Combined Targeted Treatment to Eliminate Tumorigenic Cancer Stem Cells in Human Pancreatic Cancer

Mueller, M; Hermann, Patrick C.; Witthauer, Juliane; Rubio-Viqueira, Belén; Leicht, Simon F.; Huber, Stephan; Ellwart, Joachim W.; Mustafa, Mona; Bartenstein, Peter; D’Haese, Jan G.; Schoenberg, M. H.; Berger, Frank; Jauch, Karl Walter; Hidalgo, Manuel; Heeschen, Christopher

doi:10.1053/j.gastro.2009.05.053

Cited by 318 publications

(256 citation statements)

References 27 publications

Supporting

Mentioning

243

Contrasting

Unclassified

Order By: Relevance

“…Doxorubicin, a standard component of breast cancer chemotherapy, produced a negligible effect on the proportion of CD44 þ /CD24 low CSCs in the remaining live cells, whereas metformin alone or in combination with doxorubicin significantly reduced the number of surviving CSCs. More important, doxorubicin plus metformin produced a durable regression of tumors in nude mice with tumor xenografts, even after cessation of therapy, similar to rapamycin results in the preclinical model of pancreatic cancer discussed earlier (16). These results were subsequently extended to cancer cell lines from prostate and lung adenocarcinomas, where metformin similarly inhibited CSCs (26).…”

supporting

confidence: 57%

See 1 more Smart Citation

Metformin and Cancer Stem Cells: Old Drug, New Targets

Bednar

Simeone

2012

Cancer Prevention Research

View full text Add to dashboard Cite

In this issue of the journal, Bao and colleagues report (beginning on page 355) that the antidiabetic drug metformin targets pancreatic cancer stem cells through, at least partially, the modulation of miRNA expression and subsequent regulation of stem cell renewal and signaling factors. In this Perspective, we briefly discuss the cancer stem cell hypothesis, its clinical relevance, and how targeting the mTOR pathway may yield an avenue for disrupting the cancer stem cell compartment and thus yield long-term therapeutic benefit in multiple cancers. Cancer Prev Res; 5(3); 351-4. Ó2012 AACR.

show abstract

supporting

confidence: 57%

“…Inhibition of mTOR by rapamycin has also been used in a preclinical model of pancreatic cancer (16). Gemcitabine treatment of bulk pancreatic cancer cell lines or cells derived from primary human pancreatic tumors led to the enrichment of the CD133 þ CSC population.…”

mentioning

confidence: 99%

Metformin and Cancer Stem Cells: Old Drug, New Targets

Bednar

Simeone

2012

Cancer Prevention Research

View full text Add to dashboard Cite

show abstract

“…We can not rule out that tumors obtained from metastatic PDAC patients would show different patterns, an aspect that should be evaluated in the future. In addition, other studies based on different hypothesis-driven, for instance, patterns based on hedgehog signaling [38], can complement optimal preclinical data in PDAC.…”

Section: Discussionmentioning

confidence: 99%

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

et al. 2011

View full text Add to dashboard Cite

Background Efforts to identify novel therapeutic options for human pancreatic ductal adenocarcinoma (PDAC) have failed to result in a clear improvement in patient survival to date. Pancreatic cancer requires efficient therapies that must be designed and assayed in preclinical models with improved predictor ability. Among the available preclinical models, the orthotopic approach fits with this expectation, but its use is still occasional. Methods An in vivo platform of 11 orthotopic tumor xenografts has been generated by direct implantation of fresh surgical material. In addition, a frozen tumorgraft bank has been created, ensuring future model recovery and tumor tissue availability.Results Tissue microarray studies allow showing a high degree of original histology preservation and maintenance of protein expression patterns through passages. The models display stable growth kinetics and characteristic metastatic behavior. Moreover, the molecular diversity may facilitate the identification of tumor subtypes and comparison of drug responses that complement or confirm information obtained with other preclinical models. Conclusions This panel represents a useful preclinical tool for testing new agents and treatment protocols and for further exploration of the biological basis of drug responses.

show abstract

“…15,19 Most importantly, CSCs have also been proposed as the major source of resistance to conventional chemotherapy and radiotherapy and the high recurrence rate after clinical remission in pancreatic cancer. 19,20 Therefore, novel therapies are urgently needed that are capable of eliminating CSCs while leaving normal stem cells unaffected. Lee et al 15 first reported the identification of human pancreatic CSCs, which are defined by the expression of cell-surface marker CD441CD241epithelial-specific antigen1 and account for 0.5-1.0% of all pancreatic cancer cells.…”

Section: Cancer Therapymentioning

confidence: 99%

Metronomic chemotherapy following the maximum tolerated dose is an effective anti‐tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells

Vives

Ginestà

Gracova

et al. 2013

Intl Journal of Cancer

View full text Add to dashboard Cite

In this article, the effectiveness of a multi-targeted chemo-switch (C-S) schedule that combines metronomic chemotherapy (MET) after treatment with the maximum tolerated dose (MTD) is reported. This schedule was tested with gemcitabine in two distinct human pancreatic adenocarcinoma orthotopic models and with cyclophosphamide in an orthotopic ovarian cancer model. In both models, the C-S schedule had the most favourable effect, achieving at least 80% tumour growth inhibition without increased toxicity. Moreover, in the pancreatic cancer model, although peritoneal metastases were observed in control and MTD groups, no dissemination was observed in the MET and C-S groups. C-S treatment caused a decrease in angiogenesis, and its effect on tumour growth was similar to that produced by the MTD followed by anti-angiogenic DC101 treatment. C-S treatment combined an increase in thrombospondin-1 expression with a decrease in the number of CD1331 cancer cells and triple-positive CD1331/CD441/CD241 cancer stem cells (CSCs). These findings confirm that the C-S schedule is a challenging clinical strategy with demonstrable inhibitory effects on tumour dissemination, angiogenesis and CSCs.Metronomic chemotherapy (MET; regular administration of conventional chemotherapeutic drugs at low, minimally toxic doses, with no prolonged drug-free breaks) appears to fulfil many of the requirements of an optimal multi-target therapy (minimal toxicities to allow for combinations, targeting not only the tumour but also the tumour microenvironment). 1 Although the effectiveness and rationale of maximum tolerated dose (MTD)-based chemotherapy regimens and doseescalation strategies have been questioned for many years, especially in patient populations with poor-prognosis tumours, 2 we have lacked sufficient convincing pre-clinical data to validate the potential of other alternative schedules of drug administration. Nevertheless, one such groundbreaking pre-clinical study was published 10 years ago by Browder et al. 3 working in Judah Folkman's laboratory, and the results being confirmed in Robert Kerbel's laboratory. 4 Using transplantable tumours 3 and xenograft models, 4 the two teams demonstrated that the frequent administration of low-dose chemotherapy could produce potent anti-cancer effects through the inhibition of angiogenesis.In contrast to conventional MTD chemotherapy, the main primary target of MET is thought to be the tumour's neovasculature, although this is considered to be only an initial site of action, additional mechanisms are probably involved. 5 Kerbel and Kamen 5 suggested that combining standard MTD chemotherapy with MET might have a synergistic effect. MTD chemotherapy would debulk the tumour before the initiation of MET, which would then have an anti-angiogenic effect, while abolishing the endothelial cell rebound. 6 The concepts of combining MET with MTD chemotherapy or with agents targeting vascular endothelial growth factor

show abstract

Combined Targeted Treatment to Eliminate Tumorigenic Cancer Stem Cells in Human Pancreatic Cancer

Cited by 318 publications

References 27 publications

Metformin and Cancer Stem Cells: Old Drug, New Targets

Metformin and Cancer Stem Cells: Old Drug, New Targets

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

Metronomic chemotherapy following the maximum tolerated dose is an effective anti‐tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells

Contact Info

Product

Resources

About