Montefiore Medical Center Archives - Page 2 of 2

2019

Young Investigator

Alissa Baker

New York City, NY

Executive Summary: In the process of metastasis, cancer cells break away from where they first formed the primary cancer, traveling through the blood or lymph system, to form new distantly located discrete tumors. The process by which cells become mobile and are able to travel to distant sites in the body remains unclear. The presence or absence of metastatic disease is the single most powerful predictive factor of overall survival for sarcomas, a diverse group of tumors that arise from primitive musculoskeletal cells. One third of sarcomas are characterized by recurrent genetic changes known as chromosomal translocations. A chromosome is a unit of packaged DNA which allows cells to replicate in an organized fashion. In a translocation, the abnormality results in a rearrangement of genes which can lead to changes in cellular pathways involved in cell growth, cell division, and cell death, all of which may contribute to tumor initiation, growth, or progression. Translocation-driven sarcomas are unique because there are very few, if any, other genetic mutations that occur in these tumors. However, the development of metastatic disease from a primary sarcoma has not been definitively linked to any of the chromosomal translocations; therefore, additional molecular pathways must be involved in promoting cell motility in sarcomas. Ewing sarcoma is the second most common bone tumor in adolescents and young adults. Patients who present with metastatic disease in Ewing sarcoma face a grim prognosis with a 5-year event-free survival of approximately 25%. Using a pan-Wnt inhibitor, WNT974, I have identified a unique Wnt-driven pathway that Ewing sarcoma appears to rely on for the development of metastasis. In this proposal, I will study this unique pathway in a zebrafish model of Ewing sarcoma, the only animal model available in which to study this disease, with the goal of further elucidating this pathway’s role in metastasis. Knowledge gained from elucidating this Wnt-driven pathway may additionally help to improve clinical outcomes in patients through identification of a potential new biomarker reflective of micrometastasis in Ewing sarcoma. This would allow for diagnosis of a relapse when the relapsed tumor is not large enough to visualize on imaging, allowing for an earlier initiation of therapy to help improve outcome. The goals of this project are to understand the molecular pathways that control cell motility in Ewing sarcoma in order to prevent metastatic disease and improve overall survival rates.
• Rapidly translate research findings of this novel pathway into a clinical trial using a Wnt inhibitor for patients with Ewing sarcoma to improve survival outcomes
• Discover novel treatment options focused on pathway targets elucidated in this research for patients with metastatic Ewing sarcoma to improve survival outcomes
• Identify those patients with Ewing sarcoma at highest risk of developing metastatic disease based on a potential new biomarker

2018

Scholar Grant

Daniel Weiser

Bronx, NY

Eliminating treatment failure in high-risk neuroblastoma by targeting Exportin-1 in combinatorial strategies

”
Over the last two decades, there has been dramatic intensification of cytotoxic therapy for children with high-risk neuroblastoma (NB) though only modest improvements in survival. A subset of patients with NB, the most common extracranial solid tumor of childhood, will die rapidly from disease despite highly intensive therapy, but there is currently no way to identify these “”ultra-high risk”” patients at diagnosis. Our research objective is to apply innovative methodology to identify at diagnosis those patients with the highest likelihood of death from disease, and then define unique vulnerabilities in their cancer that can be therapeutically targeted. We have shown that Exportin-1 (XPO1), a critical nuclear export protein in cancer cells, is a promising target as it is most abundant in tumors from patients with neuroblastoma at high risk for treatment failure. Therefore, we propose to develop combination treatment strategies that integrate a selective inhibitor of nuclear export compound, selinexor (Karyopharm Therapeutics), that targets XPO1 which is overexpressed in patients with the poorest outcomes. By understanding how the drug is working in neuroblastoma, we will define the subset of patients with neuroblastoma predicted to have greatest tumor response to this novel orally available chemotherapeutic agent. We will approach our research through two aims: 1) determine the cellular and molecular pathways altered by XPO1 overexpression in highly aggressive neuroblastoma, and 2) define the mechanism of synthetic lethal effects in neuroblastoma using selinexor as part of combinatorial treatment. We will then rapidly translate our research findings into an early phase clinical study. For select patients that we identify to be most responsive to novel therapy, rational combinatorial treatment that includes selinexor has potential to improve outcomes for children who otherwise have no curative treatment options.

Goals of the project:
– Break new ground and alter the current paradigm of neuroblastoma diagnosis and management, something that is urgently needed
– Rapidly apply and translate research findings to the clinic to improve outcomes in a devastating disease
– Establish a novel classification tool that can be used prospectively at diagnosis for detection of neuroblastoma at high risk for treatment failure
– Identify optimal patients, based on tumor and host features, to receive XPO1-directed therapy with selinexor as part of augmented treatment at diagnosis
– Complete pre-clinical work that will justify development of an early phase clinical trial testing selinexor combinatorial therapy strategies for patients with neuroblastoma at high risk for treatment failure”