New Indications for Established Drugs: Combined Tumor-Stroma-Targeted Cancer Therapy with PPAR&amp;#947; Agonists, COX-2 Inhibitors, mTOR Antagonists and Metronomic Chemotherapy

Hafner, Christian; Reichle, Albrecht; Vogt, Thomas

doi:10.2174/1568009054863591

Cited by 59 publications

(44 citation statements)

References 203 publications

(260 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The novelty of our study combines metronomic chemotherapy with an anti-angiogenic agent in the clinical setting. There are few published clinical trials using such a combination, mostly phase I-II or abstracts [32][33][34][35][36][37][38][39]. In contrast to our study which showed benefit of docetaxel with thalidomide in solid tumors, Colleoni found that the addition of thalidomide to metronomic chemotherapy in advanced breast cancer patients did not improve the response rate compared to chemotherapy alone [40].…”

Section: Discussioncontrasting

confidence: 96%

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

et al. 2008

View full text Add to dashboard Cite

Summary Purpose: Pre-clinical models have demonstrated the benefit of metronomic schedules of cytotoxic chemotherapy combined with anti-angiogenic compounds. This trial was undertaken to determine the toxicity of a low dose regimen using docetaxel and thalidomide. Patients and Methods: Patients with advanced solid tumors were enrolled. Thalidomide 100mg twice daily was given with escalating doses of docetaxel from 10 to 30mg/m 2 /week. One cycle consisted of 12 consecutive weeks of therapy. The maximal tolerated dose (MTD) was defined as the dose of thalidomide along with docetaxel that caused ≤grade 1 non-hematologic or ≤grade 2 hematologic toxicity for cycle one. Results: Twenty-six patients were enrolled. Doselimiting toxicities (DLTs) were bradycardia, fatigue, fever, hyperbilirubinemia, leukopenia, myocardial infarction, and neutropenia. Prolonged freedom from disease progression was observed in 44.4% of the evaluable patients. Conclusions: This anti-angiogenic regimen was well tolerated and demonstrated clinical benefit. The recommended phase II dosing schedule is thalidomide 100mg twice daily with docetaxel 25mg/m 2 /week.

show abstract

Section: Discussioncontrasting

confidence: 96%

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

et al. 2008

View full text Add to dashboard Cite

show abstract

“…In search of new strategies for the treatment of cancer, the interaction between tumor and stroma is attracting more and more attention. Several well-established drugs (such as cyclooxygenase-2 inhibitors and mTOR antagonists), which had initially been developed for other indications, also have exhibited antitumor activity (28). Current experimental data and clinical experience suggest that these drugs (especially when administered at low repeated doses) target stroma functions as well as tumorstroma interactions and, above all, angiogenesis in cancer.…”

Section: Discussionmentioning

confidence: 99%

“…After 84 days (four weekly administrations of 1 mg plus two monthly infusions of 4 mg of ZA), VEGF level reduction was yet statistically significant (-27.9%; 206.60 pg/mL; 95% CI: 83.45-352.13; P = 0.014). Figure 1 shows the behavior of VEGF levels at days 0,7,14,21,28, 56, and 84 after the first ZA administration.Secondary parameters. No significant differences have been recorded in platelet level, WBC count, or hemoglobin concentration before and after each ZA infusion.…”

mentioning

confidence: 99%

Repeated Intermittent Low-Dose Therapy with Zoledronic Acid Induces an Early, Sustained, and Long-Lasting Decrease of Peripheral Vascular Endothelial Growth Factor Levels in Cancer Patients

Santini¹,

Vincenzi²,

Galluzzo³

et al. 2007

Clinical Cancer Research

173

138

View full text Add to dashboard Cite

Purpose: On the basis of stimulating data on animals reporting that weekly regimens of zoledronic acid (ZA) were effective in reducing skeletal tumor burden, we designed a study on humans to investigate the potential antiangiogenic role of a weekly low-dose therapy with ZA in patients with malignancies. Experimental Design: Twenty-six consecutive patients with advanced solid cancer and bone metastases received 1mg of ZA every week for four times (days1, 7, 14, and 21) followed by 4 mg of ZA with a standard 28-day schedule repeated thrice (days 28, 56, and 84). Patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) just before the beginning of drug infusion (0) and again at 7, 14, 21, 28, 56, and 84 days after the first ZA infusion. Results: The median VEGF basal value showed an early statistically significant (P = 0.038) decrease 7 days after the first 1-mg infusion of ZA.This effect onVEGF-circulating levels persisted also after the following 1-mg infusions at 14 (P = 0.002), 21 (P = 0.001), and 28 days (P = 0.008). Interestingly, the decrease of VEGF-circulating levels persisted also at each programmed time point during the second phase of the study (ZA 4 mg every 4 weeks). No significant differences were recorded in platelet levels,WBC count, or hemoglobin concentration before and after each ZA infusion. Conclusions: In the present study, we report that a repeated low-dose therapy with ZA is able to induce an early significant and long-lasting decrease of VEGF levels in cancer patients.Bisphosphonates are PP i analogues and differ from one another based on their substituted side chains (1). Nitrogencontaining bisphosphonates (N-BP), including pamidronate and zoledronic acid (ZA), inhibit protein prenylation, which in turn interferes with osteoclast function inducing apoptosis of osteoclasts as well as of myeloma and breast cancer cells in vitro (2 -4). Bisphosphonates have a widely recognized role in the treatment of patients with multiple myeloma and bone metastases secondary to breast cancer (5, 6). ZA recently received broad regulatory approval for the treatment of bone metastases secondary to all solid tumor types and bone lesions from multiple myeloma based on the results of three large, randomized, phase III clinical trials enrolling more than 3,000 patients (7,8). Compelling studies suggest that, besides the strong and well-known antiosteoclastic activity, the efficacy of such compounds in oncology could also be due to their antitumor effect, which is exerted at different levels (9). In detail, growing preclinical evidence supports that at least part of the antitumor activity of bisphosphonates may be attributed to an antiangiogenic effect (10). These findings have been confirmed in vivo; systemic administration of 3 Ag/kg ZA to mice resulted in a potent inhibition of angiogenesis induced by s.c. implants impregnated with h-fibroblast growth factor (11). ZA and ibandronate, but not clodronate, decreased revascularization of the ventral prostat...

show abstract

“…Current research data and clinical experience suggest that PPARA/G can mediate both direct antitumoral and immunomodulatory effects and a broad spectrum of stroma modulating activity including antiangiogenic, antiinflammatory, and immunoaugmentative effects [21,22]. Examples of superadditive complementation of PPARG agonists by COX2 inhibitors and metronomic chemotherapy are well-documented experimentally and in clinical trials, respectively [10,16,23].…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase 2 (COX2) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Are Stage-Dependent Prognostic Markers of Malignant Melanoma

Meyer

Vogt

Landthaler

et al. 2010

From Molecular to Modular Tumor Therapy

Self Cite

View full text Add to dashboard Cite

Cyclooxygenase 2 (COX2) and peroxisome proliferator-activated receptor gamma (PPARG) are stage-dependent prognostic markers of malignant melanoma Abstract Using tissue microarrays (TMAs) we studied COX2/PPARG immunoreactivity in a broad spectrum of tumors focussing on clinicopathological correlations and the outcome of patients with malignant melanoma (MM). TMA-1 contained normal and tumor tissues (n = 3448) from 47 organs including skin neoplasms (n = 323); TMA-2 88 primary MM, 101 metastases, and 161 benign nevi. Based on a biomodulatory approach combining COX/PPAR-targeting with metronomic low-dose chemotherapy metastases of 36 patients participating in a randomized trial with metastatic (stage IV) melanoma were investigated using TMA-3. COX2/PPARG immunoreactivity significantly increased from nevi to primary MM and metastases; COX2 positivity was associated with advanced Clark levels and shorter recurrence-free survival. Patients with PPARG-positive metastases and biomodulatory metronomic chemotherapy alone or combined with COX2/PPARG-targeting showed a significantly prolonged progression-free survival. Regarding primary MM, COX2 expression indicates an increased risk of tumor recurrence. In metastatic MM, PPARG expression may be a predicitive marker for response to biomodulatory stroma-targeted therapy. Using tissue microarrays (TMAs) we studied COX2/PPARG immunoreactivity in a broad spectrum of tumors focussing on clinicopathological correlations and the outcome of patients with malignant melanoma (MM). TMA-1 contained normal and tumor tissues (n = 3448) from 47 organs including skin neoplasms (n = 323); TMA-2 88 primary MM, 101 metastases, and 161 benign nevi. Based on a biomodulatory approach combining COX/PPAR-targeting with metronomic low-dose chemotherapy metastases of 36 patients participating in a randomized trial with metastatic (stage IV) melanoma were investigated using TMA-3. COX2/PPARG immunoreactivity significantly increased from nevi to primary MM and metastases; COX2 positivity was associated with advanced Clark levels and shorter recurrence-free survival. Patients with PPARG-positive metastases and biomodulatory metronomic chemotherapy alone or combined with COX2/PPARG-targeting showed a significantly prolonged progression-free survival. Regarding primary MM, COX2 expression indicates an increased risk of tumor recurrence. In metastatic MM, PPARG expression may be a predicitive marker for response to biomodulatory stroma-targeted therapy.

show abstract

New Indications for Established Drugs: Combined Tumor-Stroma-Targeted Cancer Therapy with PPARγ Agonists, COX-2 Inhibitors, mTOR Antagonists and Metronomic Chemotherapy

Cited by 59 publications

References 203 publications

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

Repeated Intermittent Low-Dose Therapy with Zoledronic Acid Induces an Early, Sustained, and Long-Lasting Decrease of Peripheral Vascular Endothelial Growth Factor Levels in Cancer Patients

Cyclooxygenase 2 (COX2) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Are Stage-Dependent Prognostic Markers of Malignant Melanoma

Contact Info

Product

Resources

About