Vascular ALK1 May Be Biomarker Indicating Breast Cancer Metastases Interview with:
Kristian Pietras, Ph.D.
Göran & Birgitta Grosskopf Professor of Molecular Medicine
Strategic Director of Cancer Research Lund University
Dept of Laboratory Medicine Lund
Div of Translational Cancer Research Lund, Sweden

Medical Research: What is the background for this study? What are the main findings?

Dr. Pietras: Breast cancer is the largest malignant disease among women with 1.7 million new cases worldwide each year (25% of all new cancer cases for women). The prognosis for breast cancer patients is relatively good when the disease is detected at early stages (close to 90% of patients are still alive 5 years after diagnosis). Nevertheless, metastatic disease is the cause of 90% of all cancer-related deaths. Thus, learning more about the metastatic process and finding new cures for widespread disease is justifiably at the center of clinical attention.

The current study is part of our ongoing efforts to map support functions performed by the various cell types comprising the tumor stroma with the premise that decisive treatment benefit can only be achieved by targeting multiple, but distinct, cell types and pathways that collectively sustain the growth of tumors. The development of a rich vascular supply  is recognized as a key hallmark of a growing tumor necessary for the development into a clinically relevant disease.

Our focus is the role of the tumor vasculature in preventing or promoting metastatic dissemination from the primary tumor. For a metastasis to form, a cancer cell must,

1) detach from its neighboring cells in the mother tumor,
2) traverse the vascular wall to escape into the blood stream,
3) exit the vasculature to enter the metastatic site, and
4) colonize the metastatic site.

Recent evidence points to that the transmigration into and out of the vasculature is a regulated process of previously unrecognized importance for the metastatic process. Importantly, the fact that the process of escape into/from the vasculature is regulated also implies that it is possible to use drugs to block this process.

In the present study, we have combined functional studies in advanced models of cancer and computational biology approaches to investigate the specific contribution to the metastatic process of a molecular signaling pathway emanating from the ALK1 protein expressed by endothelial cells in the vasculature. Using information from 2 different patient cohorts including a total of  nearly 2000 breast tumors, we found that patients specifically having high levels of ALK1 in the vasculature of their tumor were much more likely to develop metastatic/recurrent disease. Accordingly, therapeutic administration of a drug (dalantercept) blocking the action of ALK1 prevented metastatic dissemination in multiple mouse models of breast cancer to a large degree. In addition, combination therapy of dalantercept and a commonly used chemotherapeutic drug (docetaxel) was exceedingly effective in preventing spread of the primary tumor to the lungs.

Our results suggest that the molecular features of the tumor vasculature are important to consider as potential determinants of breast cancer dissemination and that metastatic spread can be delayed by targeting the tumor vasculature.

Medical Research: What should clinicians and patients take away from your report?

Dr. Pietras: Our results suggest that the presence of high levels of ALK1 in the breast tumor vasculature is a prognostic biomarker for metastatic disease. Moreover, our work encourages clinical testing of drugs blocking ALK1 in breast cancer with prevention of metastatic dissemination as the primary outcome.

Furthermore, our study reiterates the active participation of the tumor vasculature in the process of metastatic dissemination, and highlights that specific molecular features of endothelial cells (in this case, high expression of ALK1) can serve as both prognostic biomarkers and drug targets in breast cancer.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Pietras: We are currently more in detail  describing the molecular features of a tumor vasculature conducive to metastatic dissemination, as well as those that are protective of metastatic dissemination. Our hope is that this will reveal an even more precise and global prognostic biomarker of recurrent disease, as well as identify additional and complementary drug targets. In addition, we are currently performing therapeutic studies with dalantercept in models of breast cancer in order to pinpoint the precise therapeutic regimen and disease stage at which the treatment is the most effective.


Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer

Sara I. Cunha, Matteo Bocci, John Lövrot, Nikolas Eleftheriou, Pernilla Roswall, Eugenia Cordero, Linda Lindström, Michael Bartoschek, B. Kristian Haller, R. Scott Pearsall, Aaron W. Mulivor, Ravindra Kumar, Christer Larsson, Jonas Bergh, and Kristian Pietras

Cancer Res June 15, 2015 75:2445-2456; doi:10.1158/0008-5472.CAN-14-3706

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Kristian Pietras, Ph.D., Göran & Birgitta Grosskopf Professor of Molecular Medicine, & Strategic Director of Cancer Research Lund University (2015). Vascular ALK1 May Be Biomarker Indicating Breast Cancer Metastases