# Functional identification of CLL drug response and resistance

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $305,395

## Abstract

Project Summary:
Despite impressive therapeutic advances in the treatment of CLL over the past decade, relapsed tumors that
are often resistant to known therapies remain a problem. Understanding resistance and developing new
treatment strategies will be necessary to turn CLL into a curable disease. With few notable exceptions,
responses to chemotherapy typically occur through apoptosis, a form of programmed cell death. Our goal is
to identify drugs that sensitize CLL cells to apoptosis, and to identify combinations of drugs that would
prevent relapse. While chemical screening of conventional cytotoxicity is an attractive strategy to meet this
goal, such an approach is impeded by the inability to reliably culture CLL cells for longer than 48 hours ex
vivo. This ultimately reflects a technological gap in our ability to chemically perturb CLL ex vivo, and
measure functional and clinically relevant phenotypes. Here, we will use a novel chemical screening
approach called dynamic BH3 profiling (DBP), which enables functional measurements of chemically
induced apoptotic changes, and requires only 6-24 hours of ex vivo culture, thereby maximizing
molecular fidelity and tumor cell viability. Using a panel of over 2000 drugs, not only will we identify
novel molecules that sensitize CLL cells for apoptosis, but we will also determine chemical apoptotic
sensitivities that are lost or gained on relapse for individual patients. Drugs that uniquely sensitize only
relapsed tumors present exciting opportunities for combination chemotherapy. Finally to understand
mechanisms of apoptotic vulnerabilities in pre- and post-treatment samples, we will correlate our
measurements of functional apoptotic responses with the large molecular datasets in Project 1 and 2 for at
least 104 CLL patients. In sum, the successful identification of apoptotic sensitizing drugs in CLL, will not
only advance our molecular understanding of CLL, but could result in truly novel therapeutic options.

## Key facts

- **NIH application ID:** 10005159
- **Project number:** 5P01CA206978-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** ANTHONY G LETAI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $305,395
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-09-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005159

## Citation

> US National Institutes of Health, RePORTER application 10005159, Functional identification of CLL drug response and resistance (5P01CA206978-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10005159. Licensed CC0.

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