New Anti-Nodal Monoclonal Antibodies Targeting the Nodal Pre-Helix Loop Involved in Cripto-1 Binding

Focà, Annalia; Sanguigno, Luca; Focà, Giuseppina; Strizzi, Luigi; Iannitti, Roberta; Palumbo, Rosanna; Hendrix, Mary J.C.; Leonardi, Antonio; Ruvo, Menotti; Sandomenico, Annamaria

doi:10.3390/ijms160921342

Cited by 15 publications

(16 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, a novel Nodal-targeting monoclonal antibody has been developed [169, (Strizzi et al in press)]. This monoclonal antibody (3D1), was generated against human Nodal amino acids 44–67, targeting the Cripto-1 binding site.…”

Section: Nodal and Cancermentioning

confidence: 99%

Plasticity underlies tumor progression: role of Nodal signaling

Bodenstine

Chandler

Seftor

et al. 2016

Cancer Metastasis Rev

View full text Add to dashboard Cite

The transforming growth factor beta (TGFβ) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry and primitive streak formation. Nodal signals through TGFβ family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its re-expression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition.

show abstract

Section: Nodal and Cancermentioning

confidence: 99%

Plasticity underlies tumor progression: role of Nodal signaling

Bodenstine

Chandler

Seftor

et al. 2016

Cancer Metastasis Rev

View full text Add to dashboard Cite

show abstract

“…3D1 production and generation has been previously described [ 27 ]. 3D1 binds the original antigen h Nodal [ 44 -67], whereas it recognizes less robustly the mutated peptide variant h Nodal [ 44 -67] E49A-E50A (Figure 2A ), suggesting that it preferentially interacts with the two glutamic residues involved in the binding with Cripto-1 and potentially has a neutralization activity for the Nodal/Cripto-1 receptor complex interaction [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

“…The 3D1 mAb antibody generation and production have been previously described in detail [ 27 ]. Briefly, the 3D1 antibody was generated against region 44-67 of human Nodal, which has been reported as potentially involved in the Nodal-Cripto-1 interaction [ 39 ].…”

Section: Methodsmentioning

confidence: 99%

Effects of a novel Nodal-targeting monoclonal antibody in melanoma

et al. 2015

Self Cite

View full text Add to dashboard Cite

Nodal is highly expressed in various human malignancies, thus supporting the rationale for exploring Nodal as a therapeutic target. Here, we describe the effects of a novel monoclonal antibody (mAb), 3D1, raised against human Nodal. In vitro treatment of C8161 human melanoma cells with 3D1 mAb shows reductions in anchorage-independent growth and vasculogenic network formation. 3D1 treated cells also show decreases of Nodal and downstream signaling molecules, P-Smad2 and P-ERK and of P-H3 and CyclinB1, with an increase in p27. Similar effects were previously reported in human breast cancer cells where Nodal expression was generally down-regulated; following 3D1 mAb treatment, both Nodal and P-H3 levels are reduced. Noteworthy is the reduced growth of human melanoma xenografts in Nude mice treated with 3D1 mAb, where immunostaining of representative tumor sections show diminished P-Smad2 expression. Similar effects both in vitro and in vivo were observed in 3D1 treated A375SM melanoma cells harboring the active BRAF(V600E) mutation compared to treatments with IgG control or a BRAF inhibitor, dabrafenib. Finally, we describe a 3D1-based ELISA for the detection of Nodal in serum samples from cancer patients. These data suggest the potential of 3D1 mAb for selecting and targeting Nodal expressing cancers.

show abstract

“…Nevertheless, targeting Nodal in aggressive cancers remains an area of great interest and translational promise, especially as supportive evidence continues to emerge, and new clues are revealed relevant to critical signaling pathways underlying cellular survival. 31,40 Materials and methods …”

Section: Discussionmentioning

confidence: 99%

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

et al. 2016

Self Cite

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) represents an aggressive cancer subtype characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The independence of TNBC from these growth promoting factors eliminates the efficacy of therapies which specifically target them, and limits TNBC patients to traditional systemic neo/ adjuvant chemotherapy. To better understand the growth advantage of TNBC -in the absence of ER, PR and HER2, we focused on the embryonic morphogen Nodal (associated with the cancer stem cell phenotype), which is re-expressed in aggressive breast cancers. Most notably, our previous data demonstrated that inhibition of Nodal signaling in breast cancer cells reduces their tumorigenic capacity. Furthermore, inhibiting Nodal in other cancers has resulted in improved effects of chemotherapy, although the mechanisms for this remain unknown. Thus, we hypothesized that targeting Nodal in TNBC cells in combination with conventional chemotherapy may improve efficacy and represent a potential new strategy. Our preliminary data demonstrate that Nodal is highly expressed in TNBC when compared to invasive hormone receptor positive samples. Treatment of Nodal expressing TNBC cell lines with a neutralizing anti-Nodal antibody reduces the viability of cells that had previously survived treatment with the anthracycline doxorubicin. We show that inhibiting Nodal may alter response mechanisms employed by cancer cells undergoing DNA damage. These data suggest that development of therapies which target Nodal in TNBC may lead to additional treatment options in conjunction with chemotherapy regimens -by altering signaling pathways critical to cellular survival.

show abstract

New Anti-Nodal Monoclonal Antibodies Targeting the Nodal Pre-Helix Loop Involved in Cripto-1 Binding

Cited by 15 publications

References 43 publications

Plasticity underlies tumor progression: role of Nodal signaling

Plasticity underlies tumor progression: role of Nodal signaling

Effects of a novel Nodal-targeting monoclonal antibody in melanoma

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

Contact Info

Product

Resources

About