# Functional identification of drug response and resistance in Richter's Syndrome

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2024 · $281,228

## Abstract

Summary (30 lines, broad, long-term)
With the advent of more effective therapies in CLL, there is a greater priority on identifying better treatment of
Richter's Syndrome (RS), as this has become one of the most important unmet medical needs to address for
CLL patients. The main goals of this Project are to utilize functional precision medicine techniques to better
understand biological vulnerabilities in Richter's cells and to identify novel pharmacologic interventions to
increase apoptotic signaling in these cells. Our priority is on the direct study of viable samples from RS patients
obtained in collaboration with the Biospecimens core. We seek to identify the most promising combinations to
subsequently explore in early phase clinical trials for patients with RS, funded by other mechanisms. The job
of precision medicine is to match the right patient to the right drug. A strategy of genomic sequencing has
yielded several successes, such as treating EGFR mutant lung cancer with EGFR inhibitors; however, to date
RS has not yielded to the identification of targetable genetic abnormalities, and this will be the focus of Project
1. In Project 3, we propose an alternative approach, which we call functional precision medicine. Rather than
rely on static -omic data, we propose to perturb cellular function in ways that allow us to identify active drugs.
Central to this strategy is BH3 profiling, a technique in which we expose mitochondria from living cells to
synthetic BH3 peptides and measure mitochondrial permeabilization. From this assay we can learn which anti-
apoptotic proteins the cell relies on for survival, whether BCL-2, BCL-XL, MCL-1, some combination thereof, or
none of these proteins. This information has direct translational application, as clinical BH3 mimetic inhibitors
of all three listed proteins now exist. In fact, BH3 profiling was used to direct therapy of the BCL-2 inhibitor
venetoclax to CLL and AML, two indications for which venetoclax has now received FDA approval. We
propose to use BH3 profiling to identify which BH3 mimetic(s) would be most active in RS. BH3 profiling can
also provide a summary measure of how close a cell is to the threshold of apoptosis. When coupled with a
brief preceding drug exposure, dynamic BH3 profiling (DBP) can identify drugs from any class that induce
apoptotic signaling in cancer cells, moving them closer to the threshold of apoptosis. We have previously
demonstrated in several liquid and solid tumor contexts that this strategy accurately identifies drugs with in vivo
activity for individual tumors, and can predict clinical response in patients. We propose to use DBP to identify
active drugs, after which we will explore their use in combination with each other and with the appropriate BH3
mimetics identified above. As we identify drug vulnerabilities for the panel of RS samples to be studied in this
Project, we will compare them with clinical, genomic, transcriptomic, and proteomic annotations prepa...

## Key facts

- **NIH application ID:** 10912507
- **Project number:** 5P01CA206978-09
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** ANTHONY G LETAI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $281,228
- **Award type:** 5
- **Project period:** 2016-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912507

## Citation

> US National Institutes of Health, RePORTER application 10912507, Functional identification of drug response and resistance in Richter's Syndrome (5P01CA206978-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10912507. Licensed CC0.

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