Memorial Sloan Kettering Cancer Center Archives - Page 2 of 2

2018

Scholar Grant

Alex Kentsis

New York, NY

Proteogenomics for immunotherapy of pediatric acute myeloid leukemia

urrent therapy of childhood acute myeloid leukemia (AML) remains inadequate. Strategies for rational therapy are elusive, and targets for immune therapy are largely undefined. We have now integrated ultra-sensitive proteomics methods and comprehensive genome analysis techniques to enable the discovery of neomorphic protein products, induced by epigenetic dysregulation characteristic of AML cells. The proposed project aims to elucidate neomorphic protein products, generated by dysregulated gene expression and mutations in AML, ideally suited for targeting by immune therapies. Successful completion of this proposal is expected to lead to implementation of proteogenomic profiling for improved immune therapy directed to the aberrant proteomes in acute myeloid leukemia. In particular, the investigation of neomorphic proteomes and MHC peptidomes of AML cells should yield fundamental insights into the principles of immune cancer cell presentation. In addition, the discovery of neomorphic antigens to target human AML should lead directly to their translation into clinical trials for patients, as therapeutic antibodies and chimeric antigen receptor (CAR) T cells.

2018

Young Investigator

Michael Ortiz

New York., NY

Targeting prohibitin-induced therapy resistance in Wilms tumors

“Wilms tumor is the most common kidney cancer of childhood. Improvements in therapy now enable cure for most patients with favorable histology Wilms tumors. In contrast, anaplastic and relapsed Wilms tumors are often resistant to current intensive chemotherapies. Thus, there is an urgent need to develop new therapies to improve the cure rates for these high risk patients. Using recently developed functional proteomics methods, we identified overexpression of prohibitin in diagnostic urine specimens to be associated with Wilms tumor relapse and therapy resistance, offering non-invasive means to risk stratify patients and monitor therapy response. Functional studies of genetically-engineered normal and Wilms tumor cells revealed that prohibitin overexpression is both necessary and sufficient to cause resistance to Wilms tumor therapies doxorubicin, vincristine and dactinomycin. At least in part, this was caused by an inability of the tumor cells to undergo cell death, specifically due to dysregulated mitochondrial apoptotic priming.

The objective of this project is to develop improved therapies for patients with relapsed and refractory Wilms tumors, based on the rationale that understanding the molecular mechanisms of prohibitin-mediated resistance to chemotherapy-induced cell death will yield improved targets for rational therapy. We hypothesize that prohibitin overexpression induces chemotherapy resistance by impairing release of mitochondrial cytochrome c and mediating resistance to mitochondrial apoptosis, and that rational targeting of these pathways will exhibit anti-tumor efficacy as a prelude to clinical trials in patients. We plan to test this hypothesis using two specific aims: (1) elucidate the molecular mechanisms of prohibitin-induced chemotherapy resistance, (2) investigate the anti-tumor efficacy of targeting prohibitin-mediated cytochrome c release to restore chemosensitivity in genetically-engineered and patient xenograft Wilms tumor models in vivo.

In summary, the goals of this project are to:
– Determine how elevated prohibitin impairs Wilms tumor cells from dying
– Develop effective strategies to block prohibitin in order to improve the cure rates of high risk Wilms tumors patient