# Leveraging Tumor Suppressor Inactivation for Osteosarcoma Therapy

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $413,191

## Abstract

PROJECT SUMMARY
Osteosarcoma (OS) is the most common malignant bone tumor, found in the pediatric
population and often leads to death due to tumor progression and metastasis. Despite
intensive, multimodality treatment protocols with cytotoxic chemotherapy and aggressive
surgery, 30-40% of patients still succumb to relapsed and metastatic disease. Current
treatment options for these patients are extremely limited. More importantly, the clinical
outcome for OS patients has not improved at all during the last four decades. Our long-range
goals are to reduce OS disease burden and improve long-term survival by developing
molecular-based therapies that target mechanisms of tumor growth and metastasis. The F-box
protein s-phase kinase-associated protein-2 (Skp2) is the substrate recognition component of
the Skp1-Cullin1-F-box (SCF) complex and considered a key oncogene through its ability to
target cell cycle regulators for ubiquitin degradation, regulates cell migration and metastasis.
Skp2 interacts with the accessory protein Cks1 to ubiquitinate p27 for degradation, thus
promoting cell cycle progression and cancer growth. Currently, the oncogenic mechanisms
and therapeutic potential of Skp2 in OS is largely unknown. There are specific and rational
reasons for targeting the SCF-Skp2 axis in OS, based upon preliminary data generated by the
PI and his colleagues: (1) A high Skp2 expression in OS tissues portends a poor prognosis in
patients; (2) High levels of Skp2 are observed in many OS cell types, including established cell
lines, patient-derived xenografts, and primary cultures from OS patients; (3) Skp2 deletion
effectively blocks pituitary and prostate tumorigenesis in Rb1/p53-deficient mouse models. In
OS, genomic sequencing studies reveal a high rate of Rb1/p53 co-inactivation, suggesting that
OS may be susceptible to Skp2 blockade; (4) Genetic and drug-induced depletion of Skp2
reduces the proliferation and invasion of OS cell lines and; (5) Mouse embryonic fibroblasts
(MEF) and OS tumor cells with Rb1/p53 deletion are more sensitive to SCF-Skp2 inhibition
than wild-type and Skp2-deleted cells. Taken together, these data suggest that the SCF-Skp2
complex may offer a unique therapeutic opportunity for treating a tremendously challenging
cancer such as OS. We hypothesize that blockade of the SCF-Skp2 complex in the context of
Rb1/p53 inactivation will reduce OS progression. This hypothesis will be addressed by the
following specific aims: Specific Aim 1 (Oncogenic Mechanisms): To define the pro-oncogenic
mechanisms of SCF-Skp2 in Rb1/p53-inactivated OS. Specific Aim 2 (Translational
Therapeutics): To determine the effect of inhibiting SCF-Skp2 in preclinical models of Rb1/p53-
inactivated OS. Finally, since cancer organoids represent an emerging technology that
faithfully replicates the tumor's genetic landscape, we will examine the effect of inhibiting SCF-
Skp2 in mouse OS organoids as a proof-of-concept to translate findings into patient-speci...

## Key facts

- **NIH application ID:** 10881775
- **Project number:** 5R01CA255643-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** BANG H HOANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $413,191
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881775

## Citation

> US National Institutes of Health, RePORTER application 10881775, Leveraging Tumor Suppressor Inactivation for Osteosarcoma Therapy (5R01CA255643-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10881775. Licensed CC0.

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