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Principal Investigator: John A. Tainer
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $828,132
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Cancer is linked to almost every human DNA repair (DR) pathway. Genomic instability, which results
from DR defects, is a cancer hallmark. Thus, DNA damaging cancer therapies are widely used and
are often successful. Yet, the effects of DNA damage depend on poorly understood DR complexes
that are also targets for advanced treatments, e.g. PARP inhibitors that rely on a synthetic lethality
(SL) relationship between PARP and BRCA proteins. Although effective initially, these treatments
often later fail due to various means of resistance developed in tumors. Thus, better strategies are
urgently required to delay or avoid resistance by identifying new SL partners. This revised MANTIS-
DRC R35 application will focus on the BRCA paradox (whereby BRCA-defective tumor cells survive
yet BRCA inactivation causes cell and embryonic lethality) with implications for future efforts to
modulate the DNA damage response to harness the abscopal effect (a paradox whereby ionizing
radiation is immunosuppressive yet can activate an immune response to kill tumors distant from the
radiation site). We hypothesize that answers to both the 'BRCA paradox' and the ‘abscopal paradox’
lie in changes to DNA damage response that will aid in identifying strategies to tackle resistance.
Based upon his NCI-funded experience, Prof. Tainer is poised to build program efforts to efficiently
define and test these DR changes that will inform: 1) BRCA essentiality in most cells and SL in
tumors and 2) strategies to control the abscopal effect. This work will thus leverage and apply
Tainer’s seminal contributions in integrating crystal structures with X-ray scattering to define
conformations and assemblies in solution that link structures to phenotypes. Specifically, we will focus
on defining a largely enigmatic BRCA1 interactome by producing atomic-resolution structural
information and identifying new BRCA1 SL partners: these will be key proteins and interfaces
regulating DR pathways (and potentially capable of inducing an abscopal response) that are difficult
to overcome via resistance pathways. To elucidate how DR complexes orchestrate cellular processes
on DNA, we will integrate structure and imaging to map their spatial distribution and measure their
temporal dynamics with systematic and comprehensive analyses. Rather than correlating large data
sets, we will rigorously merge suitable data sets via tested Bayesian approaches for integrating data
with maximum likelihood weighting according to the relative confidence in each measurement.
Leveraging cutting-edge clinical information at MD Anderson will enable testing relevance and impact
of our predictions by comparisons with results in patient databases. Anticipated collective results will
produce quantitative, objective and mechanistic data to combine measurements from molecules to
cells, to design dissection-of-function mutations and inhibitor tools, and to predict biological outcomes.
Terms: <Abscopal effect><Advanced Cancer><Advanced Malignant Neoplasm><BRCA 1/2 mutations><BRCA mutations><BRCA1><BRCA1 Gene Product><BRCA1 Protein><BRCA1 gene><BRCA1/2 mutations><BRCA1/2mut><BRCAmut><Bayesian Method><Bayesian Methodology><Bayesian Statistical Method><Bayesian approaches><Bayesian classification method><Bayesian classification procedure><Bayesian posterior distribution><Biological><Breast Cancer 1 Gene><Breast Cancer 1 Gene Product><Breast Cancer Type 1 Susceptibility Gene><Breast Cancer Type 1 Susceptibility Protein><Breast-Ovarian Cancer Protein><Cancer Biology><Cancer Cause><Cancer Etiology><Cancer Treatment><Cancers><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell Survival><Cell Viability><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clinical><DNA><DNA Damage><DNA Damage Repair><DNA Injury><DNA Repair><DNA Repair Pathway><DNA Structure><Data><Data Bases><Data Set><Databases><Defect><Deoxyribonucleic Acid><Dissection><Distant><Early Onset Gene Breast Cancer 1><Early Onset Protein Breast Cancer 1><Embryo><Embryonic><Funding><Future><Genetic Alteration><Genetic Change><Genetic defect><Genome Instability><Genomic Instability><Hereditary Breast Cancer 1><Image><Immune response><Immunological response><Ionizing Electromagnetic Radiation><Ionizing radiation><Knowledge><Link><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Maps><Measurement><Measures><Medicine><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Mutation><Outcome><PARP Inhibitor><PARP-1 inhibitor><PARPi><Pathway interactions><Patients><Phenotype><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) polymerase 1 inhibitor><Proteins><RNF53><Radiation><Radiation-Ionizing Total><Repair Complex><Resistance><Resistance development><Resistant development><Resolution><Roentgen Rays><Seminal><Site><Spatial Distribution><Structure><Subcellular Process><Technology><Testing><Tumor Cell><Unscheduled DNA Synthesis><Work><X-Radiation><X-Ray Radiation><X-ray><Xray><abscopal activity><abscopal response><anti-cancer therapy><biologic><brca 1 gene><cancer therapy><cancer-directed therapy><conformation><conformational><conformational state><conformationally><conformations><data base><data integration><design><designing><developing resistance><experience><genome mutation><host response><human DNA><imaging><immune system response><immunoresponse><inhibitor><ionizing output><large data sets><large datasets><malignancy><nano meter scale><nano meter sized><nanometer scale><nanometer sized><nanoscale><neoplasm/cancer><neoplastic cell><pathway><programs><resistance to therapy><resistant><resistant to therapy><resolutions><response><side effect><therapeutic resistance><therapy resistant><tool><treatment resistance><tumor>