A novel small molecule FL7N-1 for treating pediatric cancer retinoblastoma

Project Summary Abstract This is an SBIR Phase I proposal to test the feasibility of using a novel small molecule drug for the treatment of a pediatric rare cancerretinoblastomaRbRb is currently treated using drug combinations in concert with non drug treatmentsRb occurs in most cases before ageCurrent cytotoxic drug treatments produce high toxicities to childhood patientsMoreoverRb tends to metastasizebreak off and seedingcreating an additional challenge for management of this diseaseConclusivelya drug with low toxicity and high efficacy against primary and secondary cancers would help to avoid the disadvantages of current chemotherapies and potentially decrease mortality induced by the diseaseIn this projectwe will use human Rb tumor models developed from both primary and metastatic disease sites to test a novel small molecule drug for Rb treatmentPrevious studies reveal that Rb has an intact ppathwaybut this pathway is constitutively inhibited through increased levels of the oncogenic proteins MdmMdmX and survivinFurthermoregenomic and epigenetic analyses of Rb found that the proto oncoprotein SYK is usually not expressed in normal human retinabut is activated in Rband in turn decrease apoptosis via induction of MclexpressionWe have developed a small molecule FLthat effectively inhibits the expression of Mclsurvivin and MdmXas well as XIAPand cIAPin colon cancer cellsFurthermoreFLrapidly induces pprotein accumulation via inducing the degradation of MdmX in colon cancer cellsThese features of FLsuggest a potential for the treatment of RbHoweverin consideration of the fact that Rb is a pediatric cancerwe wondered whether we could find a more Rb targeted FLanalogue with even lower toxicity and higher efficacyTo this endwe synthesized a focused library ofFLanalogues and tested all of them in vivo for their efficacy and initial toxicity with the Rb cell line HTestablished xenograft tumors in miceWe identified three FLanaloguesFL NFL Nand FL Nthat showed high efficacy to inhibit HTxenograft tumor growth without obvious toxicity to animalsFL Neffectively inhibits survivinMdmX and Mcland induces pin Rb cellsTo achieve our Specific Aim of testing the feasibility of FL Nfor Rb treatmentwe will carry out the following three TasksTaskDetermine FL Ntoxicity and maximum tolerated doseMTDusing animal modelsTaskDetermine FL Ndose response and therapeutic indexTIusing Rb bearing animalsTaskDetermine FL NpharmacokineticsPKprofiles in Rb bearing miceTest of FeasibilityWe must observe that the FL NMTD in immuno competent animals is equal to or higher than in immuno compromised miceThe FL Nmost effective doseMEDmust be lower than its MTDUsing our conservative TI definitionMTD divided by MEDthe TI for FL Nmust be andgtIn SBIR Phase IIwe will carry out additional preclinical studies to define the best therapeutic schedule with dose rangeroute of administrationand other IND enabling studies for filing an FL NIND for clinical trials Narrative Retinoblastoma is the most common eye cancer in childrenWhile treatable with chemotherapy and other meansthe current chemotherapies cause long lasting or permenant damage to the nervous systemimmunesystem and other unwanted side effectsThis is a project to develop a safe chemotherapeutic approach that will not have long term negative unwanted effects