Abstract A24: Enhancing chemotherapy efficacy and antitumor immune activity by combined antisense downregulation of TS and IDO.
Bibliographic record
Abstract
Abstract Chemotherapy plays a major role in treatment of many common cancers. However, it is limited by intrinsic and/or acquired tumor cell resistance to anticancer drugs, often mediated by increased expression of genes mediating that resistance. An approach to increase chemotherapy effectiveness is to reduce expression of such genes using small molecules or RNAi to silence specific targets that cancer cells rely on for escape from death due to exogenous treatment or immune cell attack. We have previously shown that siRNA downregulation of thymidylate synthase (TS), the enzyme responsible for the de novo synthesis of thymidylate and a common target for some anti-cancer drugs (5FUdR, pemetrexed, and others) enhances the activity of these drugs in vitro. Using lower concentrations of anticancer drugs has the potential to decrease deleterious side effects, including therapy-induced toxicity to T cells capable of recognizing and killing tumor cells. In addition, certain tumor proteins including indoleamine 2,3-dioxygenase [IDO] can regulate immunosurveillance by inhibiting antitumor T and NK cell activity. IDO can also mediate tumor cell resistance to some anticancer drugs, such as imatinib. To assess the capacity of combined siRNA knockdown of TS and IDO in human tumor cells to increase sensitivity to anticancer drugs, we report that: a) TS siRNA downregulates TS by 90% in HCT-15 colon carcinoma cells, over 90% percent in A549 lung carcinoma cells, and by 80% in H441 lung carcinoma cells, b) shRNA expression vectors stably expressing IDO siRNA in multiple clonally-derived populations of A549 reduces IFNγ-induced IDO protein expression by over 95%. Transiently-transfected TS siRNA is being used, alone and in combination with stable shRNA-mediated reduction in IDO, to assess the utility of targeting both mRNAs to enhance sensitivity to TS-targeting drugs (5-FU, 5-FUdR, pemetrexed), DNA-damaging anticancer drugs (cisplatin, melphalan) and both, both in vitro and against human A549-derived tumour xenografts in immunocompromised mice without T cells but competent with respect to NK cell activity. Combined antisense targeting of both TS and IDO in human tumor cells has the potential to increase the effectiveness of anti-TS and other drugs, both by increasing tumor cell drug sensitivity and by combined enhancement of sensitivity to drug treatment and reduced inhibition of NK cell activity. Citation Format: Saman Maleki Vareki, James Koropatnick. Enhancing chemotherapy efficacy and antitumor immune activity by combined antisense downregulation of TS and IDO. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A24.
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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) | 0.003 | 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".