Children's Healthcare of Atlanta, Inc. Archives

2019

Scholar Grant

Robert Castellino

Atlanta, GA

Title: The role of PPM1D in the pathogenesis and treatment responsiveness of Group 3 medulloblastoma

Executive Summary:
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Treatment requires surgery, radiation, and multi-agent chemotherapy. Currently, the appearance of MB cells is used to guide treatment. But, this does not predict outcome.
Recent studies suggest that MB molecular classification into Wingless (WNT), Sonic Hedgehog (SHH), and Group (Grp) 3 and 4 sub-groups results in improved prognostication. While MB overall survival (OS) exceeds 70%, Grp 3 MBs are associated with OS <50%. Thus, there is an urgent need for accurate models and novel treatments.
Grp 3 MB defining features include MYC amplification and i17q (loss of chromosome 17p with gain of 17q). Grp 3 models overexpress MYC with loss of expression or function of the tumor suppressor p53 (i.e. p53 mutation). But, at diagnosis, p53 is not mutated in Grp 3 MBs.
PPM1D in Medulloblastoma
We previously correlated amplification of the phosphatase PPM1D, on chromosome 17q, with i17q in MB and showed high-level PPM1D expression in Grp 3 MBs and poor OS in MBs with high PPM1D expression. Also, PPM1D overexpression in MYC amplified MB cells promotes growth and invasion, which is inhibited by suppressing PPM1D expression or with drugs that block PPM1D function. We now find that co-expression of Myc and PPM1D accelerates growth of granule neuron precursor (GNP) cells, a known MB cell of origin. We hypothesize that PPM1D and MYC overexpression will generate a faithful model of Grp 3 MB, which can be used to develop targeted drugs for Grp 3 MBs.
Project Goals
• Since we have shown that i17q correlates with PPM1D high expression, which is associated poor MB survival, we will overexpress PPM1D and MYC in MB cells of origin to generate novel Grp 3 models.
• We will define the efficacy of combined targeting of MYC and PPM1D in Group 3 MB using targeted drugs in gene-manipulated MB cell lines and mouse models.
Specific Aims
1) We will determine the role of PPM1D in Grp 3 MB using gene expression in GNPs and genetically-engineered mouse models of Grp 3 MB.
2) We will define the efficacy of combined targeting of MYC and PPM1D in Group 3 MB models using inhibitors of MYC and PPM1D in gene-manipulated MB cell lines and mouse models.
Outcomes
We anticipate that PPM1D will cooperate with MYC amplification to transform cGNPs and neural stem cells to generate MBs that resemble Grp 3 MBs. We further anticipate that PPM1D inhibition will exhibit synergy with MYC inhibition against Grp 3 MB models, and will increase survival of Grp 3 mouse models.
Benefits to Pediatric Cancer
Currently we can cure <50% of Grp 3 MBs. PPM1D is highly expressed in Grp 3 MB and high expression is associated with poor OS. We have shown that PPM1D high expression is targetable. Preclinical validation of synergy between MYC and PPM1D inhibition will stimulate development of clinically viable drugs and support Phase I/II clinical trials using PPM1D and MYC inhibitors to treat the deadliest MBs.

2018

Scholar Grant

Kelly Goldsmith

Atlanta, GA

Characterizing and targeting the Yes-associated protein (YAP) in neuroblastoma

“High-risk neuroblastoma is an aggressive solid tumor of childhood. More than half of patients will relapse, and following relapse there is no known cure. A protein called the Yes-associated protein (YAP) is commonly activated in relapsed neuroblastomas and likely plays a part in regulating relapse and resistance to drugs used to treat neuroblastoma. YAP controls genes that promote tumor survival, growth, and therapy resistance, yet how it promotes these functions in neuroblastoma is unknown. YAP activity was also found in a mouse model of neuroblastoma that metastasized to the brain. Given the increased incidence of brain metastases seen in patients with relapsed neuroblastoma and limited therapy for such patients, we propose the following objectives to help identify treatments to improve cure rates for pediatric patients with YAP-driven neuroblastoma:

1) Define how YAP is activated and functions to promote relapse and therapy resistance in neuroblastoma.

2) Determine whether inhibition of YAP therapeutically restores responses to targeted drugs used to treat relapsed neuroblastoma. We will also develop a peptide (very early drug compound) that targets YAP to assess if it is a potent YAP inhibitor that warrants further study.

3) Determine if YAP inhibition combined with drugs targeting genetic mutations found in relapsed neuroblastoma can shrink tumors in a mouse model of CNS metastasis of neuroblastoma.

Results from this study will provide unparalleled data to support YAP inhibition in combination with relapsed neuroblastoma specific therapy. Results will also, for the first time, provide novel therapy options for brain relapse of neuroblastoma. Our studies have the potential to make an impact not just in neuroblastoma, but for other patient’s whose tumors depend on YAP for survival.”

2018

Young Investigator

Waitman Aumann

Novel Interacting Proteins and Effector Genes in CALM-AF10 Leukemia Leukemia is the most common cancer seen in childhood. Despite significant progress in the treatment of some pediatric leukemias, the prognosis for a subset of leukemias remains poor. Childhood leukemias that contain the CALM-AF10 fusion protein are especially hard to treat. The presence of CALM-AF10 leads…

Novel Interacting Proteins and Effector Genes in CALM-AF10 Leukemia

Leukemia is the most common cancer seen in childhood. Despite significant progress in the treatment of some pediatric leukemias, the prognosis for a subset of leukemias remains poor. Childhood leukemias that contain the CALM-AF10 fusion protein are especially hard to treat. The presence of CALM-AF10 leads to abnormally high levels of HOXA genes, which are involved in white blood cell development and are known to play a key role in leukemias. However, the way in which CALM-AF10 brings about elevated HOXA genes is unclear. We have previously shown that in order to activate HOXA genes, CALM-AF10 recruits another protein, CRM1, that normally functions to help move other proteins out of the cell nucleus. The involvement of CRM1 in the development of leukemias is novel and unexpected, and this proposal seeks to understand the role of CRM1 in activating HOXA genes and causing leukemia. We will first use an innovative proximity based labeling approach to identify other proteins that interact with CRM1 and allow it to increase the levels of HOXA genes. We will then investigate other non-HOXA genes that are turned on by CALM-AF10 and CRM1.

Our discovery of novel protein interactions that allow CRM1 to bind to DNA will allow for development of new drugs that can be used to target these protein interactions. This is particularly important because CRM1 may play an important role in other pediatric leukemias (especially poor-prognosis infant leukemias) – the availability of drugs that interfere with CRM1 activity could have even wider impact. Finally, the investigation of non-HOXA CALM-AF10 target genes may allow for the development of novel approaches to treat these challenging leukemias. Through these approaches, we hope to identify novel therapeutic targets for difficult-to-treat childhood leukemias.