New York, NY (January 23, 2012) – The Damon Runyon Cancer Research Foundation, announced that five scientists with novel approaches to fighting cancer have been named 2012 recipients of the Damon Runyon-Rachleff Innovation Award. The grant of $450,000 over three years is awarded each year to early career scientists whose projects have the potential to significantly impact the prevention, diagnosis and treatment of cancer.

2012 Damon Runyon-Rachleff Innovators:

Gregory L. Beatty, MD, PhD [Nadia’s Gift Foundation Innovator]
University of Pennsylvania, Philadelphia, Pennsylvania

Tumor-associated immune cells called macrophages are a key component of the tumor microenvironment and often portend a poor prognosis. Macrophages are critical regulators of tumor angiogenesis and metastasis. Interestingly, the function of macrophages is dependent on their surrounding microenvironment such that under certain conditions, macrophages can actually become tumor-suppressive. The central hypothesis of Dr. Beatty’s work is that macrophages are an important yet pliable factor in tumor behavior, which can be therapeutically targeted and instructed to attack tumors and inhibit tumor growth.

Dr. Beatty will evaluate strategies to engineer macrophages to attack tumors and to resist signals produced within tumors that ordinarily prime macrophages with tumor-promoting properties. He aims to combine these macrophage-directed approaches with standard chemotherapy. The priority is to develop the necessary data to facilitate the rapid translation of this strategic approach to the clinic for treatment of patients with pancreatic cancer and other malignancies.

Jay R. Hesselberth, PhD
University of Colorado Denver, Aurora, Colorado

Most early detection strategies for cancer focus on identifying protein biomarkers or “molecular signatures” of disease. However, discovery of new biomarkers has lagged, due in large part to the inability to efficiently sift through complex cellular protein mixtures. As a result, the number of new FDA-approved biomarker tests has declined over the last decade, and the current rate of biomarker validation is only one per year.

As proteins can be very large, they are typically cleaved into smaller units called peptides for identification and analysis. The current technology for peptide identification is very slow and lacks the sensitivity and specificity required to quantify proteins in complex samples. Dr. Hesselberth proposes that a massive acceleration in the rate of peptide sequencing would significantly impact biomarker research. To accomplish this, he seeks to develop a highly parallel peptide sequencing platform with single molecule resolution that is orders of magnitude faster than existing technology. This new approach would transform our capability to identify protein and peptide biomarkers for use in the early detection of cancer.

Matthew R. Pratt, PhD
University of Southern California, Los Angeles, California

Cellular proteins are often modified with a “flag” that affects their function. One such modification is the monosaccharide N-acetyl-glucosamine (O-GlcNAc), which is required for normal development and proper regulation of many biological pathways. During metabolism, elevated glucose levels result in elevated O-GlcNAc modification of proteins.

One common feature of all cancers is an altered metabolism that helps to protect cancer cells from the challenging environments they encounter during tumorigenesis and metastasis. Dr. Pratt has uncovered a link between this change in metabolism and O-GlcNAc modification of proteins, which directly contributes to the proliferation and survival of cancer cells. He seeks to understand the details of this link and exactly how it contributes to disease. This approach will lead to a more complete understanding of how metabolism promotes cancer and may uncover new opportunities for treatment.

Eranthie Weerapana, PhD
Boston College, Chestnut Hill, Massachusetts

Understanding proteins dysregulated in cancer is a vital step toward the discovery of effective targets for treatment. Many cellular enzymes demonstrate aberrant activity in cancer, and a significant subset of them contain cysteine amino acid residues required for their function.

Dr. Weerapana aims to use sophisticated chemical genetic approaches to develop novel small molecules that selectively target these cysteines, thus blocking protein function. Her goal is to create a “chemical library” of these small molecules and use this library to identify compounds that affect cancer cell proliferation, migration and invasion in breast and ovarian cancer cell lines. The cellular protein targets of these molecules will be identified, followed by analysis of their roles in cancer development and progression. This multidisciplinary approach, encompassing aspects of synthetic chemistry, cell biology and proteomics, will identify new therapeutic targets and small molecule drug candidates for the diagnosis and treatment of cancer.

Feng Zhang, PhD
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts

Recent genome sequencing studies have identified a large set of candidate genetic mutations implicated in a diverse range of cancer types. However, in order to determine the causal role of each mutation in disease risk and pathology, researchers must be able to test each mutation individually in cellular or animal models. This is severely limited by the difficulty of manipulating the genome of cells and organisms with precise control so that a specific disease can be definitively linked to single changes in the genome.

To address this challenge, Dr. Zhang proposes to engineer a comprehensive set of novel molecular tools to enable targeted modification of the mammalian genome. He will demonstrate the power of these tools by testing genetic mutations associated with neuroblastoma and glioma brain tumors. The development and application of these tools will establish a powerful new platform for investigating the underlying genetic and molecular mechanisms of cancer and will inform drug development. To ensure maximal benefit and impact for the cancer community and beyond, he will also facilitate teaching and rapid open-source distribution of all tools developed.

Funding Daring Research
The Damon Runyon-Rachleff Innovation Award funds cancer research by exceptionally creative thinkers with “high-risk/high-reward” ideas who lack sufficient preliminary data to obtain traditional funding. The awardees are selected through a highly competitive and rigorous process by a scientific committee comprised of leading cancer researchers who are innovators themselves. At the final stage of selection, candidates are screened by an in-person interview with committee members. Only those scientists with a strong vision and passion for curing cancer are selected to receive the prestigious award.

This program is possible through the generous support of Andy and Debbie Rachleff, the Island Outreach Foundation and Nadia’s Gift Foundation.

###

DAMON RUNYON CANCER RESEARCH FOUNDATION
To accelerate breakthroughs, the Damon Runyon Cancer Research Foundation provides today’s best young scientists with funding to pursue innovative research. The Foundation has gained worldwide prominence in cancer research by identifying outstanding researchers and physician-scientists. Eleven scientists supported by the Foundation have received the Nobel Prize, and others are heads of cancer centers and leaders of renowned research programs. Each of its award programs is extremely competitive, with less than 10% of applications funded. Since its founding in 1946, the Foundation has invested over $240 million and funded more than 3,300 young scientists. This year, it will commit approximately $10.8 million in new awards to brilliant young investigators.
100% of all donations to the Foundation are used to support scientific research. Its administrative and fundraising costs are paid from its Damon Runyon Broadway Tickets Service and endowment.

For more information visit http://www.damonrunyon.org/

CONTACT
Yung S. Lie, PhD
Chief Scientific Officer
Damon Runyon Cancer Research Foundation
yung.lie@damonrunyon.org
212.455.0521

The study appeared in the online scientific journal Nature Genetics.

“This research represents a huge step forward in identifying the specific genetic instructions that a cancer cell is interpreting,” said Benjamin P. Berman, assistant professor in the Department of Preventive Medicine, who led the study. “It brings the cancer research community closer to our goal of providing treatment that is more specific, more personalized and more effective.”

The paper also represents a landmark sequencing study for the center, which was established in 2007 to bring innovative molecular and computational analysis techniques to the study of epigenetics. Peter W. Laird, the center’s director, is the paper’s senior author.

The genome is the instruction manual for building all cells, and genome sequencing is the prominent focus of most current large-scale cancer-mapping projects. While all cells within an individual have identical or very similar genomes, different cells read those instructions in a highly selective manner.

The sub-specialty of epigenomics, which seeks to analyze the unique interactions between cells and their DNA, is essential to understanding the molecular biology of cancerous or diseased cells.

Clinical cancer research focuses on DNA methylation, a biochemical process crucial to the development of organisms because methylation information easily can be recovered from a broad range of tissue or blood samples, Berman said.

In the new study, using a unique sequencing technique, the center’s research team is one of the first groups to profile the complete methylome from a sample of a clinical colon tumor – in other words, the complete methylation profile of the tumor at the smallest unit of the tumor’s genetic information.

“We sequenced the complete methylome of a colon tumor and matched adjacent tissue samples from the same patient,” said Berman, one of the founding members of the Epigenome Center.

By comparing the tumor’s methylome to normal colon tissue from the same individual, the group identified several important new classes of alteration.

Most importantly, the researchers found that hypermethylation and hypomethylation – two common types of methylation changes – were linked to the physical three-dimensional organization of the cell nucleus, with the regions gaining alterations mostly being restricted to a specific compartment called the nuclear lamina.

This nuclear organization, which plays a key role in turning specific genes on and off, has important implications for the basic biology of cancer and the changes that take place during tumor growth. This basic mechanism provides important clues as to which aspects may be targeted therapeutically, according to Berman.

A second finding was that methylome profiling could be used to monitor the state of an important class of DNA sequences called gene enhancers.

Enhancers have a critical role in controlling the cell-type specific expression level of genes but have not been widely studied at the DNA methylation level.

The Epigenome Center currently is applying this new technique, called whole-genome bisulfite sequencing, to a number of tumor types as part of The Cancer Genome Atlas consortium.

Berman credited the USC Center for High-Performance Computing and Communications for helping to analyze the many terabytes of genomic data involved.

As sequencing time and costs decrease, the approach used in Berman’s study could have clinical applications in the future, especially for personalized treatment. New sequencing technologies have resulted in a more than 10,000-fold decrease in the cost to sequence a human genome – from about $70 million in 2005 to about $5,000 now, Berman noted.
“We’re looking for the cost to decrease even further, to $1,000, which would put this technology within reach of large numbers of cancer patients,” he said.

By Martin Booe on November 30, 2011 12:42 PM

http://uscnews.usc.edu/science_technology/usc_research_finds_clues_to_genetic_instructions.html

The peptides, molecules derived from a cancer-causing virus, target an enzyme in cancerous cells that regulates a widely researched tumor suppressor protein known as p53. The peptides inhibit the enzyme, causing p53 levels in cancer cells to rise, which leads to cell death.

Lymphoma tumors in mice injected with the two peptides showed marked regression with no significant weight loss or gross abnormalities.

The discovery is detailed in the journal Nature Structural & Molecular Biology.

Herpesvirus-associated ubiquitin specific protease (HAUSP) is an enzyme that cleaves the normally occurring protein ubiquitin from substrates like p53. In a healthy environment, ubiquitin binds to a substrate, causing it to degrade and die.

“Given the mounting evidence that HAUSP serves as a pivotal component regulating p53 protein levels, the inhibition of HAUSP should have the benefit to fully activate p53,” said Hye-Ra Lee, the study’s first author and a research fellow in the Department of Molecular Microbiology and Immunology at the Keck School of Medicine of USC.

Using co-crystal structural analysis, Lee and her colleagues found a tight, “belt-type” interaction between HAUSP and a viral protein that causes Kaposi’s sarcoma and lymphoma. The peptides derived from this viral protein bind 200 times more strongly to HAUSP than p53, making them ideal HAUSP inhibitors.

The researchers found that the peptides comprehensively prevented HAUSP from cleaving ubiquitin, allowing p53 levels to rise, thereby representing potential new chemotherapeutic molecules that can be used for anti-cancer therapies.

New research is under way with Nouri Neamati, associate professor of pharmacology and pharmaceutical sciences
at the USC School of Pharmacy, to find small molecules that mimic the peptides. The peptides and other small molecules are being tested on different cancers.

“Significant advances in scientific understanding often come at the intersection of independent lines of research from different disciplines – for instance, structure and virus study. Time after time, viruses are teaching us,” said Jae Jung, the study’s principal investigator and chairman of the Department of Molecular Microbiology and Immunology at the Keck School.

Authors of the study include researchers from the Korea Research Institute of Bioscience & Biotechnology, the Korea Advanced Institute of Science and Technology, the Korea Basic Science Institute, Korea University, the University of Science and Technology (Korea) and Ludwig-Maximilians-Universität München.

Funding came from the National Institute of Health and the National Research Foundation of Korea.

http://uscnews.usc.edu/science_technology/two_molecules_kill_lymphoma_cells_in_mice.html

By Alison Trinidad on November 8, 2011 8:37 AM

Most notably, during fiscal year (FY) 2011, the Keck School received $248.3 million in grant awards—a 14 percent increase from FY 2010 and a 43 percent increase over the previous four fiscal years (the largest four-year increase over the past 13 years). Other recent highlights include:

• Keck School plus its affiliates received $312.2 million in grant awards during FY 2011, representing a 13 percent increase from FY 2010.
• Keck School affiliate Children’s Hospital Los Angeles received $10 million more in grant awards in FY 2011 than in FY 2010.
• NIH awards comprised 73 percent of the total grants awarded in FY 2011 or $169.1 million. This is the highest percentage of NIH versus total grants in the past seven years.

“Most remarkable is the fact that the FY 2011 increase is over and above grants awarded by the American Recovery and Reinvestment Act [ARRA] economic stimulus program,” said Elizabeth Fini, vice dean for research, Keck School of Medicine. “Such success is entirely about the expertise and efforts of our faculty. Our chairs, chiefs and institute directors have recruited a good mix of junior and senior researchers, with senior researchers bringing in grants right away. Promising junior researchers, once established, can be expected to be productive for many years.”

Fini cites several reasons for the increase in grants, including team grants led by newly recruited research leaders, the $56.8 million Clinical & Translational Science Award, and the fact that every center grant under competing renewal has been renewed. But she notes that perhaps the most important factor is having recruited the right faculty members, driven by the availability of attractive research facilities. “We’re in the enviable position of having three new wet lab buildings and a new office research building opening soon on Soto Street,” Fini said.

Fini also cites recent success, thanks to support from Keck School Dean Carmen A. Puliafito, with individual NIH K-series career development awards that help provide research training to develop academic physicians and translate research findings to patient care and community health. In 2007, Keck School faculty received two NIH K-awards; this year Keck faculty received 17 individual K-awards, in addition to six more at USC affiliate Children’s Hospital Los Angeles.

Going forward, the school plans a “themes, teams and centers” approach to build critical mass in signature programs stemming from the school’s new strategic plan.

These programs bridge USC strengths and external funding opportunities such as in AIDS research, neuroimaging research and cardiovascular diseases. New research grant applications for NIH center, program project, training and other team grants are being encouraged and supported, with the goal of building research cores and other shared resources.

Source: http://uscnews.usc.edu/university/keck_school_grant_funding_increases_over_four_years.html