdisciplinary research and teaching university in Canada. York offers a modern, academic experience at the undergraduate and graduate level in Toronto, Canada’s most international city. The third largest university in the country, York is host to a dynamic academic community of 50,000 students and 7,000 faculty and staff, as well as 200,000 alumni worldwide. York’s 10 Faculties and 28 research centres conduct ambitious, groundbreaking research that is interdisciplinary, cutting across traditional academic boundaries. This distinctive and collaborative approach is preparing students for the future and bringing fresh insights and solutions to real-world challenges. York University is an autonomous, not-for-profit corporation.

References:

1/Xu G, Zhou H, Wang Q, et. al. Activin receptor-like kinase 7 induces apoptosis through up-regulation of Bax and down-regulation of Xiap in normal and malignant ovarian epithelial cell lines. Mol Cancer Res. 2006 Apr;4(4):235-46. PubMed PMID: 16603637.

2/Ye G, Fu G, Cui S, et. al. MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance. J Cell Sci. 2011 Feb 1;124(Pt 3):359-68. Epub 2011 Jan 11. PubMed PMID: 21224400.

Source: York U researchers uncovering how ovarian cancer resists chemotherapy, Press Release, York University, March 2, 2011.


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

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.

What’s Feeding Cancer Cells? — Johns Hopkins Researchers Discover How Critical Cancer Gene Controls Nutrient Use.

“Cancer cells need a lot of nutrients to multiply and survive. While much is understood about how cancer cells use blood sugar to make energy, not much is known about how they get other nutrients. Now, researchers at the Johns Hopkins University School of Medicine have discovered how the Myc cancer-promoting gene uses microRNAs to control the use of glutamine, a major energy source. The results, which shed light on a new angle of cancer that might help scientists figure out a way to stop the disease, appear Feb. 15 online at Nature. …”

“February 15, 2009- Cancer cells need a lot of nutrients to multiply and survive. While much is understood about how cancer cells use blood sugar to make energy, not much is known about how they get other nutrients. Now, researchers at the Johns Hopkins University School of Medicine have discovered how the Myc cancer-promoting gene uses microRNAs to control the use of glutamine, a major energy source. The results, which shed light on a new angle of cancer that might help scientists figure out a way to stop the disease, appear Feb. 15 online at Nature.

Chi Dang, M.D., Ph.D. The Johns Hopkins Family Professor in Oncology Research; Professor of Medicine, Cell Biology, Oncology and Pathology; and Vice Dean for Research, School of Medicine

Chi Dang, M.D., Ph.D. The Johns Hopkins Family Professor in Oncology Research; Professor of Medicine, Cell Biology, Oncology and Pathology; and Vice Dean for Research, School of Medicine

‘While we were looking for how Myc promotes cancer growth, it was unexpected to find that Myc can increase use of glutamine by cancer cells,’ says Chi V. Dang, M.D., Ph.D., the Johns Hopkins Family Professor of Oncology at Johns Hopkins. ‘This surprising discovery only came about after scientists from several disciplines came together across Hopkins to collaborate — it was a real team effort.’

In their search to learn how Myc promotes cancer, the researchers teamed up with protein experts, and using human cancer cells with Myc turned on or off, they looked for proteins in the cell’s powerhouse — the mitochondria — that appeared to respond to Myc. They found eight proteins that were distinctly turned up in response to Myc.

At the top of the list of mitochondrial proteins that respond to Myc was glutaminase, or GLS, which, according to Dang, is the first enzyme that processes glutamine and feeds chemical reactions that make cellular energy. So the team then asked if removing GLS could stop or slow cancer cell growth. Compared to cancer cells with GLS, those lacking GLS grew much slower, which led the team to conclude that yes, GLS does affect cell growth stimulated by Myc.

The researchers then wanted to figure out how Myc enhances GLS protein expression. Because Myc can control and turn on genes, the team guessed that Myc might directly turn on the GLS gene, but they found that wasn’t the case. ‘So then we thought, maybe there’s an intermediary, maybe Myc controls something that in turn controls GLS,’ says Ping Gao, Ph.D., a research associate in hematology at Johns Hopkins.

They then built on previous work done with the McKusick-Nathans Institute of Genetic Medicine at Hopkins where they discovered that Myc turns down some microRNAs, small bits of RNA that can bind to and inhibit RNAs, which contain instructions for making proteins. The team looked more carefully at the GLS RNA and found that it could be bound and regulated by two microRNAs, called miR23a and miR23b, pointing to the microRNAs as the intermediary that links Myc to GLS expression.

‘Next we want to study GLS in mice to see if removing it can slow or stop cancer growth,’ says Gao. ‘If we know how cancer cells differ from normal cells in how they make energy and use nutrients, we can identify new pathways to target for designing drugs with fewer side effects.’

This study was funded by the National Institutes of Health, the National Cancer Institute, the Rita Allen Foundation, the Leukemia and Lymphoma Society and the Sol Goldman Center for Pancreatic Cancer Research.

Authors on the paper are Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang, Yun-Sil Lee, Karen Zeller, Angelo De Marzo, Jennifer Van Eyk, Joshua Mendell and Chi V. Dang, of Johns Hopkins; and Kayoko Kita and Takfumi Ochi of Teikyo University in Japan.

On the Web:
http://www.hopkinsmedicine.org/hematology/faculty_staff/dang.html
http://www.proteomics.jhu.edu/index.php
http://www.hopkinsmedicine.org/geneticmedicine/People/Faculty/mendell.html
http://www.nature.com/nature/index.html

– JHM –

Media Contacts: Audrey Huang; 410-614-5105; audrey@jhmi.edu
Maryalice Yakutchik; 443-287-2251; myakutc1@jhmi.edu

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Quoted SourceWhat’s Feeding Cancer Cells? – Johns Hopkins Researchers Discover How Critical Cancer Gene Controls Nutrient Use, Press Release, Johns Hopkins Medicine, February 15, 2009.

Primary Citationc-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism; Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang et. al., Letter, Nature advance online publication 15 February 2009.