The Regents of the University of California, San Francisco Archives

2019

Scholar Grant

Benjamin Huang

Oakland, CA

Executive Summary:
Acute myeloid leukemia (AML) comprises 20% of childhood leukemia cases. In contrast to acute lymphoblastic leukemia (ALL), cure rates for AML remain poor with ~40% of infants, children, and adolescents dying from relapsed/refractory leukemia or treatment related toxicities. Current therapies are toxic and result in a high incidence in late effects. Furthermore, the GLIS2 and NUP98 fusion positive AMLs are associated with particularly dismal outcomes and have not been amenable to xenograft models. This underscores the need to identify novel, biologically based therapeutic targets in these high-risk molecular subtypes of pediatric AML. Therefore, I am pursuing an unbiased strategy that relies on genetically engineered mouse (GEM) models of AML and CRISPR-dCas9 screens with the overall goal of identifying novel vulnerabilities and therapeutic targets in high-risk molecular subtypes of pediatric AML.

Aim 1: To generate transplantable GEM models of pediatric AML that harbor dCas9-KRAB.
Aim 2: To perform genome-wide CRISPR-dCas9 screens to identify genetic dependencies in high-risk molecular subtypes of pediatric AML.

Goals (Lay Summary):
– Outcomes for pediatric acute myeloid leukemia (AML) are poor and current therapies result in a high incidence of late effects.
– This underscores the need to identify novel, biologically based therapeutic targets in AML.
– This research proposal leverages accurate models of AML and next-generation screening techniques to identify vulnerabilities specific to AML.

2017

Scholar Grant

Dr. Eric Alejandro

San Francisco, CA

Personalized genome-informed treatment of metastatic and relapsed osteosarcoma
Osteosarcoma (OS) is a tumor that mostly affects children and young adults. OS patients who relapse after standard therapy have a very poor prognosis. Analysis of OS genomes has identified OS as among the most heavily altered at the genomic (DNA) level among all cancers. However, currently genome analysis is not part of the standard approach to therapy in OS, unlike the situation in many adult cancers where genome analysis is now widely accepted as key to identifying the proper therapeutic option for an individual patient. Our goal is to define the role of genomic analysis in identifying new approaches for treatment of relapsed OS.

Our key goals are:

To identify key genetic alterations (called copy number alterations) that are common
in different OS patients.
To determine whether drugs that target genes altered by copy number can lead to
durable responses in OS.
To define novel combination therapies that may be useful for individual OS patients
by testing them in patient-derived tumor xenografts (PDTX).

Our most important long-term goal is to benefit OS patients by defining the use of targeted
therapies that are specific to an individual patient’s tumor and therefore more likely to provide
benefit while decreasing toxicity._