# Molecular pathways and targeted therapies in human leukemia

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $960,000

## Abstract

PROJECT SUMMARY
T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer in which
novel more effective antileukemic drugs are needed for the treatment of patients with
chemotherapy resistant disease. In this context the identification of activating mutations of
NOTCH1 in over 60% of T-ALL has brought great interest to the development of targeted anti-
NOTCH1 therapies in the treatment of this disease. However, early efforts to target NOTCH1 in
the clinic have been hampered by limited antitumor activity. We have demonstrated that
NOTCH1 is a critical regulator of cell growth and proliferation and identified MYC, the PI3K-AKT
pathway and leukemia cell metabolism as critical effectors of the oncogenic program
downstream of NOTCH1. Our central hypothesis is that leukemia persistence, disease
progression and relapse are driven by signaling, genetic, epigenetic and metabolic circuits that
bypass the antileukemic effects of NOTCH1 signaling. Here we will: (i) dissect molecular
mechanisms wiring NOTCH1 with oncogenic transcriptional programs; (ii) functionally analyze
the role of long-range enhancers in NOTCH1-induced transformation; (iii) explore the role of
tumor microenvironment signals, metabolic and epigenetic plasticity as determinants of the
therapeutic response to anti-NOTCH1 therapies and (iv) identify and functionally characterize
new drug targets and antileukemic drugs synergistic with NOTCH inhibition for the treatment of
T-ALL.

## Key facts

- **NIH application ID:** 10224720
- **Project number:** 5R35CA210065-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Adolfo A. Ferrando
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $960,000
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224720

## Citation

> US National Institutes of Health, RePORTER application 10224720, Molecular pathways and targeted therapies in human leukemia (5R35CA210065-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10224720. Licensed CC0.

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