# Translating Stress Response Targeted Therapy for B-Cell Lymphomas

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $315,208

## Abstract

Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of malignancies, the complexity of which
still remains to be fully resolved. At least 30-40% of patients are not cured with current chemo-immunotherapy
regimens. Improved treatments are urgently needed for these patients. Chemotherapy resistance and relapse
are particularly high in patients with certain molecular features, such as those with an “Activated B-cell (ABC)”
like gene expression signature, or those with translocations or overexpression of the MYC and BCL2
oncogenes (so-called “double-hit” DLBCLs). Even when cured our current best therapies are highly toxic and
carry a significant risk of inducing secondary cancers. Our research seeks to identify fundamental biological
mechanisms that drive the survival of DLBCLs including its resistant subtypes. Along these lines we find that
DLBCLs are generally addicted to particular stress response proteins. A tumor-enriched form of Hsp90 (TEHsp90)
plays an essential role in DLBCLs by supporting the actions of the BCL6, MYC and BCL2
oncoproteins, as well as maintaining B-cell receptor (BCR) signaling. Our team developed a small molecule
that selectively inhibits TE-Hsp90 without affecting general Hsp90 housekeeping functions. This molecule,
called PUH71 has an accordingly wide therapeutic window and potent activity against DLBCL cells. PUH71 is
well tolerated in our phase I clinical trial. We developed a method to accurately measure tumor exposure
through PET imaging of I124-labeled PUH71, which may serve as a companion biomarker to guide
individualized dosing and interpret clinical responses. We hypothesize that PUH71 can serve as an effective
therapeutic agent for DLBCL, including those with ABC- and double-hit molecular signatures. We predict that
response can be predicted through PUH71 imaging and biologic biomarkers. We predict that PUH71 will serve
as a platform drug for development of effective and well-tolerated combinatorial therapy regimens. Finally, we
also developed YK198, a potent and specific inhibitor of specific allosteric states of Hsp70, with activity against
DLBCL cells at least in part due to disruption of anti-apoptotic signaling pathways. We hypothesize that Hsp70
inhibitors will be useful therapeutic agents for DLBCL and may overcome possible PUH71 induced Hsp70
feedback resistance. Therefore we propose to perform a PUH71 phase II clinical trial in patients with DLBCL
with concordant imaging and biomarker studies, to compare and contrast biological dependency of Hsp90 and
Hsp70 inhibitors in DLBCL patient specimens, and to design and test rational combinatorial regimens with
PUH71 and YK198.

## Key facts

- **NIH application ID:** 9988857
- **Project number:** 5P50CA192937-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** GABRIELA CHIOSIS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $315,208
- **Award type:** 5
- **Project period:** 2016-08-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988857

## Citation

> US National Institutes of Health, RePORTER application 9988857, Translating Stress Response Targeted Therapy for B-Cell Lymphomas (5P50CA192937-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9988857. Licensed CC0.

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