R35CA263778
Project Grant
Overview
Grant Description
Understanding and Exploiting DNA Topoisomerases in Cancer Biology - Abstract
The appropriate control of DNA topology has a major impact on the stability and flow of genetic information. The present application focuses on type II DNA topoisomerases, molecular machines that modulate DNA supercoiling and remove chromosome entanglements by catalyzing the ATP-dependent transport of one DNA duplex through another.
Type II topoisomerases play a frontline role in cancer biology as factors that can both maintain and disrupt genome integrity; they are also demonstrated drug targets for treating cancer. Our past research on eukaryotic topoisomerase II (topo II) has opened up new research avenues for understanding cancer etiology and improving cancer treatment.
The present application will deliver groundbreaking solutions to key problems in the field, including how certain classes of anti-topo II drugs act on the enzyme, how topo II is localized to key sites of action where it resolves potentially deleterious chromosomal topologies, and how aberrant topo II activity can promote DNA damage and genetic instability.
We will also investigate innovative concepts and highly significant lines of inquiry raised by our new findings, such as how metabolites produced by the TCA cycle control topo II function. Our approach is distinguished by a comprehensive blend of biochemical, structural, computational, cell-based, and chemical biology methodologies.
High-impact outcomes will include defining how topo II appropriately localizes with chromatin and partner proteins to mitigate its natural DNA-damaging potential, establishing how the specificity of anti-topo II agents can be improved to enhance their utility in cancer treatment, and revealing the potential for natural amino acid sequence variation in type II topoisomerases to destabilize human chromosomes and act as cancer drivers.
Past progress and unpublished findings establish the feasibility of our planned goals.
The appropriate control of DNA topology has a major impact on the stability and flow of genetic information. The present application focuses on type II DNA topoisomerases, molecular machines that modulate DNA supercoiling and remove chromosome entanglements by catalyzing the ATP-dependent transport of one DNA duplex through another.
Type II topoisomerases play a frontline role in cancer biology as factors that can both maintain and disrupt genome integrity; they are also demonstrated drug targets for treating cancer. Our past research on eukaryotic topoisomerase II (topo II) has opened up new research avenues for understanding cancer etiology and improving cancer treatment.
The present application will deliver groundbreaking solutions to key problems in the field, including how certain classes of anti-topo II drugs act on the enzyme, how topo II is localized to key sites of action where it resolves potentially deleterious chromosomal topologies, and how aberrant topo II activity can promote DNA damage and genetic instability.
We will also investigate innovative concepts and highly significant lines of inquiry raised by our new findings, such as how metabolites produced by the TCA cycle control topo II function. Our approach is distinguished by a comprehensive blend of biochemical, structural, computational, cell-based, and chemical biology methodologies.
High-impact outcomes will include defining how topo II appropriately localizes with chromatin and partner proteins to mitigate its natural DNA-damaging potential, establishing how the specificity of anti-topo II agents can be improved to enhance their utility in cancer treatment, and revealing the potential for natural amino acid sequence variation in type II topoisomerases to destabilize human chromosomes and act as cancer drivers.
Past progress and unpublished findings establish the feasibility of our planned goals.
Awardee
Funding Goals
TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Baltimore,
Maryland
212051832
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 529% from $657,741 to $4,136,165.
The Johns Hopkins University was awarded
Exploiting DNA Topoisomerases in Cancer Biology
Project Grant R35CA263778
worth $4,136,165
from National Cancer Institute in September 2021 with work to be completed primarily in Baltimore Maryland United States.
The grant
has a duration of 7 years and
was awarded through assistance program 93.396 Cancer Biology Research.
The Project Grant was awarded through grant opportunity NCI Outstanding Investigator Award (R35 Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 8/20/25
Period of Performance
9/1/21
Start Date
8/31/28
End Date
Funding Split
$4.1M
Federal Obligation
$0.0
Non-Federal Obligation
$4.1M
Total Obligated
Activity Timeline
Transaction History
Modifications to R35CA263778
Additional Detail
Award ID FAIN
R35CA263778
SAI Number
R35CA263778-1359210657
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Private Institution Of Higher Education
Awarding Office
75NC00 NIH National Cancer Institute
Funding Office
75NC00 NIH National Cancer Institute
Awardee UEI
FTMTDMBR29C7
Awardee CAGE
5L406
Performance District
MD-07
Senators
Benjamin Cardin
Chris Van Hollen
Chris Van Hollen
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Cancer Institute, National Institutes of Health, Health and Human Services (075-0849) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,752,489 | 100% |
Modified: 8/20/25