Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 298.96K | Year: 2016
DESCRIPTION provided by applicant Hepatocellular carcinoma HCC is the most prevalent cancer in human population and will lead to over deaths in the United States this year alone However the molecular mechanisms driving hepatocellular carcinoma HCC growth and metastasis remain elusive and there is a huge unmet medical need to find new therapeutic targets We performed an unbiased genome wide RNA interference RNAi screen to identify factors that are necessary for the epigenetic silencing of a HCC tumor suppressor Hedgehog Interacting Protein HHIP The RNAi screen was based on the rationale that factors necessary for epigenetic silencing of HHIP in HCC cells could in principle promote HCC tumor growth The RNAi screen identified three new drivers of HCC B cell lymphoma BCL histone deacetylase HDAC and CDC like kinase CLK RNAi based knockdown of these genes significantly inhibited HCC cell growth in culture and in a mouse model of HCC tumorigenesis Remarkably we found that these three genes are overexpressed in patient derived samples of HCC Furthermore their overexpression correlates with liver fibrosis and microvascular invasion both of which are markers of poor prognosis For this Phase I project we have chosen to develop small molecule inhibitors of BCL because it is a novel therapeutic target currently not exploited for HCC Our hypothesis is that pharmacological inhibition of BCL will suppress the HCC malignant phenotype Aim experiments will use two existing but therapeutically limited small molecule inhibitors to demonstrate the utility of this new HCC epigenetic therapeutic strategy using appropriate in vitro and in vivo models The inhibitors will be tested for inhibition of HCC cell growth in soft agar assays a surrogate assay for mouse tumorigenesis Cell based assays will also determine whether BCL inhibitors modulate HCC cell HHIP expression and expression of other downstream effectors such as cyclin D p and PIM A BCL inhibitor with efficacy in a mouse model of lymphoma will be tested for efficacy in an orthotopic xenograft based mouse model of HCC tumorigenesis Concurrently in Aim we will utilize our medicinal chemistry capabilities to create a focused library of up to new candidate BCL small molecule inhibitors that retain the beneficial inhibitory pharmacophore features of two existing structurally distinct inhibitors but add or eliminate other chemical features to address their off target effects and pharmacokinetic structural liabilities Structural activity relationships for these new merged pharmacophore compounds will be assessed by inhibition of BCL SMRT binding and by their ability to block HCC cell growth in soft agar assays In Aim we will proceed to in vivo efficacy testing of the top five candidates in a BCL dependent mouse xenograft model of HCC A successful Phase I project will reveal new and effective HCC therapeutic strategies and provide novel BCL inhibitors for Phase II medicinal chemistry to optimize efficacy and drug like properties The long term project goal is to develop a novel epigenetic therapy to significantly improve treatment of HCC patients PUBLIC HEALTH RELEVANCE Hepatocellular carcinoma HCC is the most prevalent cancer in human population It is universally and rapidly fatal leading to over deaths every year in the United States alone We discovered that BCL is necessary for HCC cells to form tumors in vivo in mice The goal of this project is to identify novel BCL inhibitors to serve as leads fo development of new drugs to effectively treat HCC patients
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 271.24K | Year: 2015
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.70K | Year: 2014
ABSTRACT The long-term product goal of this project is a small molecule therapeutic for choroidal neovascularization (CNV, the hallmark of wet age-related macular degradation), an abnormal growth of blood vessels in the choroid layer of the eye that results in damage to the retina and consequent blindness. Our lead compound is the natural product sterculic acid, which has been shown to inhibit CNV in animal models. The main current treatment options for CNV involves intravitreal injection of anti-VEGF agents such as ranibizumab (Lucentis), aflibercept (Eylea) and (in off-label use) bevacizumab (Avastin) which, while often slowing disease progression, have a number of side-effects associated with the method of administration. A small molecule therapeutic which might be administered topically would present obvious advantages. Sterculic acid has very recently been shown to mitigate the induction of CNV in a rat model and to antagonize the inflammatory effects of 7- ketocholesterol (7KCh) in cultured human re
L2 Diagnostics, Llc | Date: 2014-09-18
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 290.34K | Year: 2012
DESCRIPTION (provided by applicant): Lyme disease, due to infection with the Ixodes tick-transmitted spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States, with over 38,000 confirmed and probable cases reported to the CDC in 2009. Spirochetes first establish infection in the skin and then disseminate to internal organs such as the heart, the joints, and the nervous system where disease can be seen. The infection is most responsive to antibiotics when identified early,but those with disseminated infection or in whom treatment is delayed can experience debilitating disease that can become unresponsive to antibiotics. The timely and accurate diagnosis of Lyme disease is essential for optimizing the response to therapy and for preventing long- term sequelae of the disease. Serologic tests (ELISA and immunoblot) that detect antibodies against B. burgdorferi are currently the most sensitive and widely available laboratory tests for Lyme disease. These tests utilize whole-cell lysates of cultured laboratory strains of B. burgdorferi as a source of antigens, and therefore do not detect antibodies to B. burgdorferi proteins expressed predominantly in vivo. The recommended two-tiered approach in which a positive or equivocal ELISA is confirmed by immunoblot has only ~30% sensitivity in early stages of infection, and specificity is reduced due to cross-reactivity of B. burgdorferi antigens with those of other infectious agents. This Phase I application seeks to improve upon the currently available serologic tests for Lyme disease through the use of in vivo expressed, B. burgdorferi- specific proteins as antigens. We have recently identified a novel panel of B. burgdorferi genes and proteins that are expressed in the first few weeksof B. burgdorferi infection and to which sera from patients with early Lyme disease react on IgG ELISA. We propose to evaluate these candidate antigens in multiplex format assay for their sensitivity and specificity using human sera samples from well-defined cases of Lyme disease, subjects who have had no known exposure to B. burgdorferi, and other infectious and rheumatic diseases. Peptide pin arrays will map the immunodominant epitopes of candidate antigens with Lyme disease sera in an ELISA format for incorporation into a refined multiplex assay. The results of this Phase I study will set the stage for the development of new sensitive and specific serologic tests for Lyme disease that more accurately reflect the B. burgdorferi antigens inciting immune responses in the infected host. PUBLIC HEALTH RELEVANCE: Lyme disease, due to infection with the spirochete Borrelia burgdorferi, can cause a multisystem illness involving the skin, heart, joints and nervous system. Current blood tests for Lyme disease are not as sensitive early in infection when the infection is most responsive to antibiotics. This application will determine whether a new assay for Lyme disease based on a novel panel of proteins expressed by spirochetes when they initially infect theskin accurately detects Lyme disease in its earliest stages.