# PROJECT 1:  Genomic Vulnerabilities in Leiomyosarcoma (LMS)

> **NIH NIH P50** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $463,494

## Abstract

Project 1: Summary/Abstract
Leiomyosarcoma (LMS) is one of the most common sarcomas and is a considerable therapeutic challenge
because 50% of patients develop metastases for which current chemotherapy provides clinical benefit to only a
small minority. We have shown that most LMS have chromosomal instability (CIN), which results in part from
defects in homologous recombination and from ubiquitous TP53 and RB1 inactivation. Our recent studies show
that these CIN aberrations are associated with hyper-dependency on DNA protein kinase (DNA-PK), which –
along with ATM and ATR – is a member of the PI3K-like kinase family of DNA damage response (DDR) enzymes.
DNA-PK is a key repair mechanism for double-strand DNA damage, thereby maintaining CIN below genotoxic
thresholds.
In Project 1, we wish to develop therapies that maximize intrinsic LMS genotoxic stress, particularly be targeting
DNA-PK and by discovering more selective ways to target the DNA-PK pathway. To this end, Aim 1 determines
whether relevant biomarkers (biochemical DNA-PK pathway activation, DNA damage response, and genomic
evidence of CIN) are found homogeneously within a metastasis and in different metastases from a given patient.
Aim 1 also determines whether partially vs. completely inactivating TP53 mutations have differing impact on LMS
CIN and DNA-PK activation levels and therefore differing predictive relevance with respect to therapies targeting
DNA-PK and DNA integrity. By determining if assays of DNA-PK activation and DNA damage are effectively
demonstrated by LMS IHC and genomic profiles, Aim 1 shows whether these assays can be used as robust and
reproducible correlative science assessments for our subsequent (Aim 3b) clinical trial combining low-dose
doxorubicin and DNA-PK inhibition. Aim 2 provides biologic insights needed to achieve efficacy and selectivity
for DNA-PK inhibition and other DDR-targeted therapies in LMS. These in vitro studies include DDR CRISPR-i
and CRISPR-a screens, which are performed with/without DNA-PKi, PARPi and doxorubicin treatment. The
CRISPR screens aim to discover DNA-PK inhibitor synthetic lethals and resistance mechanisms, and the biologic
insights from these screens are enhanced by performing RNAseq and phosphoproteome profiles in the same
LMS conditions, and by characterizing LMS cells with acquired resistance to DNA-PKi or doxorubicin. Aim 3 is
the clinical translation for Project 1, which encompasses in vitro, and murine preclinical validations and an initial
clinical trial of doxorubicin coupled with DNA-PK inhibition. Here we test the hypothesis that a very low dose of
doxorubicin sensitizes LMS cells to DNA-PKi, thereby converting CIN into a liability while minimizing
nonneoplastic cell toxicity.

## Key facts

- **NIH application ID:** 10493629
- **Project number:** 1P50CA272170-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** JONATHAN Alfred FLETCHER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $463,494
- **Award type:** 1
- **Project period:** 2022-09-16 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10493629

## Citation

> US National Institutes of Health, RePORTER application 10493629, PROJECT 1:  Genomic Vulnerabilities in Leiomyosarcoma (LMS) (1P50CA272170-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10493629. Licensed CC0.

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