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Herr D.R.,Expression Drug Designs, Llc | Herr D.R.,San Diego State University
International Review of Cell and Molecular Biology | Year: 2012

The therapeutic use of monoclonal antibodies (mAbs) is the fastest growing area of pharmaceutical development and has enjoyed significant clinical success since approval of the first mAb drug in1984. However, despite significant effort, there are still no approved therapeutic mAbs directed against the largest and most attractive family of drug targets: G protein-coupled receptors (GPCRs). GPCRs regulate essentially all cellular processes, including those that are fundamental to cancer pathology, such as proliferation, survival/drug resistance, migration, differentiation, tissue invasion, and angiogenesis. Many different GPCR isoforms are enhanced or dysregulated in multiple tumor types, and several GPCRs have known oncogenic activity. With approximately 350 distinct GPCRs in the genome, these receptors provide a rich landscape for the design of effective, targeted therapies for cancer, a uniquely heterogeneous disease family. While the generation of selective, efficacious mAbs has been problematic for these structurally complex integral membrane proteins, progress in the development of immunotherapeutics has been made by several independent groups. This chapter provides an overview of the roles of GPCRs in cancer and describes the current state of the art of GPCR-targeted mAb drugs. © 2012 Elsevier Inc. Source

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 98.32K | Year: 2009

DESCRIPTION (provided by applicant): During normal aging and in the progression of many neurodegenerative disorders the accumulation of cellular damage can perturb the normal function of the nervous system and change behaviors and memory. A growing body of evidence shows that the highly conserved macroautophagy pathway (autophagy) is involved in maintaining the mature nervous system by facilitating the bulk removal of cellular damage and protein aggregates. Recently we have examined the aging profiles of autophagy genes and found the pathway is significantly suppressed in the older Drosophila CNS. At the same time, cellular damage markers including insoluble ubiquitinated proteins (IUP) show a dramatic increase in older fly brains. Genetic analysis identifies mutations in key genes that also significantly shorten adult lifespans (35 to 60%) and cause progressive neural defects that share striking similarities to those seen in Alzheimer's patents. Both phenotypes are signs of accelerated aging and an inability of neurons to clear cellular damage effectively. Of greater significance is our recent observation that upregulating or enhancing the level of rate-limiting components of the pathway in the adult nervous system suppresses the normal age- dependent accumulation of cellular damage (IUP) and significantly extends adult longevity nearly 60%. Taken together both the acceleration and suppression of age-dependent phenotypes shows that modeling changes to the mature nervous system can be done effectively in Drosophila, in order to gain a greater understanding of cellular factors involved with aging and progressive neural decline. In this proposal we take advantage of the conserved function of autophagy and its regulation, and coupled this information together with Drosophila genetic and transgenic techniques to identify neural protective compounds that enhance autophagy and promote adult longevity and neural function. Studies in Aim 1 will use the GAL4/UAS system to express neural toxic peptides in photoreceptor cells or throughout the adult CNS. Compounds will be screened for their ability to reduce cytotoxic phenotypes associated with their expression in neural tissues and cells. For Aim 2 compounds and concentration ranges identified in Aim 1 will be used to examine the ability of drugs to enhance autophagy and clear cellular damage that naturally occurs in aging adult Drosophila nervous system. For Aim 3 once a select set of compounds are identified they will be used in long-term aging studies to test their ability to extend adult lifespans. In addition, unique drug combinations and treatment regimes can also be quickly design and rapidly tested due to the powerful genetics and compressed lifespans of Drosophila. The overall goal of this proposal is to better understand the critical role that clearance pathways play in aging and to develop a rapid in vivo method to design and test drugs that can be used for the treatment of human neurological disorders. PUBLIC HEALTH RELEVANCE: Alzheimer's disease and other age-related neurological disorders affect millions of people worldwide. At this time treatment options are limited and characterization of new therapeutic compounds requires the development of novel methods to systematically test drug efficacy. The research outlined in this proposal will develop rapid in vivo screening techniques in Drosophila that detect changes in neural degenerative phenotypes associated with aging and loss of neuronal damage-control pathways like autophagy.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 167.05K | Year: 2011

DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCRs) represent a diverse family of cell surface receptors that mediate important biological responses in nearly all cells. These responses include proliferation, migration, tissue invasion, and cell survival. As such, this large, ~700 member family represents the most attractive single family of drug targets for a variety of diseases including cancer. A great deal of work has been performed in an effort to generate specific pharmacologic antagonists for individual family members, but the success of this approach has been limited by their structural similarity. This has made it difficult to produce suitably selective compounds that are not complicated by off-target effects. One approach thatoffers the potential for unparalleled specificity is the development of monoclonal antibodies. However, GPCRs have historically been considered intractable to antibody antagonism due to poor antigenicity of critical, exposed, extracellular motifs that must be targeted to block receptor activation. Breast cancer is a physically and emotionally devastating diagnosis affecting over 2.3 million Americans living with the disease and killing over 100 women each day. Although the prognosis for this disease is gradually improving with the continued development of antineoplastic drugs, hormonal therapies, and targeted therapies, many aggressive forms of breast cancer are resistant to chemotherapy and result in a 10% mortality rate within 5 years of diagnosis. A compound known as sphingosine 1-phosphate (S1P) may be a major determinant of the aggressiveness and drug resistance of breast cancer. S1P is a small molecule normally present in high concentrations in the blood that accelerates the progression of breast cancer. It does this by promoting the growth and spreading of cancer cells and by stimulating the formation of new blood vessels, thereby increasing the supply of oxygen and nutrients to the tumor. Evidence suggests that these actions are largely the result of the stimulation of a cognate GPCR for S1P called S1P3. Since S1P has been shown to promote growth of breast cancer cells, and since it causes blood vessels to grow uncontrollably in tumors, it is likely that blocking S1P3 will inhibit the growth of mostforms of breast cancer. Animal studies suggest that loss of this receptor is not associated with undesirable effects, providing evidence for the safety of this approach. Until recently, however, there were no reports of any specific antagonists for S1P3. Our previous work (1R43CA132400) resulted in the development of a monoclonal antibody that specifically recognizes S1P3 and blocks its activation. Since this is the first-reported antibody to block a non-cytokine GPCR, it represents a breakthrough in antibody drug development. The goals of this project are to 1) quantitatively validate the functional efficacy of this antibody, and 2) demonstrate its activity and bioavailability in vivo. PUBLIC HEALTH RELEVANCE: Breast cancer is the second most common form of cancer in women causing the death of over 35,000 Americans each year. The proposed research will characterize a new drug developed at Expression Drug Designs that interrupts cellular processes known to promote growth of breast tumors, thus limiting cancer growth. Completion of the proposed project will determine if this new drug is likely to be effective in treating breast tumors.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.26M | Year: 2011

DESCRIPTION (provided by applicant): Defining the molecular mechanism that leads to cellular aging and neural degeneration has proven to be difficult. Many types of damage are thought to contribute to senescence and neural degeneration and include mitochondrial and nuclear DNA mutations, protein misfolding, aggregate formation, reactive oxygen species (ROS), and stem cell senescence. However, a consensus has not yet developed as to which mechanism plays a causal role in aging. Indeed, each tissue may have aselect set of processes, or Achilles' heel that further exacerbated cellular decline. In the nervous system there is an agreement that mitochondrial senescence, the accumulation of ROS-dependent damage and the formation of protein aggregates or inclusion containing ubiquitin are involved with the most human neurological disorders, such as Alzheimer's and Parkinson's disease. There is a growing understanding that the autophagy pathway is involved with maintaining the mature nervous system by facilitatingthe removal of cellular damage and protein aggregates. The pathway is highly conserved and we found that expression profiles of autophagy genes show a significant decrease in the aging Drosophila CNS. At the same time, markers of cellular damage and aggregates, such as insoluble ubiquitinated aggregates (IUP), show a dramatic increase. Genetic analysis also shows that mutations in key genes significantly shorten adult lifespans (35 to 60%) and cause progressive neural defects that share striking similarities to those seen with Alzheimer's and other neurodegenerative disorders. Of greater significance is our observation that enhancing autophagy in the aging nervous system suppresses the accumulation of cellular damage (IUP) and significantly extends adult life spans. This work shows that examining factors that promote healthy neuronal aging can be done using Drosophila as a model system. In this proposal we take advantage of the conserved regulation of autophagy to identify neural protective compounds that enhance the pathway, promote longevity and neural function. This project involves several validated and optimized assays proposed in our original Phase-I application that were designed to identify compounds that enhanced autophagy, suppressed aggregate formation and extend life spans. In Specific Aim 1 an additional assay, which assesses the ability of different treatments to suppress oxidative stress was included. Specific Aim 2 represents an expansion of our drug-testing platform to assess the effectivenessof different compounds to promote neuronal health and function by examining their effect on several adult behaviors that show an age-dependent decline. Specific Aim 3 takes advantage of the conserved regulation of autophgy and other key protective pathwaysto identify those neural protective compounds that alter gene expression profiles in the aging nervous system. The goal of this proposal is to better understand the role of clearance pathways on aging and to develop in vivo assays that identify drugs thatcould be used for the treatment of human neurological disorders. PUBLIC HEALTH RELEVANCE: Presently there is no effective treatment for Alzheimer's disease and other age-related disorders that affect millions worldwide. Developing an effective method for validating neural protective compounds would streamline the development of life saving therapies. The research outlined in this proposal used Drosophila to develop several medium-throughput in vivo screening techniques that can identify novel therapeutic compounds for the treatment of aging disorders.

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