SIGNABLOK, INC. — Department of Health and Human Services SBIR Phase I: 102

Description

Project Summary Abstract Carcinoma of the pancreasor pancreatic cancerPCis the fourth leading cause of cancer related death in the United StatesAccording to the American Cancer Societynew cases are expected inDespite advances in therapytheyear survival rate is less thanCurrent treatments of PC include surgeryradiation therapychemotherapyand immunotherapy but they all only slightly prolong survival or relieve symptoms in patients with PCGemcitabineGEMfirst line therapy for advanced PCis only modestly effective with a median survival of aboutmonths in randomized clinical trialsThe combination of GEM with different anticancer agents does not show significant survival advantage as compared with GEM aloneThese limitations in efficacy of available treatments highlight the need for new treatmentsPancreatic inflammation is known to increase the risk of PCHigh macrophage infiltration into the tumor mass correlates with the promotion of tumor growth and metastasis developmentTriggering receptor expressed on myeloid cellsTREMan inflammation amplifierplays a role in PC progressionExpression of TREMon tumor associated macrophagesTAMsis upregulated in patients with PC and correlates to disease severityRecentlywe demonstrated that a first in class TREMinhibitory peptide GFin free form and bound to macrophage targeted lipopeptide complexes that mimic human high density lipoproteinsGFHDLinhibits tumor growth in animal models of PCWe also showed that blockade of TREMinhibits release of cytokines and M CSF in these animal modelsThe main hypothesis of this project is that a combination therapy that includes TREMinhibitors and anticancer agents and targets cancer related inflammation and tumor cells directly can synergistically improve survival of PC patientsWe also hypothesize that this effect will be especially pronounced in PC patients with high intratumoral macrophage infiltrationOur preliminary studies strongly support this hypothesisThe long term objective of the proposed project is to develop a novel combinatorial approach to efficiently target PCThe major goal of the Phase I study is to demonstrate that specific inactivation of TREMwith first in class inhibitory peptides in combination with GEM or nanoparticle albuminnabbound paclitaxelnab PTXanother promising agent that directly targets cancer cells and is widely approved for the treatment of metastatic breast cancerBCsynergistically suppresses PC tumor progression in animal model system and improves survivalPhase I specific aims are toevaluate effects and mechanisms of GFGEM and GFnab PTX combinations in vitroandtest GFGEM and GFnab PTX combinations in two xenograft mouse models of PCNon toxic peptide GFwhich employs novelligand independent mechanisms of TREMinhibitionis anticipated to have less severe side effectsIn order to increase peptide solubilitybioavailability and targeting to TAMswe will utilize SignaBlokandapos s proprietary HDL based nanosystem for macrophage targeted delivery of water insoluble and poorly water soluble drugsWe will use in vitro macrophage uptake assay to elucidate the molecular mechanisms of a putative receptor mediated process of targeted delivery of GFto macrophagesWe will optimize GFformulations based upon their stabilityGFcontentand macrophage uptake in vitroWe will use an in vitro cytotoxicity assay and immunoblot analysis to test proliferation of BxPCand AsPCcells as well as expression of phospho stathmin and alpha tubulin in the presence of GEMnab PTX or their combinations with GFformulationsWe will use BxPCand AsPCmouse xenograft models to test the ability of GFGEM and GFnab PTX combinations to synergistically inhibit tumor progression and promote survival as compared with GFGEMand nab PTX aloneFree GFand GFHDL will be testedComprehensive histology and immunohistochemistry studies will be performed to analyze angiogenesisintratumoral macrophage infiltrationand potential non specific toxicity for organ tissuesIt is anticipated that the proposed research will identify a novel anticancer combination approach that will set the stage for the development of new targeted combination therapies of PCthereby leading to a higher survival rate of the patientsIf successfulthe Phase I will be followed in the Phase II by toxicologyabsorptiondispositionmetabolismexcretionADMEpharmacology and chemistrymanufacturingcontrolCMCstudiesfiling an Investigational New DrugINDapplication with the US Food and Drug AdministrationFDAand subsequent evaluation in humansFinal product will be the stable TREMtargeted lipopeptide formulation that can be used in combination therapies of PC patients to prolong their survivalImportantlyour recent data demonstrate that blockade of TREMsuppresses in vivo progression of not only PC but also non small cell lung cancerNSCLCThussuccessful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable to a variety of inflammationassociated tumors such as NSCLCBCcolon cancerand others Project Narrative Pancreatic cancer is the fourth leading cause of cancer related death in the United Statesand theyear survival rate is less thanCurrent treatments are substantially ineffective and only slightly prolong survival or relieve symptoms in the cancer patientsThe proposed research is expected to result in the development of novel anticancer therapeutic combinations that could substantially improve treatment of this type of cancerthereby leading to a higher survival rate of the patients