The Pennsylvania State University College of Medicine Penn State Children's Hospital Archives - Page 2 of 3

2017

Young Investigator

Dr. Chandrika Gowda

Hershey, PA

Novel combination therapy using CK2 inhibitor in high risk pediatric Leukemia

Leukemia is the most common form of childhood cancer. Despite current advancements, more than 15% of the children with 8-cell acute lymphoblastic leukemia (B-ALL) suffer relapse and half of them succumb to disease. IKZF1 (lkaros) functions as a tumor suppressor in high risk B -ALL. lkaros is a zinc finger protein, a transcription factor that regulates several important biological signaling pathways like cell cycle progression and Pl3K pathway. Casein Kinase II (CK2) is a pro-oncogenic protein that is over expressed in8-ALL which impairs lkaros regulatory functions via phosphorylation. Our preliminary data show that, 1) CX-4945 treatment represses mTOR-a key component of Pl3K/AKT/mTOR pathway expression in primary cells of high-risk B-ALL, via restoration of IKZF1 function.

Our overall hypothesis is that in high risk B-ALL, combination treatment using a CK2 inhibitor, CX-4945, and mTOR inhibitor, rapamycin will achieve superior inhibition of the mTOR pathway and enhance cytotoxicity. Using two agents that target same signaling pathway via different mechanisms will ensure effective inhibition of a particular pathway resulting in strong therapeutic effect, and also allow to use lower doses of each drug and reduce their off target effects.

Specific Aims: We will test this hypothesis using the following specific aims:

Aim 1: Establish the therapeutic efficacy of combination therapy using CX-4945 and rapamycin; in a preclinical model of High risk B-ALL

Aim 2: Determine the molecular mechanisms through which CK2 inhibition enhances cytotoxicity and increases drug sensitivity. The function of IKZF1 in regulation of gene expression and chromatin remodeling will be analyzed following treatment with CX-4945alone and in combination with rapamycin. Outcomes: The proposed experiments will establish the therapeutic efficacy of CK2 inhibitorCX-4945 in combination with rapamycin and provide a mechanistic rationale for the use of novel combination therapy for high risk pediatric Leukemia.

In summary,

Outcomes of the proposed project will not only advance the knowledge of basic molecular mechanisms that regulate proliferation of leukemia cells but also impact the clinical outcome of a specific subgroup of children with high risk leukemia.
The proposed studies use precision medicine approaches (targeting specific pathways and/or functional defects) to develop novel drug combinations to target these dysregulated pathways by a) inhibiting CK2 and restoring lkaros tumor suppressor function and b) using a specific inhibitor of the signaling pathway.
This will enable us to use lower doses of each drug (CX4945 and rapamycin) to achieve desired anti-leukemia effect with lower off target effects from each drug.
We hypothesize that the treatment will selectively target leukemia cells with less toxicity for normal cells.