Titles + affiliations
Assistant Professor, Pediatrics/Oncology
University of California, San Francisco
Validating Targeted Therapies with Curative Potential Against High-Risk Childhood Leukemia
Acute lymphoblastic leukemia is the leading cause of cancer mortality in children and young adults. Notably, almost 10% of children and adolescents cancer patients present germline predisposition mutations. Li-Fraumeni Syndrome (germline mutations in TP53), was reported the most common cancer predisposition syndrome in the Pediatric Cancer Genome Project. Low hypodiploid B-cell lymphoblastic leukemia (LH B-ALL), an aggressive leukemia characterized by mutations in TP53 in more than 90% of patients, of which nearly 50% represent Li-Fraumeni syndrome results in 70% mortality compared to 15% for B-ALL patients overall. Aiming to turn this aggressive disease into one with a much-improved prognosis, we investigated therapeutic targets specific to hypodiploid leukemia with p53 mutations. Importantly, TP53, the most commonly mutated gene in cancer is especially prevalent at relapse after aggressive therapies. We exposed LH-B-ALL patient samples to APR-246, a drug targeting the p53, already in use in late phase clinical trials. These studies revealed complete induction of cell death in LH-B-ALL by APR-246. Moreover, gene expression analyses indicated that cells expressing mutant TP53 present overexpressed surface proteins. I hypothesize that hypodiploid leukemia with mutant TP53 can be selectively identified and targeted. I, thus, propose two therapeutic opportunities (pharmacological and immunotherapy) to reverse the dim prognosis for patients with LH-B-ALL harboring p53 mutations.
As a junior faculty, my career path greatly depends on having access to funding, resources, and talented personnel to undertake the challenge of exploring unsolved questions posed by hard-to-treat cancer types. In line with the central objective of the Leukemia Research Foundation, the support provided by this funding will allow me to generate compelling data to be in a competitive position to secure larger federal funds and to provide meaningful scientific contributions to the leukemia field. It will also be instrumental for my career advancement towards tenure track. It will also support me to build a much larger research program focused on interrogating outstanding biological questions in cancer that can be addressed through the study relevant mutated genes within the context of single allele expression as presented in hypodiploid leukemia. Most importantly, these funds have provided the support for an expansion of the project with both immunotherapy as well as targeted drug approaches to further identify selective therapeutic opportunities for patients that face a grim prognosis.
Ernesto Diaz-Flores, Astrid Wintering, Kenichi Ishiyama, et al.
CD22 low/Bcl-2 high Expression Identifies Poor Response to Inotuzumab in Relapsed/ Refractory Acute Lymphoblastic Leukemia Blood (2021)
Ernesto Diaz-Flores, Ph.D., Speaker, Science journal's Webinar Series
Interrogating cancer drivers via CRISPR: Mutant TP53 as a therapeutic target in hypodiploid B-cell acute lymphoblastic leukemia
Ernesto Diaz-Flores, Ph.D., Author Profile, Science
Leukemia Research Foundation grant
$100K awarded in 2021
Acute lymphoblastic leukemia (ALL)
Treatment (targeted therapy)