Abstract B39: Tumor hypoxia induces DNA repair vulnerabilities through contextual “loss-of- heterozygosity”
Bibliographic record
Abstract
Abstract Introduction: Intratumoral hypoxia leads to decreased expression in DNA damage response (DDR) and repair pathways. Given the “two-hit” model for loss of gene function, we hypothesize that hypoxia-mediated down-regulation of gene expression and function, coupled with an already inactive allele may ultimately give rise to an exploitable contextual “loss-of-heterozygosity” phenotype. Method: To interrogate this relationship, isogenic DLD-1 cells heterozygous and homozygous null for BRCA2, were placed under normoxic (21% O2) or hypoxic (0.2% O2) conditions for 72 hours. Hypoxia-mediated changes in DDR response and DNA repair were evaluated by cell proliferation, cell cycle analysis, western blots, qPCR, immunofluorescence, clonogenic assays and repair assays. Results: No differences in proliferation and cell survival were observed between oxic and hypoxic cells (72 hours - 0.2% O2). Under chronic hypoxic conditions, confirmed by the up-regulation of VEGF and HIF1α, mRNA and protein expression of key homologous recombination (HR) genes (BRCA1, BRCA2, RAD51) were down-regulated. Functionally, BRCA2(-/-) null cells proved unable to recruit Rad51 foci and resultantly presented a profound sensitivity to PARP inhibition. Conversely, heterozygote BRCA2(+/-) cells retained the ability to recruit Rad51 foci under both oxic and hypoxic conditions, however, exposure to chronic hypoxia resulted in a reduction in the number of foci formed. Chronically hypoxic BRCA2(+/-) cells exhibited a 30 to 40% increase in sensitivity to PARP inhibition when compared to their oxic counterparts. Preliminary data shows a similar synthetically lethal relationship in genetic and tumor microenvironment induced HR deficient cells, when challenged with DNA damage response (DDR) kinase inhibitors ATRi and DNAPKi. Conclusions: Herein we illustrate through a novel mechanism of contextual “loss-of heterozygosity”, which marries the tumor microenvironment and innate genetic alterations, increased sensitivity to DDR kinase inhibitors and PARPi. Citation Format: Osman Mahamud, Melvin L.K Chua, Winnie Lo, Gaetano Zafarana, Robert G. Bristow. Tumor hypoxia induces DNA repair vulnerabilities through contextual “loss-of- heterozygosity” [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B39.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".