Five scientists named recipients of Damon Runyon-Rachleff Innovation Award for cancer research

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.

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.

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.

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.

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.

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.

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.

Source: Damon Runyon Cancer Research Foundation