# Project 2 - Targeted Therapies for T-ALL.

> **NIH NIH P50** · WASHINGTON UNIVERSITY · 2022 · $329,044

## Abstract

PROJECT SUMMARY/ABSTRACT
The long-term goal of this project is to develop novel targeted therapies for T-cell acute lymphoblastic
leukemia (T-ALL). T-ALL is an aggressive hematologic malignancy that comprises 15% of pediatric ALL and
25% of adult-ALL. Current treatment consists of intense chemotherapy that is associated with acute and
chronic life-threatening or debilitating toxicities. Five-year event-free survival is 70-75% for children, 30-40% for
adults under 60, and less than 10% for adults over age 60. The prognosis after relapse is dismal, with 3 year
event-free survival of only 10-15%. There is compelling evidence that increased MYC activity is central to the
pathogenesis of most cases of T-ALL. Although MYC is a potent oncogene, it has an Achilles heel. In
addition to providing a proliferative signal, MYC strongly induces apoptosis, in part, through an
ARF/MDM2/TP53 pathway. Indeed, without additional mutations/signals which inactivate apoptosis, increased
MYC expression is not sufficient to induce leukemia/lymphoma. In T-ALL, this second signal is likely
homozygous inactivating mutations of CDKN2A encoding p14 (ARF), which are present in ~80% of T-ALL.
Together, these data support the hypothesis that agents that target MYC-associated survival pathways
will be selectively toxic to T-ALL cells. CXCR4 is by far the most highly expressed chemokine receptor
expressed on T-ALL cells, and there is evidence that CXCL12, through interaction with CXCR4, provides a key
survival signal for T-ALL cells. Thus, we hypothesize that CXCR4 blockade may have therapeutic activity
in T-ALL. Consistent with this hypothesis, our preliminary and published preclinical data show that T-ALL
cells are exquisitely sensitive to CXCR4 inhibition. The following specific aims are proposed to test these
hypotheses.
 Aim 1. To test the combination of BL-8040 and nelarabine in adults with relapsed/refractory T-
ALL/lymphoblastic lymphoma.
Aim 2. To develop novel therapeutic strategies that target the dependence of T-ALL on MYC-signaling.

## Key facts

- **NIH application ID:** 10439622
- **Project number:** 5P50CA171963-10
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** GEOFFREY L UY
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $329,044
- **Award type:** 5
- **Project period:** 2013-09-03 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439622

## Citation

> US National Institutes of Health, RePORTER application 10439622, Project 2 - Targeted Therapies for T-ALL. (5P50CA171963-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10439622. Licensed CC0.

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