# Augmenting Quadruple Negative Breast Cancer Treatment by ADRM1 Inhibitor Up284

> **NIH NIH U54** · TUSKEGEE UNIVERSITY · 2024 · $366,390

## Abstract

Project Summary
This proposal aims to develop QNBC as the lead indication for our ADRM1 inhibitor, Up284,
and support biomarker development to select QNBC patients for ADRM1 inhibitor therapy. It
addresses critical questions for the development of effective and safe treatments for QNBC and
the reduction of the disparity in breast cancer outcomes.
Quadruple negative breast cancer (QNBC) is a subtype of breast cancer that does not express
the hormone receptors ER and PR, the growth factor receptor HER2, and the androgen
receptor AR. QNBC has the poorest prognosis among breast cancer subtypes and
disproportionately affects African Americans. Currently, there is no standard-of-care treatment
for QNBC, and there is an urgent need to develop effective and safe treatments and biomarkers
to address this unmet medical need and the disparity in breast cancer outcomes. Our research
team has recently found that elevated expression of proteasome subunit ADRM1 is associated
with both African American race and lower survival in QNBC patients. Our collaborator Up
Therapeutics developed an inhibitor called Up284 that targets ADRM1. While QNBC and triple
negative breast cancer (TNBC) cell lines show evidence of greater vulnerability to
proteasome inhibitors, approved 20S proteasome inhibitors like bortezomib have proven
ineffective against solid tumors due to their partial proteasome inhibition, inability to achieve
therapeutic doses, and poor pharmacokinetic properties. Up284 is a novel small molecule
designed to overcome these limitations. Its structure is a non-peptide spiro compound with
improved drug access and favorable pharmacokinetic properties to solid tumors compared to
peptide-based 20S inhibitors. Up284 also blocks substrate recognition and deubiquitination,
providing full proteasome inhibition and avoiding key toxicities like thrombocytopenia and
neutropenia. In vitro studies show that Up284 has broad anticancer activity, including against
QNBC lines and patient-derived organoids. It has a promising safety profile and
pharmacodynamics and can control syngeneic and xenograft tumors. By inhibiting
proteasome ubiquitin receptor ADRM1 function and its associated deubiquitinase activity,
Up284 triggers more rapid accumulation and increased molecular weight polyubiquitinated
protein aggregates than 20S inhibitors. These toxic misfolded protein aggregates produce
unresolved ER stress and activate the canonical Unfolded Protein Response (UPR) signaling
cascade, leading to more rapid apoptosis than 20S inhibitors. We plan to examine ADRM1 and
ER stress markers' expression in diverse QNBC patient samples and validate sensitivity to
Up284 to develop a biomarker for selecting patients for better therapeutic efficacy and
safety. We also will validate the synergy of Up284 efficacy in combination with in-clinic
chemotherapeutic agents used to treat TNBC to improve therapeutic response and block the
emergence of resistance. Finally, we will assess Up284's potential t...

## Key facts

- **NIH application ID:** 10933032
- **Project number:** 5U54MD007585-33
- **Recipient organization:** TUSKEGEE UNIVERSITY
- **Principal Investigator:** Balasubramanyam Karanam
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $366,390
- **Award type:** 5
- **Project period:** 1997-07-07 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933032

## Citation

> US National Institutes of Health, RePORTER application 10933032, Augmenting Quadruple Negative Breast Cancer Treatment by ADRM1 Inhibitor Up284 (5U54MD007585-33). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10933032. Licensed CC0.

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