# Targeting High-Risk Lymphoid Neoplasms

> **NIH NIH R35** · DANA-FARBER CANCER INST · 2020 · $1,077,706

## Abstract

Project Summary/Abstract
The outcomes for patients with high-risk lymphoid malignancies, including T-cell lymphomas, mantle cell
lymphoma and acute lymphoblastic leukemia that harbor CRLF2 rearrangements, remain poor. The long-term
goal of this R35 program is to build on our models, collaborations, environment and record of productivity to
iteratively define aspects of lymphoid tumor biology and translate these discoveries into therapeutic approaches
for patients. Over the previous 5 years, we identified mutations of the G protein beta subunits GNB1 and GNB2
across a range of different cancers that drive transformation and resistance to kinase inhibitors, defined the
biology of a rare subtype of follicular lymphoma, established a clinicogenetic prognostic model for follicular
lymphoma, co-developed a strategy to interrogate therapeutic sensitivity of single leukemia cells, defined the
relationship between HMGN1 triplication, Down Syndrome and ALL, helped identify chr.X genes that drive
excess cancer risk in males and piloted the use of next-generation lymphoma diagnostics in lower- and middle-
income countries. Work from my lab has led to multiple clinical trials that are currently open; each trial includes
biopsies prior to treatment, on treatment and after progression of disease. I lead a Specialized Center for
Research that is focused on developing new strategies to target T-cell lymphomas. My laboratory has also
established and banked >350 human leukemia and lymphoma patient-derived xenografts (PDXs) that serially
passage. We utilize these models to orchestrate phase II-like pre-clinical trials completely in mice, define aspects
of compartment-specific biology and elucidate mechanisms of in vivo acquired resistance. We have made the
PDXs and affiliated data available through an open source web portal (www.PRoXe.org). I collaborate closely
with bioengineers and computational biologists through an NCI Cancer Systems Biology Consortium. I have
access to state-of-the-art infrastructure, including gain- and loss-of-function screening, next-generation
sequencing, high-throughput chemical biology, proteomics and metabolite profiling. The major areas of focus
for this R35 proposal build on my current R01 awards to build innovative and faithful models of lymphoid
malignancies, interrogate in situ microenvironmental and immune responses, define mechanisms of therapeutic
response and target adaptive in vivo resistance. With the expertise to orchestrate preclinical therapeutics, my
existing relationships within academia and Pharma, a network to facilitate rapid translation into clinical trials, and
a track-record for innovative discovery, I am uniquely positioned to make transformative advances against high-
risk lymphoid malignancies over the next seven years and beyond.

## Key facts

- **NIH application ID:** 9984325
- **Project number:** 5R35CA231958-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** David Marc Weinstock
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,077,706
- **Award type:** 5
- **Project period:** 2019-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984325

## Citation

> US National Institutes of Health, RePORTER application 9984325, Targeting High-Risk Lymphoid Neoplasms (5R35CA231958-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9984325. Licensed CC0.

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