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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - STROMAMECH (Targeting stromal cells to modify tumor mechanical microenvironment and optimize drug delivery)

Teaser

Summary

Current chemotherapeutic agents are potent enough to kill cancer cells. Nonetheless, failure of standard chemotherapies for many cancer types (e.g., pancreatic and breast cancers) is primarily attributed to these agents never reaching cancer cells in amounts sufficient for complete cure. In solid tumours, blood vessels are often compressed, drastically reducing perfusion, thus resulting in insufficient drug delivery. Vessel compression is a consequence of mechanical stresses accumulated within the tumour during progression. Alleviation of these stresses has the potential to reopen compressed vessels and improve tumour perfusion. Here, we proposed to test the hypothesis that judicious depletion of stromal cells, namely the cancer-associated fibroblasts (CAFs), has the potential to alleviate stress levels in highly desmoplastic and hypoperfused tumours and, thus, enhance chemotherapy. To explore this hypothesis, a combination of cutting-edge computational and experimental techniques were employed. Specifically, in vivo studies were performed in mice using vismodegib (GDC-0449; ErivedgeÂ®), a clinically approved sonic hedgehog signalling pathway inhibitor, to reduce the population of CAFs in pancreatic and breast tumor models. CAFs reduction improved tumor perfusion and the efficacy of common cytotoxic drugs, namely gemcitabine, AbraxaneÂ® and DoxilÂ®. A mathematical model was also developed to provide insights to the model predictions about how CAFs contribute to the accumulation of forces in tumors.

Failure of standard cancer therapies has dramatic effects on the health and quality of life of cancer patients and their families, both physically and emotionally. Thus, an improved therapeutic strategy is desperately needed. The main hypothesis of the proposed study was that if the delivery of drugs to the tumor is optimized, then the treatment efficacy will be enhanced even at a lower dose of the cytotoxic drug. Therefore, from a societal point of view the benefit from the development of a new therapeutic anti-cancer strategy is that it can potentially improve the efficacy of cytotoxic drugs by optimizing their intratumoral distribution leading to the desired outcome of prolonged disease-free survival.

The overall objectives of the STROMAMECH project were:
- Execution of in vivo experiments on tumours grown in mice in order to prove the main hypothesis of the project that judicious depletion of stromal cells, namely the cancer-associated fibroblasts (CAFs), has the potential to alleviate stress levels in highly desmoplastic and hypoperfused tumours and, thus, enhance chemotherapy.
- Development of a structure-based, biomechanical model for tumour growth focusing on the contribution of CAFs to provide insights to experimental data.

Work performed

Previous studies have employed inhibitors of the Sonic Hedgehog (SHH) signaling pathway to achieve pharmacologic depletion of CAFs in pancreatic cancer animal models. CAFs depletion was shown to reduce number of CAFs and improve blood vessel functionality and the efficacy of chemotherapy. Despite these encouraging data, however phase-II clinical trials failed to show any benefit. However, these results could be due to different reasons, such as intrinsic resistance to chemotherapy as increased delivery of a drug might not benefit patients if cancer cells are or become resistant to that drug. Additionally, a series of recent in vivo studies have shown that deletion of CAFs by genetic manipulation in mouse models induces immunosuppression and promotes tumour progression in pancreatic cancers. Therefore manipulation of CAFs has been shown to both promote and restrain tumor progression, but any comparison between genetic deletion and pharmacologic depletion should be viewed with caution and take into account that these methods significantly differ from each other as genetic deletion is chronic and effects of genetic deletion are not reversible. On the other hand, pharmacologic depletion is acute and effects are reversible when the treatment stops.

In STROMAMECH, we revisited the use of SHH inhibitors to target CAFs with the aim to i) elucidate the mechanism of how CAFs depletion improves drug delivery, ii) extent and evaluate the potential use of SHH inhibitors to breast cancers, and iii) investigate whether SHH inhibition can improve not only chemotherapy, but also the efficacy of the most commonly used breast cancer nanomedicines, namely AbraxaneÂ® and DoxilÂ®. To achieve our aims, we employed vismodegib (ErivedgeÂ®) in mouse tumor models for pancreatic and breast cancers to explore its ability to normalize the tumor microenvironment, decrease solid stress levels and improve tumor perfusion and therapeutic outcomes.

To elucidate the mechanism by which depletion of CAFs improves drug delivery, we initially hypothesized that depleting stromal cells in primary pancreatic tumors will improve the functionality of tumor blood vessels. To investigate this, we employed two human pancreatic cancer cell lines, namely MiaPaCa2 and BxPC3 to develop xenograft tumor models in immunodeficient mice. We showed that vismodegib improves perfusion, increases delivery of chemotherapy and improves therapeutic outcomes. Finally, we employed a breast tumor model to study the effect of combining vismodegib with two clinically approved nanoparticles: Abraxane and Doxil and showed that vismodegib can also significantly enhance the efficacy of these common cancer nanomedicines.

Final results

In STROMAMECH, we elucidated the mechanism of how CAFs depletion improves drug delivery, extended and evaluated the potential use of SHH inhibitors to breast cancers, and proved that SHH inhibition can improve not only chemotherapy, but also the efficacy of the most commonly used breast cancer nanomedicines, namely AbraxaneÂ® and DoxilÂ®.

The main hypothesis of the proposed study was that if the delivery of drugs to the tumor is optimized, then the treatment efficacy will be enhanced even at a lower dose of the cytotoxic drug. Therefore, from a societal point of view the benefit from the development of a new therapeutic anti-cancer strategy based on the combinatorial use of vismodegib with chemotherapy or nanomedicine is that it can potentially improve the efficacy of the cytotoxic drugs by optimizing their intratumoral distribution, leading to prolonged survival. Clinical trials are now required for the results of our research to be implemented to humans.

From the economic point of view the benefit from the introduction of a new therapeutic strategy to treat cancer can also be of great significance. First of all, any cancer therapy involves high costs for the compensation of clinicians and health centers as well as for the purchase of the drugs themselves. This cost is usually covered by a public or private health insurance plan and in some cases by the patients themselves. In all cases, these cancer-treatment-associated costs are a burden to the society, which becomes evident either directly or indirectly through increased taxation and expensive health insurance cost rates. Therefore, the ability to improve cancer therapy can save funds as well as labor time both from clinicians and cancer patient and relatives.