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Targeting cooperative mechanisms of metastatic colonization in osteosarcoma

Award Number: R01CA260178
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/06/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Targeting cooperative mechanisms of metastatic colonization in osteosarcoma - While studying mechanisms of metastasis in osteosarcoma, we discovered that individual tumor cells respond differently when exposed to the foreign lung environment. Our early data suggest a hypothesis: that a small group of tumor cells survives the initial encounter with the lungs by stopping cell division and liberally producing inflammatory cytokines. The reaction of these rare “anchor” cells changes the surrounding lung tissue in ways that prepare it for colonization by rapidly proliferating tumor cells (“growth” cells). The cytokines released by anchor cells appear to alter the behavior of the surrounding lung cells, prompting a wound healing response. Unlike the normal wound healing response, however, this wound never heals. The environment created by this wound response is markedly different from that of the normal, healthy lung. Most importantly, cells and cytokines that make up the wound create an environment where growth cells not only survive, but proliferate rapidly, outcompeting the anchor cells to become the dominant subtype within the metastatic tumor. Here, we outline a research plan to test this hypothesis, rigorously evaluating our proposed mechanisms that establish the early metastatic niche and asking whether chemotherapy selectively kills growth cells, inadvertently leaving anchor cells intact to re-establish metastases once therapy ceases. The project is divided into three Aims. Aim 1 tests hypotheses relating to the mechanisms by which anchor cells create a fertile metastatic niche by activating the wound-healing machinery of the lung and facilitates identification of the lung-to-tumor signals that make this a fertile environment for growth cells. In the second Aim, we will determine how anchor and growth cells come about—whether distinct clones come pre-programmed for anchor or growth cell activity or whether dynamic developmental processes regulate maintenance of subpopulations within each tumor. Understanding this will be important for designing treatment regimens that maintain efficacy while minimizing toxicity. Finally, we will evaluate the use of pharmacologic inhibitors that target anchor cells directly or indirectly to see if these can augment the effects of conventional therapies and overcome resistance and relapse. By identifying agents that selectively target anchor cells, we can develop combination regimens that target both groups of tumor cells, rendering resistant disease treatable. The cooperation between cancer cells with discrete behaviors has immediate implications for treatment and suggests a need to develop strategies that target both growth cells and anchor cells. This work could drive a paradigm shift that would revolutionize the care of patients with osteosarcoma.


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 = $372,261 )
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cancer Biology Research	000	4	5/27/2025	NON-COMPETING CONTINUATION	$372,261
														Subtotal = $372,261

Issue Date FY: 2024 ( Subtotal = $447,149 )
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cancer Biology Research	001	3	6/27/2024	NON-COMPETING CONTINUATION	$447,149
2024	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cancer Biology Research	000	2	3/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $447,149

Issue Date FY: 2023 ( Subtotal = $392,374 )
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cancer Biology Research	000	2	8/30/2023	NON-COMPETING CONTINUATION	$392,374
														Subtotal = $392,374

Issue Date FY: 2022 ( Subtotal = $652,854 )
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cancer Biology Research	000	1	7/6/2022	NEW	$652,854
														Subtotal = $652,854

Grand Total All Awards = $1,864,638

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Targeting cooperative mechanisms of metastatic colonization in osteosarcoma

Award Number: R01CA260178

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/06/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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