Development of selective HDAC6 inhibitors to improve cancer immunotherapy
Ended Project Grant Awarded Last action
- Award ID
- R01CA249248
- Recipient
-
Georgetown University UEI TF2CMKY1HMX9
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $9,979,660
Award facts
- Assistance listing
- 93.395 Cancer Treatment Research
- Completion date
- Funding
-
- $8,774,679.21 Federal
- $1,204,981.00 Non-federal
- Place of performance
- Washington, DC, USA
Award details come from USAspending.gov.
Description
- Abstract
- The median survival for metastatic melanoma is approximately 8-16 months, and few therapies offer a significant improvement in overall survival. However, immunotherapeutic strategies that abrogate immunologic checkpoints or improve immunosurveillance have shown promise, especially in melanoma. We have found that both genetic abrogation and pharmacologic inhibition of HDAC6 leads to a decreased infiltration of pro-tumoral tumor-associated macrophages and downregulation of immunosuppressive mediators. These effects translated into a pronounced delay of in vivo melanoma tumor growth, which is, at least in part, dependent on intact immunity, as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Our findings demonstrate a significant immunoregulatory role of HDAC6 in melanoma, providing a rationale for the use of selective HDAC6IS to improve antitumor immunity. We are most interested in identifying HDAC6IS that are best able to reduce the pro-tumoral phenotype of tumor-associated macrophages and decrease the expression of immunosuppressive surface molecules such as PD-L1 and PD-L2 while showing little cytotoxicity on their own. Our goal is thus to design, synthesize, and test new HDAC6I both in vitro and in vivo for use in the treatment of melanoma and other malignancies. The aims to be accomplished under this grant are as follows: 1. Using molecular modeling, design, and synthesize ~50 new HDAC6IS per year, for the first three years and test these for hdac isozyme selectivity; the last two years of the grant will focus on compound scale-up, preclinical translational studies, and advanced admet testing. 2. Evaluate compounds that have IC50 values of
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| Original award | $586,358 | $586,358 |
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Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Biotechnologicky Ustav AV CR, V.v.i. | $13,872 | |
| University Of Illinois | $206,762 | |
| University Of Illinois | $784,798 |
Quick answers
Who received award R01CA249248?
R01CA249248 was awarded to Georgetown University by National Cancer Institute (National Institutes of Health) on February 1, 2021.
How much is award R01CA249248 worth?
$9,979,660 has been obligated on R01CA249248: $8,774,679 in federal funding and $1,204,981 in non-federal funding.
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