Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue
Abstract
:1. Introduction
2. Peroxisome Proliferator-Activated Receptor γ (PPARγ)/Cyclooxygenase-2 (COX-2) Expression in Tumors
3. PPARγ Expression in Tumor Stroma
4. Induction of Anakoinosis with Master Modulators
5. Keys for Uncovering the Therapeutic Potential of PPARγ Agonists: Selecting the Appropriate, Histology-Independent Combination of Master Modulators
5.1. Poor Monoactivity of PPARγ Agonists Across Different Tumor Histologies
5.2. PPARγ Agonists in Pro-Anakoinotic Combination Therapy with Master Modulators
5.2.1. PPARγ Agonists Combined with Metronomic Low-Dose Chemotherapy/Demethylating Agents
5.2.2. PPARγ Agonists Plus Dexamethasone
5.2.3. PPARγ Agonists Plus All-Trans Retinoic Acid
5.2.4. PPARγ Agonists Plus Interferon-α
5.2.5. PPARγ Agonists Plus COX-2 Inhibitor
5.2.6. PPARγ Agonists and IMiDs
5.3. PPARγ Agonists in Pro-Anakoinotic Combination Therapy Combined with Targeted Therapy
5.3.1. Pioglitazone and Imatinib
5.3.2. PPARγ and Mechanistic Target of Rapamycin (mTOR) Inhibitor
6. Specific Methodological Aspects of Anakoinosis Inducing Therapies
6.1. Communication Tools
6.2. What Is the Appropriate Model System: From Histology to ‘Evolution-Adjusted’ Tumor Pathophysiology?
6.3. What Is the Appropriate Dosage of Pro-Anakoinotic Therapy?
6.4. Pro-Anakoinotic Therapy Schedules: Indications and Diagnostics
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Communication-Associated Terms | Explanation |
---|---|
Anakoinosis | Anakoinosis is a novel paradigm for cancer treatment based on a key role for communicative reprogramming of tumor systems. Building on a systems biology approach to cancer, anakoinosis utilizes a range of non-cancer and cancer drugs in combination to treat advanced tumor disease, such as pioglitazone. In contrast to standard therapies, anakoinosis protocols are characterized by low toxicity and a good safety profile, with encouraging responses in a number of clinical trials to date. The use of drug repurposing, that is the use of non-cancer drugs as cancer treatments, is especially a notable feature of this approach. |
Pro-anakoinotic therapeutic tools (examples) | Transcriptional modulators, nuclear receptor agonists and antagonists, metronomic low-dose chemotherapy, cyclooxygenase-2 inhibitors, IMiDs, arsenic trioxide, liposomal encapsulated small oligonucleotide encoding small activating RNAs, etc. |
Metronomic tumor therapy | Metronomic tumor therapy may be defined as the frequent administration of (repurposed) drugs at doses significantly below the maximum tolerated dose with no prolonged drug-free breaks, or as the minimum biologically effective dose of an agent given as a continuous dosing regimen with no prolonged drug-free breaks that still leads to anti-tumor activity. |
Rationalizations | Describe the physical organization of tumor-associated normative notions (e.g. hallmarks of cancer); are to some degree histology- and genotype-independent; may be re-directed and reorganized by anakoinosis. |
Metabolism of evolution | The sum of extrinsically, i.e., therapeutically, and intrinsically inducible evolutionary processes within the tumor environment (tumor stroma, hosting organ, distant organ sites). |
Modularity | Modularity describes the degree and specificity to which systems’ objects, i.e. cells, pathways, molecules, therapeutic targets etc. may be communicatively rededicated by anakoinosis. |
Validity and denotation | Validity of systems objects, functions and hubs: Availability on demand at distinct systems stages; denotation: Current functional impact at a distinct systems stage, e.g. of potentially tumor-promoting pathways. In the bio-world, presence and functioning of an object (e.g., an enzyme), respectively. |
Glitazones in Refractory Tumors or Hematologic Neoplasia | ||||||
---|---|---|---|---|---|---|
Neoplasia | No pts | Chemotherapy (* = Metronomic) | Transcriptional Modulators | Small Molecule | Best Response | Reference |
Sarcomas | ||||||
Liposarcomas, intermediate to high-grade (case reports) | - | - | Troglitazone | - | Histological and biochemical differentiation | [45] |
Liposarcoma | 3 | Trofosfamide * | Troglitazone | - | Lineage-appropriate differentiation can be induced pharmacologically in a human solid tumor. | [46] |
Liposarcoma (Phase II study) | 12 | - | Rosiglitazone | - | Rosiglitazone is not effective as an antitumoral drug in the treatment of liposarcomas | [47] |
Kaposi sarcoma, refractory | 1 | Trofosfamide * | Pioglitazone | COX-2 inhibitor | Partial remission | [48] |
(Hem-)angiosarcomas | 12 | Trofosfamide * | Pioglitazone | COX-2 inhibitor | Continuos complete remission | [49] |
Breast cancer | ||||||
Refractory breast cancer (Phase II study) | 22 | - | Troglitazone | - | No significant effect | [50] |
Melanoma | ||||||
Melanoma III (versus DTIC), phase II Clinical Trials.gov:NCT01614301 | 6 | Trofosfamide * | Pioglitazone | Temsirolimus COX-2 inhibitor | Partial remission, Resolution of cachexia | [51] |
Melanoma (randomized) | ||||||
Melanoma II Arm M | 35 | Trofosfamide * | Pioglitazone | - | Stable disease | [52] |
Arm A/M | 32 | Trofosfamide * | Pioglitazone | COX-2 inhibitor | Partial remission | |
Hepatocellular carcinoma | ||||||
Hepatocellular carcinoma | 38 | Capecitabine * | Pioglitazone | COX-2 inhibitor | Partial remission | [4] |
Cholangiocellular carcinoma | ||||||
Cholangiocellular carcinoma | 21 | Trofosfamide * | Pioglitazone | COX-2 inhibitor | Partial remission | [18] |
Colorectal cancer | ||||||
Chemotherapy-resistant metastatic colorectal cancer (phase II study) | 25 | - | Troglitazone | - | Not active for the treatment of metastatic colorectal cancer | [53] |
Renal clear cell carcinoma (historic comparison) | ||||||
Renal clear cell carcinoma, relapsed | 18 | Capecitabine * | Pioglitazone | COX-2 inhibitor | Partial remission | [54] |
Renal clear cell carinoma, relapsed | 33 | Capecitabine * | Pioglitazone Interferon-alpha | COX-2 inhibitor | Continuous complete remission | [5] |
Prostate cancer | ||||||
Prostate cancer | 41 | - | Troglitazone | - | Lengthened stabilisation of prostate-specific antigen | [55] |
Castration-resistant prostate cancer | 61 | Treosulfan * | Pioglitazone, Dexamethasone | COX-2 inhibitor Imatinib | Long-term tumor control at minimal disease | [56] |
Castration-resistant prostate cancer | 36 | Capecitabine * | Pioglitazone, Dexamethasone | COX-2 inhibitor | Long-term tumor control | [57,58] |
Prostate carcinoma (randomized) | ||||||
Rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy | 106 | - | Rosiglitazone Versus Placebo | Rosiglitazone did not increase PSA doubling time or prolong the time to disease progression | [59] | |
Gastric cancer (randomized) | ||||||
Gastric cancer Arm A/M | 21 | Capecitabine * | Pioglitazone | COX-2 inhibitor | Partial remission | [60] |
Arm M | 21 | Capecitabine * | Pioglitazone no impact | |||
Glioblastoma | ||||||
Glioblastoma, refractory | 14 | Capecitabine * | Pioglitazone | COX-2 inhibitor | Disease stabilization | [61] |
Multiple myeloma | ||||||
Multiple myeloma, third-line Clinicaltrials.gov, NCT001010243 | 6 | Treosulfan * | Pioglitazone, Dexamethasone | Lenalidomide | Complete remission | [62] |
Langerhans cell histiocytosis | ||||||
Langerhans cell histiocytosis, refractory | 2 + 7 | Trofosfamide * | Pioglitazone Dexamethasone | COX-2 inhibitor | Continuous complete remission | [13,63,64] |
Hodgkin‘s lymphoma | ||||||
Hodgkin lymphoma, refractory | 3 | Treosulfan * | Pioglitazone, Dexamethasone | COX-2 inhibitor Everolimus | Continuous complete remission | [65] |
Chronic myelocytic leukemia | ||||||
Chronic myelocytic leukemia without moleclar CR | 24 | - | Pioglitazone | Imatinib | Molecular complete remission (54%) | [66] |
Acute myelocytic leukemia | ||||||
Acute myelocytic leukemia Refractory (on-going trial) | 5 + 7 | Azacitidine | Pioglitazone All-trans retinoic acid | Molecular complete remission Myelodysplastic synrome with phagocytically active blasts | [67,68] |
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Share and Cite
Heudobler, D.; Rechenmacher, M.; Lüke, F.; Vogelhuber, M.; Pukrop, T.; Herr, W.; Ghibelli, L.; Gerner, C.; Reichle, A. Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue. Int. J. Mol. Sci. 2018, 19, 3540. https://doi.org/10.3390/ijms19113540
Heudobler D, Rechenmacher M, Lüke F, Vogelhuber M, Pukrop T, Herr W, Ghibelli L, Gerner C, Reichle A. Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue. International Journal of Molecular Sciences. 2018; 19(11):3540. https://doi.org/10.3390/ijms19113540
Chicago/Turabian StyleHeudobler, Daniel, Michael Rechenmacher, Florian Lüke, Martin Vogelhuber, Tobias Pukrop, Wolfgang Herr, Lina Ghibelli, Christopher Gerner, and Albrecht Reichle. 2018. "Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue" International Journal of Molecular Sciences 19, no. 11: 3540. https://doi.org/10.3390/ijms19113540