# Defining and targeting ER quality control dependence in rhabdomyosarcoma

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $228,786

## Abstract

Candidate. Dr. Sabnis is a pediatric oncologist with training in genetics and molecular biology whose long-term
goal is to lead an independent laboratory defining and targeting vulnerabilities in the protein homeostasis
networks of pediatric sarcomas. He has begun to establish himself as a leader in this field through a first author
publication in PNAS detailing HSP70 dependence in rhabdomyosarcoma (RMS) and contributing authorship
on publications in Nature Medicine and Nature Genetics. This K08 award will be a critical vehicle for his
ongoing career development, providing key mentorship and instruction in 1) designing preclinical trials to
enable clinical translation of bench research, 2) probing the ER quality control mechanisms cancer cells
subvert to support their survival, and 3) using genetic manipulation and cell biologic readouts to interrogate
proteostasis in sarcoma biology.
Environment. UCSF is an outstanding research environment with 1300 principal investigators and over $500
million in support from the NIH (ranking 2nd among all institutions). Two co-mentors will help Dr. Sabnis achieve
his aims. Dr. Trever Bivona, MD PhD, is a medical oncologist with expertise in biologically defining rational
polytherapy for oncogene-driven solid tumors. Dr. Bivona has extensive research support including an NIH
Innovator’s Award and several R01s, and has mentored five post-doctoral fellows into independent positions in
the last five years. Dr. Sabnis will be co-mentored by Dr. Kevin Shannon, MD, a pediatric oncologist who has
been the primary mentor for multiple K-series award recipients from the NCI. Dr. Sabnis will also meet semi-
annually with a mentoring committee, comprised of Dr. Bivona; Dr. Shannon; Dr. Jonathan Weissman, an
expert in ER quality control and mentor to many K-supported trainees; and Dr. Kate Matthay, a pre-eminent
pediatric oncology clinical researcher who will support the clinical translation of his discoveries.
Research. High-risk RMS patients have dismal outcomes despite maximally intensified chemotherapy,
highlighting a need for new, biology-driven treatments. We found that inhibiting the cytosolic protein chaperone
HSP70 lethally activates the unfolded protein response (UPR) in RMS, but not in other cancers. I hypothesize
that RMS cells rely on HSP70, acting together with its co-chaperone DNAJC17 and the ATPase p97, to lower
ER protein load through ER-associated degradation (ERAD). ERAD inhibition in RMS thus defines a novel
therapeutic strategy. In aim 1, we will test the pharmacologic parameters and efficacy of two drugs that disrupt
ER quality control in murine RMS models. In aim 2, we will identify the structural domains of DNAJC17 that are
necessary to maintain ER homeostasis, and test the hypothesis that this HSP70-DNAJC17-p97 axis enables
ERAD and thereby ensures RMS cell survival. These aims will provide crucial molecular detail into the basis of
the RMS-specific lethality of HSP70 inhibition we discovered. Overa...

## Key facts

- **NIH application ID:** 10183189
- **Project number:** 5K08CA218691-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Amit J. Sabnis
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $228,786
- **Award type:** 5
- **Project period:** 2018-07-16 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183189

## Citation

> US National Institutes of Health, RePORTER application 10183189, Defining and targeting ER quality control dependence in rhabdomyosarcoma (5K08CA218691-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10183189. Licensed CC0.

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