Inhibiting ALK1 in Breast Cancer May Halt Metastases

Kristian Pietras, PhD

Kristian Pietras, PhD

Inhibition of the activin receptor-like kinase 1 (ALK1) protein may prevent metastasis of breast cancer,¹according to a study published inCancer Research. Kristian Pietras, PhD et al at Lund University in Sweden found that metastasis was more common in patients with breast cancer who have high levels of ALK1 protein in their tumor blood vessels.¹Therefore, inhibition of the ALK1 pathway may be beneficial in the treatment of metastatic disease.¹

ALK1, a receptor of the transforming growth factor-beta (TGF-ß) family, is selectively expressed on activated endothelial cells. ALK1 promotes vascular maturation and stabilization, angiogenesis steps that follow those regulated by vascular endothelial growth factor (VEGF).²

Pietras stated that greater knowledge of the metastatic process, coupled with efforts to minimize disease spread, is essential for effective clinical management.¹“We are investigating the role of ALK1 protein expressed by endothelial cells in promoting metastatic dissemination from primary breast tumors,” Pietras said.¹He explained that the spread of cancer involves a host of cell activity: a cancer cell must detach and transverse the vascular wall to escape into the bloodstream, then must exit the vasculature to enter the metastatic site, and colonize the new tissue.¹Because the process of escape into and from the vasculature isregulated,it may be possible to use drugs to block this process.¹

Investigative Approach

In their study aimed at understanding the role of ALK1 in breast cancer metastasis, Pietras and his team examined murine models of breast cancer; tumor samples from patients in a population-based, nested case-control study; and breast cancer gene-expression data. They also tested an ALK1 inhibitor, dalantercept.¹

Dalantercept

Dalantercept is a first-in-class angiogenesis inhibitor whose mechanism of action is distinct from that of VEGF inhibition.³This investigational agent acts by preventing BMP9 and BMP10 (proteins of the TGF-ß superfamily) from interacting with ALK1.³Dalantercept is being developed specifically for the treatment of patients with advanced cancer for whom other treatment has failed.³

Findings in Mice

The authors found that a mouse version of dalantercept prevented metastatic dissemination, and that combination treatment with chemotherapy (docetaxel + dalantercept) stopped the spread of primary breast tumor to the lungs.¹

Findings in Humans

Analysis of gene-expression patterns in tumors from 768 patients revealed a significant association between ALK1 expression and the incidence of metastatic disease.¹Similarly, gene-expression data from The Cancer Genome Atlas showed that ALK1 expression correlates with the expression of well-known endothelial markers, and that higher levels of ALK1 expression are an independent prognostic indicator of poor survival among patients with breast cancer.¹

Other Studies and Outcomes

Targeting ALK1 has become a popular anticancer research endeavor, and preclinical studies have shown promising results.⁴Dalantercept has produced potent antitumor activity and decreased tumor vascularity in a variety of preclinical models.^2,5,6

In a clinical study of 37 patients with advanced solid tumors, dalantercept monotherapy produced antitumor activity but not without side effects, which included fatigue, peripheral edema, and anemia.⁷Other adverse events, observed in patients with advanced renal cell carcinoma (RCC), include diarrhea, nausea, dysphonia, decreased appetite, hypertension, and arthralgia.⁸

Earlier this year, the combination of dalantercept and axitinib (a small-molecule tyrosine kinase inhibitor) was administered in humans, yielding favorable antitumor response in seven of 28 patients with advanced RCC, and disease stabilization in 17 patients.²

Breast Cancer Implications and Next Steps

Pietras said that their findings “encourage clinical testing of drugs blocking ALK1 in breast cancer with prevention of metastatic dissemination as the primary outcome.”¹Moreover, further research is warranted to fully elucidate the safety profile of dalantercept in patients with breast cancer. Currently, Pietras and his team are conducting therapeutic studies of dalantercept in models of breast cancer to “pinpoint the precise therapeutic regimen and disease stage at which the treatment is the most effective.”¹It is hoped that such knowledge will guide the tailoring of regimens that profoundly reduce metastasis and improve survival in humans.

References

1. American Association for Cancer Research. ALK1 protein may play a role in breast cancer metastasis [press release].http://www.eurekalert.org/pub_releases/2015-06/aafc-apm061215.php.Accessed June 15, 2015.
2. Angiogenesis-targeted combination active in advanced RCC.Targeted Onc.2015; Mar 10.http://www.targetedonc.com/articles/Angiogenesis-Targeted-Combination-Active-in-Advanced-RCC. Accessed June 12, 2015.
3. Acceleron Pharma. Dalantercept product information.http://www.acceleronpharma.com/products/dalantercept/. 2014. Accessed June 14, 2015.
4. Cunha S, Pietras K. ALK1 as an emerging target for antiangiogenic therapy of cancer.Blood.2011;117(26):6999-7006.
5. Mitchell D, Pobre EG, Mulivor AW, et al. ALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growth.Mol Cancer Ther.2010;9(2):379-388.
6. Cunha SI, Pardali E, Thorikay M, et al. Genetic and pharmacological targeting of activing receptor-like kinase 1 impairs tumor growth and angiogenesis.J Exp Med.2010;207(1):85-100.
7. Bendell JC, Gordon MS, Hurwitz HI, et al. Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activing receptor-like kinase-1 ligand trap, in patients with advanced cancer.Clin Cancer Res.2014;20(2):480-489.
8. Voss MH, Plimack ER, Rini BI, et al. The DART study part 2: a phase 2 randomized, double-blind study of dalantercept plus axitinib compared to placebo plus axitinib in patients with advanced renal cell carcinoma. Poster presented at: Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2015; Chicago, IL.