Abstract A01: Distinct mechanism of action of DNA-damaging agent dianhydrogalactitol (VAL-083) suggests combination therapy with PARP inhibitors
Bibliographic record
Abstract
Abstract DNA damage response (DDR) is a network of intracellular pathways designed to minimize the impact of DNA damage. Multiple DNA repair pathways are known, including mismatch repair (MMR), O6-methylguanine DNA methyltransferase (MGMT), non-homologous end joining (NHEJ), and homologous recombination (HR), which act either by repairing the damage, arresting cell growth or, if necessary, promoting cell death. DDR defects are a hallmark of cancer development, rendering the cancer cells highly sensitive to targeted DNA-damaging agents. Ovarian cancer is normally treated with platinum (Pt)-based chemotherapy, which forms predominantly intrastrand DNA crosslinks; however, most advanced ovarian cancer patients develop episodes of recurrent disease with progressively shorter disease-free intervals. Dysfunctional p53 diminishes the therapeutic cytotoxicity of many DNA-targeting drugs, including Pt-based agents, comprising a therapeutic challenge in high-grade serous ovarian cancer (HGSOC), where p53 is almost universally mutated (~96%). Attempts to overcome Pt-resistance in HGSOC include PARP inhibitors (PARPi), which target tumors with deficiencies in the HR pathway (50% of HGSOC), responsible for the repair of DNA double-strand breaks (DSBs). Unfortunately, PARPi resistance frequently arises, leading to a 5-year survival rate of only 40% in this cancer. VAL-083 is a first-in-class DNA-damaging agent that has demonstrated clinical activity against a range of tumor types, including ovarian cancer, in historical NCI-sponsored clinical studies. VAL-083 rapidly induces interstrand crosslinks at guanine-N7, causing DNA DSBs that, if left unrepaired, are lethal to the cancer cell. We have shown that VAL-083 treatment leads to DNA damage that activates HR and is independent of common DNA repair pathways, including MGMT, MMR, and NHEJ. Notably, VAL-083 induces persistent S/G2 phase cell cycle arrest through two parallel pathways--one p53-independent and one p53-dependent. Taken together, these data propose the potential for targeting HR-impaired tumors and for combination treatment with S-phase specific DNA-targeting agents, including PARPi. We have previously seen VAL-083 cytotoxicity against a panel of ovarian cancer cells with differing p53 status and superadditivity between VAL-083 and PARPi olaparib, in vitro. The purpose of this study was to expand on these studies by examining the cytotoxicity of VAL-083 against HR-impaired ovarian cancer cells, the impact of p53 status, and the potential for VAL-083 combination with PARPi as part of a treatment strategy for HR-impaired, p53 dysfunctional HGSOC. VAL-083 cytotoxicity was investigated using the 5-day MTT assay in A2780 ovarian cancer cells. HR-impaired A2780 were examined using BRCA1 siRNA oligos prior to VAL-083 exposure. Combinations with PARPi veliparib (catalytic) and talazoparib (trapping) were examined in HR-proficient and HR–impaired A2780. The impact of p53 status was investigated by CRISPR/cas 9 knockout of p53 in the wildtype (wt) A2780 cells and in p53-mutated OVCAR3 cancer cells. We report increased VAL-083 cytotoxicity against HR-impaired A2780 cancer cells, further supporting HR as the main repair pathway for VAL-083-induced DNA damage, and suggesting HR-impaired HGSOC as a target for VAL-083 treatment. We further report superadditivity between VAL-083 and PARPi veliparib and talazoparib. Significantly, VAL-083 cytotoxicity against wt and knockout p53 A2780 cells and against p53-mutated OVCAR3 cells differed only by a factor of ~2, supporting a p53-independent mechanism of action for VAL-083. In conclusion, our results demonstrate a distinct DNA-damaging mechanism for VAL-083, resulting in the ability to target HR-impaired tumors and overcome MGMT- , MMR- , and NHEJ-related chemoresistance. VAL-083 activity was independent of p53 status, and superadditivity with PARPi was identified in HR-proficient A2780. Studies in HR-impaired A2780 are ongoing and will also be presented. Citation Format: Jeffrey A. Bacha, Guangan He, Xiaolei Xie, Anne Steino, Dennis M. Brown, Zahid H. Siddik. Distinct mechanism of action of DNA-damaging agent dianhydrogalactitol (VAL-083) suggests combination therapy with PARP inhibitors. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A01.
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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".