Targeting PLK1 in RAS mutant chronic myelomonocytic leukemia
Targeting PLK1 in RAS mutant chronic myelomonocytic leukemia
批准号:
10656778
负责人:
Mrinal Shiv Patnaik
金额:
$42.71万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-01 至 2028-04-30
关键词:
Acute Myelocytic LeukemiaApoptosisBiological AssayBiologyBody Weight ChangesBone MarrowCBL geneCell DeathCell ProliferationCellsChIP-seqChronic Myelomonocytic LeukemiaClassificationClinicalClinical TrialsCodeCombined Modality TherapyDataDevelopmentDiseaseDoseDown-RegulationDrug KineticsEpigenetic ProcessEventFoundationsFrequenciesFutureGene ExpressionGene Expression ProfileGenesGeneticGenotypeHematologic NeoplasmsHematopoietic NeoplasmsHistologicHourHypersensitivityIn VitroIndividualKRAS2 geneKnockout MiceLaboratoriesMEKsMLL geneMaximum Tolerated DoseMitosisMitotic CheckpointMitotic spindleMononuclearMutationMyeloproliferative diseaseNF1 geneOncogenicOralOutcomePLK1 genePTPN11 genePathway interactionsPatientsPeripheral Blood Mononuclear CellPhase I Clinical TrialsPhosphorylationPhosphotransferasesProteinsRAF1 geneRNA InterferenceRNA interference screenRecommendationRefractoryRegulationRelapseResearchResistanceRiskRoleSafetySamplingSeminalSignal TransductionSpleenTPT1 geneTimeToxic effectVariantWhite Blood Cell Count procedureWorkXenograft procedurebiobankbiomarker drivenclinical efficacycohortcombinatorialdesigneffective therapygenetic variantgenome-widein vivoin vivo Modelinhibitorinnovationleukemic transformationmutantnovelnovel therapeutic interventionoverexpressionpatient derived xenograft modelpersonalized therapeuticpharmacologicphase I trialphase II trialpredicting responseprogenitorresponsesafety testingsurvival outcomesynergismtargeted treatmenttherapeutic targettranscriptome sequencingtranscriptomicstreatment strategytumor growth
中文摘要
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英文摘要
PROJECT SUMMARY
Chronic myelomonocytic leukemia (CMML) is an aggressive hematological malignancy with dismal outcomes.
There is an unmet need for CMML focused rationally derived therapies. CMML can be divided into
“proliferative” (pCMML) and “dysplastic” subtypes, with pCMML having a high frequency of RAS pathway
mutations and being associated with a median survival of <18 months. We have shown that in pCMML,
mutant NRAS is a bona fide oncogenic driver and that RAS pathway mutations are associated with a unique
gene expression profile enriched in mitotic check point kinases such as PLK1. PLK1 was among the top
protein coding genes upregulated in RAS mutant CMML and given that prior RNAi studies had shown
increased sensitivity of RAS mutant cells to PLK1 inhibition and the fact that PLK1 physically interacts with
RAF1 at the mitotic spindles, as well as the ongoing use of clinical grade PLK1 inhibitors in AML trials, we
selected PLK1 as a therapeutic target in RAS mutant pCMML. We showed differential sensitivity of RAS
mutant pCMML cells to PLK1 inhibition using in vitro (progenitor colony assays) and in vivo models (patient-
derived xenografts) and demonstrated potential synergy with hypomethylating agents (HMA). We now propose
a seminal Phase 1 clinical trial testing the safety and preliminary efficacy of Onvansertib, a novel, oral, PLK1
inhibitor in patients with relapsed/refractory pCMML, using an innovative BOIN (Bayesian Optimal Interval)
design. Samples from trial patients will be used to assess pharmacokinetics, targeting efficacy and response
correlations with PLK1 and KMT2A (regulator of RAS PLK1 axis) expression levels. We will also use our large
CMML biorepository (n=177 RAS mutant samples) to develop in vitro and in vivo models to assess mutational,
transcriptomic and epigenetic predictors of response and resistance; specifically the impact of individual RAS
pathway mutations and cooccurring TET2 and ASXL1 mutations, the two most common response defining
mutations in CMML, on Onvansertib responses. Based on our preliminary data, it is our central hypothesis that
PLK1 inhibition is an effective treatment strategy in RAS mutant pCMML, with responses being influenced by
defined mutational profiles and epigenetic features. We will address this hypothesis by first performing a Phase
1 clinical trial testing the safety and targeting efficacy of Onvansertib, an oral selective PLK1 inhibitor, in
pCMML (AIM 1). Second, we will determine the in vitro impact of individual RAS pathway mutations and
associated CMML transcriptomic and epigenetic profiles on Onvansertib responses (AIM 2). Finally, we will
assess the impact of ASXL1/TET2 mutations on response to Onvansertib and Onvansertib plus HMA in RAS-
pathway mutant CMML xenografts (AIM 3). If successful, this research will provide the first targeted therapy for
RAS mutant myeloid neoplasms, setting the stage for personalized therapeutics in hematological
malignancies.
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