Friday, October 31, 2025 10/31/2025

Dissecting and Targeting RB1-Mutant Osteosarcoma

Award Number: R01CA246130
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Dissecting and Targeting RB1-Mutant Osteosarcoma - PROJECT SUMMARY/ABSTRACT Bone cancer is one of the most common primary malignancies in children and adolescents. Osteosarcoma comprises almost 60% of the common histological subtypes of bone sarcoma. While the five-year survival rate of non-metastatic disease hovers at approximately 70%, metastatic disease, most often to the lungs, is associated with survival rates of 15% to 30%. Despite advances in surgery and multi-agent chemotherapy, lack of understanding of the molecular mechanisms of osteosarcomagenesis has prevented significant improvement in the survival of patients over the past 40 years. This malignancy makes osteosarcoma one of the leading causes of cancer mortality among children and adolescents. Therefore, elucidation of the function of individual osteosarcoma-associated genes (e.g., RB1 and p53 tumor suppressor genes) to explore the possible pathological mechanisms involved in osteosarcoma initiation, development and progression is critical for future osteosarcoma detection and treatment. Induced pluripotent stem cells (iPSCs) is one of the most promising platforms recognized by cancer researchers. Recently, several groups including us successfully apply patient-derived iPSCs to phenocopy cancer features, explore disease mechanisms, and screen therapeutic drugs. These findings strongly suggest patient- derived iPSCs is a feasible system to model and dissect cancer etiology. Patients with hereditary retinoblastoma (RB), an inherited autosomal dominant cancer disorder caused by germline mutations/deletions in the RB1 tumor suppressor gene, have increased >400 fold incidence of osteosarcoma, which provides a perfect model system to study the role of RB1 in osteosarcomagenesis. Our preliminary studies revealed that an increase of spliceosome genes in RB iPSC-derived osteoblasts. These results lead to our central hypothesis that an altered spliceosome function is important for facilitating tumor initiation and development in RB1-mutant osteosarcoma. Guided by strong preliminary data, we plan to utilize RB patient-derived iPSC disease model to pursue three Specific Aims to elucidate the pathological mechanisms involved in RB1-mutant osteosarcoma: (1) To elucidate how loss of RB1 contributes to upregulated spliceosome gene expression. (2) To evaluate the therapeutic potential of splicing modulators for osteosarcoma treatment. (3) To define the role of CUL9 in regulating RB1 function. Collectively, our proposed research will broadly impact the osteosarcoma field by characterizing the essential role of spliceosome in regulating RB1-mutant osteosarcoma development. These studies will also have potential to uncover novel molecular mechanisms regulating RB1 proteolysis controlled by CUL9 tumor suppressor. Successful completion of the proposed experiment will add valuable and novel insights to a broad range of fields including cancer genetics, dysregulation of spliceosome gene expression, and ubiquitin- proteasome proteolytic pathway, each of which bears potential clinical applications for osteosarcoma treatment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $404,705 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	5	7/14/2025	NON-COMPETING CONTINUATION	$40,469
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	1/23/2025	NON-COMPETING CONTINUATION	$364,236
														Subtotal = $404,705

Issue Date FY: 2024 ( Subtotal = $384,471 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$20,235
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	1/19/2024	NON-COMPETING CONTINUATION	$364,236
														Subtotal = $384,471

Issue Date FY: 2023 ( Subtotal = $404,808 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	004	3	2/3/2023	NON-COMPETING CONTINUATION	$404,808
2023	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	2	11/28/2022	NON-COMPETING CONTINUATION	-$420,814
2023	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	003	2	11/29/2022	NON-COMPETING CONTINUATION	$420,814
2023	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	1	11/22/2022	NEW	$439,831
2023	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	11/21/2022	NEW	-$439,831
														Subtotal = $404,808

Issue Date FY: 2022 ( Subtotal = $420,814 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	2	4/28/2022	NON-COMPETING CONTINUATION	$33,664
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	2	8/23/2022	NON-COMPETING CONTINUATION	$8,417
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	1/11/2022	NON-COMPETING CONTINUATION	$378,733
														Subtotal = $420,814

Issue Date FY: 2021 ( Subtotal = $439,831 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	2/23/2021	NEW	$439,831
														Subtotal = $439,831

Grand Total All Awards = $2,054,629

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Dissecting and Targeting RB1-Mutant Osteosarcoma

Award Number: R01CA246130

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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