Monday, June 30, 2025 6/30/2025

Targeting oncogenic Myb fusions in salivary gland cancer with the elongation inhibitor SVC112

Award Number: R01DE030683
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Targeting oncogenic Myb fusions in salivary gland cancer with the elongation inhibitor SVC112 - SUMMARY. Salivary gland cancer (SGC) is an orphan disease for which no targeted therapies are approved. SGCs are divided into histotypes, the most common being adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (MEC). We have generated one of the largest reported SGC PDX banks including major histotypes like ACC and the first reported PDX models of MEC. Our SGC PDX bank includes several cases from the same patient, collected after subsequent relapses, which has allowed an exploration of the acquisition of oncogenic gene events. Similar to other reports, our SGC models had low mutation burden by whole exome sequencing, and RNA-seq analysis identified known (MYB-NFIB), novel (NFIB-MTFR2), and even dual gene fusions in ACC cases that gave rise to oncogenic fusion protein products. Other genetic events in SGC clustered in the PI3K and mTOR pathways, which impinge upon protein synthesis. Both MEC and ACC overexpress key transcription factors such as Myc or SOX2 that dictated tumorigenicity and growth in SGC. Overall, we propose that protein synthesis is an unexplored target in SGC. SVC112 is a small molecule that inhibits protein synthesis at the elongation step by inhibiting eEF2. In our seminal studies where SVC112 was first reported, protein synthesis and growth inhibition were associated; SVC112 had greater effect on cancer over non-cancer cells; SVC112 depleted SOX2, Myc, and Cyclin D1, and arrested growth in vivo. In both ACC and MEC cell lines we found that SVC112 inhibits both native Myb and the protein products of MYB fusions and key proteins like Myc. SVC112 inhibited proliferation and sphere formation in both ACC and MEC in vitro assays, and had notable single agent activity (including actual tumor shrinkage) in 2 ACC PDX, one with a MYB fusion and another one showing non- fusion mediated Myb upregulation. We propose to study the role of oncogenic fusions in SGC, the mechanism of action of SVC112 in SGC, and the efficacy of SVC112 in complex SGC models. First, we will catalogue and prioritize MYB fusions from large patient and PDX cohorts. Then, to understand key genetic events we will insert fusions in non-cancer cell lines, and deploy CRISPR and lentiviral vectors in fusion-and non-fusion-bearing SGC cell lines, respectively; we will also test SVC112 inhibition to add an additional layer of testing of the impact of protein modulation. The hypothesis that SVC112’s selective effect is due to selective depletion of key proteins will be tested by ribosome profiling (to identify mRNA targets) and proteomics analysis (to identify proteins targets). Lastly, we will test the in vivo efficacy of SVC112 using both native SGC PDX models bearing MYB and other fusions and wild-tpy, as well as in vivo models with the CRISPR-depleted MYB fusions strains. Overall our goal is to examine dependence on fusion events vs protein overexpression by other molecular mechanisms for SVC112 susceptibility. This project will propel the translation of SVC112, a new drug for SGC discovered in Colorado, by dissecting the basis for its effect and therapeutic window, and identifying its efficacy in advanced SGC models with a plan that enables identification of which subset of SGC patients may derive more benefit.


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 = $497,893 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	5	3/7/2025	NON-COMPETING CONTINUATION	$448,104
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	001	5	5/8/2025	NON-COMPETING CONTINUATION	$49,789
														Subtotal = $497,893

Issue Date FY: 2024 ( Subtotal = $487,936 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	4	3/12/2024	NON-COMPETING CONTINUATION	$448,104
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	001	4	6/19/2024	NON-COMPETING CONTINUATION	$39,832
														Subtotal = $487,936

Issue Date FY: 2023 ( Subtotal = $497,893 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	3	3/7/2023	NON-COMPETING CONTINUATION	$497,893
														Subtotal = $497,893

Issue Date FY: 2022 ( Subtotal = $492,914 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	2	3/14/2022	NON-COMPETING CONTINUATION	$448,101
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	001	2	4/21/2022	NON-COMPETING CONTINUATION	$44,813
														Subtotal = $492,914

Issue Date FY: 2021 ( Subtotal = $497,893 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	1	3/8/2021	NEW	$497,893
														Subtotal = $497,893

Grand Total All Awards = $2,474,529

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Targeting oncogenic Myb fusions in salivary gland cancer with the elongation inhibitor SVC112

Award Number: R01DE030683

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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