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Dissecting cell composition and drug sensitivity in human adenoid cystic carcinomas (ACCs)

Award Number: R01DE028961
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Dissecting cell composition and drug sensitivity in human adenoid cystic carcinomas (ACCs) - Adenoid Cystic Carcinomas (ACCs) represent one of the most common and biologically aggressive forms of epithelial malignancy of the salivary glands, for which there are no clinically approved treatments. ACCs are characterized by a high tendency towards peri-neural infiltration and distant-site metastasis, and are largely refractory to conventional chemo-radiotherapy approaches. ACCs are also defined by a distinctive biological feature: the co-existence within malignant tissues of two phenotypically distinct sub-populations of cancer cells (ductal-like vs. myoepithelial-like) characterized by profoundly distinct gene-expression profiles and functional properties. This study will leverage a portfolio of surface markers recently identified by our laboratory that allow, for the first time, the differential purification, molecular study and functional analysis of these two cell types. The hypotheses formally tested by this study are: a) that the two cell types co-exist in a dynamic and hierarchical equilibrium, whereby one cell type functions as a progenitor for the other; and b) that biochemical pathways regulating the conversion of one cell type into the other can be leveraged to develop new therapeutic approaches against ACCs. The project envisions two specific aims: 1) to elucidate the developmental relationship between the two cellular components of ACCs: we will use fluorescence activated cell sorting (FACS) to purify the two sub-populations of cancer cells from human ACCs, and then employ prospective in vivo xenotransplantation experiments and single-cell RNA-seq technologies to test whether the two cell types: a) display robust and systematic differences in tumor-initiating capacity across patient-derived xenograft (PDX) lines from independent patients; b) are hierarchically related (i.e. whether both can plastically inter-covert into each other or whether one serves as the progenitor of the other, in a mono-directional fashion); c) contain additional, previously unrecognized cellular sub-populations, themselves characterized by distinct molecular and functional properties; 2) to test the in vitro and in vivo therapeutic efficacy of novel drug combinations against ACCs, designed to target biochemical pathways shown to affect the differential representation and preferential survival of the two cellular sub-types: we will treat 3D organoids and PDX lines shown to recapitulate the dual cell composition of primary ACCs with sequential drug regimens, designed to, in a first step, induce the differentiation of myoepithelial-like cells into ductal-like cells and, in a second step, to selectively eliminate ductal-like cells; such novel drug regimens will be tested for their capacity to: a) cause changes in the cell composition of malignant tissues (ductal/myoepithelial cell ratio); b) reduce tumor size and/or growth kinetics; c) prevent in vivo metastatic dissemination (using non-invasive bio-luminescent reporters). Significance. This study will elucidate the molecular and functional properties of the two cell types found in human ACCs, filling a major scientific gap in salivary tumor biology, and addressing an unmet clinical need in salivary gland oncology: the identification of novel drug targets for the pharmacological treatment of ACCs.


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 = $0 )
2025	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	000	5	2/19/2025	NON-COMPETING CONTINUATION	$0
2025	2023	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	6	2/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	002	5	5/15/2024	NON-COMPETING CONTINUATION	$22,815
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	000	5	4/30/2024	NON-COMPETING CONTINUATION	-$201,485
2024	2023	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	6	4/30/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$178,670
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $380,155 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	000	5	5/19/2023	NON-COMPETING CONTINUATION	$380,155
														Subtotal = $380,155

Issue Date FY: 2022 ( Subtotal = $376,486 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	000	4	5/16/2022	NON-COMPETING CONTINUATION	$376,486
														Subtotal = $376,486

Issue Date FY: 2021 ( Subtotal = $380,419 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	000	3	5/11/2021	NON-COMPETING CONTINUATION	$380,419
														Subtotal = $380,419

Issue Date FY: 2020 ( Subtotal = $380,545 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	000	2	4/22/2020	NON-COMPETING CONTINUATION	$380,545
														Subtotal = $380,545

Issue Date FY: 2019 ( Subtotal = $380,668 )
2019	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	000	1	7/19/2019	NEW	$380,668
														Subtotal = $380,668

Grand Total All Awards = $1,898,273

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Dissecting cell composition and drug sensitivity in human adenoid cystic carcinomas (ACCs)

Award Number: R01DE028961

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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