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

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

doi:10.1158/0008-5472.can-14-3706

Cited by 56 publications

(66 citation statements)

References 33 publications

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“…Unfortunately, the tumor models that we have used do not allow us to look at metastasis formation, as spontaneous metastases do not occur at high frequency. A recently published study on ALK1-Fc in breast cancer however indeed showed an effect on metastasis formation in a breast cancer model (37).…”

Section: Discussionmentioning

confidence: 92%

“…The differences in tumor subtype were also highlighted in a recently published article where the authors could show a reduction in tumor volume in breast cancer after treatment with ALK1-Fc in a different type of breast cancer (pyMT genetically engineered mouse breast cancer model; ref. 37). Another study showed that invasive lobular carcinomas have a similar microvascular density compared with invasive ductal breast carcinomas.…”

Section: Discussionmentioning

confidence: 99%

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Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors

Hawinkels

Vinuesa

Paauwe

et al. 2016

Clinical Cancer Research

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Purpose: Antiangiogenic therapy, mostly targeting VEGF, has been applied in cancer patients for the last decade. However, resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new antiangiogenic strategies are needed. In the current study, we investigated the therapeutic effect of interfering with the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway by using an ALK1-Fc ligand trap.Experimental Design: We analyzed the potential antiangiogenic and antitumor effects of ALK1-Fc protein as monotherapy and in combination with chemotherapy in vivo in mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas. ALK1-Fc sequesters BMP9 and 10 and prevents binding of these ligands to endothelial ALK1, which regulates angiogenesis.Results: Treatment of mice with ALK1-Fc strongly decreased the tumors' microvascular density in the three different mouse cancer models. However, this effect was not accompanied by a reduction in tumor volume. An immunohistochemical analysis of the tumor samples revealed that ALK1-Fc treatment increased the pericyte coverage of the remaining tumor vessels and decreased the hypoxia within the tumor. Next, we observed that combining ALK1-Fc with cisplatin inhibited tumor growth in the breast and head and neck cancer models more efficiently than chemotherapy alone.Conclusions: The addition of ALK1-Fc to the cisplatin treatment was able to enhance the cytotoxic effect of the chemotherapy. Our results provide strong rationale to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase II clinical trials with ALK1-Fc.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors

Hawinkels

Vinuesa

Paauwe

et al. 2016

Clinical Cancer Research

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“…For this purpose, tumor sections were stained for the luminal endothelial cell marker podocalyxin [28, 30, 41], that we found to be the most suitable for automated vessel density quantification (this marker was validated by CD31 and von Willebrand Factor co-stainings, data not shown). Podocalyxin staining showed a slight but significant increase in vessel density in Gdf2 −/− mice versus WT mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Pharmacological targeting of ALK1 has been evaluated using either a neutralizing anti-ALK1 antibody (PF-03446962) or a soluble form of ALK1 (Dalantercept) that will trap the biological ligands of ALK1, BMP9 and BMP10 [26, 27]. Most of the published preclinical studies, using these neutralizing tools, reported a decrease in tumor volume, tumor angiogenesis and metastasis [28–30]. Thus, several phase I/II studies using these agents are currently being conducted.…”

Section: Introductionmentioning

confidence: 99%

BMP9, but not BMP10, acts as a quiescence factor on tumor growth, vessel normalization and metastasis in a mouse model of breast cancer

Ouarné

Bouvard

Boneva

et al. 2018

J Exp Clin Cancer Res

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BackgroundAngiogenesis has become an attractive target for cancer therapy. However, despite the initial success of anti-VEGF (Vascular endothelial growth factor) therapies, the overall survival appears only modestly improved and resistance to therapy often develops. Other anti-angiogenic targets are thus urgently needed. The predominant expression of the type I BMP (bone morphogenetic protein) receptor ALK1 (activin receptor-like kinase 1) in endothelial cells makes it an attractive target, and phase I/II trials are currently being conducted. ALK1 binds with strong affinity to two ligands that belong to the TGF-ß family, BMP9 and BMP10. In the present work, we addressed their specific roles in tumor angiogenesis, cancer development and metastasis in a mammary cancer model.MethodsFor this, we used knockout (KO) mice for BMP9 (constitutive Gdf2-deficient), for BMP10 (inducible Bmp10-deficient) and double KO mice (Gdf2 and Bmp10) in a syngeneic immunocompetent orthotopic mouse model of spontaneous metastatic breast cancer (E0771).ResultsOur studies demonstrate a specific role for BMP9 in the E0771 mammary carcinoma model. Gdf2 deletion increased tumor growth while inhibiting vessel maturation and tumor perfusion. Gdf2 deletion also increased the number and the mean size of lung metastases. On the other hand, Bmp10 deletion did not significantly affect the E0771 mammary model and the double deletion (Gdf2 and Bmp10) did not lead to a stronger phenotype than the single Gdf2 deletion.ConclusionsAltogether, our data show that in a tumor environment BMP9 and BMP10 play different roles and thus blocking their shared receptor ALK1 is maybe not appropriate. Indeed, BMP9, but not BMP10, acts as a quiescence factor on tumor growth, lung metastasis and vessel normalization. Our results also support that activating rather than blocking the BMP9 pathway could be a new strategy for tumor vessel normalization in order to treat breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0885-1) contains supplementary material, which is available to authorized users.

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“…As cohort 1 is derived from a nested case–control study (20) where cases developed distant breast cancer metastasis and controls did not during the same time period, we anticipated an overrepresentation of aggressive tumors. This is most clearly demonstrated by the high number of patients with lymph node metastases (>50%, Table 1, cohort 1) and grade 3 disease (45%, Table 1, cohort 1).…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Signatures and Immunohistochemical Subtypes Add Prognostic Value to Each Other in Breast Cancer Cohorts

Lundberg

Lindström

Harrell

et al. 2017

Clinical Cancer Research

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Purpose Gene signatures and Ki67 stratify the same breast tumor into opposing good/poor prognosis groups in approximately 20% of patients. Given this discrepancy, we hypothesized that the combination of a clinically relevant signature and IHC markers may provide more prognostic information than either classifier alone. Experimental Design We assessed Ki67 alone or combined with ER, PR and HER2 (forming IHC subtypes), and the research versions of the Genomic Grade Index, 70-gene, cell-cycle score, recurrence score (RS), and PAM50 signatures on matching TMA/whole tumor sections and microarray data in two Swedish breast cancer cohorts of 379 and 209 patients, with median follow-up of 12.4 and 12.5 years, respectively. First, we fit Cox proportional hazards models and used the change in likelihood ratio (Δ LR) to determine the additional prognostic information provided by signatures beyond that of (i) Ki67 and (ii) IHC subtypes. Second and uniquely, we then assessed whether signatures could compete well with pathology-based IHC classifiers by calculating the additional prognostic information of Ki67/IHC subtypes beyond signatures. Results In cohort 1, only RS and PAM50 provided additional prognostic information beyond Ki67 and IHC subtypes (Δ LR-χ2 Ki67: RS = 12.8, PAM50 = 20.7, IHC subtypes: RS = 12.9, PAM50 = 11.7). Conversely, IHC subtypes added prognostic information beyond all signatures except PAM50. Similar results were observed in cohort 2. Conclusions RS and PAM50 provided more prognostic information than the IHC subtypes in all breast cancer patients; however, the IHC subtypes did not add any prognostic information to PAM50.

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

Cited by 56 publications

References 33 publications

Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors

Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors

BMP9, but not BMP10, acts as a quiescence factor on tumor growth, vessel normalization and metastasis in a mouse model of breast cancer

Gene Expression Signatures and Immunohistochemical Subtypes Add Prognostic Value to Each Other in Breast Cancer Cohorts

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