Maximizing cancer synthetic lethality using dual PI-3K/PARP inhibitors
Maximizing cancer synthetic lethality using dual PI-3K/PARP inhibitors
批准号:
9255563
负责人:
DONALD DURDEN
金额:
$29.97万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-22 至 2017-12-19
关键词:
1-Phosphatidylinositol 3-KinaseAcademiaAdultAntineoplastic AgentsBRCA1 geneBiological AssayCancer PatientCell DeathCellsChildhoodClinicClinicalCollaborationsComputer SimulationDNA DamageDNA Double Strand BreakDNA RepairDNA Repair PathwayDataDefectDevelopmentDockingDoseDouble Strand Break RepairDrug CombinationsEffectivenessGerm-Line MutationGoalsGrowthHumanIndividualIndustryKnowledgeLeadLegal patentLigandsMalignant Childhood NeoplasmMalignant NeoplasmsMalignant neoplasm of ovaryMaximum Tolerated DoseMedicalMissionModelingMolecular ModelsMorbidity - disease rateMusMutateMutationNeoplasm MetastasisNeuroblastomaNeuronsNormal CellOutcomePathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPhasePoly(ADP-ribose) PolymerasesProteinsPublic HealthRadiation ToleranceReportingResearchSomatic MutationStagingTestingTherapeuticToxic effectTumor Suppressor GenesWorkanalogangiogenesiscancer cellcancer stem cellcancer therapycancer typedesigndisabilityds-DNAexperiencehomologous recombinationimprovedinhibitor/antagonistinnovationkinase inhibitorloss of functionloss of function mutationmedulloblastomamolecular modelingmortalitymutantneoplastic cellnerve stem cellneuroblastoma cellnovelnovel therapeuticspatient populationpreventprogramsprototyperadioresistantradiosensitiveresearch clinical testingresponsescaffoldsingle moleculesmall moleculesmall molecule inhibitorsmall molecule therapeuticstargeted treatmenttechnology developmenttriple-negative invasive breast carcinomatumor
中文摘要
PARP抑制剂(PARPi)在缺乏BRCA1/2肿瘤抑制因子的肿瘤中特别有效
英文摘要
PARP inhibitors (PARPi) are particularly efficacious in tumors deficient in the BRCA1/2 tumor suppressor
genes but of limited activity in BRCA competent tumors. There is an unmet medical need to develop targeted
therapeutic agents which will augment PARPi activity for BRCA1/2 wild type cancers and to increase chemo-
radiosensitivity in these malignancies. BRCA1/2 proteins are essential components of the homologous
recombination (HR) double-strand DNA repair mechanism. PARPi's synthetic lethality derives from preventing
the HR DNA double-strand break (DSB) repair mechanism which the cancer cell cannot overcome resulting in
lethal DNA damage. PARPi are selectively toxic to cells with BRCA1/2 deficiencies or other DNA repair
pathway mutations as found in some triple negative breast cancers. A recent report demonstrated that PI-3
kinase (PI-3K) inhibition impairs BRCA1/2 expression and can sensitize BRCA-proficient cancers to PARP
inhibition. Hence, our central hypothesis to be tested in this proposal is that a combination dual PI-3K
inhibitors (PI-3Ki)/ PARP inhibitor will attack the cancer cell’s DNA repair mechanisms via at least two
orthogonal pathways and extend PARPi clinical activity beyond just those deficient in BRCA1/2 and/or other
DNA repair defects. An innovative component of our proposal is that we have developed in silico the first
small-molecule inhibitory chemotype which inhibits both PI-3K and PARP activity simultaneously (e.g.
SRX3128; preliminary results). We have demonstrated “proof of concept” that SRX3128: 1) augments cell
death following DNA damage 2) Inhibits both targets DNA repair and PI-3K simultaneously in the same tumor
cell and 3) displays less toxicity in normal cells compared with individual inhibitory chemotypes at equivalent
potency against targets. The significance of our proposal lies in our capacity to provide an optimizable
promising single anticancer agent which will potently inhibit DNA repair via multiple orthogonal mechanisms
and chemo-radiosensitive tumor cells to DNA damaging agents. This proposal will evaluate this approach by
achieving the following aims setting the stage for phase II efforts to optimize the expected dual inhibitor lead
compound(s) to a clinical candidate: Aim (Task) #1. Develop a dual PI-3 kinase/PARP inhibitor. Aim (Task)
#2. Develop a predictive computational PARP model for the in silico docking of designed compounds.
Approach: Improve in silico PARP-ligand fit parameters of our PARP model until a high PARP-docking/PARP-
assay-inhibition correlation is achieved. Aim (Task) #3. Determine therapeutic window for dual PI-3K/PARP
inhibition. Approach: Compare toxicity towards neuronal cancer stem cells versus normal neuronal stem cells
(NSCs) when exposed to single PARP inhibitor or PI-3K inhibitor versus dual PARP/PI-3K inhibition conditions.
The significance of this research is it will greatly expand the reach of PARP inhibition into BRCA-proficient
cancers. This innovative approach attacks cancer using two distinct proven mechanisms with a single
compound challenging the one-drug one-target dogma.
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