Abstract A38: Targeting Microenvironment Damage Responses via PARP inhibition to Enhance Prostate Cancer Therapy
Bibliographic record
Abstract
Abstract Introduction: Radiation and chemotherapeutic drugs have significantly improved the long-term outlook for patients diagnosed with prostate cancer. However, in men with metastatic prostate cancer, the development of radio and chemo resistance is almost universal. As a result, understanding and circumventing chemo/radiotherapy resistance has become a research priority. In addition to damaging neoplastic cells, radiation and chemotherapy also exert potent “bystander” effects on the tumor microenvironment (TME) by induction of a DNA Damage Secretory Program (DDSP). In this study we sought to identify and modulate master regulators of the DDSP in order to augment the effectiveness of conventional cancer therapeutics. The Nelson group and others have shown that NFkB is a master regulator of the DDSP, but pharmacological inhibition of NFkB has been challenging. As PARP can activate NFkB and PARP inhibitors (PARPi) have received clinical approval for cancer therapy, we evaluated the effects of PARPi to modulate the DDSP. Results: We used prostate (PF) and bone fibroblasts (BF) as our experimental model as this cell type comprises a substantial component of the TME in bone. We determined that ionizing radiation (IR) induced DDSP in PFs and BFs that was suppressed by PARPi, and observed significant reductions in transcripts encoding several key tumor promoting DDSP factors such as IL8, Wnt16b. Fractionated IR was more effective in increasing the transcript levels of various DDSP factors compared to single dose of IR. PARPi also suppressed DDSP-induced nuclear translocation of NFkB in fibroblasts and modulated the DDSP via the function/modification of NEMO. Conditioned media from irradiated PFs and BFs or co-culture with them induced growth and therapy resistance in prostate cancer (PCa) cells, indicative of the tumor promoting role of DDSP, which was suppressed after PARPi addition either later or in the cells treated with both IR and PARPi. Another PARP family member, PARP5 inhibition in irradiated BFs showed significant reduction in DDSP marker's transcript level, which was also reflected by inhibited growth of PCa cells when radiated BF's condition media was added along with PARP5 inhibitor. Conclusions: PARP inhibitors, developed primarily to target vulnerabilities in tumor cells directly, may provide additional anti-tumor effects via DDSP and repurposing PARPi to suppress the DDSP could augment responses to radiation and chemotherapy via microenvironment modulation. In addition to PARP1, our ongoing studies are designed to evaluate other PARP family members including PARP5 and PARP10 that may influence damage responses. Citation Format: Payel Chatterjee, Peter Nelson. Targeting Microenvironment Damage Responses via PARP inhibition to Enhance Prostate Cancer Therapy [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 A38.
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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) | 0.007 | 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".