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Genome agnostic, multi-level non-oncogene addiction-based systems pharmacology for rescuing metastatic
Dennis Christoph Harrer1, Florian Lüke1,2, Tobias Pukrop1,3
1Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.
Abstract:
Rescue therapies for relapsed/refractory (r/r) metastatic neoplasias present significant unmet needs. Tumor tissue editing regimen for 13 r/r tumor types, carcinomas, sarcomas and hematologic neoplasias, included in 15 phase I/II trials, nuclear/cytokine receptor agonists, pioglitazone, plus/minus dexamethasone or all-trans retinoic acid or interferon-α to counterbalance tumor tissue homeostasis and reprogramming of cancer hallmarks, stress response inhibitors, COX-2 inhibitor, everolimus, lenalidomide, or clarithromycin, and a stress response inducer, low-dose metronomic chemotherapy with treosulfan, trofosfamide, capecitabine, or azacitidine. CR in three, cCR in another five r/r neoplasias, as the best response occurred after transcriptional reprogramming of cancer hallmarks, inflammation control or differentiation induction. Receptor agonist combinations for cCR induction can be identical among quite different tumor types and diversified within the same tumor histology. Data reveal ubiquitous, differential transcriptional access to non-oncogene addiction (NOA) networks that cope with cancer hallmarks/stress responses and three levels of therapeutic NOA targeting. (1) Agonists of nuclear/cytokine receptor NOAs critically target tumor identity and viability, while (2) transcriptional reprogramming of NOA networks that contribute to tumor tissue addiction, thereby genome-agnostically counteracting oncogene addictions. (3) Targeting edited NOAs may improve long-term outcome with CR/cCR (everolimus, IMiD). Transcriptionally accessible NOA targets offer high specificity, modest toxicity profile, low cost of therapy and outpatient treatment, independent of comorbidities. Adaptive targeting of the transcriptomic landscapes of tumor cell compartments breaks tumor tissue addiction and overcomes M-CRAC, post-therapy metastasis, cancer cell recolonization, acquired resistance and genetic heterogeneity. Thus, editing approaches provide a template for controlling metastatic r/r tumors. In the future, diagnostics of NOA networks and transcription factors involved in tumor tissue addiction may be as valuable for therapy selection as histological/molecular genetic tumor typing for the establishment of personalized hematology/oncology.
Insights
This study introduces a novel tumor editing regimen for relapsed/refractory metastatic cancers. The approach targets non-oncogene addiction networks, showing promise in controlling difficult-to-treat tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Relapsed/refractory (r/r) metastatic neoplasias pose significant unmet clinical needs.
- Current treatment strategies often fail to address tumor tissue homeostasis and reprogramming.
- The concept of non-oncogene addiction (NOA) offers a potential avenue for novel therapeutic interventions.
Purpose of the Study:
- To investigate a tumor tissue editing regimen for various r/r tumor types.
- To evaluate the efficacy of targeting non-oncogene addiction (NOA) networks in overcoming cancer hallmarks and stress responses.
- To explore the potential of adaptive transcriptomic targeting for controlling metastatic cancers.
Main Methods:
- Conducted 15 phase I/II trials involving a tumor tissue editing regimen for 13 r/r tumor types.
- Utilized combinations of nuclear/cytokine receptor agonists, pioglitazone, dexamethasone, all-trans retinoic acid, interferon-α, stress response inhibitors, and low-dose metronomic chemotherapy.
- Focused on transcriptional reprogramming of cancer hallmarks and inflammation control.
Main Results:
- Achieved complete response (CR) in three and complete clinical response (cCR) in five r/r neoplasias.
- Observed that best responses occurred after transcriptional reprogramming, inflammation control, or differentiation induction.
- Identified ubiquitous, differential transcriptional access to non-oncogene addiction (NOA) networks across diverse tumor types.
Conclusions:
- The developed editing approaches provide a template for controlling metastatic r/r tumors by breaking tumor tissue addiction.
- Targeting edited NOAs demonstrates potential for improving long-term outcomes with CR/cCR.
- Future diagnostics of NOA networks and transcription factors may become crucial for personalized therapy selection in oncology.
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