Abstract 5341: Bifunctional integrated molecules with combined retinoic acid receptor agonist/protein deacetylase inhibitory activities as therapeutic agents for breast cancer and neuroblastoma
Bibliographic record
Abstract
Abstract All-trans retinoic acid (ATRA), the oxidized form of Vitamin A, is a potent antiproliferative and differentiating agent that acts as an agonist of the retinoic acid receptors (RARs). Both 13-cis or all-trans retinoic acid are clinically used in differentiation or maintenance therapies for APL and neuroblastoma respectively. Their efficacy is however limited by resistance mechanisms. The use of small molecule inhibitors of HDACs (HDACi) for cancer treatment has been clinically validated for pan-HDAC inhibitors like SAHA (Vorinostat) or Romidepsin (Istodax) that are approved for the treatment of cutaneous T-cell lymphoma. The use of pan-HDAC inhibitors is restricted by dose-limiting toxicities at pharmacologically relevant doses, highlighting the need for alternative strategies such as use in combined therapies. Notably, synergistic activity was observed between retinoids and HDACs, which both induce cell differentiation, in a number of cancer models. Using molecular design we engineered a series of integrated hybrid small molecules that incorporates a deacetylase inhibitory activity and retinoic acid receptor (RAR) agonist. We show that these hybrid molecules inhibit the growth and survival of a wide range of cancer cell lines. In breast cancer cell lines, hybrids were shown to induce the recruitment of co-activators to RARα to the same extent as retinoic acid (RA) and to induce the release of co-repressors from RARs. Regulation of RAR-dependent transcription was shown in breast cancer and neuroblastoma cell lines using RAR reporter assays. Compounds displayed EC50 in the 10-500 nM range and an efficacy comparable to 13 cis-RA. In addition, the ability of compounds to regulate the expression of RAR target genes was confirmed in cells of both breast and neuroblastoma origin. Biochemical enzymatic assays show that HR- hybrids differentially inhibit HDAC activities with a two-log selectivity toward HDAC6 and HDAC. This inhibitory profile translated in both increased cellular acetylation of target proteins and in the down-regulation of anti-apoptotic target genes. Cytotoxicity toward breast or neuroblastoma cells correlated positively with targets’ activities. Strikingly, under conditions where 13 cis RA, SAHA or their combination had a modest or no effect on basal breast carcinoma cells viability, compounds with dual activity displayed a pronounced cytotoxic effect in the sub-uM range. Compounds were also active in the sub-micromolar range in N-Myc-amplified neuroblastoma lines IMR-32 or BE2C. In contrast compounds did not display significant cytotoxicity in non-tumorigenic primary cell lines under conditions where SAHA strongly inhibited the survival, proliferation or differentiation of these cells. Preliminary pharmacodynamic (PK) show that compounds were orally bioavailable and displayed favorable PK characteristics. Citation Format: David Cotnoir-White, Angela Miller, Bin Zhao, Isroel Weiss, James Gleason, David Bettoun, Sylvie Mader. Bifunctional integrated molecules with combined retinoic acid receptor agonist/protein deacetylase inhibitory activities as therapeutic agents for breast cancer and neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5341. doi:10.1158/1538-7445.AM2015-5341
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".