We will determine whether targeted DXR therapy reduces or eliminates MRD and therapy-resistant LSCs in pediatric leukemia patients by inhibiting interaction between key resistance genes and/or reactivating anti-cancer immunosurveillance.
Specific Aim 1: Identify the pro- vs. anti-cancer cellular immune response to current clinical vs. targeted anthracycline treatment.
The therapeutic efficacy of anthracyclines such as DXR relies on a significant contribution from immune cells; however, it is unclear which cells are involved and how they are affected by high-dose vs. targeted DXR treatment. Here, our working hypothesis, again based on our preliminary data, is that targeted anthracycline treatment stimulates T-cell based immune responses against chemoresistant LSCs; however, high-dose anthracyclines are expected to be generally immunosuppressive.
Specific Aim 2: Determine how targeted anthracycline treatment, unlike the clinical dose, eliminates chemoresistant LSCs via the immune system.
Our working hypothesis, based on our preliminary data, is that targeted anthracycline treatment reduces immune checkpoint expression specifically in LSCs, which facilitates their being eliminated by the immune system. In contrast, immune checkpoint expression is either maintained or increased in LSCs exposed to high-dose DXR, which also activates or maintains therapeutic resistance.
Specific Aim 3: Define an anti-cancer treatment protocol optimizing anti-tumor immunity while avoiding broad cytotoxicity and the evolution of resistance.
Since preclinical cancer research typically involves testing human cancer cells grown in culture or in immunodeficient mice, therapy-induced anti-tumor immunity is largely unexamined but potentially critical for successful treatment. This aim will create and advance a novel therapeutic strategy to eliminate MRD and the risk of relapse.2021-10-31Braden's HopeJohn M. Perry2018-11-01Overcoming therapeutic resistance by repurposing a classic chemotherapeutic drug as a targeted therapy to reactivate anti-cancer immunitycmhprofilesont:personsuffixperson suffixprns:endDateend dateprns:fullNamefull nameprns:grantAwardedBygrant awarded byprns:isPrimaryPositionis primary positionprns:latitudelatitudeprns:longitudelongitudeprns:mainImagephotoprns:personIdPerson IDprns:personInPrimaryPositionperson in primary positionprns:positionInDepartmentposition in departmentprns:positionInDivisionposition in divisionprns:principalInvestigatorNameprincipal investigator nameprns:sortOrdersort orderprns:startDatestart datebibo:abstractabstractAgreementvivo:contributingRolecontributorDepartmentvivo:descriptiondescriptionDivisionGrantvivo:hrJobTitleHR job titlePositionvivo:positionInOrganizationposition in organizationvivo:preferredTitlepreferred titleResearcher Rolevivo:researcherRoleOfresearcher role ofRolevivo:roleContributesTocontributes tordf:typetyperdfs:labellabelAgentfoaf:firstNamefirst namefoaf:lastNamelast nameOrganizationPersonPhDJohnPerryJohn M. Perry0.000000000000000.00000000000000123Perry, JohnResearch Faculty PhDPediatricsResearchPrinciple InvestigatorThe idea behind this study is that the cells responsible for relapse in pediatric patients can be eliminated by repurposing a chemotherapy drug, doxorubicin (DXR), as a targeted therapy to restore anti-cancer immunity against minimal residual disease (MRD) and therapy-resistant LSCs while avoiding broad toxicity and the evolution of resistance. Completion of this project is expected to provide durable cures for pediatric patients at risk for relapse and to do so in a manner that does not result in early death related to the therapy itself.Children's Mercy Kansas Citytrue1Research Faculty PhDResearch Faculty PhD